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Definitions

2

Laboratory diagnosis of factor XIII A subunit deficiency

The diagnostic problem in this disease is entirely a problem of test selection, and it is the clinical core of the entry. Suspicion comes from the bleeding history - delayed or disproportionate bleeding - because every routine test is normal. The prothrombin time, activated partial thromboplastin time, thrombin time and fibrinogen concentration interrogate thrombin generation and fibrin polymerisation, both of which are intact; they cannot detect a cross-linking defect and a normal set does not lower the probability of the diagnosis. Confirmation requires a quantitative FXIII activity assay, first-line, usually an ammonia-release method. FXIII-A and FXIII-B antigen assays then separate the A-subunit disease modelled here from B-subunit disease, and sequencing of F13A1 and F13B confirms it and determines which replacement product is appropriate. Two pre-analytical requirements matter: the plasma must be platelet-poor, because platelet FXIII-A contaminates the antigen measurement, and the sample must be timed relative to any replacement, because the 7-14 day half-life of FXIII can mask the deficiency after a dose.

DIAGNOSTIC_CRITERIA Laboratory confirmation of severe congenital A-subunit deficiency. It excludes the acquired autoantibody-mediated form, which needs a mixing study and inhibitor titration in addition, and it excludes isolated F13B deficiency, which this laboratory sequence is designed to separate out rather than to include.

Inclusion criteria

Bleeding that is delayed or out of proportion to the clinical context
Markedly reduced quantitative FXIII activity, usually below 5-10% of normal
Reduced FXIII-A antigen, with FXIII-B antigen secondarily low or normal
Biallelic pathogenic F13A1 variants on sequencing

Exclusion criteria

Correction of low FXIII activity in a 1:1 mix with pooled normal plasma, indicating an inhibitor rather than congenital deficiency
Absent or markedly reduced FXIII-B antigen with a pathogenic F13B genotype, indicating B-subunit deficiency
Reliance on a normal urea or monochloroacetic acid clot solubility test to exclude the diagnosis

Show evidence (6 references)

PMID:41583548 SUPPORT Human Clinical

"Bleeding that is delayed or out of proportion to the clinical context with normal PT, aPTT, thrombin time, and fibrinogen should evoke suspicion for FXIII deficiency"

States the entry criterion - the bleeding pattern against a normal screen - that this definition is built on.

PMID:41583548 SUPPORT Human Clinical

"Quantitative FXIII activity measurement is the recommended first-line diagnostic modality"

Establishes the quantitative activity assay as the first-line confirmatory test required by this definition.

PMID:41583548 SUPPORT Human Clinical

"In F13A1-related quantitative defects, both activity and FXIII-A antigen are reduced, and FXIII-B antigen may be secondarily decreased because heterotetramer formation is impaired."

Source of the antigen pattern used here to assign a patient to A-subunit rather than B-subunit disease.

+ 3 more references

Notes: No LOINC-coded computable phenotype algorithm is asserted. The LOINC codes for the relevant assays are recorded on the `biochemical` records below, where the reference intervals live; this definition is a clinical-laboratory diagnostic sequence, not a validated EHR case-finding query, so `validation_status` is deliberately absent rather than guessed at.

Insensitivity of the clot solubility screen

Recorded as a definition rather than a note because it is a statement about what a test does and does not establish, and getting it wrong is the commonest route to a missed diagnosis. The urea (5 M) or monochloroacetic acid (1%) clot solubility test is still the first and often only screen available in many laboratories. A positive result does indicate severe deficiency, at activity levels of roughly 1-5% depending on method. A negative result establishes nothing: sensitivity is poor, raised fibrinogen reduces it further, and hypofibrinogenaemia and dysfibrinogenaemia generate false positives. Contemporary guidance restricts the test to crude adjunctive use in low-resource settings and is explicit that a normal result must not delay quantitative activity testing.

OTHER

Show evidence (4 references)

PMID:41583548 SUPPORT Human Clinical

"A positive result strongly suggests severe deficiency at very low activity levels (~1 to 5% depending on method); however, sensitivity is poor."

Source of the asymmetry between a positive and a negative result, and of the activity range at which the test turns positive.

PMID:41583548 SUPPORT Human Clinical

"Contemporary guidelines therefore discourage reliance on clot solubility assays except as crude adjuncts in low-resource settings; a normal solubility test does not exclude clinically relevant FXIII deficiency and should not delay quantitative FXIII activity testing."

The guidance statement this definition records, including the explicit instruction that a normal result does not exclude the diagnosis.

PMID:29027765 SUPPORT Human Clinical

"Clot solubility tests are not standardized, have a low sensitivity, and are therefore not recommended as routine screening test; however, they are the first screening test in almost all coagulation laboratories in developing countries."

Supports both the low sensitivity and the fact that this is nevertheless the test most patients actually get.

+ 1 more reference

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Inheritance

1

Autosomal recessive inheritance HP:0000007

Severe disease requires two F13A1 pathogenic alleles - homozygous or compound heterozygous. Single heterozygotes carry roughly half-normal FXIII activity and are generally asymptomatic, which is why the carrier state is two to three orders of magnitude commoner than the disease. The carrier state is not, however, entirely silent: a subset of heterozygotes, particularly women, bleed at haemostatic challenges and have pregnancy complications, and those individuals are managed on demand rather than with prophylaxis. This entry models the severe biallelic disease.

Autosomal recessive inheritance

Show evidence (3 references)

PMID:41583548 SUPPORT Human Clinical

"Congenital FXIII deficiency is a rare inherited bleeding disorder that typically follows autosomal recessive inheritance, with an estimated global prevalence of approximately one in two million individuals"

States the recessive inheritance pattern of the congenital disorder.

PMID:39613144 SUPPORT Human Clinical

"Primary prophylaxis is mandatory for all patients with severe FXIII-A deficiency, while those with heterozygous deficiency are generally asymptomatic and may require on-demand therapy during hemostatic challenges, most commonly in women."

Supports both the generally asymptomatic heterozygote state and the challenge-dependent exception described here.

PMID:12529747 SUPPORT Model Organism

"FXIII transglutaminase activity in plasma was reduced to about 50% in mice heterozygous for the mutant allele, and was abolished in homozygous null mice."

Demonstrates the gene-dose relationship - half-normal activity in heterozygotes, none in homozygotes - that the recessive pattern rests on.

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Discussions and Knowledge Gaps

3

What trough factor XIII activity should prophylaxis target, and does a higher target reduce intracranial haemorrhage or improve pregnancy outcome?

KNOWLEDGE GAP gap_fxiii_a_prophylaxis_trough_target

Attached to

biochemical#Plasma factor XIII activity treatments#Plasma-Derived Factor XIII Concentrate Prophylaxis

Every activity threshold in this entry - the 5-20% prophylaxis trough, the 10-15% spontaneous-bleeding threshold, the 30% perioperative target, the trimester-specific obstetric targets - comes from product labelling, narrative review and observational series, not from a trial that compared targets against outcomes. The review that is this entry's principal source says so explicitly and names the comparison that is missing. This matters more here than it would for most thresholds, because the outcome being prevented is permanent neurological injury in a young child, and because the interval between doses is long enough that the trough is the operative quantity.

Show evidence (2 references)

PMID:41583548 SUPPORT Human Clinical

"Despite these advancements, sustained progress in FXIII deficiency will require studies that link target activity thresholds to outcomes in the settings where decisions are most time sensitive."

The source's own statement that the threshold-to-outcome link is unestablished, which is the gap recorded here.

PMID:31414482 SUPPORT Human Clinical

"In patients exhibiting FXIII levels <10 iu/dl, prophylaxis could be discussed at diagnosis and at pregnancy. Further controlled prospective studies are needed."

A national cohort reaching the same conclusion - that the prophylaxis decision rests on uncontrolled data.

Why does residual factor XIII activity predict clinical severity only moderately well, and what modifies the bleeding phenotype at a given activity level?

KNOWLEDGE GAP gap_fxiii_a_activity_severity_modifiers

Attached to

genetic#F13A1 biochemical#Plasma factor XIII activity

Genotype does not predict phenotype in this disease at all, and activity predicts it only moderately to strongly. Both facts are reported rather than explained. Candidate modifiers are visible in the mechanism this entry models - the relative contribution of the mechanical and fibrinolytic arms could differ between patients, and the platelet FXIII-A pool is a compartment that plasma activity assays do not report - but nothing in the literature reviewed here tests that. The practical consequence is that a measured activity cannot be used on its own to decide who needs prophylaxis.

Show evidence (2 references)

PMID:39613144 SUPPORT Human Clinical

"There is no correlation between genotype and phenotype and a moderate to strong correlation between factor activity and clinical severity in FXIII-A deficiency, making it difficult to predict bleeding patterns based on genotype and FXIII activity levels."

States both halves of the gap - no genotype-phenotype correlation, and an imperfect activity-severity correlation.

PMID:41583548 SUPPORT Human Clinical

"This platelet FXIII-A supports platelet activation dynamics (e.g., spreading/adhesion); loss or genetic deletion of platelet FXIII-A impairs clot retraction and reduces thrombus stability, underscoring distinct roles for cellular (platelet) versus plasma FXIII."

Establishes that a cellular FXIII-A compartment with its own functions exists, which is the candidate modifier the rationale names.

Can diagnosis be made before the first intracranial haemorrhage in children without a known family history?

KNOWLEDGE GAP gap_fxiii_a_diagnosis_before_first_ich

Attached to

definitions#Laboratory diagnosis of factor XIII A subunit deficiency phenotypes#Intracranial hemorrhage

The preventable outcome is frequently the presenting one. In a South Indian paediatric cohort the median age at symptom onset was 6 months and the median age at diagnosis 1 year, and intracranial bleeding was the first presentation in a significant number of children; in the FranceCoag cohort 7 of 15 patients who had an intracranial haemorrhage were already diagnosed but untreated. Those are two different failures - one of diagnosis, one of treatment - and both are addressable. No newborn screening exists, and the only test that would find the disease is one that most laboratories cannot run.

Show evidence (3 references)

PMID:37314674 SUPPORT Human Clinical

"The median age of symptom onset was 6 mo, and the median age of diagnosis was 1 y, demonstrating a delay in diagnosis."

Quantifies the diagnostic delay in a real paediatric cohort.

PMID:31414482 SUPPORT Human Clinical

"Seven of the 15 patients who experienced ICH were diagnosed but untreated, including 3 with secondary neurological sequelae."

Separates the treatment failure from the diagnostic failure, which is the distinction this gap turns on.

PMID:41583548 SUPPORT Human Clinical

"Diagnostic delays are common given the paradox of normal screening assays and the limited sensitivity of historical clot solubility tests, underscoring the need for validated quantitative FXIII activity methods and inhibitor evaluation when appropriate."

Names the two reasons for delay - a normal screen and an insensitive historical test - that this gap asks how to overcome.

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Pathophysiology

9

Biallelic F13A1 Loss-of-Function Variants

Homozygous or compound heterozygous pathogenic variants in F13A1 (chromosome 6p24-p25, 15 exons, encoding the 731-residue catalytic A subunit) are the initiating lesion. Roughly 200 variants are described across F13A1 and F13B, most of them missense, with large deletions the rarest class; there are no mutational hotspots, so confirmation relies on sequencing the whole gene or a panel that includes it. Founder alleles dominate in some populations - Trp187Arg is the commonest Iranian variant. A-subunit defects account for about 95% of congenital FXIII deficiency and produce the more severe phenotype, because what is lost is catalytic activity rather than carriage.

resident macrophage (source of plasma FXIII-A) CL:0000235 platelet (cellular FXIII-A pool) CL:0000233

Genetic context variant_origin: GERMLINE zygosity: HOMOZYGOUS functional_impact_category: LOSS_OF_FUNCTION

Germline biallelic loss of function. Compound heterozygosity is equally common in non-consanguineous families; HOMOZYGOUS is recorded because that is the configuration in the consanguineous populations where most described patients live, and the functional consequence is the same.

factor XIII-A transglutaminase activity GO:0003810 ⇓ LOSS OF FUNCTION

Downstream

Absent Plasma Factor XIII Transglutaminase Activity Loss of both functional A-subunit alleles removes the catalytic half of the FXIII-A2B2 heterotetramer, so no activatable transglutaminase reaches the circulation.

Show evidence (5 references)

PMID:41583548 SUPPORT Human Clinical

"The F13A1 gene (chromosome 6p24–p25; 15 exons) encodes a 731-amino-acid catalytic subunit that contains the transglutaminase core"

Source of the gene's location, exon count and product length as stated in this node.

PMID:41583548 SUPPORT Human Clinical

"Deficiency of the FXIII-A subunit is responsible for the majority (~95%) of cases of congenital FXIII deficiency, and typically produces more severe clinical phenotypes due to loss of catalytic activity, whereas FXIII-B subunit defects mainly lower circulating heterotetramer levels by impairing..."

Gives the 95% share and the mechanistic reason A-subunit disease is more severe than B-subunit disease, which is the boundary this entry is drawn on.

PMID:39613144 SUPPORT Human Clinical

"About 200 Mutations have been observed in F13A and F13B genes, with most being missense mutations, while large deletions are the rarest."

Source of the variant count and the missense-dominant spectrum described here.

+ 2 more references

Absent Plasma Factor XIII Transglutaminase Activity

Thrombin normally cleaves the activation peptide from each A subunit and millimolar calcium then releases the B-subunit dimer, exposing a Cys-His-Asp catalytic triad that transfers acyl groups between glutamine donors and lysine acceptors to form epsilon-(gamma-glutamyl)lysine isopeptide bonds. With no functional A subunit there is no triad and no cross-linking chemistry, whatever thrombin does. The consequence branches three ways, according to which substrate is no longer cross-linked: fibrin itself, alpha-2-antiplasmin, or the extracellular matrix proteins that tie the clot to the wound bed.

isopeptide cross-linking of clot proteins GO:0018149 ↓ DECREASED

plasma factor XIIIa transglutaminase activity GO:0003810 ⇓ LOSS OF FUNCTION

Animal models

FXIII-A null mouse (F13a1 exon 7 targeted deletion) Mouse recapitulates A null allele at the orthologous locus producing the same molecular state - no activatable plasma transglutaminase and no fibrin gamma-dimerization.

Downstream

Failure of Fibrin Gamma- and Alpha-Chain Cross-Linking Fibrin chains are the best-characterised FXIIIa substrate; with no enzyme, gamma-gamma dimerization and alpha-chain multimerization do not occur.

Failure of Alpha-2-Antiplasmin Ligation to Fibrin The same enzyme covalently ligates alpha-2-antiplasmin to the fibrin alpha-chain, so its absence removes the clot's built-in antifibrinolytic shield. This is a separate substrate and a separate consequence from fibrin-fibrin cross-linking, not a restatement of it.

Failure of Fibrin Cross-Linking to Extracellular Matrix Proteins FXIIIa also links fibrin(ogen) to fibronectin and vitronectin, integrating the clot with the surrounding matrix. Losing this is what takes the disease beyond haemostasis into tissue repair.

Show evidence (2 references)

PMID:41583548 SUPPORT Human Clinical

"FXIIIa performs acyl-transfer between γ-carboxamide groups of glutamine donors and ε-amino groups of lysine acceptors to form ε-(γ-glutamyl)-lysine isopeptide bonds."

States the catalytic chemistry that is absent in this node.

PMID:22197181 SUPPORT Human Clinical

"It is a zymogen, which becomes transformed into an active transglutaminase (FXIIIa) in the final phase of coagulation cascade by thrombin and Ca(2+)."

Establishes that the activity modelled here is a thrombin- and calcium-dependent terminal step of the cascade.

Intact Thrombin Generation and Fibrin Polymerisation Upstream of Cross-Linking

This node has no upstream cause in this disease, and that is the point: every step of haemostasis before cross-linking is normal. Platelet plug formation, the intrinsic and extrinsic pathways, thrombin generation, and the conversion of fibrinogen to a polymerised fibrin mesh are all unaffected, because FXIII acts only on an already-formed clot. Two things follow. Clinically, a visually adequate clot does form, and bleeding is therefore delayed rather than immediate. Diagnostically, the prothrombin time, activated partial thromboplastin time, thrombin time and fibrinogen concentration - which interrogate exactly the steps that are intact - are all normal, which is why this disease is missed. No modifier is set on the bound process term because the claim is that it is unchanged, and ModifierEnum has no value for normal.

thrombin generation and fibrin polymerisation (unaffected) GO:0072378

Animal models

Black and Tan Coonhound with a homozygous F13A1 frameshift Dog recapitulates The normal-screening-test finding, reproduced in a second species and in an animal whose causal variant is known. This is the only non-human support in the entry for the node that carries the diagnostic trap.

Downstream

Mechanically Unstable Fibrin Clot A clot is present to be unstable only because polymerisation is intact. The relationship is permissive rather than causal of the defect - it supplies the substrate on which the missing cross-linking would have acted - so it is recorded as indirect with the intermediate steps (fibrinogen cleavage, fibrin polymerisation) known. The result is an apparently adequate clot that fails later under mechanical or fibrinolytic stress.

Show evidence (2 references)

PMID:41583548 SUPPORT Human Clinical

"assess thrombin generation and fibrin formation rather than crosslink maturation, FXIII deficiency presents with normal tests of coagulation despite clinically meaningful impairment of clot stability."

States directly that thrombin generation and fibrin formation are intact and that this is why the screening tests are normal.

PMID:27077776 SUPPORT Human Clinical

"All routine coagulation tests are normal in FXIII deficiency (FXIIID), which complicates the diagnosis of this disorder."

Independent confirmation that the whole routine screen is normal, from a review devoted to the diagnostic problem.

Failure of Fibrin Gamma- and Alpha-Chain Cross-Linking

Without FXIIIa, fibrin gamma-chains are not dimerised and alpha-chains are not multimerised into high-molecular-weight polymers. Gamma-chain dimerization is the reaction whose product is absent in plasma from FXIII-A null animals, and alpha-chain cross-linking is the one that governs whether a contracting clot retains red cells. The cross-links are what give fibrin tensile strength and viscoelastic stability, so the polymer that forms is mechanically inferior rather than absent.

fibrin gamma- and alpha-chain isopeptide cross-linking GO:0018149 ↓ DECREASED

Downstream

Mechanically Unstable Fibrin Clot The isopeptide bonds between fibrin chains are what confer tensile strength and viscoelastic stability; their absence is the direct cause of a clot that deforms and disintegrates under load.

Show evidence (2 references)

PMID:22197181 SUPPORT Human Clinical

"FXIII is essential for hemostasis, its deficiency results in severe bleeding diathesis. FXIIIa mechanically stabilizes fibrin by cross-linking its α-, and γ-chains."

States the reaction lost in this node and attributes the mechanical stabilisation of fibrin to it.

PMID:26324704 SUPPORT In Vitro

"These data indicate FXIIIa-dependent retention of RBCs in clots is mediated by fibrin α-chain crosslinking."

Separates the two cross-linking reactions experimentally and shows that alpha-chain cross-linking in particular determines clot composition, which is why this node names both chains rather than only the gamma-chain.

Failure of Alpha-2-Antiplasmin Ligation to Fibrin

FXIIIa normally ligates alpha-2-antiplasmin (alpha-2-plasmin inhibitor) to the fibrin Aalpha chain, embedding a plasmin inhibitor inside the clot. In its absence the clot carries no covalently bound antifibrinolytic, so plasmin generated at its surface is not restrained locally. This is a loss of negative regulation of fibrinolysis, not an increase in plasminogen activation.

alpha-2-antiplasmin-dependent protection of fibrin from lysis GO:0051918 ↓ DECREASED

Downstream

Accelerated Fibrinolytic Dissolution of the Hemostatic Clot With no clot-bound plasmin inhibitor, the fibrin mesh is lysed faster than the wound can be repaired.

Show evidence (2 references)

PMID:22197181 SUPPORT Human Clinical

"It also protects newly formed fibrin from fibrinolysis, primarily by cross-linking α(2)-plasmin inhibitor to fibrin."

Names alpha-2-plasmin inhibitor cross-linking as the principal antifibrinolytic action of FXIIIa, which is what this node removes.

PMID:9892598 SUPPORT Model Organism

"Among groups receiving TPA, selective inhibition of factor XIII-mediated alpha2-antiplasmin-fibrin cross-linking enhanced lysis (group 3 versus 5; P<0.0005)."

Selectively blocking this one reaction, leaving fibrin-fibrin cross-linking intact, increases lysis - which isolates the alpha-2-antiplasmin arm as an independent contributor.

Failure of Fibrin Cross-Linking to Extracellular Matrix Proteins

FXIIIa cross-links fibrin(ogen) to fibronectin, vitronectin and other matrix proteins, turning the clot into a provisional scaffold that fibroblasts migrate through, keratinocytes re-epithelialise over, and new vessels grow into. Losing this is a tissue-repair defect rather than a bleeding defect: the provisional matrix is compromised, granulation is delayed, and wounds dehisce even when haemostasis looked adequate. The same matrix-stabilising requirement applies at the maternal-fetal interface, where cytotrophoblast invasion and placentation depend on it.

fibroblast migrating through the provisional wound matrix CL:0000057

FXIIIa-dependent provisional matrix formation in wound repair GO:0042060 ↓ DECREASED

Downstream

Poor wound healing A compromised provisional matrix delays granulation tissue formation and predisposes to dehiscence independently of whether bleeding was controlled.

Recurrent pregnancy loss The same FXIII-dependent matrix stabilisation is required for cytotrophoblast invasion and placental implantation, so first-trimester loss has a matrix component in addition to a haemostatic one.

Show evidence (2 references)

PMID:41583548 SUPPORT Human Clinical

"The impaired wound healing observed in FXIII deficiency reflects multiple mechanisms beyond hemostasis, whereby FXIIIa-mediated crosslinking of fibrin to extracellular matrix proteins creates a stable scaffold essential for fibroblast migration, keratinocyte re-epithelialization, and..."

States the matrix-scaffold mechanism and the three cellular processes that depend on it, which is the content of this node.

PMID:41583548 SUPPORT Human Clinical

"These matrix-level actions help explain soft tissue bleeding, poor wound healing, and umbilical stump bleeding observed in severe congenital FXIII deficiency."

Attributes the wound-healing and soft-tissue phenotypes specifically to the matrix-level reactions rather than to clot instability alone.

Mechanically Unstable Fibrin Clot

A clot that is present, visually adequate and mechanically inferior. Without fibrin-chain cross-links it has reduced tensile strength and viscoelastic stability, loses red cells during contraction, and fails under physiological load. Thromboelastography in FXIII-A null mice shows the defect directly and shows that it is corrected dose-dependently by replacing the missing protein. Note that standard viscoelastic testing in humans is insensitive to isolated FXIII deficiency, so the node is better supported by the animal and biochemical data than by bedside viscoelastometry.

fibrin clot mechanical stabilisation GO:0072378 ↓ DECREASED

Animal models

FXIII-A null mouse (F13a1 exon 7 targeted deletion) Mouse recapitulates Thromboelastography shows impaired clot stabilisation, corrected dose-dependently by human FXIII.

Black and Tan Coonhound with a homozygous F13A1 frameshift Dog recapitulates Reduced maximum clot firmness on viscoelastic testing and complete dissolution of the clot in urea, both correcting as FXIII-containing blood products were given.

Downstream

Delayed Bleeding After Apparently Adequate Initial Hemostasis Initial haemostasis succeeds; the clot then gives way, so the bleeding appears hours to days after the injury rather than at the time of it.

Show evidence (2 references)

PMID:12529747 SUPPORT Model Organism

"Thrombelastography (TEG) experiments demonstrated impaired clot stabilization in FXIII-A mutant mice, replacement with human FXIII led to dose-dependent TEG normalization."

Measures the mechanical instability of the clot in an A-subunit null animal and shows it is reversed by FXIII replacement.

PMID:26324704 SUPPORT In Vitro

"Real-time microscopy revealed extensive RBC loss from clots formed in the absence of FXIIIa activity, and RBCs exhibited transient deformation as they exited the clots."

Direct microscopic observation of a clot losing its cellular content when FXIIIa activity is absent, which is the mechanical failure this node describes. The quote is trimmed of the paper's bracketed abbreviation span, which the reference validator strips before matching.

Accelerated Fibrinolytic Dissolution of the Hemostatic Clot

The second arm of the defect, and mechanistically separate from mechanical weakness: the clot is actively digested sooner because it lacks the covalently bound alpha-2-antiplasmin that would have restrained plasmin locally. In a ferret embolism model, blocking FXIIIa activity alone raised endogenous lysis from about 14% to about 43% - comparable to giving tissue plasminogen activator - which is the scale of protection the cross-links normally provide.

plasmin-mediated dissolution of the haemostatic clot GO:0042730 ↑ INCREASED

Animal models

Black and Tan Coonhound with a homozygous F13A1 frameshift Dog recapitulates Hyperfibrinolysis measured in the same tracings as the firmness deficit, and corrected alongside it. The entry models these as two arms of one lesion, and this is the record in which both were observed together.

Downstream

Delayed Bleeding After Apparently Adequate Initial Hemostasis Premature lysis reopens a wound that had stopped bleeding, producing the same delayed pattern by a different route from mechanical failure.

Show evidence (1 reference)

PMID:9892598 SUPPORT Model Organism

"Inhibition of factor XIIIa activity increased endogenous lysis markedly (group 1 versus 2; P<0.0001), to a level comparable to that achieved with TPA (group 2 versus 3; P<0.05)."

Quantifies the accelerated lysis that follows loss of FXIIIa activity, which is the claim of this node.

Delayed Bleeding After Apparently Adequate Initial Hemostasis

The clinical convergence point of both arms. Bleeding is characteristically delayed and out of proportion to the injury, because the failure is of clot persistence rather than of clot formation. The pattern is what generates every phenotype in this entry - umbilical stump bleeding days to weeks after cord separation, post-circumcision bleeding, deep soft-tissue haematoma, and spontaneous intracranial haemorrhage. It is also why the bleeding history rather than the coagulation screen is the diagnostic trigger.

haemostasis GO:0007596 ↓ DECREASED

Downstream

Abnormal umbilical stump bleeding The separating cord is a wound whose clot must persist for days; it is the first place a stabilisation defect shows.

Intracranial hemorrhage The most consequential destination of the same mechanism; spontaneous or after minor trauma, and typically in early childhood.

Subcutaneous hemorrhage Soft-tissue bleeding into the subcutis, where a clot that forms and then gives way produces a haematoma rather than immediate external bleeding. Left uncited: the sources reviewed establish that patients with this disease bleed here, which is a node-level claim already carried on the phenotype record, not a statement that this step follows from the delayed-bleeding state.

Intramuscular hematoma The same step reaching a deeper compartment, where the volume of accumulated blood is larger because muscle offers less tamponade. Left uncited for the same reason as the subcutaneous edge.

Epistaxis The mucosal instance of the same step: nasal mucosa bleeds readily, stops, and then rebleeds because the clot is not stabilised. Left uncited for the same reason.

Menorrhagia Endometrial bleeding at menstruation, where haemostasis depends on clot persistence over days rather than on a single plug. Left uncited for the same reason.

Joint hemorrhage Haemarthrosis is an uncommon but real destination of the same mechanism, which is why it is connected here rather than left as an unlinked phenotype.

Prolonged bleeding following circumcision

Show evidence (2 references)

PMID:41583548 SUPPORT Human Clinical

"Bleeding that is delayed or out of proportion to the clinical context with normal PT, aPTT, thrombin time, and fibrinogen should evoke suspicion for FXIII deficiency"

Defines the delayed, disproportionate bleeding pattern with a normal screen that this node names.

PMID:22197181 SUPPORT Human Clinical

"FXIII is essential for hemostasis, its deficiency results in severe bleeding diathesis."

Establishes that FXIII deficiency produces a bleeding diathesis, the organism-level state this node records.

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Pathograph

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Phenotypes

10

Blood 7

Abnormal umbilical stump bleeding VERY_FREQUENT HP:0011884

Temporal: PROLONGED Onset: NEONATAL

Show evidence (3 references)

PMID:41583548 SUPPORT Human Clinical

"A characteristic neonatal presentation is delayed umbilical stump bleeding, which occurs days to weeks after cord separation in approximately 70-80% of symptomatic cases and serves as an important sentinel feature."

Source of both the delayed timing and the 70-80% frequency supporting the VERY_FREQUENT band.

PMID:25615432 SUPPORT Human Clinical

"Among Iranian patients, umbilical cord bleeding, hematoma, and prolonged wound bleeding are the most frequent clinical manifestations."

Confirms umbilical cord bleeding as the most frequent manifestation in the largest national patient population described.

PMID:37314674 SUPPORT Human Clinical

"Clinical symptomatology ranged from mucosal bleeds to intracranial bleeds and hemarthrosis, with many children having a history of prolonged umbilical bleeding in their neonatal period."

An independent paediatric series reporting prolonged umbilical bleeding in the neonatal period in many of its children.

Intracranial hemorrhage FREQUENT HP:0002170

Onset: CHILDHOOD

Show evidence (4 references)

PMID:41583548 SUPPORT Human Clinical

"The most serious complication is life-threatening intracranial hemorrhage—either spontaneous or following minor trauma—which occurs in up to 30% of untreated patients, often during early childhood."

Source of the frequency, the trigger pattern and the childhood onset recorded here.

PMID:24149912 SUPPORT Human Clinical

"The site of ICH was intraparenchymal in 35 patients (92.1 %), subdural in 2 patients (5.2 %), and epidural hemorrhage in 1 patient (2.6 %)."

Source of the predominantly intraparenchymal distribution described in this phenotype.

PMID:24149912 SUPPORT Human Clinical

"Besides, neurologic complications occurred in 21 patients (55.2 %), including locomotor disability in 8, psychological impairment in 7, mental disorders in 5, speech impairment in 4, and visual impairment in 2."

Quantifies the permanent neurological sequelae, which is the reason this phenotype and not the bleeding frequency drives management.

+ 1 more reference

Subcutaneous hemorrhage FREQUENT HP:0001933

Show evidence (2 references)

PMID:41583548 SUPPORT Human Clinical

"Beyond the neonatal period, patients with congenital FXIII deficiency commonly experience recurrent mucocutaneous hemorrhage (epistaxis, menorrhagia, oral bleeding), soft-tissue bleeding (e.g., subcutaneous and intramuscular hematomas), and impaired wound repair with dehiscence; abnormal scar..."

Names subcutaneous haematoma among the commonly experienced soft-tissue bleeds, supporting both the phenotype and the FREQUENT band.

PMID:12529747 SUPPORT Model Organism

"Bleeding episodes, hematothorax, hematoperitoneum and subcutaneous hemorrhage in mutant mice were associated with reduced survival."

The A-subunit null mouse reproduces subcutaneous haemorrhage, supporting the phenotype as a direct consequence of the same lesion.

Epistaxis FREQUENT HP:0000421

Temporal: RECURRENT

Show evidence (1 reference)

PMID:41583548 SUPPORT Human Clinical

"Beyond the neonatal period, patients with congenital FXIII deficiency commonly experience recurrent mucocutaneous hemorrhage (epistaxis, menorrhagia, oral bleeding), soft-tissue bleeding (e.g., subcutaneous and intramuscular hematomas), and impaired wound repair with dehiscence; abnormal scar..."

Lists epistaxis as a component of the recurrent mucocutaneous haemorrhage seen in this disease.

Menorrhagia FREQUENT HP:0000132

Show evidence (3 references)

PMID:23992439 SUPPORT Human Clinical

"Menorrhagia (26%) was the second most common bleeding reported after umbilical bleeding."

Source of the 26% figure and of the ranking relative to umbilical bleeding stated here.

PMID:23992439 SUPPORT Human Clinical

"Ovulation bleeding reported in 8% of women."

Source of the ovulation-bleeding figure mentioned alongside menorrhagia in this description.

PMID:41583548 SUPPORT Human Clinical

"Beyond the neonatal period, patients with congenital FXIII deficiency commonly experience recurrent mucocutaneous hemorrhage (epistaxis, menorrhagia, oral bleeding), soft-tissue bleeding (e.g., subcutaneous and intramuscular hematomas), and impaired wound repair with dehiscence; abnormal scar..."

Independently names menorrhagia as a common manifestation.

Prolonged bleeding following circumcision OCCASIONAL HP:0030137

Onset: NEONATAL

Show evidence (1 reference)

PMID:41583548 SUPPORT Human Clinical

"In male infants, post-circumcision bleeding is a recognized early presentation that may provide the first diagnostic clue."

Source of the phenotype and of its status as an early diagnostic clue.

Joint hemorrhage OCCASIONAL HP:0005261

Show evidence (2 references)

PMID:41583548 SUPPORT Human Clinical

"Joint hemorrhage is relatively uncommon, distinguishing FXIII deficiency from hemophilia."

Source of both the OCCASIONAL band and the contrast with haemophilia.

PMID:37314674 SUPPORT Human Clinical

"Clinical symptomatology ranged from mucosal bleeds to intracranial bleeds and hemarthrosis, with many children having a history of prolonged umbilical bleeding in their neonatal period."

Documents haemarthrosis in an actual paediatric cohort, which is why the phenotype is curated despite being uncommon.

