Factor XIII B Subunit Deficiency

Mendelian MONDO:0013190 Pathograph 15 Show in embeddings browser Bleeding Disorder Coagulation Disorder Rare Bleeding Disorder

Congenital deficiency of the non-catalytic B subunit of coagulation factor XIII, caused by biallelic pathogenic variants in F13B. Plasma factor XIII circulates as the heterotetramer FXIII-A2B2: the catalytic A subunit is made by cells of haematopoietic origin and the B subunit by hepatocytes, and the two meet only in plasma. FXIII-B carries and protects FXIII-A, so when the B subunit is missing the A subunit is cleared from the circulation quickly and a secondary FXIII-A deficiency follows even though F13A1 is intact. FXIII-B also binds fibrinogen and speeds thrombin activation of FXIII-A on the clot, so its loss slows fibrin cross-linking by a second route. The clinical picture is a milder version of A-subunit disease. Plasma FXIII activity is low but usually not absent, and bleeding tends to be provoked or late-presenting rather than the umbilical-stump and intracranial haemorrhage of infancy that defines severe A-subunit deficiency. Routine screening tests (prothrombin time, activated partial thromboplastin time, thrombin time) are normal, so diagnosis requires a FXIII activity assay followed by separate A and B subunit antigen measurement and F13B sequencing. The distinction matters for treatment: recombinant FXIII-A2 cannot replace the missing carrier and is not appropriate, whereas plasma-derived concentrate supplies both subunits. Severe B-subunit deficiency is much rarer than A-subunit deficiency; heterozygous F13B variants are commoner and cause mild or no bleeding.

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1
Inheritance
9
Pathophys.
3
Phenotypes
1
Gaps
15
Pathograph
1
Genes
1
Medical Actions
2
Differentials
1
Models
2
References
1
Deep Research
👪

Inheritance

1
Autosomal recessive inheritance HP:0000007
Severe deficiency requires two F13B pathogenic alleles, homozygous or compound heterozygous. Heterozygous F13B variants are found more often than biallelic ones and are associated with mild FXIII deficiency; the reviews describe such heterozygotes as generally asymptomatic. Whether their bleeding is specifically provoked by trauma or surgery is stated for heterozygous FXIII deficiency in general rather than for F13B heterozygotes, so it is not asserted here.
Autosomal recessive inheritance
Show evidence (3 references)
PMID:8639893 SUPPORT Human Clinical
"Restriction digestion of amplified DNAs confirmed that the proband and her sister were homozygotes, and their family members were heterozygotes of this mutant allele."
Affected sisters homozygous for the F13B allele with heterozygous relatives, the segregation pattern of recessive inheritance.
PMID:26247044 SUPPORT BACKGROUND Human Clinical
"Defects in the F13B gene (Factor XIIIB subunit) occur more frequently in mild FXIII deficiency patients than in severe FXIII deficiency."
Supports the statement that F13B variants are mostly found as heterozygous, mild deficiency rather than as severe biallelic disease.
PMID:39613144 SUPPORT REVIEW SYNTHESIS Other
"patients with severe FXIII-B deficiency may only require on-demand therapy, while heterozygotes are generally asymptomatic."
The heterozygote statement this description now makes, in the review's own words. It says