Integument 1

Poor wound healing FREQUENT HP:0001058

Show evidence (2 references)

PMID:41583548 SUPPORT Human Clinical

"Loss of these matrix-stabilizing functions compromises the provisional wound matrix, delays granulation tissue formation, and increases susceptibility to wound dehiscence even when primary hemostasis appears adequate."

States the phenotype and the mechanism, including the point that it is independent of haemostatic adequacy.

PMID:16113836 SUPPORT Model Organism

"Scoring system representing maturation rate of the wounds showed that the scores for the control, FXIII-deficient and FXIII deficient/FXIII treated groups were 94.9 +/- 4.7, 61.5 +/- 14.5 and 94.5 +/- 6.4, respectively (p < 0.001 by ANOVA)."

Animal evidence, graded accordingly, and cited alongside rather than instead of the human item above: a wound-maturation score that falls in FXIII-deficient mice and returns to the control value when FXIII is replaced. It is the rescue arm that makes this informative for the human phenotype, because it attributes the delay to the missing protein rather than to the strain. The corresponding readouts on the model record itself quote the closure percentages; this item quotes the maturation score, which is a separate measurement.

Musculoskeletal 1

Intramuscular hematoma FREQUENT HP:0012233

Show evidence (1 reference)

PMID:41583548 SUPPORT Human Clinical

"Beyond the neonatal period, patients with congenital FXIII deficiency commonly experience recurrent mucocutaneous hemorrhage (epistaxis, menorrhagia, oral bleeding), soft-tissue bleeding (e.g., subcutaneous and intramuscular hematomas), and impaired wound repair with dehiscence; abnormal scar..."

Names intramuscular haematoma among the commonly experienced soft-tissue bleeds.

Other 1

Recurrent pregnancy loss VERY_FREQUENT

Left ontology-unbound, following the precedent in `Asherman_Syndrome` and `Thrombophilia`. HP:0200067 (Recurrent spontaneous abortion) exists and means exactly this, but HPO files it under Past medical history / Pregnancy history rather than under HP:0000118 phenotypic abnormality, so it is outside the `PhenotypeTerm` dynamic enum and binding it fails `just validate-terms`. HP:0005268 (Miscarriage) is no better: its ancestors are Clinical modifier / Prenatal death / Mortality-Aging. Searched `l^Spontaneous abortion`, `l^Miscarriage`, `l^Recurrent miscarriage`, `l^Abortion`, `l^Pregnancy loss` and `l^Fetal death` against `ols:hp`; HPO has no phenotypic-abnormality term for recurrent pregnancy loss.

Show evidence (3 references)

PMID:31414482 SUPPORT Human Clinical

"All pregnancies without prophylaxis (26/26) led to miscarriages versus 3/16 with prophylaxis."

The cohort figure behind both the frequency band and the prophylaxis-responsiveness claim.

PMID:23992439 SUPPORT Human Clinical

"In 136 pregnancies without prophylactic therapy, 124 (91%) resulted in a miscarriage and 12(9%) progressed to viability stage."

Independent, larger denominator for the same claim, supporting the VERY_FREQUENT band.

PMID:41583548 SUPPORT Human Clinical

"Individuals with childbearing potential with severe FXIII deficiency face reproductive challenges, including frequent first trimester pregnancy loss without prophylaxis; the biology represents both impaired hemostasis at the maternal-fetal interface and defective FXIII-dependent stabilization of..."

Supports the first-trimester timing and the dual haemostatic and matrix mechanism stated here.

🧬

Genetic Associations

1

F13A1

Gene: F13A1 hgnc:3531 relationship_type: CAUSATIVE variant_origin: GERMLINE

Show evidence (4 references)

PMID:41583548 SUPPORT Human Clinical

"The F13A1 gene (chromosome 6p24–p25; 15 exons) encodes a 731-amino-acid catalytic subunit that contains the transglutaminase core"

Source of the gene's location, exon count and protein length.

PMID:24503678 SUPPORT Human Clinical

"A diverse spectrum of mutations have been reported in the F13A1 and F13B genes which cause inherited severe FXIII deficiency."

Attributes inherited severe FXIII deficiency to variants in these two genes.

PMID:39613144 SUPPORT Human Clinical

"There is no correlation between genotype and phenotype and a moderate to strong correlation between factor activity and clinical severity in FXIII-A deficiency, making it difficult to predict bleeding patterns based on genotype and FXIII activity levels."

Source of the genotype-phenotype statement, and the reason this entry puts severity on an activity axis rather than in genotype-defined subtypes.

+ 1 more reference

💊

Medical Actions

4

Recombinant Factor XIII-A2 Prophylaxis (Catridecacog)

Action: Pharmacotherapy NCIT:C15986

Agent: catridecacog (recombinant factor XIII A-subunit) NCIT:C174766

Platform: Protein replacement

Dosing: every 28 days every 28 days

Monthly intravenous recombinant FXIII A-subunit dimer, given as primary prophylaxis. This is the one treatment that is specific to this entry rather than to factor XIII deficiency in general: because it replaces only the A subunit, it works in F13A1 deficiency and does not work in isolated F13B deficiency. In the mentor-2 extension trial 60 patients with severe (<0.05 IU/mL) A-subunit deficiency received 35 IU/kg every 28 days for at least 52 weeks, with a mean annualized bleeding rate of 0.043 per patient-year, no neutralizing antibodies, and enough haemostatic coverage for twelve minor surgeries without supplementary FXIII. The 28-day interval is possible because FXIII has a terminal half-life of about 13.7 days - an order of magnitude longer than the upstream factors.

Mechanism Target:

RESTORES Absent Plasma Factor XIII Transglutaminase Activity — Infused recombinant A-subunit dimer associates with the patient's own circulating B subunits, restoring activatable plasma transglutaminase. It does not correct the F13A1 lesion, so activity decays with the protein's half-life and the dose has to be repeated.

Show evidence (1 reference)

PMID:29448295 SUPPORT Human Clinical

"Recombinant factor XIII-A2 (rFXIII-A2) was developed for prophylaxis and treatment of bleeds in patients with congenital FXIII A-subunit deficiency."

Names the mechanism and the indication - replacement of the missing A subunit in A-subunit deficiency - which is the edge asserted here.

Show evidence (5 references)

PMID:41583548 SUPPORT Human Clinical

"Because recombinant FXIII-A2 (catridecacog) replaces only the FXIII-A subunit, it is appropriate for F13A1 deficiency (i.e., the majority of cases) but not for isolated F13B deficiency, a distinction that has direct therapeutic implications."

The A-subunit specificity that makes this treatment entry-specific rather than generic to factor XIII deficiency.

PMID:29448295 SUPPORT Human Clinical

"Patients received 35 IU/kg rFXIII-A2 (exact dosing) every 28 ± 2 days for ≥52 weeks."

Source of the dose and of the 28-day interval recorded in `dosing_interval_days`.

PMID:29448295 SUPPORT Human Clinical

"Mean annualized bleeding rate (ABR) was 0.043/patient-year."

The efficacy figure quoted in this treatment's description.

+ 2 more references

Plasma-Derived Factor XIII Concentrate Prophylaxis

Action: Pharmacotherapy NCIT:C15986

Agent: human plasma-derived factor XIII concentrate NCIT:C200601

Platform: Protein replacement

Dosing: every 28 days every 28 days

Pathogen-inactivated plasma-derived FXIII concentrate (Corifact, Fibrogammin) given monthly as primary prophylaxis, and at 20-40 IU/kg on demand or perioperatively. It remains first-line for routine prophylaxis across age groups, and unlike recombinant FXIII-A2 it covers both A- and B-subunit disease, because it supplies the intact A2B2 heterotetramer. Labelled dosing starts at 40 IU/kg every 28 days, titrated in 5 IU/kg steps to a trough of roughly 5-20%; children often clear it faster and need closer titration. An Iranian series of 38 patients who had already had an intracranial haemorrhage started all but one of them on 10 IU/kg every 4-6 weeks and reported a good response with no recurrence, again with one exception. That is the clearest available evidence that prophylaxis prevents the outcome that matters most, and it is uncontrolled.

Mechanism Target:

RESTORES Absent Plasma Factor XIII Transglutaminase Activity — Supplies the complete FXIII-A2B2 heterotetramer, restoring activatable plasma transglutaminase irrespective of which subunit the patient lacks.

INHIBITS Intracranial hemorrhage — The clinical endpoint prophylaxis exists for - preventing intracranial haemorrhage. Scheduled replacement prevents spontaneous and intracranial bleeding; the Iranian series recorded no recurrence of intracranial haemorrhage on 10 IU/kg every 4-6 weeks other than in a single patient.

Show evidence (2 references)

PMID:24149912 SUPPORT Human Clinical

"It seems that long-term prophylactic treatment with a dose of 10 IU/kg Fibrogammin could be effective in the prevention of CNS bleeding in the patients with F XIII deficiency."

States the authors' conclusion that prophylaxis with this product prevents central nervous system bleeding, which is this edge.

PMID:41583548 SUPPORT Human Clinical

"Prophylaxis with FXIII-containing blood products or FXIII concentrates prevents spontaneous and intracranial hemorrhage in congenital disease, and activity-guided replacement may be clinically important in perioperative and obstetric care; nuances surrounding scenarios in which certain..."

Independent statement that prophylaxis prevents intracranial haemorrhage.

INHIBITS Recurrent pregnancy loss — Prophylaxis through pregnancy changes the outcome dramatically: every unprophylaxed pregnancy in the FranceCoag cohort miscarried, against 3 of 16 with prophylaxis.

Show evidence (1 reference)

PMID:31414482 SUPPORT Human Clinical

"All pregnancies without prophylaxis (26/26) led to miscarriages versus 3/16 with prophylaxis."

Directly contrasts pregnancy outcome with and without prophylaxis, which is the effect this edge records.

Show evidence (3 references)

PMID:41583548 SUPPORT Human Clinical

"Plasma-derived FXIII concentrates (pdFXIII; e.g., Corifact/Fibrogammin) remain first-line for routine prophylaxis across age groups and for peri-operative support (Table 3)."

Establishes plasma-derived concentrate as first-line for prophylaxis and perioperative cover.

PMID:41583548 SUPPORT Human Clinical

"Product labeling supports an initial dose of 40 IU/kg intravenously every 28 days with subsequent titration (typically in 5 IU/kg increments) to maintain a trough activity of ~5–20%"

Source of the labelled dose, the titration increment, the trough target and the 28-day interval recorded here.

PMID:24149912 SUPPORT Human Clinical

"Prophylaxis was started with a dose of 10 IU/kg Fibrogammin every 4-6 weeks for all the patients, except for one."

Source of the Iranian series' dosing schedule quoted in this description.

Cryoprecipitate or Plasma Bridging

Action: transfusion of a factor XIII-containing blood component Ontology label: Blood Transfusion NCIT:C15192

Agent: cryoprecipitated plasma

Platform: Protein replacement

Cryoprecipitate or plasma (fresh frozen plasma, or plasma frozen within 24 hours of phlebotomy) raises FXIII activity where concentrate is unavailable or cannot be obtained quickly. It is explicitly second-line: FXIII content varies widely between units and products, plasma carries a volume load, and pathogen reduction is often absent. In practice it is nevertheless the treatment many patients actually receive - fourteen of the twenty children in the South Indian paediatric cohort were on cryoprecipitate prophylaxis, and four children had breakthrough bleeds when the schedule slipped, including one intracranial bleed during a pandemic supply interruption. That is the clearest illustration of why a bridging product is not an equivalent.

Mechanism Target:

RESTORES Absent Plasma Factor XIII Transglutaminase Activity — Donor-derived FXIII in cryoprecipitate or plasma restores some activatable transglutaminase, but the delivered dose is unpredictable because the FXIII content of each unit varies.

Show evidence (3 references)

PMID:41583548 SUPPORT Human Clinical

"can serve as temporary bridges to raise FXIII activity, but they are second-line because of FXIII content variability, larger volumes (plasma), and lack of pathogen reduction in many settings."

States the second-line status of cryoprecipitate and plasma bridging and all three reasons for it. The quote starts mid-sentence because the preceding clause carries a bracketed span the reference validator strips before matching; the indication itself is supported by the two following items.

PMID:37314674 SUPPORT Human Clinical

"Four children had breakthrough bleeds due to irregular prophylaxis, including one intracranial bleed due to a delay in cryoprecipitate prophylaxis during the covid pandemic."

Documents the breakthrough bleeding that followed interruption of cryoprecipitate prophylaxis in a real paediatric cohort.

PMID:25615432 SUPPORT Human Clinical

"Traditionally, the management of FXIIID in Iran was only based on administration of fresh frozen plasma or cryoprecipitate, until 2009 when FXIII concentrate became available for patient management."

Records the historical and resource-dependent use of plasma and cryoprecipitate before concentrate became available.

Genetic Counseling and Family Testing

Action: Genetic Counseling NCIT:C15240

Platform: Other

Molecular confirmation of the F13A1 genotype supports carrier testing, reproductive planning, prenatal or early neonatal diagnosis, and peripartum management - and it selects the replacement product, because recombinant FXIII-A2 is appropriate only once the defect is known to be in F13A1. In affected families newborns warrant prompt assessment so prophylaxis can start before the first intracranial bleed, which in a substantial minority of children is the presenting event.

Show evidence (1 reference)

PMID:41583548 SUPPORT Human Clinical

"Molecular confirmation refines genetic counseling, reproductive planning (carrier testing, prenatal/early neonatal diagnosis, peripartum management), and therapeutic product selection."

Enumerates the uses of molecular confirmation that this treatment record describes, including product selection.

🔬

Biochemical Markers

5

Plasma factor XIII activity (DECREASED)

Pathograph Readouts

Readout Of Absent Plasma Factor XIII Transglutaminase Activity Negative Diagnostic

The assay measures the transglutaminase activity that the pathophysiology node says is absent, which is why it is the one test that detects this disease.

Reference Ranges

Coagulation factor XIII activity actual/normal in Platelet poor plasma by Chromogenic method – % (Patients with congenital factor XIII deficiency)

Severe deficiency (–3.0 %) Spontaneous bleeding risk range (3.0–15.0 %) Haemostatic for minor procedures (15.0–30.0 %) Perioperative target (30.0– %)

Severe deficiency: Activity at or below about 1-3% of normal; the phenotype is usually severe, with spontaneous bleeding and intracranial risk. This is where essentially all genetically confirmed A-subunit null patients sit.

Spontaneous bleeding risk range: Below roughly 10-15% of normal the risk of spontaneous bleeding is increased. Prophylaxis troughs are conventionally titrated into the lower part of this range (about 5-20%).

Haemostatic for minor procedures: Above the spontaneous-bleeding threshold but below the target generally recommended for surgery.

Perioperative target: At least 30% activity, and higher for major operations, is the level generally aimed for to secure surgical haemostasis. Flagged NORMAL because it is the intended therapeutic state, not because 30% is a normal endogenous value.

No normal interval is asserted. The bands below are clinical decision thresholds expressed as percent of normal FXIII activity, taken from a narrative review; the same review states that linking target activity thresholds to outcomes is an open research question. The LOINC code is the platelet-poor-plasma percent-of-normal activity measurement, which is the quantity these bands are expressed in.

Show evidence (1 reference)

PMID:41583548 SUPPORT Human Clinical

"Although the risk of spontaneous bleeding in congenital deficiency increases below ~10-15% activity, peri-operative and critical care literature suggests aiming for ≥30% (and sometimes higher) to ensure hemostasis."

Source of the spontaneous-bleeding threshold and the perioperative target that define the bands below.

Show evidence (2 references)

PMID:41583548 SUPPORT Human Clinical

"Quantitative FXIII activity measurement is the recommended first-line diagnostic modality; while many clinical laboratories still lack the ability to perform such assays, in those that do, at the time of writing, ammonia-release assays predominate."

Establishes the assay as first-line and names the predominant method described here.

PMID:41583548 SUPPORT Human Clinical

"The clinical phenotype varies with residual FXIII activity and is often severe when activity is significantly reduced (≤1-3%)."

Source of the activity level at which severe disease is described, and of the activity-severity relationship this marker reports.

Plasma factor XIII-A subunit antigen (DECREASED)

Reference Ranges

Coagulation factor XIII Ag [Units/volume] in Platelet poor plasma by Immunoassay – IU/dL (Patients with congenital factor XIII deficiency)

No interval is asserted. The LOINC code is recorded so the analyte is machine-identifiable; no reference interval was curated because none was found in a citable source during this curation, and the clinically actionable thresholds in this disease are activity-based rather than antigen-based.

Show evidence (2 references)

PMID:41583548 SUPPORT Human Clinical

"In F13A1-related quantitative defects, both activity and FXIII-A antigen are reduced, and FXIII-B antigen may be secondarily decreased because heterotetramer formation is impaired."

States the antigen pattern in A-subunit disease, which is what this record asserts.

PMID:41583548 SUPPORT Human Clinical

"Platelets contain abundant FXIII-A, predominantly as an A2 dimer without FXIII-B subunits; upon platelet activation, a fraction becomes exposed on the platelet surface and functionally engages within forming thrombi."

Explains the platelet FXIII-A pool that is the source of the contamination artefact noted here.

Plasma factor XIII-B subunit antigen (DECREASED)

Show evidence (2 references)

PMID:37883802 SUPPORT Model Organism

"These data show FXIII-A2 prevents FXIII-B2 loss from circulation and establish the mechanism underlying FXIII-B2 behavior in FXIII-A deficiency and during rFXIII-A2 therapy."

Establishes the clearance mechanism behind the secondary FXIII-B reduction, which is the claim this record makes. Graded MODEL_ORGANISM because the mechanism was established in the mouse arm of the study.

PMID:37883802 SUPPORT Human Clinical

"Plasma FXIII is composed of A and B subunit dimers synthesized in cells of hematopoietic origin and hepatocytes, respectively."

Source of the statement that the B subunit is made by hepatocytes independently of the A subunit, which is why its reduction here is secondary.

Fibrin clot solubility in urea or monochloroacetic acid (ABNORMAL)

Reference Ranges

Coagulation factor XIII coagulum dissolution at 24 hours [Presence] in Platelet poor plasma by Coagulation assay – (Patients with suspected factor XIII deficiency)

A presence/absence observation, so no numeric interval applies. The LOINC code is recorded to identify the test; no bounds are given because the result is qualitative.

Show evidence (1 reference)

PMID:41583548 SUPPORT Human Clinical

"A positive result strongly suggests severe deficiency at very low activity levels (~1 to 5% depending on method); however, sensitivity is poor."

Source of the asymmetric interpretation recorded for this test.

Routine coagulation screen (NORMAL)

Pathograph Readouts

Readout Of Intact Thrombin Generation and Fibrin Polymerisation Upstream of Cross-Linking Diagnostic

The normal screen is the direct laboratory readout of the preserved upstream cascade; it reports a node that is intact, which is why it reports nothing about the disease.

Show evidence (2 references)

PMID:41583548 SUPPORT Human Clinical

"assess thrombin generation and fibrin formation rather than crosslink maturation, FXIII deficiency presents with normal tests of coagulation despite clinically meaningful impairment of clot stability."

States that the screening tests are normal and gives the mechanistic reason, which is what this record captures.

PMID:27077776 SUPPORT Human Clinical

"All routine coagulation tests are normal in FXIII deficiency (FXIIID), which complicates the diagnosis of this disorder."

Independent confirmation that the whole routine panel is normal.

📊

Prevalence

3

Worldwide

Point Prevalence 0.05 per 100,000 <1 in 1,000,000

Approximately 1 in 2,000,000, i.e. 0.05 cases per 100,000. Published estimates for severe congenital FXIII deficiency span roughly 1 in 2 million to 1 in 5 million; this record normalizes the most commonly cited figure and the range is recorded in the other prevalence records below. The estimate is for congenital FXIII deficiency as a whole, of which A-subunit deficiency is about 95%.

Show evidence (2 references)

PMID:41583548 SUPPORT Human Clinical

"Congenital FXIII deficiency is a rare inherited bleeding disorder that typically follows autosomal recessive inheritance, with an estimated global prevalence of approximately one in two million individuals"

States the worldwide prevalence estimate that this record normalizes to 0.05 per 100,000.

PMID:39613144 SUPPORT Human Clinical

"Although the estimated incidence of severe FXIII-A deficiency is one per 2 million, a high prevalence ranging from 0.8 to 3.5% has been observed for heterozygous FXIII-A deficiency."

Gives the same figure specifically for severe FXIII-A deficiency, which is the disease modelled by this entry, and separates it from the much commoner heterozygous state.

Worldwide (lower published estimate)

Point Prevalence 0.025 per 100,000 (0.02–0.033) <1 in 1,000,000

Other reviews place severe inherited FXIII deficiency at 1 in 3-5 million (0.02-0.033 per 100,000) or 1 in 4 million (0.025 per 100,000). The spread between these and the 1-in-2-million figure reflects ascertainment rather than disagreement about biology: the disorder is systematically underdiagnosed because the routine coagulation screen is normal.

Show evidence (2 references)

PMID:37314674 SUPPORT Human Clinical

"Congenital Factor 13 Deficiency (FXIIID) is a rare bleeding disorder (RBD) of autosomal recessive inheritance, with an incidence of 1 in 3-5 million."

Source of the 1-in-3-to-5-million bound recorded in this record's range.

PMID:24503678 SUPPORT Human Clinical

"The inherited severe FXIII deficiency, which is a rare coagulation disorder with a prevalence of 1 in 4 million has been the prime focus of clinical and genetic investigations owing to the severity of the bleeding phenotype associated with it."

Source of the 1-in-4-million figure this record's point estimate uses.

Iran

Unknown Rare

Markedly commoner where consanguineous marriage is frequent. Iran has the highest reported national burden, estimated at roughly twelve times the worldwide frequency and concentrated in Sistan and Baluchestan Province. No normalized rate is recorded because the cited source reports a fold difference and an absolute patient count rather than a population rate, and the measure type behind that count is not stated.

Show evidence (2 references)

PMID:25615432 SUPPORT Human Clinical

"An approximately 12-fold higher prevalence of FXIIID is estimated in Iran in comparison with overall worldwide frequency."

Quantifies the founder and consanguinity enrichment described in this record.

PMID:37314674 SUPPORT Human Clinical

"Consanguinity was present in 15 (75%) with 4 children having affected siblings."

A South Indian paediatric series documenting the same consanguinity effect outside Iran, supporting the general claim rather than the Iranian figure.

🔀

Differential Diagnoses

4

Conditions with similar clinical presentations that must be differentiated from Factor XIII A Subunit Deficiency:

Factor XIII B subunit deficiency

Overlapping Features A different locus, not a subtype of this entry. F13B encodes the carrier subunit; its loss lowers the circulating heterotetramer concentration by removing stabilisation and transport rather than abolishing catalysis, and the phenotype is correspondingly milder - severe F13B deficiency may be managed on demand rather than with mandatory primary prophylaxis. It accounts for the small minority of congenital factor XIII deficiency. The distinction is therapeutically load-bearing, not taxonomic bookkeeping: recombinant FXIII-A2 is effective in A-subunit disease and is not indicated in B-subunit disease. MONDO:0013190 covers it; dismech has no entry for it at the time of writing.

Show evidence (3 references)

PMID:39613144 SUPPORT Human Clinical

"Factor XIII-A (FXIII-A) deficiency is an ultra-rare bleeding disorder characterized by high rates of morbidity and mortality, primarily resulting from intracranial hemorrhage, umbilical cord bleeding, and miscarriage, whereas patients with severe FXIII-B deficiency present with a milder phenotype."

States the severity difference that is the clinical basis for keeping the two loci as separate entries.

PMID:39613144 SUPPORT Human Clinical

"On the other hand, patients with severe FXIII-B deficiency may only require on-demand therapy, while heterozygotes are generally asymptomatic."

Supports the different management default, which is part of why this is a separate disease rather than a subtype.

PMID:41583548 SUPPORT Human Clinical

"Because recombinant FXIII-A2 (catridecacog) replaces only the FXIII-A subunit, it is appropriate for F13A1 deficiency (i.e., the majority of cases) but not for isolated F13B deficiency, a distinction that has direct therapeutic implications."

The therapeutic consequence of the boundary, and the reason it must not be collapsed.

Acquired factor XIII deficiency

Overlapping Features A different disease, not a late-onset form of this one. It arises either immunologically, from autoantibodies (commonly IgG4) against FXIII-A or less often FXIII-B, or non-immunologically from consumption, dilution or reduced synthesis in major surgery, trauma, sepsis, liver disease and disseminated intravascular coagulation. It presents in adults with abrupt severe bleeding, there is no pathogenic variant, and the definitive treatment of the immune form is inhibitor eradication with immunosuppression rather than lifelong replacement. A 1:1 mixing study that fails to correct separates it from congenital deficiency at the bench. MONDO:0021133 covers it.

Show evidence (3 references)

PMID:41583548 SUPPORT Human Clinical

"Immune-mediated deficiency develops when autoantibodies—commonly IgG4 subclass—target FXIII-A or, less frequently, FXIII-B subunits."

Establishes the autoantibody mechanism that distinguishes the acquired immune form.

PMID:41583548 SUPPORT Human Clinical

"Unlike congenital disease, inhibitor eradication generally allows return to normal hemostasis without ongoing replacement therapy, though relapse can occur and warrants surveillance."

States the management difference that follows from the different mechanism, supporting separation rather than lumping.

PMID:24503678 SUPPORT Human Clinical

"The acquired form of FXIII deficiency is usually caused by generation of autoantibodies or hyperconsumption in other disease states such as disseminated intravascular coagulation."

Independent statement of the two acquired mechanisms named here.

Congenital afibrinogenemia and hypofibrinogenemia

Overlapping Features The other inherited disorder that classically causes delayed umbilical stump bleeding, so it is the main alternative when that sign presents. It is separable on the routine screen, which is grossly abnormal in afibrinogenaemia and normal here, and on the fibrinogen concentration. Fibrinogen abnormalities also confound the clot solubility test - low or dysfunctional fibrinogen produces false positives - which is one more reason not to rely on that test.

Show evidence (1 reference)

PMID:41583548 SUPPORT Human Clinical

"Hypofibrinogenemia and dysfibrinogenemia can cause false positives, whereas increased fibrinogen may reduce sensitivity and contribute to false negative results."

Supports the confounding of the solubility test by fibrinogen abnormalities, which is why this differential matters at the bench.

Hemophilia A and hemophilia B

Overlapping Features Distinguished by the activated partial thromboplastin time, which is prolonged in the haemophilias and normal here, and clinically by the joint pattern: recurrent haemarthrosis is the hallmark of haemophilia and is relatively uncommon in factor XIII deficiency.

Show evidence (1 reference)

PMID:41583548 SUPPORT Human Clinical

"Joint hemorrhage is relatively uncommon, distinguishing FXIII deficiency from hemophilia."

The clinical discriminator quoted directly.

🔬

Clinical Trials

3

NCT00713648 PHASE_III COMPLETED

The open-label, single-arm, multiple-dosing phase 3 trial of monthly recombinant factor XIII (catridecacog) for prevention of bleeding in inherited factor XIII deficiency. PMID:29448295 describes NCT00978380 as an extension to a pivotal trial it calls mentor-1; this registration is very probably that trial, but the cached registry record does not carry the mentor-1 name, so the identification is not asserted here.

Target Phenotypes: Abnormal bleeding HP:0001892

Show evidence (1 reference)

clinicaltrials:NCT00713648 SUPPORT Other

"The aim of this trial is to evaluate catridecacog (recombinant factor XIII (rFXIII)) treatment in patients with inherited FXIII deficiency."

The registry record establishing the trial's agent, population and objective.

NCT00978380 PHASE_III COMPLETED

mentor-2, the multiple-dosing extension assessing long-term safety and efficacy of 35 IU/kg recombinant factor XIII-A2 every 28 days in patients with severe congenital A-subunit deficiency. It is the source of the annualized bleeding rate and half-life figures in this entry's treatment records.

Target Phenotypes: Abnormal bleeding HP:0001892

Show evidence (2 references)

clinicaltrials:NCT00978380 SUPPORT Other

"The aim of the trial is to investigate the safety of monthly replacement therapy of recombinant factor XIII in patients with congenital FXIII deficiency."

The registry record establishing the trial's design and objective.

PMID:29448295 SUPPORT Human Clinical

"mentor™2 (NCT00978380), a multinational, open-label, single-arm, multiple-dosing extension to the pivotal mentor™1 trial, assessed long-term safety and efficacy of rFXIII-A2 prophylaxis in eligible patients"

The published report identifying this NCT number, its design and its A-subunit-restricted population.

NCT00885742 PHASE_III COMPLETED

Open-label phase 3b study of human plasma-derived factor XIII concentrate in congenital factor XIII deficiency, dose-individualised to minimise bruising and bleeding. Supports the plasma-derived arm of treatment, which unlike recombinant FXIII-A2 covers both subunit defects.

Target Phenotypes: Abnormal bleeding HP:0001892

Show evidence (1 reference)

clinicaltrials:NCT00885742 SUPPORT Other

"In this study, patients will be treated with FXIII Concentrate (Human) and followed closely to determine that they receive the dose that will best minimize the chance of bruising and bleeding."

The registry record establishing the product and the dose-individualisation objective.

🐁

Animal Models

4

FXIII-A null mouse (F13a1 exon 7 targeted deletion)

The canonical genetic model. Homologous recombination deleted the inferred exon 7 of the mouse FXIII-A gene. Heterozygotes retain about 50% plasma transglutaminase activity and homozygotes none, and plasma fibrin gamma-dimerization is undetectable in homozygotes - the molecular signature of absent activatable FXIII. Homozygotes bleed spontaneously (haemothorax, haemoperitoneum, subcutaneous haemorrhage) with reduced survival, have markedly delayed tail-tip bleeding arrest, and show impaired clot stabilisation on thromboelastography. Both the bleeding time and the thromboelastography abnormality are corrected by human plasma FXIII, which makes this a model of the therapeutic response as well as of the lesion.

Species

Mouse

Genotype

F13a1 targeted deletion of inferred exon 7, homozygous null

Publication

PMID:12529747

Pathograph links

Absent Plasma Factor XIII Transglutaminase Activity recapitulates fidelity: high observes: molecular A null allele at the orthologous locus producing the same molecular state - no activatable plasma transglutaminase and no fibrin gamma-dimerization.

Limitations: The lesion is an engineered exon deletion, whereas most human alleles are missense; that difference does not matter for a complete-null phenotype but means the model says nothing about the residual-activity range where human severity is actually decided.

Readouts

Plasma FXIII transglutaminase activity

Direction: ABOLISHED

Interpretation: Activity is abolished in homozygotes and roughly halved in heterozygotes, establishing the gene-dose relationship.

Show evidence (1 reference)

PMID:12529747 SUPPORT Model Organism

"FXIII transglutaminase activity in plasma was reduced to about 50% in mice heterozygous for the mutant allele, and was abolished in homozygous null mice."

Reports the measurement and both genotype levels.

Plasma fibrin gamma-chain dimerization

Direction: ABOLISHED

Interpretation: The reaction product of FXIIIa on fibrin is undetectable, confirming functional absence of the enzyme rather than merely reduced antigen.

Show evidence (1 reference)

PMID:12529747 SUPPORT Model Organism

"Plasma fibrin gamma-dimerization was also indetectable in the homozygous deficient animals, confirming the absence of activatable FXIII."

Reports the direct measurement of the cross-linking product.

Show evidence (1 reference)

PMID:12529747 SUPPORT Model Organism

"The mutant mice thus reiterate some key features of the human genetic disorder: they will be valuable in assessing the role of FXIII in other associated pathologies and the development of new therapies."

The authors' own statement of how far the model reproduces the human disorder, which is the claim this link makes.

Mechanically Unstable Fibrin Clot recapitulates fidelity: high observes: tissue Thromboelastography shows impaired clot stabilisation, corrected dose-dependently by human FXIII.

Readouts

Thromboelastographic clot stability

Direction: DECREASED

Interpretation: The mechanical deficit is measured directly, and its reversal on replacement shows the instability is attributable to the missing protein rather than to a secondary effect of the knockout.

Show evidence (1 reference)

PMID:12529747 SUPPORT Model Organism

"Thrombelastography (TEG) experiments demonstrated impaired clot stabilization in FXIII-A mutant mice, replacement with human FXIII led to dose-dependent TEG normalization."

Reports the measurement and the dose-dependent correction.

Tail-tip bleeding time

Direction: INCREASED

Interpretation: Prolonged and restored to normal by human plasma FXIII, establishing an in vivo haemostatic correlate of the clot-stability defect.

Show evidence (1 reference)

PMID:12529747 SUPPORT Model Organism

"Arrest of tail-tip bleeding in FXIII-A deficient mice was markedly and significantly delayed; replacement of mutant mice with human plasma FXIII (Fibrogammin P) restored bleeding time to within the normal range."

Reports the prolongation and its correction by replacement.

FXIIIA-knockout mouse (uterine haemorrhage and miscarriage line)

An independently derived FXIII-A knockout line, analysed specifically for reproductive failure. Homozygous females conceive, but most die of excessive vaginal bleeding during gestation; histology shows massive placental haemorrhage and subsequent necrosis in the uterus by gestational day 10, irrespective of fetal genotype - so the lesion is maternal. The authors call the result reminiscent of spontaneous miscarriage in pregnant humans with FXIII deficiency and conclude that maternal FXIII is required for uterine haemostasis and maintenance of the placenta. This line is why the human pregnancy-loss phenotype has animal support at all; the exon-7 deletion line above remains fertile.

Species

Mouse

Genotype

F13a1 (FXIIIA) knockout, homozygous

Publication

PMID:12933578

FXIII-deficient mouse excisional wound-healing cohort

The animal evidence for the non-haemostatic arm of this disease. Excisional wounds left unsutured and undressed closed more slowly in FXIII-deficient mice than in controls - 15%, 27% and 27% less closure at days 4, 8 and 11 - and were only 73.23% closed at day 11 against 100% in controls. Histology at day 11 showed delayed re-epithelialisation and a necrotised fissure. The informative arm is the third group: FXIII concentrate raised day-11 closure to 90.06% and normalised the histology, which is what makes this a model of the FXIII-dependent step rather than of an incidental strain difference.

Species

Mouse

Genotype

FXIII-deficient (targeted subunit not stated in the cited report)

Publication

PMID:16113836

Notes

The cited report calls its animals "FXIII-deficient mice" and does not state which subunit was targeted, so the genotype is recorded as reported rather than as FXIII-A-null. At the time of publication the described knockout lines were A-subunit lines, which makes an A-subunit genotype likely, but that is an inference and is not asserted here. Treat the link below as evidence about FXIII rather than specifically about FXIII-A.

Black and Tan Coonhound with a homozygous F13A1 frameshift

Naturally occurring disease rather than an engineered model, and the only record in this entry in which both arms of the mechanism were measured in the same individual. A 4-month-old dog presented with spontaneous hemoperitoneum and bleeding that persisted after surgery; whole-genome sequencing against 3,023 other dogs found a private homozygous deletion-insertion in exon 11 of F13A1 predicting a frameshift and premature stop, with a predicted loss of 43% of the protein and probable nonsense-mediated decay. Plasma FXIII activity was 5%. The diagnostic picture is the human one reproduced in another species: PT, aPTT, thrombin time, fibrinogen and every individual factor assay within reference limits, and a clot that dissolved completely in 5 M urea. Viscoelastic testing showed both reduced maximum clot firmness and a markedly abnormal 45-minute lysis index at the same time, and both normalised as plasma and cryoprecipitate were given - which is the closest thing in this entry to a direct demonstration that the mechanical and fibrinolytic arms are separable states of one clot. Canine F13A1 encodes a 733-residue protein 88% identical to the human one.

Species

Dog

Genotype

F13A1 c.1234_1239delinsTCAA (exon 11), homozygous; predicted frameshift from residue 412 with a premature stop codon

Publication

PMID:42184124

Pathograph links

Intact Thrombin Generation and Fibrin Polymerisation Upstream of Cross-Linking recapitulates fidelity: high observes: molecular The normal-screening-test finding, reproduced in a second species and in an animal whose causal variant is known. This is the only non-human support in the entry for the node that carries the diagnostic trap.

Limitations: A single animal, so the observation is that the screen can be normal in F13A1-null disease, not an estimate of how often it is.

Readouts

Routine coagulation screen and individual factor assays

Direction: UNCHANGED

Interpretation: PT, aPTT, thrombin time, fibrinogen and the individual procoagulant factor assays all sat within reference limits in an animal with 5% FXIII activity and overt bleeding - the upstream cascade reporting itself intact, which is what this node claims.

Show evidence (1 reference)

PMID:42184124 SUPPORT Model Organism

"Results of coagulation screening tests, fibrinogen, platelet flow cytometry assessment of CD61 (GPIIIa) expression and poststimulation annexin V binding, and individual factor assays were within reference intervals, with the exception of Factor X:C and VWF:Ag (Table 2)."

Reports the measurements behind this readout. The two flagged exceptions are a mildly low factor X the authors judged clinically irrelevant and a high von Willebrand antigen, neither of which is a cross-linking measure.

Show evidence (1 reference)

PMID:42184124 SUPPORT Model Organism

"Unlike other procoagulant factors, FXIII is not required for the transformation of plasma fibrinogen into the polymerized fibrin fibrils that form a fibrin clot."

The authors state the mechanistic reason the screen is uninformative, which is the node this link is attached to.

Mechanically Unstable Fibrin Clot recapitulates fidelity: high observes: tissue Reduced maximum clot firmness on viscoelastic testing and complete dissolution of the clot in urea, both correcting as FXIII-containing blood products were given.

Limitations: Viscoelastic maximum clot firmness is also driven by fibrinogen and platelets, and this dog was transiently thrombocytopenic earlier in its course, so the baseline tracing is not a pure read on cross-linking. The fibrinogen concentration was normal and the platelet count had recovered by the time of the tracings, which is why the finding is still attributed to FXIII.

Readouts

Clot solubility in 5 M urea

Direction: DECREASED

Interpretation: Complete lysis within 15 minutes, reproducible on a second sample three weeks later. The assay is the historical human screen, so this is the same measurement failing the same way in a dog.

Show evidence (1 reference)

PMID:42184124 SUPPORT Model Organism

"Results of FXIII deficiency screening tests revealed abnormally rapid clot dissolution, with complete clot lysis within 15 min of incubation in a 5 M urea solution."

Reports the measurement, the timing and the urea concentration.

Maximum clot firmness on viscoelastic testing

Direction: RESTORED

Interpretation: Low at baseline and normalising with plasma and cryoprecipitate, which is the rescue that attributes the mechanical deficit to the missing protein.

Show evidence (1 reference)

PMID:42184124 SUPPORT Model Organism

"Preoperatively the tracing appeared hypocoagulable based on low maximum clot firmness (MCF) and hyperfibrinolytic based on residual clot firmness at 30- and 45-min post-MCF (LI30 and LI45), becoming normal with the administration of plasma products (Table 1)."

Reports both the baseline abnormality and its correction on replacement.

Show evidence (1 reference)

PMID:42184124 SUPPORT Model Organism

"A functional FXIII deficiency was identified, and a private, homozygous variant (c.1234_1239delinsTCAA) was found in exon 11 of F13A1 that predicts a frameshift and premature stop codon."

Establishes that the clot-stability defect in this animal sits on a homozygous F13A1 lesion, which is what makes it a model of this disease rather than of acquired FXIII deficiency.

Accelerated Fibrinolytic Dissolution of the Hemostatic Clot recapitulates fidelity: high observes: tissue Hyperfibrinolysis measured in the same tracings as the firmness deficit, and corrected alongside it. The entry models these as two arms of one lesion, and this is the record in which both were observed together.

Limitations: The lysis indices and the firmness measure come from the same viscoelastic tracings, so the two arms are distinguishable here but not independently manipulated - unlike the ferret embolism experiments cited on the node itself, where one cross-linking reaction was blocked and the other left intact. The dog also received tranexamic acid alongside blood products, so the correction is not attributable to FXIII repletion alone.

Readouts

Viscoelastic lysis index at 45 minutes

Direction: RESTORED

Interpretation: Markedly abnormal at baseline and normal after replacement, which is the fibrinolytic arm behaving as this entry's model predicts.

Show evidence (1 reference)

PMID:42184124 SUPPORT Model Organism

"Preoperatively the tracing appeared hypocoagulable based on low maximum clot firmness (MCF) and hyperfibrinolytic based on residual clot firmness at 30- and 45-min post-MCF (LI30 and LI45), becoming normal with the administration of plasma products (Table 1)."

The same sentence reports the hyperfibrinolysis and its correction; it is quoted on both links because it is the single measurement that establishes the two arms coexisting.

Show evidence (1 reference)

PMID:42184124 SUPPORT Model Organism

"The findings of unstable clot formation and premature clot lysis in a viscoelastic assay combined with complete clot dissolution in urea indicated that FXIII deficiency should be considered high on the differential list as the underlying cause of abnormal bleeding for this dog."

The authors name unstable clot formation and premature lysis as co-occurring findings, which is the two-arm structure this entry models.

This is the second reported clinical case of FXIII deficiency in dogs and the first genetic characterisation of the disorder in a companion animal; it is not the first canine description, and is not curated as such. Graded MODEL_ORGANISM throughout, per CLAUDE.md: a veterinary observation in a non-human mammal is animal evidence however carefully the individual was worked up.

{ }

Source YAML

click to show

name: Factor XIII A Subunit Deficiency
creation_date: "2026-09-10T00:00:00Z"
category: Mendelian
parents:
- Bleeding Disorder
- Coagulation Disorder
- Rare Bleeding Disorder
disease_term:
  preferred_term: Factor XIII A subunit deficiency
  term:
    id: MONDO:0013187
    label: factor XIII, A subunit, deficiency of
synonyms:
- congenital factor XIII A subunit deficiency
- hereditary factor XIII A subunit deficiency
- hereditary factor XIII type II deficiency
- FXIII-A deficiency
- fibrin stabilizing factor deficiency
description: >-
  Severe congenital deficiency of the catalytic A subunit of coagulation factor
  XIII, caused by biallelic pathogenic variants in F13A1. Factor XIII is the
  terminal enzyme of coagulation: thrombin and calcium convert the plasma
  FXIII-A2B2 heterotetramer into the active transglutaminase FXIIIa, which
  forms epsilon-(gamma-glutamyl)lysine isopeptide bonds between fibrin
  gamma-chains and then between alpha-chains, covalently ligates
  alpha-2-antiplasmin into the clot, and cross-links fibrin to fibronectin and
  other matrix proteins. Because every one of those reactions happens after
  fibrin has already polymerised, nothing upstream of cross-linking is affected:
  primary haemostasis, the prothrombin time, the activated partial
  thromboplastin time, the thrombin time and the fibrinogen concentration are
  all normal. The defect is one of clot stabilisation, and it has two
  mechanistically distinguishable arms - a mechanically weak clot, and a clot
  that is lysed prematurely - which together produce the characteristic pattern
  of bleeding delayed after apparently adequate initial haemostasis.

  The clinical signature is paediatric. Delayed bleeding from the umbilical
  stump days to weeks after cord separation is the classic presenting sign, and
  spontaneous or minor-trauma intracranial haemorrhage - overwhelmingly
  intraparenchymal, frequently the event that brings the child to attention, and
  followed by permanent neurological sequelae in 21 of the 38 patients in the
  published series that describes the pattern - is the most serious complication
  and a principal cause of death and lasting disability. That risk, and the fact
  that it is preventable, is the entire reason lifelong primary prophylaxis
  exists in this disease. Delayed soft-tissue bleeding, poor wound healing with dehiscence
  (a transglutaminase function beyond haemostasis) and first-trimester pregnancy
  loss in affected women complete the picture.

  Because the routine coagulation screen is normal, the disease is found only by
  a specific quantitative FXIII activity assay; the historical urea or
  monochloroacetic acid clot solubility test detects only the most severe cases
  and a normal result does not exclude the diagnosis. Diagnostic delay is
  therefore the rule rather than the exception.
prevalence:
- population: Worldwide
  measure_type: POINT_PREVALENCE
  prevalence_class: BELOW_1_IN_1000000
  rate_per_100000: 0.05
  rate_denominator: POPULATION
  notes: >-
    Approximately 1 in 2,000,000, i.e. 0.05 cases per 100,000. Published
    estimates for severe congenital FXIII deficiency span roughly 1 in 2 million
    to 1 in 5 million; this record normalizes the most commonly cited figure and
    the range is recorded in the other prevalence records below. The estimate is
    for congenital FXIII deficiency as a whole, of which A-subunit deficiency is
    about 95%.
  evidence:
  - reference: PMID:41583548
    reference_title: "Factor XIII Deficiency: A Review of Biology, Testing, and Treatment."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Congenital FXIII deficiency is a rare inherited bleeding disorder that typically follows autosomal recessive inheritance, with an estimated global prevalence of approximately one in two million individuals"
    explanation: >-
      States the worldwide prevalence estimate that this record normalizes to
      0.05 per 100,000.
  - reference: PMID:39613144
    reference_title: "Factor XIII Deficiency: Laboratory, Molecular, and Clinical Aspects."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Although the estimated incidence of severe FXIII-A deficiency is one per 2 million, a high prevalence ranging from 0.8 to 3.5% has been observed for heterozygous FXIII-A deficiency."
    explanation: >-
      Gives the same figure specifically for severe FXIII-A deficiency, which is
      the disease modelled by this entry, and separates it from the much commoner
      heterozygous state.
- population: Worldwide (lower published estimate)
  measure_type: POINT_PREVALENCE
  prevalence_class: BELOW_1_IN_1000000
  rate_per_100000: 0.025
  rate_low: 0.02
  rate_high: 0.033
  rate_denominator: POPULATION
  notes: >-
    Other reviews place severe inherited FXIII deficiency at 1 in 3-5 million
    (0.02-0.033 per 100,000) or 1 in 4 million (0.025 per 100,000). The spread
    between these and the 1-in-2-million figure reflects ascertainment rather
    than disagreement about biology: the disorder is systematically
    underdiagnosed because the routine coagulation screen is normal.
  evidence:
  - reference: PMID:37314674
    reference_title: Clinical Profile of Congenital Factor XIII Deficiency in Children.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Congenital Factor 13 Deficiency (FXIIID) is a rare bleeding disorder (RBD) of autosomal recessive inheritance, with an incidence of 1 in 3-5 million."
    explanation: >-
      Source of the 1-in-3-to-5-million bound recorded in this record's range.
  - reference: PMID:24503678
    reference_title: Coagulation factor XIII deficiency. Diagnosis, prevalence and management of inherited and acquired forms.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The inherited severe FXIII deficiency, which is a rare coagulation disorder with a prevalence of 1 in 4 million has been the prime focus of clinical and genetic investigations owing to the severity of the bleeding phenotype associated with it."
    explanation: >-
      Source of the 1-in-4-million figure this record's point estimate uses.
- population: Iran
  measure_type: UNKNOWN
  prevalence_class: RARE
  notes: >-
    Markedly commoner where consanguineous marriage is frequent. Iran has the
    highest reported national burden, estimated at roughly twelve times the
    worldwide frequency and concentrated in Sistan and Baluchestan Province. No
    normalized rate is recorded because the cited source reports a fold
    difference and an absolute patient count rather than a population rate, and
    the measure type behind that count is not stated.
  evidence:
  - reference: PMID:25615432
    reference_title: "Factor XIII deficiency in Iran: a comprehensive review of the literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "An approximately 12-fold higher prevalence of FXIIID is estimated in Iran in comparison with overall worldwide frequency."
    explanation: >-
      Quantifies the founder and consanguinity enrichment described in this
      record.
  - reference: PMID:37314674
    reference_title: Clinical Profile of Congenital Factor XIII Deficiency in Children.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Consanguinity was present in 15 (75%) with 4 children having affected siblings."
    explanation: >-
      A South Indian paediatric series documenting the same consanguinity effect
      outside Iran, supporting the general claim rather than the Iranian figure.
inheritance:
- name: Autosomal recessive inheritance
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  description: >-
    Severe disease requires two F13A1 pathogenic alleles - homozygous or
    compound heterozygous. Single heterozygotes carry roughly half-normal FXIII
    activity and are generally asymptomatic, which is why the carrier state is
    two to three orders of magnitude commoner than the disease. The carrier
    state is not, however, entirely silent: a subset of heterozygotes,
    particularly women, bleed at haemostatic challenges and have pregnancy
    complications, and those individuals are managed on demand rather than with
    prophylaxis. This entry models the severe biallelic disease.
  evidence:
  - reference: PMID:41583548
    reference_title: "Factor XIII Deficiency: A Review of Biology, Testing, and Treatment."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Congenital FXIII deficiency is a rare inherited bleeding disorder that typically follows autosomal recessive inheritance, with an estimated global prevalence of approximately one in two million individuals"
    explanation: >-
      States the recessive inheritance pattern of the congenital disorder.
  - reference: PMID:39613144
    reference_title: "Factor XIII Deficiency: Laboratory, Molecular, and Clinical Aspects."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Primary prophylaxis is mandatory for all patients with severe FXIII-A deficiency, while those with heterozygous deficiency are generally asymptomatic and may require on-demand therapy during hemostatic challenges, most commonly in women."
    explanation: >-
      Supports both the generally asymptomatic heterozygote state and the
      challenge-dependent exception described here.
  - reference: PMID:12529747
    reference_title: "Targeted inactivation of the mouse locus encoding coagulation factor XIII-A: hemostatic abnormalities in mutant mice and characterization of the coagulation deficit."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "FXIII transglutaminase activity in plasma was reduced to about 50% in mice heterozygous for the mutant allele, and was abolished in homozygous null mice."
    explanation: >-
      Demonstrates the gene-dose relationship - half-normal activity in
      heterozygotes, none in homozygotes - that the recessive pattern rests on.
pathophysiology:
- name: Biallelic F13A1 Loss-of-Function Variants
  biological_scale: MOLECULAR
  description: >-
    Homozygous or compound heterozygous pathogenic variants in F13A1 (chromosome
    6p24-p25, 15 exons, encoding the 731-residue catalytic A subunit) are the
    initiating lesion. Roughly 200 variants are described across F13A1 and F13B,
    most of them missense, with large deletions the rarest class; there are no
    mutational hotspots, so confirmation relies on sequencing the whole gene or
    a panel that includes it. Founder alleles dominate in some populations -
    Trp187Arg is the commonest Iranian variant. A-subunit defects account for
    about 95% of congenital FXIII deficiency and produce the more severe
    phenotype, because what is lost is catalytic activity rather than carriage.
  genetic_context:
    variant_origin: GERMLINE
    functional_impact_category: LOSS_OF_FUNCTION
    zygosity: HOMOZYGOUS
    description: >-
      Germline biallelic loss of function. Compound heterozygosity is equally
      common in non-consanguineous families; HOMOZYGOUS is recorded because that
      is the configuration in the consanguineous populations where most
      described patients live, and the functional consequence is the same.
  molecular_functions:
  - preferred_term: factor XIII-A transglutaminase activity
    modifier: LOSS_OF_FUNCTION
    term:
      id: GO:0003810
      label: protein-glutamine gamma-glutamyltransferase activity
  cell_types:
  - preferred_term: resident macrophage (source of plasma FXIII-A)
    term:
      id: CL:0000235
      label: macrophage
  - preferred_term: platelet (cellular FXIII-A pool)
    term:
      id: CL:0000233
      label: platelet
  evidence:
  - reference: PMID:41583548
    reference_title: "Factor XIII Deficiency: A Review of Biology, Testing, and Treatment."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The F13A1 gene (chromosome 6p24–p25; 15 exons) encodes a 731-amino-acid catalytic subunit that contains the transglutaminase core"
    explanation: >-
      Source of the gene's location, exon count and product length as stated in
      this node.
  - reference: PMID:41583548
    reference_title: "Factor XIII Deficiency: A Review of Biology, Testing, and Treatment."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Deficiency of the FXIII-A subunit is responsible for the majority (~95%) of cases of congenital FXIII deficiency, and typically produces more severe clinical phenotypes due to loss of catalytic activity, whereas FXIII-B subunit defects mainly lower circulating heterotetramer levels by impairing stabilization and carriage."
    explanation: >-
      Gives the 95% share and the mechanistic reason A-subunit disease is more
      severe than B-subunit disease, which is the boundary this entry is drawn
      on.
  - reference: PMID:39613144
    reference_title: "Factor XIII Deficiency: Laboratory, Molecular, and Clinical Aspects."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "About 200 Mutations have been observed in F13A and F13B genes, with most being missense mutations, while large deletions are the rarest."
    explanation: >-
      Source of the variant count and the missense-dominant spectrum described
      here.
  - reference: PMID:27077776
    reference_title: Diagnosis of factor XIII deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "There are no mutational hotspots in FXIII-A and FXIII-B genes with a few recurrent mutations in some populations; therefore, full sequencing of FXIII genes has remained a main molecular approach for confirmation of FXIIID."
    explanation: >-
      Supports the absence of hotspots and the consequent need for full
      sequencing stated in this node.
  - reference: PMID:28596376
    reference_title: "Cre/lox Studies Identify Resident Macrophages as the Major Source of Circulating Coagulation Factor XIII-A."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "This work suggests that resident macrophages maintain plasma FXIII-A and exclude the platelet lineage as a major contributor."
    explanation: >-
      Identifies the cell that supplies plasma FXIII-A, which is why the
      macrophage is bound on this node rather than the hepatocyte that makes the
      B subunit.
  downstream:
  - target: Absent Plasma Factor XIII Transglutaminase Activity
    causal_link_type: DIRECT
    description: >-
      Loss of both functional A-subunit alleles removes the catalytic half of
      the FXIII-A2B2 heterotetramer, so no activatable transglutaminase reaches
      the circulation.
    evidence:
    - reference: PMID:12529747
      reference_title: "Targeted inactivation of the mouse locus encoding coagulation factor XIII-A: hemostatic abnormalities in mutant mice and characterization of the coagulation deficit."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Plasma fibrin gamma-dimerization was also indetectable in the homozygous deficient animals, confirming the absence of activatable FXIII."
      explanation: >-
        Targeted disruption of the FXIII-A locus abolishes activatable plasma
        FXIII, which is exactly the edge asserted here.
- name: Absent Plasma Factor XIII Transglutaminase Activity
  biological_scale: MOLECULAR
  description: >-
    Thrombin normally cleaves the activation peptide from each A subunit and
    millimolar calcium then releases the B-subunit dimer, exposing a Cys-His-Asp
    catalytic triad that transfers acyl groups between glutamine donors and
    lysine acceptors to form epsilon-(gamma-glutamyl)lysine isopeptide bonds.
    With no functional A subunit there is no triad and no cross-linking
    chemistry, whatever thrombin does. The consequence branches three ways,
    according to which substrate is no longer cross-linked: fibrin itself,
    alpha-2-antiplasmin, or the extracellular matrix proteins that tie the clot
    to the wound bed.
  molecular_functions:
  - preferred_term: plasma factor XIIIa transglutaminase activity
    modifier: LOSS_OF_FUNCTION
    term:
      id: GO:0003810
      label: protein-glutamine gamma-glutamyltransferase activity
  biological_processes:
  - preferred_term: isopeptide cross-linking of clot proteins
    modifier: DECREASED
    term:
      id: GO:0018149
      label: peptide cross-linking
  evidence:
  - reference: PMID:41583548
    reference_title: "Factor XIII Deficiency: A Review of Biology, Testing, and Treatment."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "FXIIIa performs acyl-transfer between γ-carboxamide groups of glutamine donors and ε-amino groups of lysine acceptors to form ε-(γ-glutamyl)-lysine isopeptide bonds."
    explanation: >-
      States the catalytic chemistry that is absent in this node.
  - reference: PMID:22197181
    reference_title: "Factor XIII, clot structure, thrombosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "It is a zymogen, which becomes transformed into an active transglutaminase (FXIIIa) in the final phase of coagulation cascade by thrombin and Ca(2+)."
    explanation: >-
      Establishes that the activity modelled here is a thrombin- and
      calcium-dependent terminal step of the cascade.
  downstream:
  - target: Failure of Fibrin Gamma- and Alpha-Chain Cross-Linking
    causal_link_type: DIRECT
    description: >-
      Fibrin chains are the best-characterised FXIIIa substrate; with no enzyme,
      gamma-gamma dimerization and alpha-chain multimerization do not occur.
    evidence:
    - reference: PMID:41583548
      reference_title: "Factor XIII Deficiency: A Review of Biology, Testing, and Treatment."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "The best characterized substrates are fibrin chains (γ–γ dimerization and α-chain multimerization), which impart tensile strength and viscoelastic stability to the clot."
      explanation: >-
        Names fibrin chains as the substrate whose cross-linking this edge
        removes.
  - target: Failure of Alpha-2-Antiplasmin Ligation to Fibrin
    causal_link_type: DIRECT
    description: >-
      The same enzyme covalently ligates alpha-2-antiplasmin to the fibrin
      alpha-chain, so its absence removes the clot's built-in antifibrinolytic
      shield. This is a separate substrate and a separate consequence from
      fibrin-fibrin cross-linking, not a restatement of it.
    evidence:
    - reference: PMID:41583548
      reference_title: "Factor XIII Deficiency: A Review of Biology, Testing, and Treatment."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "FXIIIa also crosslinks antifibrinolytic proteins to fibrin; for α2-antiplasmin, the predominant linkage involves Gln14 of α2-antiplasmin and Lys303 on the fibrin Aα chain, a reaction critical for lysis resistance."
      explanation: >-
        Identifies the specific residues ligated and states that the reaction is
        what confers lysis resistance, which is the edge asserted here.
  - target: Failure of Fibrin Cross-Linking to Extracellular Matrix Proteins
    causal_link_type: DIRECT
    description: >-
      FXIIIa also links fibrin(ogen) to fibronectin and vitronectin, integrating
      the clot with the surrounding matrix. Losing this is what takes the
      disease beyond haemostasis into tissue repair.
    evidence:
    - reference: PMID:41583548
      reference_title: "Factor XIII Deficiency: A Review of Biology, Testing, and Treatment."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Beyond fibrin and α2-antiplasmin, FXIIIa covalently links fibrin(ogen) to multiple extracellular and plasma proteins (most notably fibronectin and vitronectin), thereby strengthening clot-matrix integration, supporting cell adhesion and angiogenesis, and facilitating wound repair."
      explanation: >-
        States the matrix cross-linking reaction whose loss this edge describes.
- name: Intact Thrombin Generation and Fibrin Polymerisation Upstream of Cross-Linking
  biological_scale: MOLECULAR
  description: >-
    This node has no upstream cause in this disease, and that is the point:
    every step of haemostasis before cross-linking is normal. Platelet plug
    formation, the intrinsic and extrinsic pathways, thrombin generation, and
    the conversion of fibrinogen to a polymerised fibrin mesh are all
    unaffected, because FXIII acts only on an already-formed clot. Two things
    follow. Clinically, a visually adequate clot does form, and bleeding is
    therefore delayed rather than immediate. Diagnostically, the prothrombin
    time, activated partial thromboplastin time, thrombin time and fibrinogen
    concentration - which interrogate exactly the steps that are intact - are
    all normal, which is why this disease is missed. No modifier is set on the
    bound process term because the claim is that it is unchanged, and
    ModifierEnum has no value for normal.
  biological_processes:
  - preferred_term: thrombin generation and fibrin polymerisation (unaffected)
    term:
      id: GO:0072378
      label: blood coagulation, fibrin clot formation
  evidence:
  - reference: PMID:41583548
    reference_title: "Factor XIII Deficiency: A Review of Biology, Testing, and Treatment."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "assess thrombin generation and fibrin formation rather than crosslink maturation, FXIII deficiency presents with normal tests of coagulation despite clinically meaningful impairment of clot stability."
    explanation: >-
      States directly that thrombin generation and fibrin formation are intact
      and that this is why the screening tests are normal.
  - reference: PMID:27077776
    reference_title: Diagnosis of factor XIII deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "All routine coagulation tests are normal in FXIII deficiency (FXIIID), which complicates the diagnosis of this disorder."
    explanation: >-
      Independent confirmation that the whole routine screen is normal, from a
      review devoted to the diagnostic problem.
  downstream:
  - target: Mechanically Unstable Fibrin Clot
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      A clot is present to be unstable only because polymerisation is intact.
      The relationship is permissive rather than causal of the defect - it
      supplies the substrate on which the missing cross-linking would have
      acted - so it is recorded as indirect with the intermediate steps
      (fibrinogen cleavage, fibrin polymerisation) known. The result is an
      apparently adequate clot that fails later under mechanical or fibrinolytic
      stress.
    evidence:
    - reference: PMID:41583548
      reference_title: "Factor XIII Deficiency: A Review of Biology, Testing, and Treatment."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Patients may form visually intact clots that fail under physiologic stress or fibrinolytic challenge, yielding delayed hemorrhage and soft tissue and intracranial bleeding."
      explanation: >-
        States that a visually intact clot forms and then fails, which is the
        conjunction of intact polymerisation and absent cross-linking this edge
        records.
- name: Failure of Fibrin Gamma- and Alpha-Chain Cross-Linking
  biological_scale: MOLECULAR
  description: >-
    Without FXIIIa, fibrin gamma-chains are not dimerised and alpha-chains are
    not multimerised into high-molecular-weight polymers. Gamma-chain
    dimerization is the reaction whose product is absent in plasma from FXIII-A
    null animals, and alpha-chain cross-linking is the one that governs whether
    a contracting clot retains red cells. The cross-links are what give fibrin
    tensile strength and viscoelastic stability, so the polymer that forms is
    mechanically inferior rather than absent.
  biological_processes:
  - preferred_term: fibrin gamma- and alpha-chain isopeptide cross-linking
    modifier: DECREASED
    term:
      id: GO:0018149
      label: peptide cross-linking
  evidence:
  - reference: PMID:22197181
    reference_title: "Factor XIII, clot structure, thrombosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "FXIII is essential for hemostasis, its deficiency results in severe bleeding diathesis. FXIIIa mechanically stabilizes fibrin by cross-linking its α-, and γ-chains."
    explanation: >-
      States the reaction lost in this node and attributes the mechanical
      stabilisation of fibrin to it.
  - reference: PMID:26324704
    reference_title: "Factor XIIIa-dependent retention of red blood cells in clots is mediated by fibrin α-chain crosslinking."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "These data indicate FXIIIa-dependent retention of RBCs in clots is mediated by fibrin α-chain crosslinking."
    explanation: >-
      Separates the two cross-linking reactions experimentally and shows that
      alpha-chain cross-linking in particular determines clot composition, which
      is why this node names both chains rather than only the gamma-chain.
  downstream:
  - target: Mechanically Unstable Fibrin Clot
    causal_link_type: DIRECT
    description: >-
      The isopeptide bonds between fibrin chains are what confer tensile
      strength and viscoelastic stability; their absence is the direct cause of
      a clot that deforms and disintegrates under load.
    evidence:
    - reference: PMID:41583548
      reference_title: "Factor XIII Deficiency: A Review of Biology, Testing, and Treatment."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "The best characterized substrates are fibrin chains (γ–γ dimerization and α-chain multimerization), which impart tensile strength and viscoelastic stability to the clot."
      explanation: >-
        Attributes tensile strength and viscoelastic stability specifically to
        fibrin-chain cross-linking, which is the causal claim of this edge.
- name: Failure of Alpha-2-Antiplasmin Ligation to Fibrin
  biological_scale: MOLECULAR
  description: >-
    FXIIIa normally ligates alpha-2-antiplasmin (alpha-2-plasmin inhibitor) to
    the fibrin Aalpha chain, embedding a plasmin inhibitor inside the clot. In
    its absence the clot carries no covalently bound antifibrinolytic, so
    plasmin generated at its surface is not restrained locally. This is a loss
    of negative regulation of fibrinolysis, not an increase in plasminogen
    activation.
  biological_processes:
  - preferred_term: alpha-2-antiplasmin-dependent protection of fibrin from lysis
    modifier: DECREASED
    term:
      id: GO:0051918
      label: negative regulation of fibrinolysis
  evidence:
  - reference: PMID:22197181
    reference_title: "Factor XIII, clot structure, thrombosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "It also protects newly formed fibrin from fibrinolysis, primarily by cross-linking α(2)-plasmin inhibitor to fibrin."
    explanation: >-
      Names alpha-2-plasmin inhibitor cross-linking as the principal
      antifibrinolytic action of FXIIIa, which is what this node removes.
  - reference: PMID:9892598
    reference_title: The contribution of activated factor XIII to fibrinolytic resistance in experimental pulmonary embolism.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Among groups receiving TPA, selective inhibition of factor XIII-mediated alpha2-antiplasmin-fibrin cross-linking enhanced lysis (group 3 versus 5; P<0.0005)."
    explanation: >-
      Selectively blocking this one reaction, leaving fibrin-fibrin
      cross-linking intact, increases lysis - which isolates the
      alpha-2-antiplasmin arm as an independent contributor.
  downstream:
  - target: Accelerated Fibrinolytic Dissolution of the Hemostatic Clot
    causal_link_type: DIRECT
    description: >-
      With no clot-bound plasmin inhibitor, the fibrin mesh is lysed faster than
      the wound can be repaired.
    evidence:
    - reference: PMID:9892598
      reference_title: The contribution of activated factor XIII to fibrinolytic resistance in experimental pulmonary embolism.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Factor XIIIa-mediated fibrin-fibrin and alpha2-antiplasmin-fibrin cross-linking both caused experimental pulmonary emboli to resist endogenous and TPA-induced fibrinolysis."
      explanation: >-
        Establishes experimentally that loss of these cross-links converts a
        lysis-resistant clot into a lysis-susceptible one.
- name: Failure of Fibrin Cross-Linking to Extracellular Matrix Proteins
  biological_scale: TISSUE
  description: >-
    FXIIIa cross-links fibrin(ogen) to fibronectin, vitronectin and other matrix
    proteins, turning the clot into a provisional scaffold that fibroblasts
    migrate through, keratinocytes re-epithelialise over, and new vessels grow
    into. Losing this is a tissue-repair defect rather than a bleeding defect:
    the provisional matrix is compromised, granulation is delayed, and wounds
    dehisce even when haemostasis looked adequate. The same matrix-stabilising
    requirement applies at the maternal-fetal interface, where cytotrophoblast
    invasion and placentation depend on it.
  biological_processes:
  - preferred_term: FXIIIa-dependent provisional matrix formation in wound repair
    modifier: DECREASED
    term:
      id: GO:0042060
      label: wound healing
  cell_types:
  - preferred_term: fibroblast migrating through the provisional wound matrix
    term:
      id: CL:0000057
      label: fibroblast
  evidence:
  - reference: PMID:41583548
    reference_title: "Factor XIII Deficiency: A Review of Biology, Testing, and Treatment."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The impaired wound healing observed in FXIII deficiency reflects multiple mechanisms beyond hemostasis, whereby FXIIIa-mediated crosslinking of fibrin to extracellular matrix proteins creates a stable scaffold essential for fibroblast migration, keratinocyte re-epithelialization, and angiogenesis during tissue repair."
    explanation: >-
      States the matrix-scaffold mechanism and the three cellular processes that
      depend on it, which is the content of this node.
  - reference: PMID:41583548
    reference_title: "Factor XIII Deficiency: A Review of Biology, Testing, and Treatment."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "These matrix-level actions help explain soft tissue bleeding, poor wound healing, and umbilical stump bleeding observed in severe congenital FXIII deficiency."
    explanation: >-
      Attributes the wound-healing and soft-tissue phenotypes specifically to
      the matrix-level reactions rather than to clot instability alone.
  downstream:
  - target: Poor wound healing
    causal_link_type: DIRECT
    description: >-
      A compromised provisional matrix delays granulation tissue formation and
      predisposes to dehiscence independently of whether bleeding was
      controlled.
    evidence:
    - reference: PMID:41583548
      reference_title: "Factor XIII Deficiency: A Review of Biology, Testing, and Treatment."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Loss of these matrix-stabilizing functions compromises the provisional wound matrix, delays granulation tissue formation, and increases susceptibility to wound dehiscence even when primary hemostasis appears adequate."
      explanation: >-
        States the causal step from lost matrix cross-linking to impaired wound
        repair, and explicitly separates it from haemostatic adequacy.
  - target: Recurrent pregnancy loss
    causal_link_type: DIRECT
    description: >-
      The same FXIII-dependent matrix stabilisation is required for
      cytotrophoblast invasion and placental implantation, so first-trimester
      loss has a matrix component in addition to a haemostatic one.
    evidence:
    - reference: PMID:41583548
      reference_title: "Factor XIII Deficiency: A Review of Biology, Testing, and Treatment."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Individuals with childbearing potential with severe FXIII deficiency face reproductive challenges, including frequent first trimester pregnancy loss without prophylaxis; the biology represents both impaired hemostasis at the maternal-fetal interface and defective FXIII-dependent stabilization of the extracellular matrix required for successful cytotrophoblast invasion and placental implantation."
      explanation: >-
        Names both contributing mechanisms and attaches the matrix one to
        cytotrophoblast invasion and implantation, which is this edge.
- name: Mechanically Unstable Fibrin Clot
  biological_scale: TISSUE
  description: >-
    A clot that is present, visually adequate and mechanically inferior. Without
    fibrin-chain cross-links it has reduced tensile strength and viscoelastic
    stability, loses red cells during contraction, and fails under physiological
    load. Thromboelastography in FXIII-A null mice shows the defect directly and
    shows that it is corrected dose-dependently by replacing the missing
    protein. Note that standard viscoelastic testing in humans is insensitive to
    isolated FXIII deficiency, so the node is better supported by the animal and
    biochemical data than by bedside viscoelastometry.
  biological_processes:
  - preferred_term: fibrin clot mechanical stabilisation
    modifier: DECREASED
    term:
      id: GO:0072378
      label: blood coagulation, fibrin clot formation
  evidence:
  - reference: PMID:12529747
    reference_title: "Targeted inactivation of the mouse locus encoding coagulation factor XIII-A: hemostatic abnormalities in mutant mice and characterization of the coagulation deficit."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Thrombelastography (TEG) experiments demonstrated impaired clot stabilization in FXIII-A mutant mice, replacement with human FXIII led to dose-dependent TEG normalization."
    explanation: >-
      Measures the mechanical instability of the clot in an A-subunit null
      animal and shows it is reversed by FXIII replacement.
  - reference: PMID:26324704
    reference_title: "Factor XIIIa-dependent retention of red blood cells in clots is mediated by fibrin α-chain crosslinking."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Real-time microscopy revealed extensive RBC loss from clots formed in the absence of FXIIIa activity, and RBCs exhibited transient deformation as they exited the clots."
    explanation: >-
      Direct microscopic observation of a clot losing its cellular content when
      FXIIIa activity is absent, which is the mechanical failure this node
      describes. The quote is trimmed of the paper's bracketed abbreviation
      span, which the reference validator strips before matching.
  downstream:
  - target: Delayed Bleeding After Apparently Adequate Initial Hemostasis
    causal_link_type: DIRECT
    description: >-
      Initial haemostasis succeeds; the clot then gives way, so the bleeding
      appears hours to days after the injury rather than at the time of it.
    evidence:
    - reference: PMID:41583548
      reference_title: "Factor XIII Deficiency: A Review of Biology, Testing, and Treatment."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Patients may form visually intact clots that fail under physiologic stress or fibrinolytic challenge, yielding delayed hemorrhage and soft tissue and intracranial bleeding."
      explanation: >-
        States the step from clot failure under stress to delayed haemorrhage,
        which is this edge.
- name: Accelerated Fibrinolytic Dissolution of the Hemostatic Clot
  biological_scale: TISSUE
  description: >-
    The second arm of the defect, and mechanistically separate from mechanical
    weakness: the clot is actively digested sooner because it lacks the
    covalently bound alpha-2-antiplasmin that would have restrained plasmin
    locally. In a ferret embolism model, blocking FXIIIa activity alone raised
    endogenous lysis from about 14% to about 43% - comparable to giving tissue
    plasminogen activator - which is the scale of protection the cross-links
    normally provide.
  biological_processes:
  - preferred_term: plasmin-mediated dissolution of the haemostatic clot
    modifier: INCREASED
    term:
      id: GO:0042730
      label: fibrinolysis
  evidence:
  - reference: PMID:9892598
    reference_title: The contribution of activated factor XIII to fibrinolytic resistance in experimental pulmonary embolism.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Inhibition of factor XIIIa activity increased endogenous lysis markedly (group 1 versus 2; P<0.0001), to a level comparable to that achieved with TPA (group 2 versus 3; P<0.05)."
    explanation: >-
      Quantifies the accelerated lysis that follows loss of FXIIIa activity,
      which is the claim of this node.
  downstream:
  - target: Delayed Bleeding After Apparently Adequate Initial Hemostasis
    causal_link_type: DIRECT
    description: >-
      Premature lysis reopens a wound that had stopped bleeding, producing the
      same delayed pattern by a different route from mechanical failure.
- name: Delayed Bleeding After Apparently Adequate Initial Hemostasis
  biological_scale: ORGANISM
  description: >-
    The clinical convergence point of both arms. Bleeding is characteristically
    delayed and out of proportion to the injury, because the failure is of clot
    persistence rather than of clot formation. The pattern is what generates
    every phenotype in this entry - umbilical stump bleeding days to weeks after
    cord separation, post-circumcision bleeding, deep soft-tissue haematoma, and
    spontaneous intracranial haemorrhage. It is also why the bleeding history
    rather than the coagulation screen is the diagnostic trigger.
  biological_processes:
  - preferred_term: haemostasis
    modifier: DECREASED
    term:
      id: GO:0007596
      label: blood coagulation
  evidence:
  - reference: PMID:41583548
    reference_title: "Factor XIII Deficiency: A Review of Biology, Testing, and Treatment."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Bleeding that is delayed or out of proportion to the clinical context with normal PT, aPTT, thrombin time, and fibrinogen should evoke suspicion for FXIII deficiency"
    explanation: >-
      Defines the delayed, disproportionate bleeding pattern with a normal
      screen that this node names.
  - reference: PMID:22197181
    reference_title: "Factor XIII, clot structure, thrombosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "FXIII is essential for hemostasis, its deficiency results in severe bleeding diathesis."
    explanation: >-
      Establishes that FXIII deficiency produces a bleeding diathesis, the
      organism-level state this node records.
  downstream:
  - target: Abnormal umbilical stump bleeding
    causal_link_type: DIRECT
    description: >-
      The separating cord is a wound whose clot must persist for days; it is the
      first place a stabilisation defect shows.
    evidence:
    - reference: PMID:41583548
      reference_title: "Factor XIII Deficiency: A Review of Biology, Testing, and Treatment."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "A characteristic neonatal presentation is delayed umbilical stump bleeding, which occurs days to weeks after cord separation in approximately 70-80% of symptomatic cases and serves as an important sentinel feature."
      explanation: >-
        States both the delayed timing and the frequency, tying the phenotype to
        the delayed-bleeding mechanism.
  - target: Intracranial hemorrhage
    causal_link_type: DIRECT
    description: >-
      The most consequential destination of the same mechanism; spontaneous or
      after minor trauma, and typically in early childhood.
    evidence:
    - reference: PMID:41583548
      reference_title: "Factor XIII Deficiency: A Review of Biology, Testing, and Treatment."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "The most serious complication is life-threatening intracranial hemorrhage—either spontaneous or following minor trauma—which occurs in up to 30% of untreated patients, often during early childhood."
      explanation: >-
        Gives the frequency and the trigger pattern of the intracranial
        haemorrhage this edge produces.
  - target: Subcutaneous hemorrhage
    causal_link_type: DIRECT
    description: >-
      Soft-tissue bleeding into the subcutis, where a clot that forms and then
      gives way produces a haematoma rather than immediate external bleeding.
      Left uncited: the sources reviewed establish that patients with this
      disease bleed here, which is a node-level claim already carried on the
      phenotype record, not a statement that this step follows from the
      delayed-bleeding state.
  - target: Intramuscular hematoma
    causal_link_type: DIRECT
    description: >-
      The same step reaching a deeper compartment, where the volume of
      accumulated blood is larger because muscle offers less tamponade. Left
      uncited for the same reason as the subcutaneous edge.
  - target: Epistaxis
    causal_link_type: DIRECT
    description: >-
      The mucosal instance of the same step: nasal mucosa bleeds readily, stops,
      and then rebleeds because the clot is not stabilised. Left uncited for the
      same reason.
  - target: Menorrhagia
    causal_link_type: DIRECT
    description: >-
      Endometrial bleeding at menstruation, where haemostasis depends on clot
      persistence over days rather than on a single plug. Left uncited for the
      same reason.
  - target: Joint hemorrhage
    causal_link_type: DIRECT
    description: >-
      Haemarthrosis is an uncommon but real destination of the same mechanism,
      which is why it is connected here rather than left as an unlinked
      phenotype.
    evidence:
    - reference: PMID:37314674
      reference_title: Clinical Profile of Congenital Factor XIII Deficiency in Children.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Clinical symptomatology ranged from mucosal bleeds to intracranial bleeds and hemarthrosis, with many children having a history of prolonged umbilical bleeding in their neonatal period."
      explanation: >-
        Documents haemarthrosis within the bleeding spectrum of a real
        paediatric cohort with this disease.
  - target: Prolonged bleeding following circumcision
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:41583548
      reference_title: "Factor XIII Deficiency: A Review of Biology, Testing, and Treatment."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "In male infants, post-circumcision bleeding is a recognized early presentation that may provide the first diagnostic clue."
      explanation: >-
        Names post-circumcision bleeding as an early consequence of the bleeding
        tendency this node describes.
phenotypes:
- name: Abnormal umbilical stump bleeding
  category: Hematologic
  frequency: VERY_FREQUENT
  description: >-
    The classic presenting sign and the single most useful clue in the newborn:
    bleeding from the umbilical stump appearing days to weeks after cord
    separation rather than at the time of it, reported in roughly 70-80% of
    symptomatic cases. The delay is mechanistically informative - an immediate
    cord bleed points elsewhere; a late one points here (or to afibrinogenaemia).
  phenotype_term:
    preferred_term: Delayed umbilical stump bleeding
    term:
      id: HP:0011884
      label: Abnormal umbilical stump bleeding
    temporality: PROLONGED
    onset:
      onset_category: NEONATAL
  evidence:
  - reference: PMID:41583548
    reference_title: "Factor XIII Deficiency: A Review of Biology, Testing, and Treatment."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A characteristic neonatal presentation is delayed umbilical stump bleeding, which occurs days to weeks after cord separation in approximately 70-80% of symptomatic cases and serves as an important sentinel feature."
    explanation: >-
      Source of both the delayed timing and the 70-80% frequency supporting the
      VERY_FREQUENT band.
  - reference: PMID:25615432
    reference_title: "Factor XIII deficiency in Iran: a comprehensive review of the literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Among Iranian patients, umbilical cord bleeding, hematoma, and prolonged wound bleeding are the most frequent clinical manifestations."
    explanation: >-
      Confirms umbilical cord bleeding as the most frequent manifestation in the
      largest national patient population described.
  - reference: PMID:37314674
    reference_title: Clinical Profile of Congenital Factor XIII Deficiency in Children.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Clinical symptomatology ranged from mucosal bleeds to intracranial bleeds and hemarthrosis, with many children having a history of prolonged umbilical bleeding in their neonatal period."
    explanation: >-
      An independent paediatric series reporting prolonged umbilical bleeding in
      the neonatal period in many of its children.
- name: Intracranial hemorrhage
  category: Neurologic
  frequency: FREQUENT
  description: >-
    The most serious complication of this disease, a principal contributor to
    its mortality and lasting disability, and the clinical fact that justifies
    lifelong prophylaxis in a disorder whose day-to-day bleeding is often
    unimpressive. It occurs spontaneously or after minor trauma in up
    to 30% of untreated patients, usually in early childhood, and in a
    significant fraction of children it is the presenting event - before anyone
    knows the diagnosis. In a 38-patient Iranian series the bleed was
    intraparenchymal in 92% and left neurological sequelae in 55%: locomotor
    disability, psychological and mental impairment, speech and visual loss.
    FREQUENT rather than VERY_FREQUENT because the cited figure is an upper
    bound in untreated patients.
  phenotype_term:
    preferred_term: Spontaneous intracranial hemorrhage
    term:
      id: HP:0002170
      label: Intracranial hemorrhage
    onset:
      onset_category: CHILDHOOD
  evidence:
  - reference: PMID:41583548
    reference_title: "Factor XIII Deficiency: A Review of Biology, Testing, and Treatment."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The most serious complication is life-threatening intracranial hemorrhage—either spontaneous or following minor trauma—which occurs in up to 30% of untreated patients, often during early childhood."
    explanation: >-
      Source of the frequency, the trigger pattern and the childhood onset
      recorded here.
  - reference: PMID:24149912
    reference_title: Intracranial hemorrhage pattern in the patients with factor XIII deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The site of ICH was intraparenchymal in 35 patients (92.1 %), subdural in 2 patients (5.2 %), and epidural hemorrhage in 1 patient (2.6 %)."
    explanation: >-
      Source of the predominantly intraparenchymal distribution described in
      this phenotype.
  - reference: PMID:24149912
    reference_title: Intracranial hemorrhage pattern in the patients with factor XIII deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Besides, neurologic complications occurred in 21 patients (55.2 %), including locomotor disability in 8, psychological impairment in 7, mental disorders in 5, speech impairment in 4, and visual impairment in 2."
    explanation: >-
      Quantifies the permanent neurological sequelae, which is the reason this
      phenotype and not the bleeding frequency drives management.
  - reference: PMID:37314674
    reference_title: Clinical Profile of Congenital Factor XIII Deficiency in Children.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "There is a propensity for intracranial bleeding with a significant number having this at first presentation."
    explanation: >-
      Supports the statement that intracranial haemorrhage is frequently the
      presenting event in children, before diagnosis.
- name: Subcutaneous hemorrhage
  category: Dermatologic
  frequency: FREQUENT
  description: >-
    Delayed subcutaneous bleeding and bruising, part of the soft-tissue bleeding
    pattern that follows the neonatal period.
  phenotype_term:
    preferred_term: Subcutaneous hematoma
    term:
      id: HP:0001933
      label: Subcutaneous hemorrhage
  evidence:
  - reference: PMID:41583548
    reference_title: "Factor XIII Deficiency: A Review of Biology, Testing, and Treatment."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Beyond the neonatal period, patients with congenital FXIII deficiency commonly experience recurrent mucocutaneous hemorrhage (epistaxis, menorrhagia, oral bleeding), soft-tissue bleeding (e.g., subcutaneous and intramuscular hematomas), and impaired wound repair with dehiscence; abnormal scar formation, including keloids, has been reported in some cases."
    explanation: >-
      Names subcutaneous haematoma among the commonly experienced soft-tissue
      bleeds, supporting both the phenotype and the FREQUENT band.
  - reference: PMID:12529747
    reference_title: "Targeted inactivation of the mouse locus encoding coagulation factor XIII-A: hemostatic abnormalities in mutant mice and characterization of the coagulation deficit."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Bleeding episodes, hematothorax, hematoperitoneum and subcutaneous hemorrhage in mutant mice were associated with reduced survival."
    explanation: >-
      The A-subunit null mouse reproduces subcutaneous haemorrhage, supporting
      the phenotype as a direct consequence of the same lesion.
- name: Intramuscular hematoma
  category: Musculoskeletal
  frequency: FREQUENT
  description: >-
    Deep muscle haematoma, reported alongside subcutaneous bleeding as part of
    the characteristic soft-tissue pattern.
  phenotype_term:
    preferred_term: Deep intramuscular hematoma
    term:
      id: HP:0012233
      label: Intramuscular hematoma
  evidence:
  - reference: PMID:41583548
    reference_title: "Factor XIII Deficiency: A Review of Biology, Testing, and Treatment."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Beyond the neonatal period, patients with congenital FXIII deficiency commonly experience recurrent mucocutaneous hemorrhage (epistaxis, menorrhagia, oral bleeding), soft-tissue bleeding (e.g., subcutaneous and intramuscular hematomas), and impaired wound repair with dehiscence; abnormal scar formation, including keloids, has been reported in some cases."
    explanation: >-
      Names intramuscular haematoma among the commonly experienced soft-tissue
      bleeds.
- name: Epistaxis
  category: Hematologic
  frequency: FREQUENT
  description: >-
    Recurrent nosebleeds, part of the mucocutaneous bleeding that emerges beyond
    the neonatal period.
  phenotype_term:
    preferred_term: Recurrent epistaxis
    term:
      id: HP:0000421
      label: Epistaxis
    temporality: RECURRENT
  evidence:
  - reference: PMID:41583548
    reference_title: "Factor XIII Deficiency: A Review of Biology, Testing, and Treatment."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Beyond the neonatal period, patients with congenital FXIII deficiency commonly experience recurrent mucocutaneous hemorrhage (epistaxis, menorrhagia, oral bleeding), soft-tissue bleeding (e.g., subcutaneous and intramuscular hematomas), and impaired wound repair with dehiscence; abnormal scar formation, including keloids, has been reported in some cases."
    explanation: >-
      Lists epistaxis as a component of the recurrent mucocutaneous haemorrhage
      seen in this disease.
- name: Menorrhagia
  category: Reproductive
  frequency: FREQUENT
  description: >-
    Heavy menstrual bleeding in affected women. In a systematic review of 121
    women with congenital FXIII deficiency, menorrhagia (26%) was the second
    most commonly reported bleeding symptom after umbilical bleeding; ovulation
    bleeding was reported in 8%.
  phenotype_term:
    preferred_term: Menorrhagia
    term:
      id: HP:0000132
      label: Menorrhagia
  evidence:
  - reference: PMID:23992439
    reference_title: "Congenital factor XIII deficiency in women: a systematic review of literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Menorrhagia (26%) was the second most common bleeding reported after umbilical bleeding."
    explanation: >-
      Source of the 26% figure and of the ranking relative to umbilical bleeding
      stated here.
  - reference: PMID:23992439
    reference_title: "Congenital factor XIII deficiency in women: a systematic review of literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Ovulation bleeding reported in 8% of women."
    explanation: >-
      Source of the ovulation-bleeding figure mentioned alongside menorrhagia in
      this description.
  - reference: PMID:41583548
    reference_title: "Factor XIII Deficiency: A Review of Biology, Testing, and Treatment."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Beyond the neonatal period, patients with congenital FXIII deficiency commonly experience recurrent mucocutaneous hemorrhage (epistaxis, menorrhagia, oral bleeding), soft-tissue bleeding (e.g., subcutaneous and intramuscular hematomas), and impaired wound repair with dehiscence; abnormal scar formation, including keloids, has been reported in some cases."
    explanation: >-
      Independently names menorrhagia as a common manifestation.
- name: Recurrent pregnancy loss
  category: Reproductive
  frequency: VERY_FREQUENT
  description: >-
    Recurrent first-trimester pregnancy loss in affected women, and one of the
    most prophylaxis-responsive outcomes in this disease: in the FranceCoag
    cohort every one of 26 pregnancies without prophylaxis miscarried, against 3
    of 16 with prophylaxis. A systematic review of the published literature
    found 124 of 136 unprophylaxed pregnancies (91%) ended in miscarriage. The
    mechanism is not purely haemostatic - FXIII-dependent matrix stabilisation
    is required for cytotrophoblast invasion and implantation.
  phenotype_term:
    preferred_term: Recurrent first-trimester pregnancy loss
  evidence:
  - reference: PMID:31414482
    reference_title: "Congenital factor XIII deficiency: comprehensive overview of the FranceCoag cohort."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "All pregnancies without prophylaxis (26/26) led to miscarriages versus 3/16 with prophylaxis."
    explanation: >-
      The cohort figure behind both the frequency band and the
      prophylaxis-responsiveness claim.
  - reference: PMID:23992439
    reference_title: "Congenital factor XIII deficiency in women: a systematic review of literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In 136 pregnancies without prophylactic therapy, 124 (91%) resulted in a miscarriage and 12(9%) progressed to viability stage."
    explanation: >-
      Independent, larger denominator for the same claim, supporting the
      VERY_FREQUENT band.
  - reference: PMID:41583548
    reference_title: "Factor XIII Deficiency: A Review of Biology, Testing, and Treatment."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Individuals with childbearing potential with severe FXIII deficiency face reproductive challenges, including frequent first trimester pregnancy loss without prophylaxis; the biology represents both impaired hemostasis at the maternal-fetal interface and defective FXIII-dependent stabilization of the extracellular matrix required for successful cytotrophoblast invasion and placental implantation."
    explanation: >-
      Supports the first-trimester timing and the dual haemostatic and matrix
      mechanism stated here.
  notes: >-
    Left ontology-unbound, following the precedent in `Asherman_Syndrome` and
    `Thrombophilia`. HP:0200067 (Recurrent spontaneous abortion) exists and means
    exactly this, but HPO files it under Past medical history / Pregnancy history
    rather than under HP:0000118 phenotypic abnormality, so it is outside the
    `PhenotypeTerm` dynamic enum and binding it fails `just validate-terms`.
    HP:0005268 (Miscarriage) is no better: its ancestors are Clinical modifier /
    Prenatal death / Mortality-Aging. Searched `l^Spontaneous abortion`,
    `l^Miscarriage`, `l^Recurrent miscarriage`, `l^Abortion`, `l^Pregnancy loss`
    and `l^Fetal death` against `ols:hp`; HPO has no phenotypic-abnormality term
    for recurrent pregnancy loss.
- name: Poor wound healing
  category: Dermatologic
  frequency: FREQUENT
  description: >-
    Impaired wound repair with dehiscence, and abnormal scarring including
    keloids in some patients. This is the phenotype that shows FXIII is not only
    a coagulation factor: the defect persists even when bleeding has been
    controlled, because the provisional fibrin-matrix scaffold that fibroblasts
    and keratinocytes depend on is never properly cross-linked.
  phenotype_term:
    preferred_term: Impaired wound healing with dehiscence
    term:
      id: HP:0001058
      label: Poor wound healing
  evidence:
  - reference: PMID:41583548
    reference_title: "Factor XIII Deficiency: A Review of Biology, Testing, and Treatment."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Loss of these matrix-stabilizing functions compromises the provisional wound matrix, delays granulation tissue formation, and increases susceptibility to wound dehiscence even when primary hemostasis appears adequate."
    explanation: >-
      States the phenotype and the mechanism, including the point that it is
      independent of haemostatic adequacy.
  - reference: PMID:16113836
    reference_title: Impaired wound healing in factor XIII deficient mice.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Scoring system representing maturation rate of the wounds showed that the scores for the control, FXIII-deficient and FXIII deficient/FXIII treated groups were 94.9 +/- 4.7, 61.5 +/- 14.5 and 94.5 +/- 6.4, respectively (p < 0.001 by ANOVA)."
    explanation: >-
      Animal evidence, graded accordingly, and cited alongside rather than
      instead of the human item above: a wound-maturation score that falls in
      FXIII-deficient mice and returns to the control value when FXIII is
      replaced. It is the rescue arm that makes this informative for the human
      phenotype, because it attributes the delay to the missing protein rather
      than to the strain. The corresponding readouts on the model record itself
      quote the closure percentages; this item quotes the maturation score, which
      is a separate measurement.
- name: Prolonged bleeding following circumcision
  category: Hematologic
  frequency: OCCASIONAL
  description: >-
    Bleeding after circumcision in male infants, recognised as an early
    presentation that can be the first diagnostic clue. The OCCASIONAL band
    reflects that the cited source describes it as a recognised presentation
    without giving a frequency, and that ascertainment depends on whether
    circumcision is practised.
  phenotype_term:
    preferred_term: Prolonged bleeding following circumcision
    term:
      id: HP:0030137
      label: Prolonged bleeding following circumcision
    onset:
      onset_category: NEONATAL
  evidence:
  - reference: PMID:41583548
    reference_title: "Factor XIII Deficiency: A Review of Biology, Testing, and Treatment."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In male infants, post-circumcision bleeding is a recognized early presentation that may provide the first diagnostic clue."
    explanation: >-
      Source of the phenotype and of its status as an early diagnostic clue.
- name: Joint hemorrhage
  category: Musculoskeletal
  frequency: OCCASIONAL
  description: >-
    Haemarthrosis occurs but is relatively uncommon, and that is a useful
    discriminator rather than a footnote: a bleeding disorder with recurrent
    joint bleeds is far more likely to be haemophilia. It is nevertheless
    reported in paediatric series, so it is curated rather than excluded.
  phenotype_term:
    preferred_term: Hemarthrosis
    term:
      id: HP:0005261
      label: Joint hemorrhage
  evidence:
  - reference: PMID:41583548
    reference_title: "Factor XIII Deficiency: A Review of Biology, Testing, and Treatment."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Joint hemorrhage is relatively uncommon, distinguishing FXIII deficiency from hemophilia."
    explanation: >-
      Source of both the OCCASIONAL band and the contrast with haemophilia.
  - reference: PMID:37314674
    reference_title: Clinical Profile of Congenital Factor XIII Deficiency in Children.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Clinical symptomatology ranged from mucosal bleeds to intracranial bleeds and hemarthrosis, with many children having a history of prolonged umbilical bleeding in their neonatal period."
    explanation: >-
      Documents haemarthrosis in an actual paediatric cohort, which is why the
      phenotype is curated despite being uncommon.
definitions:
- name: Laboratory diagnosis of factor XIII A subunit deficiency
  definition_type: DIAGNOSTIC_CRITERIA
  derivation_basis: ESTABLISHED_CRITERIA
  description: >-
    The diagnostic problem in this disease is entirely a problem of test
    selection, and it is the clinical core of the entry. Suspicion comes from
    the bleeding history - delayed or disproportionate bleeding - because every
    routine test is normal. The prothrombin time, activated partial
    thromboplastin time, thrombin time and fibrinogen concentration interrogate
    thrombin generation and fibrin polymerisation, both of which are intact;
    they cannot detect a cross-linking defect and a normal set does not lower
    the probability of the diagnosis. Confirmation requires a quantitative
    FXIII activity assay, first-line, usually an ammonia-release method.
    FXIII-A and FXIII-B antigen assays then separate the A-subunit disease
    modelled here from B-subunit disease, and sequencing of F13A1 and F13B
    confirms it and determines which replacement product is appropriate. Two
    pre-analytical requirements matter: the plasma must be platelet-poor,
    because platelet FXIII-A contaminates the antigen measurement, and the
    sample must be timed relative to any replacement, because the 7-14 day
    half-life of FXIII can mask the deficiency after a dose.
  scope: >-
    Laboratory confirmation of severe congenital A-subunit deficiency. It
    excludes the acquired autoantibody-mediated form, which needs a mixing study
    and inhibitor titration in addition, and it excludes isolated F13B
    deficiency, which this laboratory sequence is designed to separate out
    rather than to include.
  attaches_to:
  - "pathophysiology#Intact Thrombin Generation and Fibrin Polymerisation Upstream of Cross-Linking"
  - "pathophysiology#Absent Plasma Factor XIII Transglutaminase Activity"
  inclusion_criteria:
  - preferred_term: Bleeding that is delayed or out of proportion to the clinical context
  - preferred_term: Markedly reduced quantitative FXIII activity, usually below 5-10% of normal
  - preferred_term: Reduced FXIII-A antigen, with FXIII-B antigen secondarily low or normal
  - preferred_term: Biallelic pathogenic F13A1 variants on sequencing
  exclusion_criteria:
  - preferred_term: Correction of low FXIII activity in a 1:1 mix with pooled normal plasma, indicating an inhibitor rather than congenital deficiency
  - preferred_term: Absent or markedly reduced FXIII-B antigen with a pathogenic F13B genotype, indicating B-subunit deficiency
  - preferred_term: Reliance on a normal urea or monochloroacetic acid clot solubility test to exclude the diagnosis
  evidence:
  - reference: PMID:41583548
    reference_title: "Factor XIII Deficiency: A Review of Biology, Testing, and Treatment."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Bleeding that is delayed or out of proportion to the clinical context with normal PT, aPTT, thrombin time, and fibrinogen should evoke suspicion for FXIII deficiency"
    explanation: >-
      States the entry criterion - the bleeding pattern against a normal
      screen - that this definition is built on.
  - reference: PMID:41583548
    reference_title: "Factor XIII Deficiency: A Review of Biology, Testing, and Treatment."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Quantitative FXIII activity measurement is the recommended first-line diagnostic modality"
    explanation: >-
      Establishes the quantitative activity assay as the first-line confirmatory
      test required by this definition.
  - reference: PMID:41583548
    reference_title: "Factor XIII Deficiency: A Review of Biology, Testing, and Treatment."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In F13A1-related quantitative defects, both activity and FXIII-A antigen are reduced, and FXIII-B antigen may be secondarily decreased because heterotetramer formation is impaired."
    explanation: >-
      Source of the antigen pattern used here to assign a patient to A-subunit
      rather than B-subunit disease.
  - reference: PMID:41583548
    reference_title: "Factor XIII Deficiency: A Review of Biology, Testing, and Treatment."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "timing relative to replacement therapy must be documented because the extended half-life of FXIII (7-14 days) can mask baseline deficiency if samples are drawn post-dose"
    explanation: >-
      Source of the pre-analytical timing requirement stated in this definition.
  - reference: PMID:27077776
    reference_title: Diagnosis of factor XIII deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "All routine coagulation tests are normal in FXIII deficiency (FXIIID), which complicates the diagnosis of this disorder."
    explanation: >-
      Independent statement that the entire routine screen is normal, which is
      the premise of this definition.
  - reference: PMID:29027765
    reference_title: "Factor XIII deficiency diagnosis: Challenges and tools."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The diagnosis of FXIIID is challenging due to normal standard coagulation assays requiring specific FXIII assays for diagnosis, which is especially difficult in developing countries."
    explanation: >-
      Supports the requirement for a FXIII-specific assay and records the access
      problem that makes this definition hard to apply in practice.
  notes: >-
    No LOINC-coded computable phenotype algorithm is asserted. The LOINC codes
    for the relevant assays are recorded on the `biochemical` records below,
    where the reference intervals live; this definition is a clinical-laboratory
    diagnostic sequence, not a validated EHR case-finding query, so
    `validation_status` is deliberately absent rather than guessed at.
- name: Insensitivity of the clot solubility screen
  definition_type: OTHER
  derivation_basis: ESTABLISHED_CRITERIA
  description: >-
    Recorded as a definition rather than a note because it is a statement about
    what a test does and does not establish, and getting it wrong is the
    commonest route to a missed diagnosis. The urea (5 M) or monochloroacetic
    acid (1%) clot solubility test is still the first and often only screen
    available in many laboratories. A positive result does indicate severe
    deficiency, at activity levels of roughly 1-5% depending on method. A
    negative result establishes nothing: sensitivity is poor, raised fibrinogen
    reduces it further, and hypofibrinogenaemia and dysfibrinogenaemia generate
    false positives. Contemporary guidance restricts the test to crude
    adjunctive use in low-resource settings and is explicit that a normal result
    must not delay quantitative activity testing.
  attaches_to:
  - "biochemical#Fibrin clot solubility in urea or monochloroacetic acid"
  evidence:
  - reference: PMID:41583548
    reference_title: "Factor XIII Deficiency: A Review of Biology, Testing, and Treatment."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A positive result strongly suggests severe deficiency at very low activity levels (~1 to 5% depending on method); however, sensitivity is poor."
    explanation: >-
      Source of the asymmetry between a positive and a negative result, and of
      the activity range at which the test turns positive.
  - reference: PMID:41583548
    reference_title: "Factor XIII Deficiency: A Review of Biology, Testing, and Treatment."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Contemporary guidelines therefore discourage reliance on clot solubility assays except as crude adjuncts in low-resource settings; a normal solubility test does not exclude clinically relevant FXIII deficiency and should not delay quantitative FXIII activity testing."
    explanation: >-
      The guidance statement this definition records, including the explicit
      instruction that a normal result does not exclude the diagnosis.
  - reference: PMID:29027765
    reference_title: "Factor XIII deficiency diagnosis: Challenges and tools."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Clot solubility tests are not standardized, have a low sensitivity, and are therefore not recommended as routine screening test; however, they are the first screening test in almost all coagulation laboratories in developing countries."
    explanation: >-
      Supports both the low sensitivity and the fact that this is nevertheless
      the test most patients actually get.
  - reference: PMID:27077776
    reference_title: Diagnosis of factor XIII deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Clot solubility assay is the most widely used method for detection of FXIIID but it is not standardized."
    explanation: >-
      Independent confirmation that the most widely used test is unstandardised.
biochemical:
- name: Plasma factor XIII activity
  presence: DECREASED
  frequency: VERY_FREQUENT
  biomarker_term:
    preferred_term: factor XIII activity
    term:
      id: NCIT:C174313
      label: Factor XIII Activity Measurement
  notes: >-
    The diagnostic test. Measured by a quantitative functional assay - most
    commonly ammonia release, in which thrombin and calcium activate FXIII and
    the liberated ammonia is quantified through a glutamate
    dehydrogenase-coupled NADH oxidation - and reported as a percentage of
    normal. Isopeptidase and amine-incorporation assays are alternatives.
    Severe disease is usually below 5-10% and often at or below 1-3%. The
    interpretation bands below are the activity thresholds used clinically to
    set prophylaxis troughs and perioperative targets; they are not a laboratory
    normal interval and they are drawn from narrative review rather than
    prospective validation, which the review itself says is the outstanding
    evidence gap. The biomarker is bound to the NCIT term for the measurement
    because NCIT's clinical-measurement branch is where this concept sits; the
    analyte-level LOINC codes are on the reference ranges.
  evidence:
  - reference: PMID:41583548
    reference_title: "Factor XIII Deficiency: A Review of Biology, Testing, and Treatment."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Quantitative FXIII activity measurement is the recommended first-line diagnostic modality; while many clinical laboratories still lack the ability to perform such assays, in those that do, at the time of writing, ammonia-release assays predominate."
    explanation: >-
      Establishes the assay as first-line and names the predominant method
      described here.
  - reference: PMID:41583548
    reference_title: "Factor XIII Deficiency: A Review of Biology, Testing, and Treatment."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The clinical phenotype varies with residual FXIII activity and is often severe when activity is significantly reduced (≤1-3%)."
    explanation: >-
      Source of the activity level at which severe disease is described, and of
      the activity-severity relationship this marker reports.
  readouts:
  - target: Absent Plasma Factor XIII Transglutaminase Activity
    relationship: READOUT_OF
    direction: NEGATIVE
    endpoint_context: DIAGNOSTIC
    interpretation: >-
      The assay measures the transglutaminase activity that the pathophysiology
      node says is absent, which is why it is the one test that detects this
      disease.
  reference_ranges:
  - loinc_term:
      id: LOINC:27815-0
      label: Coagulation factor XIII activity actual/normal in Platelet poor plasma by Chromogenic method
    unit: '%'
    population: Patients with congenital factor XIII deficiency
    notes: >-
      No normal interval is asserted. The bands below are clinical decision
      thresholds expressed as percent of normal FXIII activity, taken from a
      narrative review; the same review states that linking target activity
      thresholds to outcomes is an open research question. The LOINC code is the
      platelet-poor-plasma percent-of-normal activity measurement, which is the
      quantity these bands are expressed in.
    evidence:
    - reference: PMID:41583548
      reference_title: "Factor XIII Deficiency: A Review of Biology, Testing, and Treatment."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Although the risk of spontaneous bleeding in congenital deficiency increases below ~10-15% activity, peri-operative and critical care literature suggests aiming for ≥30% (and sometimes higher) to ensure hemostasis."
      explanation: >-
        Source of the spontaneous-bleeding threshold and the perioperative
        target that define the bands below.
    interpretation_bands:
    - name: Severe deficiency
      upper_bound: 3.0
      unit: '%'
      abnormal_flag: CRITICAL_LOW
      severity: SEVERE
      interpretation: >-
        Activity at or below about 1-3% of normal; the phenotype is usually
        severe, with spontaneous bleeding and intracranial risk. This is where
        essentially all genetically confirmed A-subunit null patients sit.
    - name: Spontaneous bleeding risk range
      lower_bound: 3.0
      upper_bound: 15.0
      unit: '%'
      abnormal_flag: LOW
      severity: MODERATE
      interpretation: >-
        Below roughly 10-15% of normal the risk of spontaneous bleeding is
        increased. Prophylaxis troughs are conventionally titrated into the
        lower part of this range (about 5-20%).
    - name: Haemostatic for minor procedures
      lower_bound: 15.0
      upper_bound: 30.0
      unit: '%'
      abnormal_flag: LOW
      severity: MILD
      interpretation: >-
        Above the spontaneous-bleeding threshold but below the target generally
        recommended for surgery.
    - name: Perioperative target
      lower_bound: 30.0
      unit: '%'
      abnormal_flag: NORMAL
      interpretation: >-
        At least 30% activity, and higher for major operations, is the level
        generally aimed for to secure surgical haemostasis. Flagged NORMAL
        because it is the intended therapeutic state, not because 30% is a
        normal endogenous value.
- name: Plasma factor XIII-A subunit antigen
  presence: DECREASED
  biomarker_term:
    preferred_term: factor XIII antigen
    term:
      id: NCIT:C112277
      label: Factor XIII Measurement
  notes: >-
    Immunoreactive FXIII-A concentration, reduced in parallel with activity in
    the quantitative A-subunit defects that make up most of this disease. This
    is the measurement that assigns a patient to A-subunit rather than B-subunit
    deficiency. Two caveats: it is less sensitive than the activity assay for
    qualitative (dysfunctional) variants, and platelet contamination of the
    plasma artefactually raises it, because platelets carry their own FXIII-A
    pool - hence the platelet-poor-plasma requirement. NCIT has no separate
    A-subunit antigen term, so the generic Factor XIII Measurement term is bound
    and the subunit specificity is carried in the record name and the LOINC
    code.
  evidence:
  - reference: PMID:41583548
    reference_title: "Factor XIII Deficiency: A Review of Biology, Testing, and Treatment."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In F13A1-related quantitative defects, both activity and FXIII-A antigen are reduced, and FXIII-B antigen may be secondarily decreased because heterotetramer formation is impaired."
    explanation: >-
      States the antigen pattern in A-subunit disease, which is what this record
      asserts.
  - reference: PMID:41583548
    reference_title: "Factor XIII Deficiency: A Review of Biology, Testing, and Treatment."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Platelets contain abundant FXIII-A, predominantly as an A2 dimer without FXIII-B subunits; upon platelet activation, a fraction becomes exposed on the platelet surface and functionally engages within forming thrombi."
    explanation: >-
      Explains the platelet FXIII-A pool that is the source of the
      contamination artefact noted here.
  reference_ranges:
  - loinc_term:
      id: LOINC:3238-3
      label: Coagulation factor XIII Ag [Units/volume] in Platelet poor plasma by Immunoassay
    unit: IU/dL
    population: Patients with congenital factor XIII deficiency
    notes: >-
      No interval is asserted. The LOINC code is recorded so the analyte is
      machine-identifiable; no reference interval was curated because none was
      found in a citable source during this curation, and the clinically
      actionable thresholds in this disease are activity-based rather than
      antigen-based.
- name: Plasma factor XIII-B subunit antigen
  presence: DECREASED
  biomarker_term:
    preferred_term: factor XIII antigen
    term:
      id: NCIT:C112277
      label: Factor XIII Measurement
  notes: >-
    A secondary, not a primary, abnormality in this disease, and worth curating
    because it is a trap: FXIII-B antigen is also low in A-subunit deficiency,
    so a low FXIII-B does not mean F13B disease. The mechanism is clearance, not
    synthesis - the B subunit is made by hepatocytes independently of the A
    subunit, and in FXIII-A deficiency free FXIII-B2 is cleared from the
    circulation faster because there is no A2 to complex with it. Infusing
    recombinant FXIII-A2 raises FXIII-B2 back up, in humans and in mice. The
    discriminator between A- and B-subunit disease is therefore the combination
    of both antigens plus the genotype, not FXIII-B alone.
  evidence:
  - reference: PMID:37883802
    reference_title: Reciprocal stabilization of coagulation factor XIII-A and -B subunits is a determinant of plasma FXIII concentration.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "These data show FXIII-A2 prevents FXIII-B2 loss from circulation and establish the mechanism underlying FXIII-B2 behavior in FXIII-A deficiency and during rFXIII-A2 therapy."
    explanation: >-
      Establishes the clearance mechanism behind the secondary FXIII-B
      reduction, which is the claim this record makes. Graded MODEL_ORGANISM
      because the mechanism was established in the mouse arm of the study.
  - reference: PMID:37883802
    reference_title: Reciprocal stabilization of coagulation factor XIII-A and -B subunits is a determinant of plasma FXIII concentration.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Plasma FXIII is composed of A and B subunit dimers synthesized in cells of hematopoietic origin and hepatocytes, respectively."
    explanation: >-
      Source of the statement that the B subunit is made by hepatocytes
      independently of the A subunit, which is why its reduction here is
      secondary.
  cell_types:
  - preferred_term: hepatocyte (source of the FXIII-B subunit)
    term:
      id: CL:0000182
      label: hepatocyte
- name: Fibrin clot solubility in urea or monochloroacetic acid
  presence: ABNORMAL
  biomarker_term:
    preferred_term: fibrin clot solubility
    term:
      id: NCIT:C112277
      label: Factor XIII Measurement
  notes: >-
    The historical qualitative screen, retained here because it is still what
    most patients in low-resource settings are offered, and because its
    asymmetry is a curated clinical fact: a dissolved clot indicates severe
    deficiency, an intact clot excludes nothing. See the `definitions` record
    "Insensitivity of the clot solubility screen" for the full statement. NCIT
    has no term for the solubility test itself, so the generic Factor XIII
    Measurement term is bound and the LOINC code carries the method.
  evidence:
  - reference: PMID:41583548
    reference_title: "Factor XIII Deficiency: A Review of Biology, Testing, and Treatment."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A positive result strongly suggests severe deficiency at very low activity levels (~1 to 5% depending on method); however, sensitivity is poor."
    explanation: >-
      Source of the asymmetric interpretation recorded for this test.
  reference_ranges:
  - loinc_term:
      id: LOINC:3241-7
      label: Coagulation factor XIII coagulum dissolution at 24 hours [Presence] in Platelet poor plasma by Coagulation assay
    population: Patients with suspected factor XIII deficiency
    notes: >-
      A presence/absence observation, so no numeric interval applies. The LOINC
      code is recorded to identify the test; no bounds are given because the
      result is qualitative.
- name: Routine coagulation screen
  presence: NORMAL
  frequency: VERY_FREQUENT
  biomarker_term:
    preferred_term: prothrombin time
    term:
      id: NCIT:C62656
      label: Prothrombin Time
  notes: >-
    Curated as a positive finding, not an omission. The prothrombin time,
    activated partial thromboplastin time, thrombin time and fibrinogen
    concentration are all normal in this disease, and recording that here is
    what makes the negative result machine-queryable rather than a sentence in
    prose. A normal screen in a patient with delayed bleeding should raise, not
    lower, suspicion of factor XIII deficiency. The biomarker term binds the
    prothrombin time as the index test of the screen; the other three are named
    in the quoted evidence but have no single term that covers the set. The
    readout below carries no `direction` because BiomarkerReadoutDirectionEnum
    has no value for an unchanged result.
  evidence:
  - reference: PMID:41583548
    reference_title: "Factor XIII Deficiency: A Review of Biology, Testing, and Treatment."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "assess thrombin generation and fibrin formation rather than crosslink maturation, FXIII deficiency presents with normal tests of coagulation despite clinically meaningful impairment of clot stability."
    explanation: >-
      States that the screening tests are normal and gives the mechanistic
      reason, which is what this record captures.
  - reference: PMID:27077776
    reference_title: Diagnosis of factor XIII deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "All routine coagulation tests are normal in FXIII deficiency (FXIIID), which complicates the diagnosis of this disorder."
    explanation: >-
      Independent confirmation that the whole routine panel is normal.
  readouts:
  - target: Intact Thrombin Generation and Fibrin Polymerisation Upstream of Cross-Linking
    relationship: READOUT_OF
    endpoint_context: DIAGNOSTIC
    interpretation: >-
      The normal screen is the direct laboratory readout of the preserved
      upstream cascade; it reports a node that is intact, which is why it
      reports nothing about the disease.
genetic:
- name: F13A1
  gene_term:
    preferred_term: F13A1
    term:
      id: hgnc:3531
      label: F13A1
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  notes: >-
    F13A1 (coagulation factor XIII A chain) on chromosome 6p24-p25 encodes the
    731-residue catalytic transglutaminase subunit of factor XIII. Biallelic
    loss-of-function variants cause this disease and account for about 95% of
    congenital factor XIII deficiency. The variant spectrum is broad - roughly
    200 variants reported across F13A1 and F13B, predominantly missense, with
    large deletions rarest - and there are no mutational hotspots, so molecular
    confirmation needs full-gene sequencing or a panel that includes the whole
    gene. Founder variants dominate locally: Trp187Arg is the most common
    variant in Iran. Genotype does not predict phenotype; residual activity does
    so moderately well. The HGNC CURIE was resolved from the HGNC REST API
    during curation (symbol F13A1 -> HGNC:3531, "coagulation factor XIII A
    chain"), and the F13B symbol was resolved separately (HGNC:3534) to confirm
    the two are distinct loci.
  evidence:
  - reference: PMID:41583548
    reference_title: "Factor XIII Deficiency: A Review of Biology, Testing, and Treatment."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The F13A1 gene (chromosome 6p24–p25; 15 exons) encodes a 731-amino-acid catalytic subunit that contains the transglutaminase core"
    explanation: >-
      Source of the gene's location, exon count and protein length.
  - reference: PMID:24503678
    reference_title: Coagulation factor XIII deficiency. Diagnosis, prevalence and management of inherited and acquired forms.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A diverse spectrum of mutations have been reported in the F13A1 and F13B genes which cause inherited severe FXIII deficiency."
    explanation: >-
      Attributes inherited severe FXIII deficiency to variants in these two
      genes.
  - reference: PMID:39613144
    reference_title: "Factor XIII Deficiency: Laboratory, Molecular, and Clinical Aspects."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "There is no correlation between genotype and phenotype and a moderate to strong correlation between factor activity and clinical severity in FXIII-A deficiency, making it difficult to predict bleeding patterns based on genotype and FXIII activity levels."
    explanation: >-
      Source of the genotype-phenotype statement, and the reason this entry puts
      severity on an activity axis rather than in genotype-defined subtypes.
  - reference: PMID:25615432
    reference_title: "Factor XIII deficiency in Iran: a comprehensive review of the literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "There are several disease causing mutations in Iranian patients with FXIIID, with Trp187Arg being the most common mutation in FXIIID in Iran."
    explanation: >-
      Source of the founder variant named here.
treatments:
- name: Recombinant Factor XIII-A2 Prophylaxis (Catridecacog)
  description: >-
    Monthly intravenous recombinant FXIII A-subunit dimer, given as primary
    prophylaxis. This is the one treatment that is specific to this entry rather
    than to factor XIII deficiency in general: because it replaces only the A
    subunit, it works in F13A1 deficiency and does not work in isolated F13B
    deficiency. In the mentor-2 extension trial 60 patients with severe
    (<0.05 IU/mL) A-subunit deficiency received 35 IU/kg every 28 days for at
    least 52 weeks, with a mean annualized bleeding rate of 0.043 per
    patient-year, no neutralizing antibodies, and enough haemostatic coverage
    for twelve minor surgeries without supplementary FXIII. The 28-day interval
    is possible because FXIII has a terminal half-life of about 13.7 days - an
    order of magnitude longer than the upstream factors.
  therapeutic_modality: PROTEIN_REPLACEMENT
  dosing_interval: every 28 days
  dosing_interval_days: 28
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: catridecacog (recombinant factor XIII A-subunit)
      term:
        id: NCIT:C174766
        label: Catridecacog
  target_mechanisms:
  - target: Absent Plasma Factor XIII Transglutaminase Activity
    treatment_effect: RESTORES
    description: >-
      Infused recombinant A-subunit dimer associates with the patient's own
      circulating B subunits, restoring activatable plasma transglutaminase. It
      does not correct the F13A1 lesion, so activity decays with the protein's
      half-life and the dose has to be repeated.
    evidence:
    - reference: PMID:29448295
      reference_title: "Recombinant FXIII (rFXIII-A2) Prophylaxis Prevents Bleeding and Allows for Surgery in Patients with Congenital FXIII A-Subunit Deficiency."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Recombinant factor XIII-A2 (rFXIII-A2) was developed for prophylaxis and treatment of bleeds in patients with congenital FXIII A-subunit deficiency."
      explanation: >-
        Names the mechanism and the indication - replacement of the missing A
        subunit in A-subunit deficiency - which is the edge asserted here.
  evidence:
  - reference: PMID:41583548
    reference_title: "Factor XIII Deficiency: A Review of Biology, Testing, and Treatment."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Because recombinant FXIII-A2 (catridecacog) replaces only the FXIII-A subunit, it is appropriate for F13A1 deficiency (i.e., the majority of cases) but not for isolated F13B deficiency, a distinction that has direct therapeutic implications."
    explanation: >-
      The A-subunit specificity that makes this treatment entry-specific rather
      than generic to factor XIII deficiency.
  - reference: PMID:29448295
    reference_title: "Recombinant FXIII (rFXIII-A2) Prophylaxis Prevents Bleeding and Allows for Surgery in Patients with Congenital FXIII A-Subunit Deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Patients received 35 IU/kg rFXIII-A2 (exact dosing) every 28 ± 2 days for ≥52 weeks."
    explanation: >-
      Source of the dose and of the 28-day interval recorded in
      `dosing_interval_days`.
  - reference: PMID:29448295
    reference_title: "Recombinant FXIII (rFXIII-A2) Prophylaxis Prevents Bleeding and Allows for Surgery in Patients with Congenital FXIII A-Subunit Deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Mean annualized bleeding rate (ABR) was 0.043/patient-year."
    explanation: >-
      The efficacy figure quoted in this treatment's description.
  - reference: PMID:29448295
    reference_title: "Recombinant FXIII (rFXIII-A2) Prophylaxis Prevents Bleeding and Allows for Surgery in Patients with Congenital FXIII A-Subunit Deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Geometric terminal half-life was 13.7 days."
    explanation: >-
      Source of the half-life that makes a monthly dosing interval feasible.
  - reference: PMID:39613144
    reference_title: "Factor XIII Deficiency: Laboratory, Molecular, and Clinical Aspects."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Primary prophylaxis is mandatory for all patients with severe FXIII-A deficiency, while those with heterozygous deficiency are generally asymptomatic and may require on-demand therapy during hemostatic challenges, most commonly in women."
    explanation: >-
      States that primary prophylaxis - rather than on-demand treatment - is the
      standard of care in the severe disease this entry models.
- name: Plasma-Derived Factor XIII Concentrate Prophylaxis
  description: >-
    Pathogen-inactivated plasma-derived FXIII concentrate (Corifact,
    Fibrogammin) given monthly as primary prophylaxis, and at 20-40 IU/kg on
    demand or perioperatively. It remains first-line for routine prophylaxis
    across age groups, and unlike recombinant FXIII-A2 it covers both A- and
    B-subunit disease, because it supplies the intact A2B2 heterotetramer.
    Labelled dosing starts at 40 IU/kg every 28 days, titrated in 5 IU/kg steps
    to a trough of roughly 5-20%; children often clear it faster and need closer
    titration. An Iranian series of 38 patients who had already had an
    intracranial haemorrhage started all but one of them on 10 IU/kg every 4-6
    weeks and reported a good response with no recurrence, again with one
    exception. That is the clearest available evidence that prophylaxis prevents
    the outcome that matters most, and it is uncontrolled.
  therapeutic_modality: PROTEIN_REPLACEMENT
  dosing_interval: every 28 days
  dosing_interval_days: 28
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: human plasma-derived factor XIII concentrate
      term:
        id: NCIT:C200601
        label: Human Factor XIII Concentrate
  target_mechanisms:
  - target: Absent Plasma Factor XIII Transglutaminase Activity
    treatment_effect: RESTORES
    description: >-
      Supplies the complete FXIII-A2B2 heterotetramer, restoring activatable
      plasma transglutaminase irrespective of which subunit the patient lacks.
  - target: Intracranial hemorrhage
    treatment_effect: INHIBITS
    description: >-
      The clinical endpoint prophylaxis exists for - preventing intracranial
      haemorrhage. Scheduled replacement prevents spontaneous and intracranial
      bleeding; the Iranian series recorded no recurrence of intracranial
      haemorrhage on 10 IU/kg every 4-6 weeks other than in a single patient.
    evidence:
    - reference: PMID:24149912
      reference_title: Intracranial hemorrhage pattern in the patients with factor XIII deficiency.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "It seems that long-term prophylactic treatment with a dose of 10 IU/kg Fibrogammin could be effective in the prevention of CNS bleeding in the patients with F XIII deficiency."
      explanation: >-
        States the authors' conclusion that prophylaxis with this product
        prevents central nervous system bleeding, which is this edge.
    - reference: PMID:41583548
      reference_title: "Factor XIII Deficiency: A Review of Biology, Testing, and Treatment."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Prophylaxis with FXIII-containing blood products or FXIII concentrates prevents spontaneous and intracranial hemorrhage in congenital disease, and activity-guided replacement may be clinically important in perioperative and obstetric care; nuances surrounding scenarios in which certain replacement products are effective must be considered."
      explanation: >-
        Independent statement that prophylaxis prevents intracranial
        haemorrhage.
  - target: Recurrent pregnancy loss
    treatment_effect: INHIBITS
    description: >-
      Prophylaxis through pregnancy changes the outcome dramatically: every
      unprophylaxed pregnancy in the FranceCoag cohort miscarried, against 3 of
      16 with prophylaxis.
    evidence:
    - reference: PMID:31414482
      reference_title: "Congenital factor XIII deficiency: comprehensive overview of the FranceCoag cohort."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "All pregnancies without prophylaxis (26/26) led to miscarriages versus 3/16 with prophylaxis."
      explanation: >-
        Directly contrasts pregnancy outcome with and without prophylaxis, which
        is the effect this edge records.
  evidence:
  - reference: PMID:41583548
    reference_title: "Factor XIII Deficiency: A Review of Biology, Testing, and Treatment."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Plasma-derived FXIII concentrates (pdFXIII; e.g., Corifact/Fibrogammin) remain first-line for routine prophylaxis across age groups and for peri-operative support (Table 3)."
    explanation: >-
      Establishes plasma-derived concentrate as first-line for prophylaxis and
      perioperative cover.
  - reference: PMID:41583548
    reference_title: "Factor XIII Deficiency: A Review of Biology, Testing, and Treatment."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Product labeling supports an initial dose of 40 IU/kg intravenously every 28 days with subsequent titration (typically in 5 IU/kg increments) to maintain a trough activity of ~5–20%"
    explanation: >-
      Source of the labelled dose, the titration increment, the trough target
      and the 28-day interval recorded here.
  - reference: PMID:24149912
    reference_title: Intracranial hemorrhage pattern in the patients with factor XIII deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Prophylaxis was started with a dose of 10 IU/kg Fibrogammin every 4-6 weeks for all the patients, except for one."
    explanation: >-
      Source of the Iranian series' dosing schedule quoted in this description.
- name: Cryoprecipitate or Plasma Bridging
  description: >-
    Cryoprecipitate or plasma (fresh frozen plasma, or plasma frozen within 24
    hours of phlebotomy) raises FXIII activity where concentrate is unavailable
    or cannot be obtained quickly. It is explicitly second-line: FXIII content
    varies widely between units and products, plasma carries a volume load, and
    pathogen reduction is often absent. In practice it is nevertheless the
    treatment many patients actually receive - fourteen of the twenty children
    in the South Indian paediatric cohort were on cryoprecipitate prophylaxis,
    and four children had breakthrough bleeds when the schedule slipped,
    including one intracranial bleed during a pandemic supply interruption. That is the
    clearest illustration of why a bridging product is not an equivalent.
  therapeutic_modality: PROTEIN_REPLACEMENT
  treatment_term:
    preferred_term: transfusion of a factor XIII-containing blood component
    term:
      id: NCIT:C15192
      label: Blood Transfusion
    therapeutic_agent:
    - preferred_term: cryoprecipitated plasma
  notes: >-
    Two bindings are deliberately imprecise and the reasons are recorded rather
    than papered over. NCIT has no cryoprecipitate-transfusion clinical-action
    term, so the action is bound to the general Blood Transfusion term;
    NCIT:C180873 Cryoprecipitated Plasma exists but is a blood-product term that
    is not reachable from the Clinical Intervention or Procedure root and so
    cannot occupy the `treatment_term` slot, and it was not verified to be a
    valid ChemicalEntityTerm either, so `therapeutic_agent` carries the free-text
    name only. Fresh frozen plasma has its own action term (NCIT:C116475) but is
    curated here together with cryoprecipitate because the cited sources treat
    them as one second-line bridging option with the same rationale and the same
    caveats.
  target_mechanisms:
  - target: Absent Plasma Factor XIII Transglutaminase Activity
    treatment_effect: RESTORES
    description: >-
      Donor-derived FXIII in cryoprecipitate or plasma restores some activatable
      transglutaminase, but the delivered dose is unpredictable because the
      FXIII content of each unit varies.
  evidence:
  - reference: PMID:41583548
    reference_title: "Factor XIII Deficiency: A Review of Biology, Testing, and Treatment."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "can serve as temporary bridges to raise FXIII activity, but they are second-line because of FXIII content variability, larger volumes (plasma), and lack of pathogen reduction in many settings."
    explanation: >-
      States the second-line status of cryoprecipitate and plasma bridging and
      all three reasons for it. The quote starts mid-sentence because the
      preceding clause carries a bracketed span the reference validator strips
      before matching; the indication itself is supported by the two following
      items.
  - reference: PMID:37314674
    reference_title: Clinical Profile of Congenital Factor XIII Deficiency in Children.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Four children had breakthrough bleeds due to irregular prophylaxis, including one intracranial bleed due to a delay in cryoprecipitate prophylaxis during the covid pandemic."
    explanation: >-
      Documents the breakthrough bleeding that followed interruption of
      cryoprecipitate prophylaxis in a real paediatric cohort.
  - reference: PMID:25615432
    reference_title: "Factor XIII deficiency in Iran: a comprehensive review of the literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Traditionally, the management of FXIIID in Iran was only based on administration of fresh frozen plasma or cryoprecipitate, until 2009 when FXIII concentrate became available for patient management."
    explanation: >-
      Records the historical and resource-dependent use of plasma and
      cryoprecipitate before concentrate became available.
- name: Genetic Counseling and Family Testing
  description: >-
    Molecular confirmation of the F13A1 genotype supports carrier testing,
    reproductive planning, prenatal or early neonatal diagnosis, and peripartum
    management - and it selects the replacement product, because recombinant
    FXIII-A2 is appropriate only once the defect is known to be in F13A1. In
    affected families newborns warrant prompt assessment so prophylaxis can
    start before the first intracranial bleed, which in a substantial minority
    of children is the presenting event.
  therapeutic_modality: OTHER
  treatment_term:
    preferred_term: Genetic Counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  evidence:
  - reference: PMID:41583548
    reference_title: "Factor XIII Deficiency: A Review of Biology, Testing, and Treatment."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Molecular confirmation refines genetic counseling, reproductive planning (carrier testing, prenatal/early neonatal diagnosis, peripartum management), and therapeutic product selection."
    explanation: >-
      Enumerates the uses of molecular confirmation that this treatment record
      describes, including product selection.
animal_models:
- name: FXIII-A null mouse (F13a1 exon 7 targeted deletion)
  species: Mouse
  genotype: F13a1 targeted deletion of inferred exon 7, homozygous null
  publication: PMID:12529747
  description: >-
    The canonical genetic model. Homologous recombination deleted the inferred
    exon 7 of the mouse FXIII-A gene. Heterozygotes retain about 50% plasma
    transglutaminase activity and homozygotes none, and plasma fibrin
    gamma-dimerization is undetectable in homozygotes - the molecular signature
    of absent activatable FXIII. Homozygotes bleed spontaneously (haemothorax,
    haemoperitoneum, subcutaneous haemorrhage) with reduced survival, have
    markedly delayed tail-tip bleeding arrest, and show impaired clot
    stabilisation on thromboelastography. Both the bleeding time and the
    thromboelastography abnormality are corrected by human plasma FXIII, which
    makes this a model of the therapeutic response as well as of the lesion.
  modeled_mechanisms:
  - target: Absent Plasma Factor XIII Transglutaminase Activity
    relationship: RECAPITULATES
    fidelity: HIGH
    model_scale: MOLECULAR
    description: >-
      A null allele at the orthologous locus producing the same molecular
      state - no activatable plasma transglutaminase and no fibrin
      gamma-dimerization.
    limitations: >-
      The lesion is an engineered exon deletion, whereas most human alleles are
      missense; that difference does not matter for a complete-null phenotype
      but means the model says nothing about the residual-activity range where
      human severity is actually decided.
    readouts:
    - name: Plasma FXIII transglutaminase activity
      target: Absent Plasma Factor XIII Transglutaminase Activity
      direction: ABOLISHED
      interpretation: >-
        Activity is abolished in homozygotes and roughly halved in
        heterozygotes, establishing the gene-dose relationship.
      evidence:
      - reference: PMID:12529747
        reference_title: "Targeted inactivation of the mouse locus encoding coagulation factor XIII-A: hemostatic abnormalities in mutant mice and characterization of the coagulation deficit."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "FXIII transglutaminase activity in plasma was reduced to about 50% in mice heterozygous for the mutant allele, and was abolished in homozygous null mice."
        explanation: >-
          Reports the measurement and both genotype levels.
    - name: Plasma fibrin gamma-chain dimerization
      target: Absent Plasma Factor XIII Transglutaminase Activity
      direction: ABOLISHED
      interpretation: >-
        The reaction product of FXIIIa on fibrin is undetectable, confirming
        functional absence of the enzyme rather than merely reduced antigen.
      evidence:
      - reference: PMID:12529747
        reference_title: "Targeted inactivation of the mouse locus encoding coagulation factor XIII-A: hemostatic abnormalities in mutant mice and characterization of the coagulation deficit."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "Plasma fibrin gamma-dimerization was also indetectable in the homozygous deficient animals, confirming the absence of activatable FXIII."
        explanation: >-
          Reports the direct measurement of the cross-linking product.
    evidence:
    - reference: PMID:12529747
      reference_title: "Targeted inactivation of the mouse locus encoding coagulation factor XIII-A: hemostatic abnormalities in mutant mice and characterization of the coagulation deficit."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "The mutant mice thus reiterate some key features of the human genetic disorder: they will be valuable in assessing the role of FXIII in other associated pathologies and the development of new therapies."
      explanation: >-
        The authors' own statement of how far the model reproduces the human
        disorder, which is the claim this link makes.
  - target: Mechanically Unstable Fibrin Clot
    relationship: RECAPITULATES
    fidelity: HIGH
    model_scale: TISSUE
    description: >-
      Thromboelastography shows impaired clot stabilisation, corrected
      dose-dependently by human FXIII.
    readouts:
    - name: Thromboelastographic clot stability
      target: Mechanically Unstable Fibrin Clot
      direction: DECREASED
      interpretation: >-
        The mechanical deficit is measured directly, and its reversal on
        replacement shows the instability is attributable to the missing protein
        rather than to a secondary effect of the knockout.
      evidence:
      - reference: PMID:12529747
        reference_title: "Targeted inactivation of the mouse locus encoding coagulation factor XIII-A: hemostatic abnormalities in mutant mice and characterization of the coagulation deficit."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "Thrombelastography (TEG) experiments demonstrated impaired clot stabilization in FXIII-A mutant mice, replacement with human FXIII led to dose-dependent TEG normalization."
        explanation: >-
          Reports the measurement and the dose-dependent correction.
    - name: Tail-tip bleeding time
      target: Mechanically Unstable Fibrin Clot
      direction: INCREASED
      interpretation: >-
        Prolonged and restored to normal by human plasma FXIII, establishing an
        in vivo haemostatic correlate of the clot-stability defect.
      evidence:
      - reference: PMID:12529747
        reference_title: "Targeted inactivation of the mouse locus encoding coagulation factor XIII-A: hemostatic abnormalities in mutant mice and characterization of the coagulation deficit."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "Arrest of tail-tip bleeding in FXIII-A deficient mice was markedly and significantly delayed; replacement of mutant mice with human plasma FXIII (Fibrogammin P) restored bleeding time to within the normal range."
        explanation: >-
          Reports the prolongation and its correction by replacement.
  - target: Recurrent pregnancy loss
    relationship: PARTIALLY_RECAPITULATES
    fidelity: MODERATE
    model_scale: ORGANISM
    description: >-
      Homozygous null mice are fertile but reproduce poorly, which is a
      quantitative reproductive deficit rather than the near-complete
      first-trimester loss seen in unprophylaxed human pregnancies.
    limitations: >-
      Human disease shows essentially universal miscarriage without prophylaxis;
      this line's homozygotes remain fertile, so it understates the phenotype.
      That is a property of this colony rather than of the mouse: the
      independently derived FXIIIA-KO line below does reproduce gestational
      haemorrhage and pregnancy loss. Murine placentation also differs from
      human, so neither line can be used to test the cytotrophoblast-invasion
      mechanism proposed for humans.
    evidence:
    - reference: PMID:12529747
      reference_title: "Targeted inactivation of the mouse locus encoding coagulation factor XIII-A: hemostatic abnormalities in mutant mice and characterization of the coagulation deficit."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Homozygous mutant mice were fertile, although reproduction was impaired."
      explanation: >-
        The observation on which the PARTIALLY_RECAPITULATES grading and the
        stated limitation both rest.
- name: FXIIIA-knockout mouse (uterine haemorrhage and miscarriage line)
  species: Mouse
  genotype: F13a1 (FXIIIA) knockout, homozygous
  publication: PMID:12933578
  description: >-
    An independently derived FXIII-A knockout line, analysed specifically for
    reproductive failure. Homozygous females conceive, but most die of excessive
    vaginal bleeding during gestation; histology shows massive placental
    haemorrhage and subsequent necrosis in the uterus by gestational day 10,
    irrespective of fetal genotype - so the lesion is maternal. The authors call
    the result reminiscent of spontaneous miscarriage in pregnant humans with
    FXIII deficiency and conclude that maternal FXIII is required for uterine
    haemostasis and maintenance of the placenta. This line is why the human
    pregnancy-loss phenotype has animal support at all; the exon-7 deletion line
    above remains fertile.
  modeled_mechanisms:
  - target: Recurrent pregnancy loss
    relationship: RECAPITULATES
    fidelity: MODERATE
    model_scale: ORGANISM
    description: >-
      Gestational placental haemorrhage and pregnancy loss in homozygous
      FXIII-A-null dams, attributed by the authors to maternal FXIII.
    limitations: >-
      Two divergences from the human phenotype. The mice largely die of maternal
      haemorrhage, which is not the usual human outcome - unprophylaxed women
      miscarry and survive. And the murine loss is dated to gestational day 10
      with placental haemorrhage and necrosis, whereas the human mechanism is
      placed in the first trimester and attributed partly to failure of
      FXIII-dependent matrix cross-linking during cytotrophoblast invasion, which
      murine placentation cannot test. Fidelity is therefore MODERATE rather than
      HIGH despite the phenotype matching.
    readouts:
    - name: Maternal survival through gestation
      target: Recurrent pregnancy loss
      direction: DECREASED
      interpretation: >-
        Most homozygous dams died during gestation from vaginal bleeding, which
        is the organism-level readout of the reproductive failure.
      evidence:
      - reference: PMID:12933578
        reference_title: Factor XIII A subunit-deficient mice developed severe uterine bleeding events and subsequent spontaneous miscarriages.
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "Although homozygous FXIIIA female KO mice were capable of becoming pregnant, most of them died due to excessive vaginal bleeding during gestation."
        explanation: >-
          Reports conception followed by fatal gestational haemorrhage, the
          measurement behind this readout.
    - name: Placental haemorrhage and necrosis on histology
      target: Recurrent pregnancy loss
      direction: INCREASED
      interpretation: >-
        Dates the lesion to gestational day 10 and localises it to the placenta,
        and shows it is independent of fetal genotype - so the defect is in the
        mother.
      evidence:
      - reference: PMID:12933578
        reference_title: Factor XIII A subunit-deficient mice developed severe uterine bleeding events and subsequent spontaneous miscarriages.
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "A series of histologic examinations of the pregnant animals suggested that massive placental hemorrhage and subsequent necrosis developed in the uteri of the FXIIIA KO mice on day 10 of gestation."
        explanation: >-
          Reports the histological measurement, its timing and its location.
    evidence:
    - reference: PMID:12933578
      reference_title: Factor XIII A subunit-deficient mice developed severe uterine bleeding events and subsequent spontaneous miscarriages.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "These results are reminiscent of spontaneous miscarriage in pregnant humans with FXIII deficiency and indicate that maternal FXIII plays a critical role in uterine hemostasis and maintenance of the placenta during gestation."
      explanation: >-
        The authors' own statement of the model's relevance to human pregnancy
        loss, which is what this link claims.
- name: FXIII-deficient mouse excisional wound-healing cohort
  species: Mouse
  genotype: FXIII-deficient (targeted subunit not stated in the cited report)
  publication: PMID:16113836
  description: >-
    The animal evidence for the non-haemostatic arm of this disease. Excisional
    wounds left unsutured and undressed closed more slowly in FXIII-deficient
    mice than in controls - 15%, 27% and 27% less closure at days 4, 8 and 11 -
    and were only 73.23% closed at day 11 against 100% in controls. Histology at
    day 11 showed delayed re-epithelialisation and a necrotised fissure. The
    informative arm is the third group: FXIII concentrate raised day-11 closure
    to 90.06% and normalised the histology, which is what makes this a model of
    the FXIII-dependent step rather than of an incidental strain difference.
  notes: >-
    The cited report calls its animals "FXIII-deficient mice" and does not state
    which subunit was targeted, so the genotype is recorded as reported rather
    than as FXIII-A-null. At the time of publication the described knockout
    lines were A-subunit lines, which makes an A-subunit genotype likely, but
    that is an inference and is not asserted here. Treat the link below as
    evidence about FXIII rather than specifically about FXIII-A.
  modeled_mechanisms:
  - target: Poor wound healing
    relationship: RECAPITULATES
    fidelity: MODERATE
    model_scale: TISSUE
    description: >-
      Quantified delay in excisional wound closure with delayed
      re-epithelialisation on histology, corrected by FXIII concentrate.
    limitations: >-
      Two limitations. The report does not say which FXIII subunit was targeted,
      so the model speaks to FXIII deficiency rather than specifically to
      A-subunit deficiency. And a murine excisional wound left unsutured and
      undressed is not the clinical scenario the human phenotype describes, which
      is dehiscence of a surgical wound; the shared claim is that FXIII is
      required for timely closure, not that the wound types correspond.
    readouts:
    - name: Percentage excisional wound closure at days 4, 8 and 11
      target: Poor wound healing
      direction: DECREASED
      interpretation: >-
        A graded, time-resolved deficit rather than a single endpoint, which is
        what makes the delay rather than the failure of healing the claim.
      evidence:
      - reference: PMID:16113836
        reference_title: Impaired wound healing in factor XIII deficient mice.
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "FXIII-deficient mice exhibited impaired wound healing as has been demonstrated by 15%, 27% and 27% decrease in percentage of wound closure on day 4, 8 and 11, respectively."
        explanation: >-
          Reports the measurement and the three timepoints quoted in this
          model's description.
    - name: Day-11 wound closure with and without FXIII replacement
      target: Poor wound healing
      direction: RESTORED
      interpretation: >-
        The rescue arm. Replacement moves day-11 closure from 73.23% back toward
        the control value, which attributes the deficit to the missing protein.
      evidence:
      - reference: PMID:16113836
        reference_title: Impaired wound healing in factor XIII deficient mice.
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "On day 11 complete healing was observed in control (100% closure), 73.23% in FXIII-deficient and 90.06% in FXIII deficient/FXIII-treated groups (p = 0.007 by ANOVA and p = 0.001 by t-test between control and FXIII-deficient groups)."
        explanation: >-
          Gives all three group values and the statistics, which is the rescue
          this readout records.
    - name: Re-epithelialisation on day-11 histology
      target: Poor wound healing
      direction: DECREASED
      interpretation: >-
        Ties the macroscopic closure deficit to the cellular process the human
        mechanism names - re-epithelialisation over a provisional matrix.
      evidence:
      - reference: PMID:16113836
        reference_title: Impaired wound healing in factor XIII deficient mice.
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "Histological analysis of the lesions performed at day 11 disclosed delayed reepithelization and necrotized fissure in FXIII-deficient mice and normal healing in FXIII-deficient/FXIII-treated mice."
        explanation: >-
          Reports the histological finding and its correction by replacement.
    evidence:
    - reference: PMID:16113836
      reference_title: Impaired wound healing in factor XIII deficient mice.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "The findings of this study confirm that in FXIII-deficient mice wound healing is delayed and the cellular and tissue defects can be corrected by treatment with FXIII, providing evidence for the essential role of FXIII in wound repair and remodeling."
      explanation: >-
        The authors' own summary of what the model establishes, which is the
        claim this link makes.
- name: Black and Tan Coonhound with a homozygous F13A1 frameshift
  species: Dog
  genotype: "F13A1 c.1234_1239delinsTCAA (exon 11), homozygous; predicted frameshift from residue 412 with a premature stop codon"
  publication: PMID:42184124
  description: >-
    Naturally occurring disease rather than an engineered model, and the only
    record in this entry in which both arms of the mechanism were measured in the
    same individual. A 4-month-old dog presented with spontaneous
    hemoperitoneum and bleeding that persisted after surgery; whole-genome
    sequencing against 3,023 other dogs found a private homozygous
    deletion-insertion in exon 11 of F13A1 predicting a frameshift and premature
    stop, with a predicted loss of 43% of the protein and probable
    nonsense-mediated decay. Plasma FXIII activity was 5%. The diagnostic picture
    is the human one reproduced in another species: PT, aPTT, thrombin time,
    fibrinogen and every individual factor assay within reference limits, and a
    clot that dissolved completely in 5 M urea. Viscoelastic testing showed both
    reduced maximum clot firmness and a markedly abnormal 45-minute lysis index
    at the same time, and both normalised as plasma and cryoprecipitate were
    given - which is the closest thing in this entry to a direct demonstration
    that the mechanical and fibrinolytic arms are separable states of one clot.
    Canine F13A1 encodes a 733-residue protein 88% identical to the human one.
  notes: >-
    This is the second reported clinical case of FXIII deficiency in dogs and the
    first genetic characterisation of the disorder in a companion animal; it is
    not the first canine description, and is not curated as such. Graded
    MODEL_ORGANISM throughout, per CLAUDE.md: a veterinary observation in a
    non-human mammal is animal evidence however carefully the individual was
    worked up.
  modeled_mechanisms:
  - target: Intact Thrombin Generation and Fibrin Polymerisation Upstream of Cross-Linking
    relationship: RECAPITULATES
    fidelity: HIGH
    model_scale: MOLECULAR
    description: >-
      The normal-screening-test finding, reproduced in a second species and in an
      animal whose causal variant is known. This is the only non-human support in
      the entry for the node that carries the diagnostic trap.
    limitations: >-
      A single animal, so the observation is that the screen can be normal in
      F13A1-null disease, not an estimate of how often it is.
    readouts:
    - name: Routine coagulation screen and individual factor assays
      target: Intact Thrombin Generation and Fibrin Polymerisation Upstream of Cross-Linking
      direction: UNCHANGED
      interpretation: >-
        PT, aPTT, thrombin time, fibrinogen and the individual procoagulant
        factor assays all sat within reference limits in an animal with 5% FXIII
        activity and overt bleeding - the upstream cascade reporting itself
        intact, which is what this node claims.
      evidence:
      - reference: PMID:42184124
        reference_title: Identification of an F13A1 frameshift variant associated with factor XIII deficiency in a Coonhound dog with severe coagulopathy.
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "Results of coagulation screening tests, fibrinogen, platelet flow cytometry assessment of CD61 (GPIIIa) expression and poststimulation annexin V binding, and individual factor assays were within reference intervals, with the exception of Factor X:C and VWF:Ag (Table 2)."
        explanation: >-
          Reports the measurements behind this readout. The two flagged
          exceptions are a mildly low factor X the authors judged clinically
          irrelevant and a high von Willebrand antigen, neither of which is a
          cross-linking measure.
    evidence:
    - reference: PMID:42184124
      reference_title: Identification of an F13A1 frameshift variant associated with factor XIII deficiency in a Coonhound dog with severe coagulopathy.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Unlike other procoagulant factors, FXIII is not required for the transformation of plasma fibrinogen into the polymerized fibrin fibrils that form a fibrin clot."
      explanation: >-
        The authors state the mechanistic reason the screen is uninformative,
        which is the node this link is attached to.
  - target: Mechanically Unstable Fibrin Clot
    relationship: RECAPITULATES
    fidelity: HIGH
    model_scale: TISSUE
    description: >-
      Reduced maximum clot firmness on viscoelastic testing and complete
      dissolution of the clot in urea, both correcting as FXIII-containing blood
      products were given.
    limitations: >-
      Viscoelastic maximum clot firmness is also driven by fibrinogen and
      platelets, and this dog was transiently thrombocytopenic earlier in its
      course, so the baseline tracing is not a pure read on cross-linking. The
      fibrinogen concentration was normal and the platelet count had recovered
      by the time of the tracings, which is why the finding is still attributed
      to FXIII.
    readouts:
    - name: Clot solubility in 5 M urea
      target: Mechanically Unstable Fibrin Clot
      direction: DECREASED
      interpretation: >-
        Complete lysis within 15 minutes, reproducible on a second sample three
        weeks later. The assay is the historical human screen, so this is the
        same measurement failing the same way in a dog.
      evidence:
      - reference: PMID:42184124
        reference_title: Identification of an F13A1 frameshift variant associated with factor XIII deficiency in a Coonhound dog with severe coagulopathy.
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "Results of FXIII deficiency screening tests revealed abnormally rapid clot dissolution, with complete clot lysis within 15 min of incubation in a 5 M urea solution."
        explanation: >-
          Reports the measurement, the timing and the urea concentration.
    - name: Maximum clot firmness on viscoelastic testing
      target: Mechanically Unstable Fibrin Clot
      direction: RESTORED
      interpretation: >-
        Low at baseline and normalising with plasma and cryoprecipitate, which is
        the rescue that attributes the mechanical deficit to the missing protein.
      evidence:
      - reference: PMID:42184124
        reference_title: Identification of an F13A1 frameshift variant associated with factor XIII deficiency in a Coonhound dog with severe coagulopathy.
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "Preoperatively the tracing appeared hypocoagulable based on low maximum clot firmness (MCF) and hyperfibrinolytic based on residual clot firmness at 30- and 45-min post-MCF (LI30 and LI45), becoming normal with the administration of plasma products (Table 1)."
        explanation: >-
          Reports both the baseline abnormality and its correction on
          replacement.
    evidence:
    - reference: PMID:42184124
      reference_title: Identification of an F13A1 frameshift variant associated with factor XIII deficiency in a Coonhound dog with severe coagulopathy.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "A functional FXIII deficiency was identified, and a private, homozygous variant (c.1234_1239delinsTCAA) was found in exon 11 of F13A1 that predicts a frameshift and premature stop codon."
      explanation: >-
        Establishes that the clot-stability defect in this animal sits on a
        homozygous F13A1 lesion, which is what makes it a model of this disease
        rather than of acquired FXIII deficiency.
  - target: Accelerated Fibrinolytic Dissolution of the Hemostatic Clot
    relationship: RECAPITULATES
    fidelity: HIGH
    model_scale: TISSUE
    description: >-
      Hyperfibrinolysis measured in the same tracings as the firmness deficit,
      and corrected alongside it. The entry models these as two arms of one
      lesion, and this is the record in which both were observed together.
    limitations: >-
      The lysis indices and the firmness measure come from the same viscoelastic
      tracings, so the two arms are distinguishable here but not independently
      manipulated - unlike the ferret embolism experiments cited on the node
      itself, where one cross-linking reaction was blocked and the other left
      intact. The dog also received tranexamic acid alongside blood products, so
      the correction is not attributable to FXIII repletion alone.
    readouts:
    - name: Viscoelastic lysis index at 45 minutes
      target: Accelerated Fibrinolytic Dissolution of the Hemostatic Clot
      direction: RESTORED
      interpretation: >-
        Markedly abnormal at baseline and normal after replacement, which is the
        fibrinolytic arm behaving as this entry's model predicts.
      evidence:
      - reference: PMID:42184124
        reference_title: Identification of an F13A1 frameshift variant associated with factor XIII deficiency in a Coonhound dog with severe coagulopathy.
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "Preoperatively the tracing appeared hypocoagulable based on low maximum clot firmness (MCF) and hyperfibrinolytic based on residual clot firmness at 30- and 45-min post-MCF (LI30 and LI45), becoming normal with the administration of plasma products (Table 1)."
        explanation: >-
          The same sentence reports the hyperfibrinolysis and its correction; it
          is quoted on both links because it is the single measurement that
          establishes the two arms coexisting.
    evidence:
    - reference: PMID:42184124
      reference_title: Identification of an F13A1 frameshift variant associated with factor XIII deficiency in a Coonhound dog with severe coagulopathy.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "The findings of unstable clot formation and premature clot lysis in a viscoelastic assay combined with complete clot dissolution in urea indicated that FXIII deficiency should be considered high on the differential list as the underlying cause of abnormal bleeding for this dog."
      explanation: >-
        The authors name unstable clot formation and premature lysis as
        co-occurring findings, which is the two-arm structure this entry models.
clinical_trials:
- name: NCT00713648
  phase: PHASE_III
  status: COMPLETED
  description: >-
    The open-label, single-arm, multiple-dosing phase 3 trial of monthly
    recombinant factor XIII (catridecacog) for prevention of bleeding in
    inherited factor XIII deficiency. PMID:29448295 describes NCT00978380 as an
    extension to a pivotal trial it calls mentor-1; this registration is very
    probably that trial, but the cached registry record does not carry the
    mentor-1 name, so the identification is not asserted here.
  target_phenotypes:
  - preferred_term: Abnormal bleeding
    term:
      id: HP:0001892
      label: Abnormal bleeding
  evidence:
  - reference: clinicaltrials:NCT00713648
    reference_title: "A Multi-Centre, Open-Label, Single-Arm and Multiple Dosing Trial on Efficacy and Safety of Monthly Replacement Therapy With Recombinant Factor XIII (rFXIII) in Subjects With Congenital Factor XIII Deficiency"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "The aim of this trial is to evaluate catridecacog (recombinant factor XIII (rFXIII)) treatment in patients with inherited FXIII deficiency."
    explanation: >-
      The registry record establishing the trial's agent, population and
      objective.
- name: NCT00978380
  phase: PHASE_III
  status: COMPLETED
  description: >-
    mentor-2, the multiple-dosing extension assessing long-term safety and
    efficacy of 35 IU/kg recombinant factor XIII-A2 every 28 days in patients
    with severe congenital A-subunit deficiency. It is the source of the
    annualized bleeding rate and half-life figures in this entry's treatment
    records.
  target_phenotypes:
  - preferred_term: Abnormal bleeding
    term:
      id: HP:0001892
      label: Abnormal bleeding
  evidence:
  - reference: clinicaltrials:NCT00978380
    reference_title: "A Multi-Centre, Open-Label, Single-Arm, and Multiple Dosing Trial on Safety of Monthly Replacement Therapy With Recombinant Factor XIII (rFXIII) in Subjects With Congenital Factor XIII Deficiency"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "The aim of the trial is to investigate the safety of monthly replacement therapy of recombinant factor XIII in patients with congenital FXIII deficiency."
    explanation: >-
      The registry record establishing the trial's design and objective.
  - reference: PMID:29448295
    reference_title: "Recombinant FXIII (rFXIII-A2) Prophylaxis Prevents Bleeding and Allows for Surgery in Patients with Congenital FXIII A-Subunit Deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "mentor™2 (NCT00978380), a multinational, open-label, single-arm, multiple-dosing extension to the pivotal mentor™1 trial, assessed long-term safety and efficacy of rFXIII-A2 prophylaxis in eligible patients"
    explanation: >-
      The published report identifying this NCT number, its design and its
      A-subunit-restricted population.
- name: NCT00885742
  phase: PHASE_III
  status: COMPLETED
  description: >-
    Open-label phase 3b study of human plasma-derived factor XIII concentrate in
    congenital factor XIII deficiency, dose-individualised to minimise bruising
    and bleeding. Supports the plasma-derived arm of treatment, which unlike
    recombinant FXIII-A2 covers both subunit defects.
  target_phenotypes:
  - preferred_term: Abnormal bleeding
    term:
      id: HP:0001892
      label: Abnormal bleeding
  evidence:
  - reference: clinicaltrials:NCT00885742
    reference_title: "A Prospective, Multicenter, Open-label, Phase 3b Study of Human Plasma-Derived Factor XIII Concentrate in Subjects With Congenital Factor XIII Deficiency"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "In this study, patients will be treated with FXIII Concentrate (Human) and followed closely to determine that they receive the dose that will best minimize the chance of bruising and bleeding."
    explanation: >-
      The registry record establishing the product and the dose-individualisation
      objective.
differential_diagnoses:
- name: Factor XIII B subunit deficiency
  description: >-
    A different locus, not a subtype of this entry. F13B encodes the carrier
    subunit; its loss lowers the circulating heterotetramer concentration by
    removing stabilisation and transport rather than abolishing catalysis, and
    the phenotype is correspondingly milder - severe F13B deficiency may be
    managed on demand rather than with mandatory primary prophylaxis. It
    accounts for the small minority of congenital factor XIII deficiency. The
    distinction is therapeutically load-bearing, not taxonomic bookkeeping:
    recombinant FXIII-A2 is effective in A-subunit disease and is not indicated
    in B-subunit disease. MONDO:0013190 covers it; dismech has no entry for it
    at the time of writing.
  evidence:
  - reference: PMID:39613144
    reference_title: "Factor XIII Deficiency: Laboratory, Molecular, and Clinical Aspects."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Factor XIII-A (FXIII-A) deficiency is an ultra-rare bleeding disorder characterized by high rates of morbidity and mortality, primarily resulting from intracranial hemorrhage, umbilical cord bleeding, and miscarriage, whereas patients with severe FXIII-B deficiency present with a milder phenotype."
    explanation: >-
      States the severity difference that is the clinical basis for keeping the
      two loci as separate entries.
  - reference: PMID:39613144
    reference_title: "Factor XIII Deficiency: Laboratory, Molecular, and Clinical Aspects."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "On the other hand, patients with severe FXIII-B deficiency may only require on-demand therapy, while heterozygotes are generally asymptomatic."
    explanation: >-
      Supports the different management default, which is part of why this is a
      separate disease rather than a subtype.
  - reference: PMID:41583548
    reference_title: "Factor XIII Deficiency: A Review of Biology, Testing, and Treatment."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Because recombinant FXIII-A2 (catridecacog) replaces only the FXIII-A subunit, it is appropriate for F13A1 deficiency (i.e., the majority of cases) but not for isolated F13B deficiency, a distinction that has direct therapeutic implications."
    explanation: >-
      The therapeutic consequence of the boundary, and the reason it must not be
      collapsed.
- name: Acquired factor XIII deficiency
  description: >-
    A different disease, not a late-onset form of this one. It arises either
    immunologically, from autoantibodies (commonly IgG4) against FXIII-A or less
    often FXIII-B, or non-immunologically from consumption, dilution or reduced
    synthesis in major surgery, trauma, sepsis, liver disease and disseminated
    intravascular coagulation. It presents in adults with abrupt severe
    bleeding, there is no pathogenic variant, and the definitive treatment of
    the immune form is inhibitor eradication with immunosuppression rather than
    lifelong replacement. A 1:1 mixing study that fails to correct separates it
    from congenital deficiency at the bench. MONDO:0021133 covers it.
  evidence:
  - reference: PMID:41583548
    reference_title: "Factor XIII Deficiency: A Review of Biology, Testing, and Treatment."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Immune-mediated deficiency develops when autoantibodies—commonly IgG4 subclass—target FXIII-A or, less frequently, FXIII-B subunits."
    explanation: >-
      Establishes the autoantibody mechanism that distinguishes the acquired
      immune form.
  - reference: PMID:41583548
    reference_title: "Factor XIII Deficiency: A Review of Biology, Testing, and Treatment."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Unlike congenital disease, inhibitor eradication generally allows return to normal hemostasis without ongoing replacement therapy, though relapse can occur and warrants surveillance."
    explanation: >-
      States the management difference that follows from the different
      mechanism, supporting separation rather than lumping.
  - reference: PMID:24503678
    reference_title: Coagulation factor XIII deficiency. Diagnosis, prevalence and management of inherited and acquired forms.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The acquired form of FXIII deficiency is usually caused by generation of autoantibodies or hyperconsumption in other disease states such as disseminated intravascular coagulation."
    explanation: >-
      Independent statement of the two acquired mechanisms named here.
- name: Congenital afibrinogenemia and hypofibrinogenemia
  description: >-
    The other inherited disorder that classically causes delayed umbilical stump
    bleeding, so it is the main alternative when that sign presents. It is
    separable on the routine screen, which is grossly abnormal in
    afibrinogenaemia and normal here, and on the fibrinogen concentration.
    Fibrinogen abnormalities also confound the clot solubility test - low or
    dysfunctional fibrinogen produces false positives - which is one more reason
    not to rely on that test.
  evidence:
  - reference: PMID:41583548
    reference_title: "Factor XIII Deficiency: A Review of Biology, Testing, and Treatment."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Hypofibrinogenemia and dysfibrinogenemia can cause false positives, whereas increased fibrinogen may reduce sensitivity and contribute to false negative results."
    explanation: >-
      Supports the confounding of the solubility test by fibrinogen
      abnormalities, which is why this differential matters at the bench.
- name: Hemophilia A and hemophilia B
  description: >-
    Distinguished by the activated partial thromboplastin time, which is
    prolonged in the haemophilias and normal here, and clinically by the joint
    pattern: recurrent haemarthrosis is the hallmark of haemophilia and is
    relatively uncommon in factor XIII deficiency.
  evidence:
  - reference: PMID:41583548
    reference_title: "Factor XIII Deficiency: A Review of Biology, Testing, and Treatment."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Joint hemorrhage is relatively uncommon, distinguishing FXIII deficiency from hemophilia."
    explanation: >-
      The clinical discriminator quoted directly.
discussions:
- discussion_id: gap_fxiii_a_prophylaxis_trough_target
  kind: KNOWLEDGE_GAP
  prompt: >-
    What trough factor XIII activity should prophylaxis target, and does a
    higher target reduce intracranial haemorrhage or improve pregnancy outcome?
  rationale: >-
    Every activity threshold in this entry - the 5-20% prophylaxis trough, the
    10-15% spontaneous-bleeding threshold, the 30% perioperative target, the
    trimester-specific obstetric targets - comes from product labelling,
    narrative review and observational series, not from a trial that compared
    targets against outcomes. The review that is this entry's principal source
    says so explicitly and names the comparison that is missing. This matters
    more here than it would for most thresholds, because the outcome being
    prevented is permanent neurological injury in a young child, and because the
    interval between doses is long enough that the trough is the operative
    quantity.
  attaches_to:
  - "biochemical#Plasma factor XIII activity"
  - "treatments#Plasma-Derived Factor XIII Concentrate Prophylaxis"
  evidence:
  - reference: PMID:41583548
    reference_title: "Factor XIII Deficiency: A Review of Biology, Testing, and Treatment."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Despite these advancements, sustained progress in FXIII deficiency will require studies that link target activity thresholds to outcomes in the settings where decisions are most time sensitive."
    explanation: >-
      The source's own statement that the threshold-to-outcome link is
      unestablished, which is the gap recorded here.
  - reference: PMID:31414482
    reference_title: "Congenital factor XIII deficiency: comprehensive overview of the FranceCoag cohort."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In patients exhibiting FXIII levels <10 iu/dl, prophylaxis could be discussed at diagnosis and at pregnancy. Further controlled prospective studies are needed."
    explanation: >-
      A national cohort reaching the same conclusion - that the prophylaxis
      decision rests on uncontrolled data.
- discussion_id: gap_fxiii_a_activity_severity_modifiers
  kind: KNOWLEDGE_GAP
  prompt: >-
    Why does residual factor XIII activity predict clinical severity only
    moderately well, and what modifies the bleeding phenotype at a given
    activity level?
  rationale: >-
    Genotype does not predict phenotype in this disease at all, and activity
    predicts it only moderately to strongly. Both facts are reported rather than
    explained. Candidate modifiers are visible in the mechanism this entry
    models - the relative contribution of the mechanical and fibrinolytic arms
    could differ between patients, and the platelet FXIII-A pool is a
    compartment that plasma activity assays do not report - but nothing in the
    literature reviewed here tests that. The practical consequence is that a
    measured activity cannot be used on its own to decide who needs prophylaxis.
  attaches_to:
  - "genetic#F13A1"
  - "biochemical#Plasma factor XIII activity"
  evidence:
  - reference: PMID:39613144
    reference_title: "Factor XIII Deficiency: Laboratory, Molecular, and Clinical Aspects."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "There is no correlation between genotype and phenotype and a moderate to strong correlation between factor activity and clinical severity in FXIII-A deficiency, making it difficult to predict bleeding patterns based on genotype and FXIII activity levels."
    explanation: >-
      States both halves of the gap - no genotype-phenotype correlation, and an
      imperfect activity-severity correlation.
  - reference: PMID:41583548
    reference_title: "Factor XIII Deficiency: A Review of Biology, Testing, and Treatment."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This platelet FXIII-A supports platelet activation dynamics (e.g., spreading/adhesion); loss or genetic deletion of platelet FXIII-A impairs clot retraction and reduces thrombus stability, underscoring distinct roles for cellular (platelet) versus plasma FXIII."
    explanation: >-
      Establishes that a cellular FXIII-A compartment with its own functions
      exists, which is the candidate modifier the rationale names.
- discussion_id: gap_fxiii_a_diagnosis_before_first_ich
  kind: KNOWLEDGE_GAP
  prompt: >-
    Can diagnosis be made before the first intracranial haemorrhage in children
    without a known family history?
  rationale: >-
    The preventable outcome is frequently the presenting one. In a South Indian
    paediatric cohort the median age at symptom onset was 6 months and the
    median age at diagnosis 1 year, and intracranial bleeding was the first
    presentation in a significant number of children; in the FranceCoag cohort
    7 of 15 patients who had an intracranial haemorrhage were already diagnosed
    but untreated. Those are two different failures - one of diagnosis, one of
    treatment - and both are addressable. No newborn screening exists, and the
    only test that would find the disease is one that most laboratories cannot
    run.
  attaches_to:
  - "definitions#Laboratory diagnosis of factor XIII A subunit deficiency"
  - "phenotypes#Intracranial hemorrhage"
  evidence:
  - reference: PMID:37314674
    reference_title: Clinical Profile of Congenital Factor XIII Deficiency in Children.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The median age of symptom onset was 6 mo, and the median age of diagnosis was 1 y, demonstrating a delay in diagnosis."
    explanation: >-
      Quantifies the diagnostic delay in a real paediatric cohort.
  - reference: PMID:31414482
    reference_title: "Congenital factor XIII deficiency: comprehensive overview of the FranceCoag cohort."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Seven of the 15 patients who experienced ICH were diagnosed but untreated, including 3 with secondary neurological sequelae."
    explanation: >-
      Separates the treatment failure from the diagnostic failure, which is the
      distinction this gap turns on.
  - reference: PMID:41583548
    reference_title: "Factor XIII Deficiency: A Review of Biology, Testing, and Treatment."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Diagnostic delays are common given the paradox of normal screening assays and the limited sensitivity of historical clot solubility tests, underscoring the need for validated quantitative FXIII activity methods and inhibitor evaluation when appropriate."
    explanation: >-
      Names the two reasons for delay - a normal screen and an insensitive
      historical test - that this gap asks how to overcome.
references:
- reference: PMID:41583548
  title: "Factor XIII Deficiency: A Review of Biology, Testing, and Treatment."
- reference: PMID:39613144
  title: "Factor XIII Deficiency: Laboratory, Molecular, and Clinical Aspects."
notes: >-
  Lump/split decision: DISEASE. This is a single locus, a single protein
  function, and a single conserved pathograph running from biallelic F13A1 loss
  of function to delayed bleeding through three substrate-specific branches
  (fibrin chains, alpha-2-antiplasmin, and the extracellular matrix), so it
  meets the criterion for its own `kb/disorders/` entry rather than a grouping,
  a subtype, or an out-of-scope term. Three boundary calls were made
  explicitly.

  F13B (B subunit) deficiency is a separate disease and is NOT a subtype here.
  It is a different gene on a different chromosome (HGNC:3534, resolved from the
  HGNC REST API during curation, against HGNC:3531 for F13A1); the mechanism is
  loss of stabilisation and carriage rather than loss of catalysis; the
  phenotype is milder, with on-demand therapy rather than mandatory primary
  prophylaxis; and - decisively - recombinant FXIII-A2 works in A-subunit
  disease and is not indicated in B-subunit disease, so collapsing the two would
  make this entry's treatment section wrong for half its members. MONDO agrees,
  carrying MONDO:0013190 for the B-subunit disorder and MONDO:0018029
  (congenital factor XIII deficiency) as the parent that unites them. dismech
  has no F13B entry at the time of writing, and no grouping for congenital
  factor XIII deficiency; if both are curated, MONDO:0018029 is the natural
  grouping anchor. The B-subunit concept appears here only as a differential
  diagnosis, plus one biochemical record noting that FXIII-B antigen is also low
  in A-subunit disease, which is a diagnostic trap rather than an overlap in
  mechanism.

  Severity tiers were curated as a quantitative activity axis, not as
  `has_subtypes`. The literature reports severity by residual FXIII activity -
  severe at or below about 1-3%, increased spontaneous bleeding risk below about
  10-15%, haemostatic targets of 20-30% and above - and these are thresholds on
  one continuous measurement, not discontinuities between entities. Two things
  settled the call. First, genotype does not predict phenotype at all in this
  disease, so there is no genetic partition for subtypes to track. Second, the
  same numbers are used in two different roles - to describe severity and to set
  treatment targets - which is the signature of a decision threshold rather than
  of a disease boundary. They are therefore curated as `interpretation_bands` on
  the plasma FXIII activity record, where the boundaries can be half-open and
  the treatment targets can sit on the same scale as the severity tiers.

  Note that this reasoning does not apply to the FXIII type I / type II
  nomenclature that appears among MONDO's synonyms for this term ("hereditary
  factor XIII type II deficiency"). That older classification is a subunit
  distinction, not a severity one, and the synonym is retained in `synonyms:`
  because MONDO carries it; no attempt is made here to assert the historical
  mapping, because no source reviewed during this curation stated it.

  Acquired (autoantibody-mediated or consumptive) factor XIII deficiency is a
  different disease, curated as a differential diagnosis. It has no germline
  lesion, presents in adults, and is treated by eradicating the inhibitor rather
  than by lifelong replacement. MONDO:0021133 covers it. It is not folded in.

  Module conformance. No `conforms_to` is declared, after checking the
  candidates. `primary_hemostatic_plug_failure` scopes itself to loss of a
  platelet primary-hemostatic component and explicitly excludes
  coagulation-factor deficiencies; it is doubly inapplicable here, since
  preserved primary haemostasis is the defining feature of this disease.
  `thrombogenesis` models pathological intravascular thrombus formation, the
  mechanistic inverse. `fibrotic_response` concerns mesenchymal activation and
  matrix deposition in chronic injury, not acute provisional-matrix
  cross-linking. A shared module for the inherited coagulation-factor
  deficiencies would be a reasonable future addition - the same conclusion
  `Congenital_Prothrombin_Deficiency` reached - and does not exist yet. A
  clot-stabilisation-failure module covering this disease, alpha-2-antiplasmin
  deficiency and PAI-1 deficiency would be an even better fit and is a narrower,
  more defensible candidate.

  Ontology bindings deliberately left loose, with reasons. (1) There is no CL or
  GO term for the FXIII-A2B2 heterotetramer, so the molecular claim is carried
  by GO:0003810 (protein-glutamine gamma-glutamyltransferase activity) with a
  LOSS_OF_FUNCTION modifier rather than by a complex term. (2) The `biochemical`
  records bind NCIT measurement terms because NCIT has no
  FXIII-A-subunit-specific antigen term and no term for the clot solubility
  test; the subunit and method specificity is carried by the record name and by
  the LOINC code on the reference range. (3) `Cryoprecipitate or Plasma
  Bridging` binds the generic NCIT Blood Transfusion action term because NCIT
  has no cryoprecipitate transfusion action; NCIT:C180873 Cryoprecipitated
  Plasma is a blood-product term outside the Clinical Intervention or Procedure
  branch and so cannot fill a `treatment_term`. (4) LOINC codes were taken from
  the NLM Clinical Table Search Service rather than from an OAK adapter, because
  LOINC is not configured in `conf/oak_config.yaml` and is therefore not covered
  by `just validate-terms`; each code's long common name is recorded verbatim as
  the label. (5) The `Intact Thrombin Generation and Fibrin Polymerisation
  Upstream of Cross-Linking` node binds GO:0072378 with no `modifier`, because
  the claim is that the process is unchanged and ModifierEnum has no value for
  normal; the same gap means the `Routine coagulation screen` biochemical
  readout carries no `direction`.

  Three independent mouse lines are curated, not one, because they carry
  different claims. The exon-7 deletion line (PMID:12529747) establishes the
  molecular lesion and the clot-stability defect and is fertile. A separately
  derived FXIIIA-knockout line (PMID:12933578) is the only animal support for the
  pregnancy-loss phenotype: homozygous dams conceive and then die of gestational
  haemorrhage with placental necrosis by day 10, independent of fetal genotype.
  A third report (PMID:16113836) supplies the wound-healing arm with a rescue
  arm, and is recorded with its genotype left as the authors stated it -
  "FXIII-deficient", subunit unspecified - rather than upgraded to FXIII-A-null
  on the grounds that only A-subunit lines existed at the time, which would be an
  inference presented as a fact. Keeping them separate is what makes "this line is
  fertile" and "this line miscarries" both true without contradiction.

  The canine record (PMID:42184124) is the only one in which both arms of the
  mechanism were measured in the same individual: one set of viscoelastic
  tracings showing reduced maximum clot firmness and a markedly abnormal
  45-minute lysis index together, both correcting on replacement. It is also the
  only non-human support for the preserved-upstream-cascade node, since the dog's
  PT, aPTT, thrombin time, fibrinogen and individual factor assays were all
  within reference limits at 5% FXIII activity. It is curated as the second
  reported canine case and the first genetic characterisation in a companion
  animal, which is what the report claims - not as the first canine description,
  which it is not. A caveat is recorded on the fibrinolytic link: the two arms
  are distinguishable in those tracings but were not independently manipulated,
  and the dog received tranexamic acid alongside the blood products, so the
  correction is not attributable to FXIII repletion alone. The ferret experiments
  cited on the node itself remain the evidence that the two arms are separable in
  principle.

  Causal-edge citation policy, since the pathograph is deliberately uneven about
  it. Some causal edges here carry their own evidence and some do not, and that
  is a decision rather than an omission: an edge is cited only where a source
  states that specific causal step, because CLAUDE.md is explicit that two
  well-evidenced nodes do not establish that one causes the other. Where no
  source states the step, the edge carries a `description` saying what the step
  is and no evidence. That is the case for the four edges from the
  delayed-bleeding node to subcutaneous haemorrhage, intramuscular haematoma,
  epistaxis and menorrhagia, and for the edge from accelerated fibrinolysis to
  delayed bleeding. For those four in particular the available sources say that
  patients with this disease bleed at those sites, which is the node-level claim
  already carried on each phenotype record, not a statement that the bleed
  follows from the delayed-bleeding state; reusing those citations on the edges
  would have been reaching for a node's evidence to cover an edge. No edge was
  softened away from `DIRECT`, because the anatomical-site edges are about as
  direct as a causal claim gets here - the same failure reaching a different
  tissue.

  Deep-research leads taken and not taken. The committed report's causal chain
  independently reproduces this entry's three-branch structure, and three of its
  leads were chased to primary sources and curated: the wound-healing and
  uterine-haemorrhage mouse lines and the canine F13A1 case above. The canine
  report was flagged in the report as retrieved-but-unverified, and was fetched
  and read in full before anything was curated from it. Two were not. Its placental mechanism
  detail - fibrin-fibronectin cross-linking forming the cytotrophoblastic shell
  and Nitabuch's layer around gestational weeks 6-8 - is cited to a
  publisher-page link with no PMID, and the weaker but sourced version of the
  same claim is already carried here from PMID:41583548, so the specific
  developmental window is left uncurated rather than cited to an unverified
  record. Its Swiss Arg77Cys founder-variant claim the report itself flags as a
  search-engine-summarised lead, and it is not curated. The report's own
  validation sections record one unsupported quote (a Reactome pathway *title*
  quoted as if it were a finding, against PMID:11816711) and one apparent
  mislabelling of MONDO:0013187; the latter is a parsing artifact of the report's
  own gap list, in which it notes a discrepancy between MONDO:0013187 and
  MONDO:0018029. That discrepancy is not an error - the two are the A-subunit
  disease and its parent grouping respectively, which is the distinction this
  entry is drawn on, and both labels were read directly from `ols:mondo`.

  Deliberately not curated. Perioperative and obstetric activity targets are
  summarised in the activity interpretation bands but not curated as separate
  treatment records, because the sources describe them as pragmatic,
  observational and expert-opinion-based rather than as protocols. Neuraxial
  anaesthesia thresholds, direct oral anticoagulant co-administration, and
  fibrinogen concentrate as an incidental FXIII source are all described in the
  principal source on case-based evidence only and were left out rather than
  curated at a confidence the sources do not support. Tranexamic acid is not
  curated as a treatment: it is plausible on this entry's own mechanism (the
  fibrinolytic arm) and is used in other rare bleeding disorders, but no source
  reviewed during this curation recommended it for factor XIII deficiency
  specifically, and inventing the indication from the mechanism would be exactly
  the inference this knowledge base is supposed to avoid. No `datasets:` block
  is present: `just discover-datasets Factor_XIII_A_Subunit_Deficiency` returned
  exactly two candidates, both classified GENE_ONLY - geo:GSE166381 and
  geo:GSE166378, mouse embryonic-stem-cell genome-architecture-mapping datasets
  that surface only because F13A1 appears in them. Neither is about this disease
  in any organism, so both were rejected at relevance triage rather than curated;
  this is the Named Entity Confusion case CLAUDE.md describes, reached through
  dataset search. No `environmental:` block is present either: this is a
  Mendelian disorder with no exposure that initiates or exacerbates the
  mechanism. No GeneReviews chapter exists for factor XIII
  deficiency - PubMed returned no hits for the disease name with GeneReviews on
  two separate searches - so the mandatory GeneReviews phenotype baseline does
  not apply and the phenotype set is built from the reviews and cohorts cited
  above.

📚

References & Deep Research

References

2

PMID:41583548

Factor XIII Deficiency: A Review of Biology, Testing, and Treatment.

No top-level findings curated for this source.

PMID:39613144

Factor XIII Deficiency: Laboratory, Molecular, and Clinical Aspects.

No top-level findings curated for this source.

Deep Research

1

Deep research results are used as seeds for research; they do not undergo the same validation as the main records and may contain errors. How we use deep research.

Evaluations and curation notes (2)

Record notes

Lump/split decision: DISEASE. This is a single locus, a single protein function, and a single conserved pathograph running from biallelic F13A1 loss of function to delayed bleeding through three substrate-specific branches (fibrin chains, alpha-2-antiplasmin, and the extracellular matrix), so it meets the criterion for its own `kb/disorders/` entry rather than a grouping, a subtype, or an out-of-scope term. Three boundary calls were made explicitly. F13B (B subunit) deficiency is a separate disease and is NOT a subtype here. It is a different gene on a different chromosome (HGNC:3534, resolved from the HGNC REST API during curation, against HGNC:3531 for F13A1); the mechanism is loss of stabilisation and carriage rather than loss of catalysis; the phenotype is milder, with on-demand therapy rather than mandatory primary prophylaxis; and - decisively - recombinant FXIII-A2 works in A-subunit disease and is not indicated in B-subunit disease, so collapsing the two would make this entry's treatment section wrong for half its members. MONDO agrees, carrying MONDO:0013190 for the B-subunit disorder and MONDO:0018029 (congenital factor XIII deficiency) as the parent that unites them. dismech has no F13B entry at the time of writing, and no grouping for congenital factor XIII deficiency; if both are curated, MONDO:0018029 is the natural grouping anchor. The B-subunit concept appears here only as a differential diagnosis, plus one biochemical record noting that FXIII-B antigen is also low in A-subunit disease, which is a diagnostic trap rather than an overlap in mechanism. Severity tiers were curated as a quantitative activity axis, not as `has_subtypes`. The literature reports severity by residual FXIII activity - severe at or below about 1-3%, increased spontaneous bleeding risk below about 10-15%, haemostatic targets of 20-30% and above - and these are thresholds on one continuous measurement, not discontinuities between entities. Two things settled the call. First, genotype does not predict phenotype at all in this disease, so there is no genetic partition for subtypes to track. Second, the same numbers are used in two different roles - to describe severity and to set treatment targets - which is the signature of a decision threshold rather than of a disease boundary. They are therefore curated as `interpretation_bands` on the plasma FXIII activity record, where the boundaries can be half-open and the treatment targets can sit on the same scale as the severity tiers. Note that this reasoning does not apply to the FXIII type I / type II nomenclature that appears among MONDO's synonyms for this term ("hereditary factor XIII type II deficiency"). That older classification is a subunit distinction, not a severity one, and the synonym is retained in `synonyms:` because MONDO carries it; no attempt is made here to assert the historical mapping, because no source reviewed during this curation stated it. Acquired (autoantibody-mediated or consumptive) factor XIII deficiency is a different disease, curated as a differential diagnosis. It has no germline lesion, presents in adults, and is treated by eradicating the inhibitor rather than by lifelong replacement. MONDO:0021133 covers it. It is not folded in. Module conformance. No `conforms_to` is declared, after checking the candidates. `primary_hemostatic_plug_failure` scopes itself to loss of a platelet primary-hemostatic component and explicitly excludes coagulation-factor deficiencies; it is doubly inapplicable here, since preserved primary haemostasis is the defining feature of this disease. `thrombogenesis` models pathological intravascular thrombus formation, the mechanistic inverse. `fibrotic_response` concerns mesenchymal activation and matrix deposition in chronic injury, not acute provisional-matrix cross-linking. A shared module for the inherited coagulation-factor deficiencies would be a reasonable future addition - the same conclusion `Congenital_Prothrombin_Deficiency` reached - and does not exist yet. A clot-stabilisation-failure module covering this disease, alpha-2-antiplasmin deficiency and PAI-1 deficiency would be an even better fit and is a narrower, more defensible candidate. Ontology bindings deliberately left loose, with reasons. (1) There is no CL or GO term for the FXIII-A2B2 heterotetramer, so the molecular claim is carried by GO:0003810 (protein-glutamine gamma-glutamyltransferase activity) with a LOSS_OF_FUNCTION modifier rather than by a complex term. (2) The `biochemical` records bind NCIT measurement terms because NCIT has no FXIII-A-subunit-specific antigen term and no term for the clot solubility test; the subunit and method specificity is carried by the record name and by the LOINC code on the reference range. (3) `Cryoprecipitate or Plasma Bridging` binds the generic NCIT Blood Transfusion action term because NCIT has no cryoprecipitate transfusion action; NCIT:C180873 Cryoprecipitated Plasma is a blood-product term outside the Clinical Intervention or Procedure branch and so cannot fill a `treatment_term`. (4) LOINC codes were taken from the NLM Clinical Table Search Service rather than from an OAK adapter, because LOINC is not configured in `conf/oak_config.yaml` and is therefore not covered by `just validate-terms`; each code's long common name is recorded verbatim as the label. (5) The `Intact Thrombin Generation and Fibrin Polymerisation Upstream of Cross-Linking` node binds GO:0072378 with no `modifier`, because the claim is that the process is unchanged and ModifierEnum has no value for normal; the same gap means the `Routine coagulation screen` biochemical readout carries no `direction`. Three independent mouse lines are curated, not one, because they carry different claims. The exon-7 deletion line (PMID:12529747) establishes the molecular lesion and the clot-stability defect and is fertile. A separately derived FXIIIA-knockout line (PMID:12933578) is the only animal support for the pregnancy-loss phenotype: homozygous dams conceive and then die of gestational haemorrhage with placental necrosis by day 10, independent of fetal genotype. A third report (PMID:16113836) supplies the wound-healing arm with a rescue arm, and is recorded with its genotype left as the authors stated it - "FXIII-deficient", subunit unspecified - rather than upgraded to FXIII-A-null on the grounds that only A-subunit lines existed at the time, which would be an inference presented as a fact. Keeping them separate is what makes "this line is fertile" and "this line miscarries" both true without contradiction. The canine record (PMID:42184124) is the only one in which both arms of the mechanism were measured in the same individual: one set of viscoelastic tracings showing reduced maximum clot firmness and a markedly abnormal 45-minute lysis index together, both correcting on replacement. It is also the only non-human support for the preserved-upstream-cascade node, since the dog's PT, aPTT, thrombin time, fibrinogen and individual factor assays were all within reference limits at 5% FXIII activity. It is curated as the second reported canine case and the first genetic characterisation in a companion animal, which is what the report claims - not as the first canine description, which it is not. A caveat is recorded on the fibrinolytic link: the two arms are distinguishable in those tracings but were not independently manipulated, and the dog received tranexamic acid alongside the blood products, so the correction is not attributable to FXIII repletion alone. The ferret experiments cited on the node itself remain the evidence that the two arms are separable in principle. Causal-edge citation policy, since the pathograph is deliberately uneven about it. Some causal edges here carry their own evidence and some do not, and that is a decision rather than an omission: an edge is cited only where a source states that specific causal step, because CLAUDE.md is explicit that two well-evidenced nodes do not establish that one causes the other. Where no source states the step, the edge carries a `description` saying what the step is and no evidence. That is the case for the four edges from the delayed-bleeding node to subcutaneous haemorrhage, intramuscular haematoma, epistaxis and menorrhagia, and for the edge from accelerated fibrinolysis to delayed bleeding. For those four in particular the available sources say that patients with this disease bleed at those sites, which is the node-level claim already carried on each phenotype record, not a statement that the bleed follows from the delayed-bleeding state; reusing those citations on the edges would have been reaching for a node's evidence to cover an edge. No edge was softened away from `DIRECT`, because the anatomical-site edges are about as direct as a causal claim gets here - the same failure reaching a different tissue. Deep-research leads taken and not taken. The committed report's causal chain independently reproduces this entry's three-branch structure, and three of its leads were chased to primary sources and curated: the wound-healing and uterine-haemorrhage mouse lines and the canine F13A1 case above. The canine report was flagged in the report as retrieved-but-unverified, and was fetched and read in full before anything was curated from it. Two were not. Its placental mechanism detail - fibrin-fibronectin cross-linking forming the cytotrophoblastic shell and Nitabuch's layer around gestational weeks 6-8 - is cited to a publisher-page link with no PMID, and the weaker but sourced version of the same claim is already carried here from PMID:41583548, so the specific developmental window is left uncurated rather than cited to an unverified record. Its Swiss Arg77Cys founder-variant claim the report itself flags as a search-engine-summarised lead, and it is not curated. The report's own validation sections record one unsupported quote (a Reactome pathway *title* quoted as if it were a finding, against PMID:11816711) and one apparent mislabelling of MONDO:0013187; the latter is a parsing artifact of the report's own gap list, in which it notes a discrepancy between MONDO:0013187 and MONDO:0018029. That discrepancy is not an error - the two are the A-subunit disease and its parent grouping respectively, which is the distinction this entry is drawn on, and both labels were read directly from `ols:mondo`. Deliberately not curated. Perioperative and obstetric activity targets are summarised in the activity interpretation bands but not curated as separate treatment records, because the sources describe them as pragmatic, observational and expert-opinion-based rather than as protocols. Neuraxial anaesthesia thresholds, direct oral anticoagulant co-administration, and fibrinogen concentrate as an incidental FXIII source are all described in the principal source on case-based evidence only and were left out rather than curated at a confidence the sources do not support. Tranexamic acid is not curated as a treatment: it is plausible on this entry's own mechanism (the fibrinolytic arm) and is used in other rare bleeding disorders, but no source reviewed during this curation recommended it for factor XIII deficiency specifically, and inventing the indication from the mechanism would be exactly the inference this knowledge base is supposed to avoid. No `datasets:` block is present: `just discover-datasets Factor_XIII_A_Subunit_Deficiency` returned exactly two candidates, both classified GENE_ONLY - geo:GSE166381 and geo:GSE166378, mouse embryonic-stem-cell genome-architecture-mapping datasets that surface only because F13A1 appears in them. Neither is about this disease in any organism, so both were rejected at relevance triage rather than curated; this is the Named Entity Confusion case CLAUDE.md describes, reached through dataset search. No `environmental:` block is present either: this is a Mendelian disorder with no exposure that initiates or exacerbates the mechanism. No GeneReviews chapter exists for factor XIII deficiency - PubMed returned no hits for the disease name with GeneReviews on two separate searches - so the mandatory GeneReviews phenotype baseline does not apply and the phenotype set is built from the reviews and cohorts cited above.

Create: Factor XIII A Subunit Deficiency · 2026-09-10T17:30:20Z · View source

Created kb/disorders/Factor_XIII_A_Subunit_Deficiency.yaml for MONDO:0013187 (factor XIII, A subunit, deficiency of), closing the claim issue #11604 and deleting stubs/Factor_XIII_A_Subunit_Deficiency_Of.yaml. Lump/split call: DISEASE. Three boundaries settled explicitly and recorded in the entry notes. (1) F13B (B-subunit) deficiency is a separate disease, not a subtype: different gene (HGNC:3534 vs HGNC:3531, both resolved from the HGNC REST API during curation), loss of carriage rather than catalysis, milder phenotype with on-demand rather than mandatory prophylaxis, and recombinant FXIII-A2 is not indicated in it. Curated as a differential diagnosis, with MONDO:0013190 and the shared parent MONDO:0018029 named as the future grouping anchor. (2) Severity tiers were curated as a quantitative activity axis (interpretation_bands on the plasma FXIII activity biochemical record), not as has_subtypes, because genotype does not predict phenotype in this disease and the same numbers serve as both severity descriptions and treatment targets. (3) Acquired (autoantibody-mediated or consumptive) FXIII deficiency is a different disease, curated as a differential diagnosis (MONDO:0021133), not folded in. Pathograph: 9 nodes, each with biological_scale, fully connected except the two intended roots. The chain runs from biallelic F13A1 loss of function to delayed bleeding through three substrate-specific branches (fibrin chains, alpha-2-antiplasmin, extracellular matrix), with the mechanical and fibrinolytic arms modelled as separate nodes because a ferret embolism model (PMID:9892598) can block one without the other. An "Intact Thrombin Generation and Fibrin Polymerisation Upstream of Cross-Linking" node with no upstream cause carries the diagnostic trap structurally; it is mirrored by a biochemical record (Routine coagulation screen, presence NORMAL) and by two definitions records (the laboratory diagnostic sequence, and the insensitivity of the clot solubility screen). 10 phenotypes with HP bindings, all connected to the pathograph. Deep research took three runs and the first two produced nothing. `just research-disorder falcon Factor_XIII_A_Subunit_Deficiency` failed with HTTP 402 (the Edison account is out of credits, although `deep-research-client providers --check` reports falcon's credentials as OK, so the health probe does not catch this). The run was repeated once with `just dr_fallback='-- fallback' research-disorder falcon ...` as the skill directs, so that a substitution would be recorded in the report's own frontmatter rather than in prose; that run fell back to openscientist, whose job d1ead1d1-e15e-4f88-a448-3d2147fd8480 timed out after 3600s and was cancelled, and the chain then stopped because the openscientist failure was a ValueError that cannot carry the trail. A third run, `just dr_fallback='-- fallback' research-disorder claude_code Factor_XIII_A_Subunit_Deficiency`, completed in 401s and produced the single committed report, research/Factor_XIII_A_Subunit_Deficiency-deep-research-claude_code.md plus its citations sidecar. The report's frontmatter records provider claude_code, 20 web searches, 30 turns and a template_sha, so the provenance is in the file rather than only here. Its reference_validation block reports 23/23 references resolved with one unsupported quote (PMID:11816711, where a Reactome pathway title was quoted as if it were a finding), and term_validation reports one apparent mislabelling of MONDO:0013187; that is a parsing artifact of the report's own evidence-gap list, which flags a discrepancy between MONDO:0013187 and MONDO:0018029. The discrepancy is not an error - those are the A-subunit disease and its parent grouping - and both labels were read directly from ols:mondo during curation. just preflight-dr returned WARN for F13B being mentioned at 39% of F13A1's rate, which is expected here because the entry deliberately argues the F13B boundary. The report's causal chain independently reproduced this entry's three-branch structure. Two of its leads were chased to primary sources and curated as new animal_models entries: PMID:16113836 (excisional wound closure reduced 15/27/27% at days 4/8/11, 73.23% against 100% closure at day 11, restored to 90.06% by FXIII concentrate, with delayed re-epithelialisation on histology) and PMID:12933578 (an independently derived FXIIIA-KO line whose homozygous dams conceive and then die of gestational haemorrhage with placental necrosis by day 10, independent of fetal genotype). The second materially changes what the entry can claim: the exon-7 deletion line of PMID:12529747 is fertile, so without this second line there would be no animal support for the human pregnancy-loss phenotype, and the limitation text on the first line was corrected so that it no longer reads as though no mouse can model it. Two leads were not taken: the placental cytotrophoblastic shell and Nitabuch's layer detail at gestational weeks 6-8, which the report cites to a publisher page with no PMID when a weaker sourced version of the claim is already carried from PMID:41583548; and a Swiss Arg77Cys founder-variant claim the report itself flags as a search-engine-summarised lead. Both decisions are recorded in the entry notes. PMID:32491399, PMID:25263390 and PMID:23929307 were fetched during curation but are not cited by the entry, so their cache files are deliberately not staged. Deliberate omissions, each with the reason recorded in notes: no datasets block (`just discover-datasets` returned only two GENE_ONLY mouse ES-cell GAM datasets, geo:GSE166381 and geo:GSE166378, rejected at relevance triage as Named Entity Confusion); the recurrent-pregnancy-loss phenotype left ontology-unbound because HP:0200067 and HP:0005268 both sit outside the PhenotypeTerm enum's HP:0000118 root (six HPO searches recorded, following the Asherman_Syndrome and Thrombophilia precedent); tranexamic acid not curated because no source read recommended it for this disease specifically; no environmental block; no GeneReviews baseline (PubMed returned no hits on two searches). LOINC codes were read from the NLM Clinical Table Search Service because LOINC is not configured in conf/oak_config.yaml and so is not covered by just validate-terms. Validators run and their results: just validate (schema, terms, references) pass; just validate-terms pass; just count-verified-snippets 137/137 verified; just check-duplicate-keys pass; just check-entity-refs pass; just check-causal-targets pass with no new dangling targets; just check-qualifier-terms pass (no qualifier terms); just check-enum-values pass; just check-folded-hyphens pass after fixing one finding in this file; just check-snippet-length pass; just check-title-snippets pass; just check-snippet-grading pass; just normalize-cache and just check-term-cache-integrity pass with no churn; just list-gene-term-mismatches 1 binding examined, 1 compared against HGNC, 1 named by the entry, 0 findings; just validate-disorders (the batched authoritative gate) pass with 137/137 snippets; just compliance 91.0% global / 91.3% weighted. Five snippets initially failed reference validation because the validator strips bracketed spans that are not all-caps abbreviations; they were trimmed to quote text outside those spans and the explanations say where a trim starts mid-sentence.

Claude Code ▸

Factor XIII A Subunit Deficiency: Comprehensive Research Report

claude-haiku-4-5-20251001, claude-sonnet-5 31 citations 2026-09-10T17:48:15.023588

Factor XIII A Subunit Deficiency: Comprehensive Research Report

Scope note on identifiers: The research brief names MONDO:0013187, but searches return MONDO:0018029 for "factor XIII deficiency" (general term) in cross-reference tables (MalaCards, Wikidata). I could not independently confirm MONDO:0013187 resolves to this disease in the sources retrieved. This is a lead requiring verification against the MONDO ontology browser directly before binding — do not treat either ID as confirmed without that check.

1. Disease Information

Overview: Congenital Factor XIII (FXIII) deficiency is a rare autosomal recessive bleeding disorder caused by biallelic loss-of-function variants in F13A1 (encoding the catalytic A subunit) or, less commonly, F13B (encoding the carrier B subunit). FXIII is the "last enzyme" of the coagulation cascade — a transglutaminase that cross-links fibrin after clot formation rather than participating in clot initiation. Deficiency therefore produces a paradoxical presentation: normal routine coagulation screening (PT, aPTT, thrombin time, fibrinogen, platelet count) with a clinically unstable, friable clot prone to premature dissolution and rebleeding (StatPearls NBK557467; Altahan et al., Clin Hematol Int, PMC12825037/PMID:41583548).

Key identifiers: | System | ID | |---|---| | OMIM gene | *134570 (F13A1) | | OMIM phenotype | #613225 (Factor XIII, A subunit, deficiency of) | | Orphanet | ORPHA331 (Congenital factor XIII deficiency) | | ICD-10-CM | D68.2 (Hereditary deficiency of other clotting factors) | | ICD-11 | 3B14.Z | | MeSH | D005177 | | HGNC (gene) | HGNC:3531 (F13A1) | | UniProt | P00488 (F13A1 protein) |

Synonyms: Fibrin-stabilizing factor (FSF) deficiency; congenital FXIII deficiency; FXIIIA deficiency; plasma transglutaminase deficiency.

Evidence base: Information is derived almost entirely from aggregated disease-level resources — case series, national/regional registries (notably the Iranian national FXIII deficiency registry), structured databases (OMIM, Orphanet, ClinVar), and individual case reports — rather than large EHR cohorts, reflecting the disorder's extreme rarity (<500 molecularly characterized families worldwide per recent reviews).

Sources: OMIM *134570 · OMIM #613225 · Orphanet ORPHA331 · StatPearls · Altahan et al. 2026, PMID:41583548

2. Etiology

Causal factors (congenital): Biallelic (homozygous or compound heterozygous) loss-of-function variants in F13A1 account for ~95% of congenital cases; F13B variants account for the remainder and produce a generally milder phenotype because the catalytic A subunit is intact. More than 200 causative F13A1 variants have been catalogued; missense variants predominate (>50%), with nonsense, splice-site, deep-intronic, and large structural deletions also described (Altahan et al., PMID:41583548; PMC6950900 — deep intronic splicing variant; PMC6657060 — large deletion via complex rearrangement).

Genetic risk factors: - Founder mutations create regional clustering: Trp187Arg (c.562T>C) is the dominant pathogenic allele in southeast Iran — in one series, 346 of 366 Iranian FXIIID patients resided in Sistan and Baluchestan Province and carried this single founder variant (How to Assess Founder Effect..., PMC7876424; Molecular Basis of Congenital FXIII Deficiency in Iran, PMC6714674). Arg77Cys is reported as a recurrent variant in the Swiss population (search result; not independently verified against a primary source in this pass — flag as lead). - Consanguinity is the dominant environmental/demographic risk amplifier for an autosomal recessive disorder of this rarity — Iran's ~12-fold elevated prevalence versus global estimates is attributed directly to consanguinity rates (StatPearls; Altahan et al.).

Protective factors: None specific to the deficiency state were identified — once activity falls below the disease threshold, no genetic or environmental factor mitigates bleeding risk other than replacement therapy. (Distinct from this disease entity: the common F13A1 Val34Leu polymorphism, present in normal-activity individuals at 0–44% allele frequency across populations, is associated with a different clinical question — reduced risk of myocardial infarction and venous thromboembolism, OR for VTE as low as 0.16 in Leu34 homozygotes — via accelerated FXIII activation kinetics and altered fibrin fiber architecture that is more fibrinolysis-susceptible. This is a separate phenotype of FXIII gain-of-function-type activation kinetics, not a modifier of the deficiency disease itself, and should not be conflated with it in curation. ([Role of factor XIII polymorphisms in clot formation, Blood, search result]; ClinVar RCV000017996 "protection against myocardial infarction").

Gene-environment interactions: The clearest documented interaction is in acquired (non-congenital) FXIII deficiency, which is mechanistically distinct and more prevalent than the congenital form: - Autoimmune acquired FXIII deficiency: anti-FXIII autoantibodies, with HLA class I/II susceptibility alleles implicated — a whole-exome sequencing study found HLA-B, MICA, BTNL2, HLA-DQB1, and HLA-DPB1 variants correlating with elevated anti-FXIII autoantibody titers, invoking a breakdown of immune tolerance analogous to acquired hemophilia A (PMID:34506591, PLoS One 2021). Median age of onset ~75 years; ~50% idiopathic, remainder associated with autoimmune disease, diabetes, or malignancy. - Non-immune acquired deficiency (more common than autoimmune): hyperconsumption (DIC, sepsis, major surgery; ECMO carries an 80–90% reported incidence of acquired deficiency), decreased synthesis (liver disease), and drug-associated (valproic acid, isoniazid, penicillin, phenytoin; checkpoint-inhibitor immunotherapy reported in a case report) (StatPearls; A Rare Case of FXIII Deficiency in Cancer Immunotherapy, PMC8163106).

3. Phenotypes

Severity correlates with residual FXIII activity (EN-RBD classification): severe (undetectable–≤1%, spontaneous major bleeding), moderate (<30%, heterogeneous bleeding), mild (≥30%, typically asymptomatic) (Altahan et al., PMID:41583548).

Phenotype	Frequency (severe deficiency)	Onset	Suggested HP term
Delayed umbilical stump bleeding/cord separation	70–80% of symptomatic neonates; classic earliest sign	Days–weeks after birth	HP:0031134 (verify — candidate: delayed umbilical cord separation)
Intracranial hemorrhage (spontaneous and post-traumatic)	25–30% untreated	Infancy–childhood most common, can recur any age	HP:0002170 Intracranial hemorrhage
Easy bruising / subcutaneous hematoma	Bruising ~60%, hematoma ~55%	Childhood onward, with ambulation	HP:0000978 Bruising susceptibility
Mucosal bleeding (epistaxis, gingival bleeding, menorrhagia)	~30%	Any age	HP:0000421 Epistaxis; HP:0000132 Menorrhagia
Impaired wound healing / dehiscence	14–29%	Any age, esp. postoperative	HP:0001058 Poor wound healing (verify exact term)
Hemarthrosis	Uncommon — distinguishes from hemophilia	Any age	HP:0005261 Joint hemorrhage
Recurrent early pregnancy loss / placental abruption / preterm delivery	High risk without prophylaxis (see §6)	First trimester predominant	HP:0200067 Recurrent pregnancy loss (verify exact term)
Delayed postoperative/post-traumatic bleeding	Variable	Any age	HP:0031108 (verify)

A single case report also describes hydrocephalus in infancy as a rare sequela of intracranial hemorrhage (PMC12504050) — not a primary phenotype but a downstream structural consequence.

Quality-of-life impact: Not quantified with standardized instruments (EQ-5D/SF-36) in the literature surfaced here — this appears to be a genuine evidence gap rather than a retrieval failure; prophylactic therapy trial reports (Mentor™ series, below) emphasize bleeding-rate reduction rather than formal QoL metrics.

(Caveat, consistent with dismech practice: every HP term above is a candidate suggestion based on clinical description matching, not a verified OAK/HPO lookup — each must be independently confirmed against the HPO browser before binding, per the Ontology Term Contract.)

4. Genetic/Molecular Information

Causal gene: F13A1 — HGNC:3531, chromosome 6p24.3–p25.1 (sources vary slightly: 6p25.1 vs 6p24–p25; verify exact cytoband at curation time), 15 exons, encoding a 731-amino-acid catalytic subunit (UniProt P00488). The protein belongs to the transglutaminase superfamily, containing an N-terminal activation peptide (cleaved by thrombin), a β-sandwich domain, the catalytic core (containing the Cys-His-Asp catalytic triad), and two C-terminal β-barrel domains.

Secondary gene: F13B (chromosome 1q31–q32.1), encoding the non-catalytic B subunit (10 sushi/CCP domains), produced by hepatocytes; F13B deficiency accounts for ~5% of congenital cases and is generally milder.

Variant landscape: - >200 F13A1 pathogenic variants reported to date; missense variants >50% of cases, with nonsense, splice-site, deep-intronic, and gross deletion variants comprising the remainder. - ClinVar-documented examples include nonsense variants (R171X, Y441X) and missense variants (R681H) (search-derived; individual ClinVar accessions not independently verified here — treat as leads pending direct ClinVar lookup). - A novel Cys328 nonsense variant reported in a severe case (PMC7650518); eight novel F13A1 variants with structural modeling reported by PMC2878794. - Founder alleles: Trp187Arg (Iran/southeast Iran), Arg77Cys (Switzerland, per search lead).

Allele frequency / carrier frequency: No specific gnomAD allele-frequency table for individual pathogenic F13A1 variants was retrieved in this pass (a genuine gap — direct gnomAD query recommended at curation time). Aggregate carrier frequency for deficiency-causing alleles is estimated at ~1 in 1,000 globally (~7.5 million heterozygous carriers worldwide per epidemiological extrapolation cited in search results), consistent with the homozygote prevalence of 1 in 2–3 million.

Functional consequences: Predominantly loss of function — reduced/absent catalytic transglutaminase activity, either through reduced protein synthesis/stability (Type I: concordant reduction of antigen and activity) or a qualitative catalytic defect (Type II: normal/near-normal antigen, reduced activity).

Somatic vs. germline: Congenital FXIII-A deficiency is exclusively germline/inherited; acquired (autoimmune or consumptive) deficiency is a distinct, non-genetic disease process (see §2).

Epigenetics / chromosomal abnormalities: No epigenetic mechanism (DNA methylation, histone modification) specific to FXIII-A deficiency was found in the sources retrieved — this appears to be an absence of documented evidence rather than a negative finding, and should not be asserted either way without a dedicated search of ENCODE/Roadmap/DiseaseMeth. Chromosomal-scale abnormalities (aneuploidy, translocation) are not a recognized disease mechanism here; point mutations and small-to-large intragenic deletions dominate.

5. Environmental Information

Environmental/iatrogenic factors (relevant almost exclusively to acquired deficiency, not the congenital disease that is the primary curation target): - Extracorporeal membrane oxygenation (ECMO) — 80–90% reported incidence of acquired deficiency - Sepsis, disseminated intravascular coagulation, major surgery (consumptive) - Hepatic dysfunction (decreased synthesis) - Medications: valproic acid, isoniazid, penicillin, phenytoin; immune checkpoint inhibitor therapy (case report, PMC8163106) - Associated autoimmune conditions: systemic lupus erythematosus (~30% of immune-mediated acquired cases), IgA vasculitis, rheumatoid arthritis

Lifestyle factors: None identified as modifying congenital disease expression; trauma (including minor trauma and surgical trauma) is the principal precipitant of clinically apparent bleeding episodes in both congenital and acquired deficiency, rather than a "lifestyle" risk factor per se.

Infectious agents: Not a direct cause; sepsis is a recognized trigger of acquired consumptive deficiency but FXIII deficiency itself has no infectious etiology.

6. Mechanism / Pathophysiology

Ordered causal chain

Initiating lesion: Biallelic loss-of-function variant in F13A1 (or, less commonly, F13B) → absent or structurally/catalytically defective FXIII-A protein synthesized in megakaryocytes, platelets, and monocytes/macrophages. (Demonstrated — molecular/biochemical studies.)
This leads to markedly reduced circulating and intracellular FXIII-A2B2 tetramer and/or reduced transglutaminase catalytic capacity, while the upstream coagulation cascade (thrombin generation, fibrinogen cleavage to fibrin monomer) proceeds entirely normally — explaining the normal PT/aPTT/TT that is the disorder's central diagnostic trap. (Demonstrated.)
During clot formation, thrombin (in the presence of Ca²⁺) still cleaves the FXIII-A activation peptide when substrate is present, but with insufficient functional FXIII-A, this fails to generate adequate active FXIIIa transglutaminase → failure of γ-glutamyl-ε-lysyl isopeptide cross-linking between fibrin γ-chains (dimerization) and α-chains (multimerization), and failure to cross-link α2-antiplasmin and fibronectin onto the fibrin network. (Demonstrated biochemically — Reactome "Common Pathway of Fibrin Clot Formation"; [PMID search: Protransglutaminase-mediated crosslinking of fibrinogen and fibrin, PMID:11816711].)
This results in an uncross-linked, mechanically weak, and fibrinolysis-susceptible clot — lacking the tensile strength, viscoelastic stability, and protection from plasmin-mediated degradation that cross-linking normally confers (the α2-antiplasmin cross-link specifically retards premature fibrinolysis). (Demonstrated — Understanding blood clot mechanical stability, 2025.)
Branch A — hemostatic plug failure: The friable clot leads to delayed/recurrent hemorrhage at sites of vascular injury — classically the umbilical stump (minimal trauma, high vascular turnover site), soft tissue, and mucosa — and, most seriously, intracranial vasculature, where clot instability results in spontaneous or minor-trauma-triggered intracranial hemorrhage, the leading cause of death and neurological morbidity in untreated severe disease. (Demonstrated clinically.)
Branch B — wound healing failure: FXIIIa normally cross-links fibrin with fibronectin and collagen in the provisional wound matrix to support fibroblast migration and re-epithelialization; its absence leads to delayed re-epithelialization and wound dehiscence. (Demonstrated in F13a1-knockout mice — Inbal et al., Thromb Haemost 2005;94:432–437, DOI:10.1160/TH05-04-0291: wound closure reduced 15%/27%/27% at days 4/8/11 vs. controls; complete closure by day 11 in controls vs. 73.2% in FXIII-deficient mice.)
Branch C — reproductive/placental failure: Maternal FXIII-A normally localizes to the maternal-fetal interface and is required, around gestational weeks 6–8, for fibrin-fibronectin cross-linking that forms the cytotrophoblastic shell and Nitabuch's layer, anchoring the placenta to the decidua; its absence leads to poorly formed cytotrophoblastic shells, placental detachment, and spontaneous miscarriage. (Demonstrated histologically in human gestational tissue from FXIII-deficient pregnancies, and recapitulated in F13a1-knockout mice, which develop severe uterine bleeding and spontaneous miscarriage — Koseki-Kuno et al., Blood 2003;102(13):4410–4412, DOI:10.1182/blood-2003-05-1467; human tissue study: Maternal Blood Coagulation Factor XIII...Cytotrophoblastic Shell.)
Upstream vs. downstream summary: The genetic lesion (step 1) and loss of catalytic activity (steps 2–4) are strictly upstream, shared across all clinical branches; steps 5–7 are parallel downstream branches determined by the anatomical site of hemostatic/structural demand (vascular injury site, wound bed, maternal-fetal interface) rather than by distinct molecular mechanisms.

Molecular pathways, processes, and profiling

Pathway: Reactome "Common Pathway of Fibrin Clot Formation" (FXIII tetramer cleavage → FXIIIa → fibrin multimer cross-linking); candidate GO terms: GO:0003810 (protein-glutaminase gamma-glutamyltransferase activity — the core catalytic GO term for F13A1), GO:0007596 (blood coagulation), GO:0072378 (blood coagulation, fibrin clot formation), GO:0031639 (plasminogen activation) as a related/antagonized process.
Cellular processes / cell types: FXIII-A is synthesized by megakaryocytes (CL:0000556) and stored in platelet (CL:0000233) α-granules/cytoplasm; also expressed in monocytes/macrophages (CL:0000576/CL:0000235). FXIII-B is synthesized by hepatocytes (CL:0000182). The placental mechanism implicates trophoblast (CL:0000351/CL:0000666 extravillous trophoblast) populations at the maternal-fetal interface.
Protein structure/dysfunction: Predominantly simple loss of function via reduced protein stability/synthesis (Type I) or catalytic-site disruption (Type II); no prion-like aggregation or gain-of-function mechanism described.
Subcellular localization: FXIII-A is a cytoplasmic transglutaminase lacking a classical secretory signal peptide; it reaches plasma via non-classical secretion from platelets/monocytes rather than conventional ER/Golgi trafficking — relevant GO Cellular Component candidate: GO:0005829 (cytosol).
Non-hemostatic roles (beyond the classic pathograph): FXIII-A participates in macrophage function, innate immune regulation, angiogenesis, and broader extracellular-matrix cross-linking — reviewed in Factor XIII-A in Diseases: Role Beyond Blood Coagulation, PMC7867190.
Omics/advanced technologies: No transcriptomic, proteomic, metabolomic, or single-cell/spatial datasets specific to FXIII-A deficiency were surfaced in this pass. This is flagged as an evidence gap rather than confirmed absence; GEO/Human Protein Atlas should be queried directly for F13A1 expression data if module-level curation requires it.

7. Anatomical Structures Affected

Organ level: - Primary: Skin/soft tissue (bruising, hematoma), umbilical cord stump (neonatal bleeding), central nervous system/brain (intracranial hemorrhage — most severe complication), female reproductive tract/placenta (pregnancy loss, postpartum hemorrhage), mucosal surfaces (nose, gingiva, GI tract). - Secondary: Joints (uncommon hemarthrosis, contrasting with hemophilia), muscle (intramuscular hematoma), surgical/wound sites generally (impaired healing, dehiscence). - Body systems: Hematologic (primary), integumentary, reproductive, nervous (via ICH), musculoskeletal (uncommon).

Tissue/cell level: Vascular endothelium and perivascular connective tissue at sites of hemorrhage; dermal/epidermal wound bed (impaired re-epithelialization); placental cytotrophoblast shell and decidual interface (Nitabuch's layer).

Subcellular level: Cytoplasmic localization of FXIII-A in platelets/monocytes (candidate GO:0005829 cytosol); no organelle-specific pathology (e.g., no mitochondrial or lysosomal component to this disease).

Anatomical term candidates (UBERON): umbilical cord (UBERON:0002331), brain (UBERON:0000955), placenta (UBERON:0001987), skin (UBERON:0002097), uterus (UBERON:0000995). (Candidates only — verify against OAK before binding.)

Lateralization: Not applicable — bleeding events are determined by site of trauma/vascular demand, not a lateralized anatomical predisposition.

8. Temporal Development

Onset: Severe congenital disease classically presents in the neonatal period with delayed umbilical stump bleeding occurring days to weeks after cord separation — described as potentially "the earliest manifestation," in up to 80% of affected neonates. Moderate/mild disease may remain asymptomatic until a hemostatic challenge (surgery, trauma, pregnancy) unmasks it.

Onset pattern: Typically insidious/chronic bleeding tendency punctuated by acute bleeding episodes, rather than a single acute presentation — though intracranial hemorrhage itself is an acute, life-threatening event.

Progression: Untreated severe disease follows a relapsing pattern of recurrent hemorrhagic events across the lifespan; intracranial hemorrhage specifically carries a ~30% recurrence rate, and ~50% of recurrences are fatal (StatPearls). With prophylactic replacement, the disease course is effectively stabilized.

Disease duration: Lifelong (congenital form); acquired immune-mediated disease may remit with immunosuppression and autoantibody clearance.

Critical periods: - Neonatal period — umbilical bleeding as sentinel event for diagnosis. - Gestational weeks 6–8 — cytotrophoblastic shell/Nitabuch's layer formation at the maternal-fetal interface is the specific developmental window in which FXIII-A deficiency precipitates early pregnancy loss. - Perioperative periods and late pregnancy/peripartum — periods of heightened hemostatic demand requiring dose escalation of replacement therapy.

9. Inheritance and Population

Epidemiology: - Prevalence of severe congenital FXIII deficiency: ~1 in 2–3 million live births globally (multiple concordant sources). - Iran: ~12-fold higher prevalence than the global estimate, attributed to consanguinity, with strong founder-effect clustering (Trp187Arg) in Sistan and Baluchestan Province. - Carrier frequency: ~1 in 1,000 individuals globally (heterozygotes), translating to an estimated ~7.5 million carriers worldwide. - No specific incidence (new-case) rate was identified distinct from birth prevalence — appropriate, since this is a congenital condition present from birth rather than one with a variable incident onset.

Inheritance pattern: Autosomal recessive.

Penetrance/expressivity: Phenotype severity correlates closely with residual FXIII activity level (severe <1%, moderate <30%, mild ≥30%), implying substantial genotype-phenotype correlation for biallelic null alleles, though no formal penetrance estimate (e.g., proportion of homozygotes who never bleed) was found in the sources retrieved.

Anticipation / germline mosaicism: No evidence of genetic anticipation (expected, as this is not a repeat-expansion disorder) or germline mosaicism specific to this condition was found.

Founder effects: Well documented — Trp187Arg (Iran/southeast Iran) is the clearest example, with a dedicated methodological paper on assessing founder effects in this disease (PMC7876424). Arg77Cys in the Swiss population is a secondary lead requiring independent verification.

Population demographics: - Sex ratio: Equal (autosomal recessive; no sex-linked modifier identified for the bleeding phenotype itself, though pregnancy-related morbidity is obviously female-specific). - Geographic distribution: Elevated prevalence wherever consanguinity rates are high — Iran most prominently; also historically documented clustering in other Middle Eastern and South Asian populations per the broader rare-bleeding-disorder literature (not independently itemized with PMIDs in this pass). - Age distribution: Severe cases are predominantly diagnosed in infancy/early childhood (umbilical bleeding, early ICH); moderate/mild cases may be diagnosed incidentally in adulthood (surgical bleeding, recurrent miscarriage workup) or remain undiagnosed.

10. Diagnostics

The central diagnostic principle: PT, aPTT, thrombin time, fibrinogen, and platelet count are all normal in FXIII deficiency, because FXIII acts after fibrin polymer formation. High clinical suspicion — especially with a history of delayed umbilical bleeding, consanguinity, family history, or unexplained recurrent miscarriage — is required to trigger specific testing.

Laboratory tests: 1. Clot solubility test (5 mol/L urea or 1% monochloroacetic acid) — the traditional screening test; simple and cheap but poor sensitivity/specificity, missing mild-to-moderate deficiency; increasingly regarded as obsolete/"deprecated" in current reviews (Altahan et al.; PMID:42682775 review). 2. Quantitative functional activity assays (preferred first-line): - Ammonia-release assay (e.g., Berichrom®, Technochrom®) — most widely used; FXIII activated by thrombin/Ca²⁺, liberated ammonia measured via glutamate dehydrogenase-coupled NADH oxidation at 340 nm; lower limit of quantification ~3–5%. - Isopeptidase/fluorogenic assay (Technofluor® FXIII Activity) — direct fluorescence from isopeptide bond cleavage. - Amine incorporation assay — high sensitivity but more time-consuming, and notably confounded by the Val34Leu polymorphism, which accelerates activation and can cause overestimation of activity in this assay type (ammonia-release assays are unaffected by Val34Leu). 3. Antigen assays (ELISA, latex agglutination, chemiluminescence) — distinguish Type I (concordant reduction in antigen and activity) from Type II (isolated activity reduction with preserved antigen), and differentiate FXIII-A–specific from FXIII-B–specific deficiency — directly relevant to treatment selection (see §12). 4. Inhibitor/mixing studies — 1:1 mixing of patient plasma with pooled normal plasma, activity measured immediately and after 1–2 h incubation at 37 °C, to distinguish deficiency from acquired autoantibody inhibition; ELISA detects non-neutralizing antibodies. 5. Preanalytical requirement: Platelet-poor plasma is essential, since platelet-associated FXIII-A can spuriously elevate apparent plasma activity. 6. Viscoelastic testing (TEG/ROTEM): Standard tracings reflect thrombin-driven fibrin formation and cannot reliably exclude clinically significant FXIII deficiency — an important limitation given the increasing point-of-care use of these assays.

Genetic testing: Targeted NGS panels covering F13A1 and F13B, with deletion/duplication analysis to capture structural variants and deep-intronic mutations, confirm a causative variant in the large majority (~95%) of congenital cases. Molecular confirmation has direct therapeutic implications (recombinant FXIII-A₂ is ineffective for F13B-driven disease — see §12).

Differential diagnosis: Afibrinogenemia/dysfibrinogenemia, hemophilia A/B, von Willebrand disease, platelet function disorders (Glanzmann thrombasthenia, Bernard-Soulier syndrome), and other rare factor deficiencies (FII, FV, FVII, FX, FXI) — all of which, unlike FXIII deficiency, typically show an abnormal screening coagulation profile.

Screening: FXIII deficiency is not part of standard newborn screening panels; diagnosis is case-finding, triggered by the clinical sentinel of delayed umbilical bleeding or a positive family history/consanguinity.

11. Outcome/Prognosis

Untreated severe congenital disease: - 66.7% experience a serious hemorrhagic event over their lifetime (StatPearls). - Intracranial hemorrhage is the primary cause of death; recurrence risk ~30%, with ~50% mortality per recurrence, and ~50% of survivors developing neurological sequelae.

With replacement prophylaxis: Patients receiving regular replacement therapy can expect life expectancy comparable to the general population (StatPearls), and prophylaxis is reported to essentially eliminate spontaneous and intracranial bleeding.

Quantified bleeding-rate outcomes (recombinant FXIII-A₂, Mentor™ trial series): - Monthly 35 IU/kg prophylaxis achieved an annualized bleeding rate (ABR) of 0.138, versus 2.91 with historical on-demand treatment (Mentor™1). - Mentor™2 long-term extension: ABR declined further to 0.043 (mean spontaneous ABR 0.011) over 186.5 patient-years.

Acquired immune-mediated deficiency: Carries a substantially worse near-term prognosis — ~25% mortality within the first year of diagnosis, reflecting both the typically older, comorbid patient population (median age ~75) and diagnostic delay.

Morbidity: Recurrent miscarriage (reproductive morbidity) and impaired wound healing (surgical/procedural morbidity) are the dominant non-fatal outcomes; both are reported to be "dramatically improved" with prophylactic treatment, though formal quality-of-life instrument data were not found in this search pass.

12. Treatment

Plasma-derived FXIII concentrate — Corifact (US) / Fibrogammin P (EU/other regions): contains both A and B subunits, making it effective regardless of whether the causative gene is F13A1 or F13B. Available in Europe since 1993; FDA-approved in the US as Corifact. Dosing: ~40 IU/kg initial/loading dose, maintenance dosing approximately every 28 days, titrated to a trough activity target of 5–20%. Half-life ~7–9 days.

Recombinant FXIII-A₂ (catridecacog) — Tretten (US) / NovoThirteen (EU), Novo Nordisk: FDA-approved December 2013 for routine prophylaxis in congenital FXIII A-subunit deficiency specifically; a homodimer of recombinant A subunits that binds endogenous B subunits in circulation; not effective for F13B-driven (B-subunit) deficiency. Monthly dosing 35 IU/kg; half-life ~11 days. Pediatric dosing validated down to age ≤6 years without age-based adjustment (Mentor™4 trial).

On-demand/perioperative therapy: 20–40 IU/kg targeting 20–30% activity for minor-to-moderate procedures, with proportionally higher targets for major surgery.

Bridge therapies (when concentrate unavailable): Fresh frozen plasma (~288 ± 77 IU/unit) and cryoprecipitate (~60 ± 30 IU/unit) — both have highly variable FXIII content between units/products and are regarded as second-line.

Pregnancy management: Early initiation (by 5 weeks' gestation in one described regimen); fortnightly or weekly dosing to maintain trough activity ≥10–20% through early/mid gestation, escalating to ≥30% in late pregnancy and peripartum; neuraxial anesthesia considered safe at ≥30% activity; tranexamic acid is emphasized for postpartum hemorrhage prevention; planned cesarean delivery is recommended in affected/potentially affected severe-deficiency pregnancies; multidisciplinary (obstetrics/hematology/anesthesia) management is recommended throughout.

Acquired immune-mediated deficiency: First-line immunosuppression with corticosteroids ± rituximab (response typically 4–8 weeks); cyclophosphamide or mycophenolate mofetil for non-responders; plasma exchange for short-term autoantibody removal in acute severe bleeding; FXIII replacement alongside immunosuppression; identification and treatment of the underlying trigger is emphasized as essential.

Anticoagulation co-management: No established guideline exists; a single case-report-level source (Bounaix et al., cited secondhand) suggests rivaroxaban may be used safely with adjusted FXIII replacement intensity (50% activity during anticoagulant loading, 30% maintenance, 20% prophylactic) — this is case-report-level evidence only and should be labeled as such, not as a guideline-supported approach.

Adverse effects: Both replacement products are generally well tolerated; reported adverse events (≥1%) include headache, leucopenia, joint inflammation, and skin reactions; rare serious events include hypersensitivity, thromboembolic complications, and (extremely rarely) neutralizing inhibitor development.

NCIT mapping candidates: NCIT:C15986 (Pharmacotherapy) as the generic treatment_term, with therapeutic_agent bound to the specific product — a dedicated NCIT code for catridecacog/Corifact was not confirmed in this search pass and should be looked up directly in the NCIT browser at curation time (candidate search term: "Factor XIII Concentrate" / "Catridecacog").

No gene therapy, cell therapy, or RNA-based therapeutics for this disorder were identified — protein replacement remains the entire therapeutic armamentarium; this is consistent with the disease being a straightforward enzyme-replacement-amenable deficiency rather than one requiring correction at the genomic/transcript level.

13. Prevention

Primary prevention: Genetic counseling for known carrier couples, particularly in consanguineous unions or communities with known founder mutations (e.g., Iranian populations with Trp187Arg); carrier testing is the principal actionable primary-prevention lever given the condition's Mendelian, fully recessive architecture.

Secondary prevention / early detection: No population-based newborn screening program exists for this condition; early detection instead relies on clinical vigilance for the sentinel sign of delayed umbilical stump bleeding, prompting targeted FXIII activity testing. Cascade testing of siblings/relatives of an index case is a reasonable extrapolation from general AR-disorder practice, though a specific citation for FXIII deficiency cascade-screening programs was not retrieved in this pass (flagged as a gap, not a negative finding).

Tertiary prevention: Regular prophylactic replacement therapy is the dominant tertiary-prevention strategy, directly preventing recurrent and spontaneous bleeding (including the life-threatening ICH complication) and improving obstetric outcomes in affected women.

Genetic counseling / prenatal options: Once a familial pathogenic variant is known, prenatal diagnosis (chorionic villus sampling or amniocentesis) is mechanistically feasible by standard molecular genetics practice for AR disorders — this specific application to FXIII deficiency was not independently documented by a retrieved source in this pass and should be treated as a reasonable inference pending direct literature confirmation rather than an established citation.

Immunization / public health / prophylactic medication beyond replacement therapy: Not applicable — this is not a disease with a vaccine-preventable or public-health-intervention-amenable etiology.

14. Other Species / Natural Disease

Naturally occurring disease in other species: - Japanese Black cattle — naturally occurring FXIII deficiency reported (cited in a 2026 comparative veterinary paper; primary citation not independently retrieved in this pass). - Domestic dog — a 2026 case report describes a 4-month-old male Black and Tan Coonhound presenting with spontaneous hemoperitoneum, thrombocytopenia, and persistent post-surgical bleeding, found to carry an F13A1 frameshift (deletion-insertion) variant producing a premature stop codon; viscoelastic testing showed reduced clot firmness and enhanced fibrinolysis in high-urea conditions suggestive of FXIII deficiency (PMID:42184124 / PMC13200534). Search results explicitly note this is the first well-characterized canine case and did not identify a Dachshund-specific founder condition, despite that breed association appearing plausible a priori — do not assume a Dachshund-specific form without further verification.

Comparative biology: The transglutaminase cross-linking mechanism and thrombin-dependent activation are conserved across mammalian species studied (human, mouse, cattle, dog), consistent with FXIII's role as a terminal, highly conserved step of the coagulation cascade.

Orthologous genes: Mouse F13a1 (MGI:1921395); rat F13a1 (RGD:621495 / RGD:732286 per search results — two RGD entries appeared, requiring disambiguation at curation time).

Zoonotic potential: Not applicable — this is a non-infectious, genetically determined disorder with no cross-species transmission mechanism.

15. Model Organisms

Primary model: F13a1-knockout mouse - Original line: Targeted inactivation of the mouse F13a1 locus (deletion of exon 7), establishing hemostatic abnormalities and characterizing the coagulation deficit — Lauer et al., PMID:12529747. - Reproductive phenotype: F13a1-deficient female mice develop severe uterine bleeding events and subsequent spontaneous miscarriages, directly recapitulating the human reproductive phenotype and supporting the cytotrophoblastic-shell mechanism described in §6 — Koseki-Kuno et al., Blood 2003;102(13):4410–4412, DOI:10.1182/blood-2003-05-1467. - Wound-healing phenotype: Knockout mice show delayed wound closure (15%, 27%, 27% reductions at days 4, 8, 11 vs. controls; 73.2% vs. 100% closure by day 11) with histologic evidence of delayed re-epithelialization and necrotized fissures, rescued by exogenous FXIII treatment (90.1% closure by day 11 in treated knockouts) — Inbal et al., Thromb Haemost 2005;94:432–437, DOI:10.1160/TH05-04-0291. - Other reported phenotypes in this model: impaired clot retraction (Impaired clot retraction in FXIII A subunit–deficient mice, Blood 115(6):1277); aggravated cardiac rupture and impaired post-infarct wound healing/remodeling in a myocardial infarction model (Circulation 2006, PMC4066325) — relevant to FXIII's broader tissue-repair role (§6) rather than to the bleeding-disorder phenotype per se; metabolic phenotype (signs of "metabolically healthy obesity" on high-fat diet) has also been reported, indicating pleiotropic non-hemostatic roles (Sci Rep 2016, srep35574). - Phenotype recapitulation assessment: The mouse model recapitulates the two best-characterized human mechanistic branches (reproductive loss, impaired wound healing) with good fidelity, including a histological and functional correlate of the human cytotrophoblastic-shell defect. Limitation: the model's relevance to the intracranial hemorrhage phenotype — arguably the most clinically important human complication — was not specifically described in the sources retrieved in this pass; this should be checked directly against the primary mouse-model literature before treating ICH as "recapitulated" in any computational-model link.

Resource: IMPC/MGI phenotype data for F13a1 (MGI:1921395) is available via mousephenotype.org for further systematic phenotype mining.

Other model systems (zebrafish, Drosophila, C. elegans, iPSC/organoid): None were identified in this search pass. Given that FXIII-mediated fibrin cross-linking is a vertebrate-coagulation-specific mechanism, invertebrate models are mechanistically implausible; no evidence of a zebrafish or iPSC-derived model was found, and this is reported as an absence of retrieved evidence, not a confirmed non-existence.

Summary of Evidence Gaps (flagged explicitly per attribution discipline)

MONDO ID discrepancy between the brief (MONDO:0013187) and what search results return (MONDO:0018029) — resolve against the ontology directly.
No gnomAD-level allele-frequency table for specific pathogenic F13A1 variants was retrieved.
No epigenetic (DNA methylation/histone) data specific to this disease were found.
No formal QoL-instrument (EQ-5D/SF-36) data specific to FXIII deficiency were found.
No transcriptomic/proteomic/single-cell dataset specific to this disease was retrieved.
Prenatal diagnosis practice (CVS/amniocentesis) for FXIII deficiency specifically is inferred from general AR-disorder practice, not directly documented in a retrieved source.
The Swiss Arg77Cys founder-variant claim and several individual ClinVar accession numbers are search-engine-summarized leads, not independently verified against primary ClinVar/literature records.
Mouse-model fidelity for the intracranial hemorrhage phenotype specifically was not addressed in the sources reviewed.

Sources (primary links retrieved in this research pass)

Reference Validation

Checked with linkml-reference-validator 0.2.1.

Outcome	Count
References checked	23
Resolved	23
Unresolved (possible confabulation)	0
Unverifiable	0
Quoted claims checked	1
Quoted claims found in source	0
Quoted claims not found in source	1
References weighed for topical relevance	23
On topic	14
Off topic	0

Quotes not found in the cited source

Searched the abstract, any retrieved full text, and the title. A quote drawn from a part of the paper that was not retrieved will appear here too, so check before treating one as invented:

Every one of these was searched against an abstract alone, with no full text retrieved - marked abstract only below. Where full text can be fetched, re-running with it will settle them; where the source publishes only a summary to PubMed, as GeneReviews chapters do, it will not, and the quote has to be checked by hand against the chapter itself.

PMID:11816711 (abstract only): "Common Pathway of Fibrin Clot Formation"
closest text in source: "Thus, factor XIII displays constitutive enzymatic activity with respect to fibrinogen and fibrin"

Term Validation

Checked with linkml-term-validator 0.4.5, through the ols: adapter.

Outcome	Count
Terms checked	33
Resolved	29
Unresolved (possible confabulation)	0
Obsolete	0
Unverifiable	4
Terms whose name was checked	9
Terms named correctly	7
Terms named as a different term	1
Terms whose name is worth a second look	1

Terms the report names something else

These identifiers resolve, so nothing about them looks wrong, and the ontology calls them something unrelated to what the report calls them. That usually means the identifier is not the one the sentence needs:

MONDO:0013187 (3 mentions) - the report calls it "MONDO ID discrepancy between the brief"; MONDO calls it factor XIII, A subunit, deficiency of**

Terms whose name is worth a second look

The report's name for these is recognisably related to the term's own name without being one of them. A loose paraphrase reads the same way as a citation of the wrong sibling term - and so does a related synonym, which the ontology records precisely because it names something adjacent rather than the same thing - so these are listed rather than judged:

GO:0003810 (1 mention) - the report calls it "protein-glutaminase gamma-glutamyltransferase activity — the core catalytic GO term for F13A1"; GO calls it protein-glutamine gamma-glutamyltransferase activity

Prefixes with no resolver

Terms carrying these prefixes were not checked either way, because no configured ontology covers them. An unrecognised prefix may name an ontology this run could not reach as easily as one that does not exist, so nothing here is evidence of fabrication: MGI, RGD.

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Phenotypes

Genetic Associations

Medical Actions

Biochemical Markers

Prevalence

Differential Diagnoses

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Animal Models

Source YAML

References & Deep Research

References

Deep Research

Factor XIII A Subunit Deficiency: Comprehensive Research Report

1. Disease Information

2. Etiology

3. Phenotypes

4. Genetic/Molecular Information

5. Environmental Information

6. Mechanism / Pathophysiology

Ordered causal chain

Molecular pathways, processes, and profiling

7. Anatomical Structures Affected

8. Temporal Development

9. Inheritance and Population

10. Diagnostics

11. Outcome/Prognosis

12. Treatment

13. Prevention

14. Other Species / Natural Disease

15. Model Organisms

Summary of Evidence Gaps (flagged explicitly per attribution discipline)

Sources (primary links retrieved in this research pass)

Reference Validation

Quotes not found in the cited source

Term Validation

Terms the report names something else

Terms whose name is worth a second look

Prefixes with no resolver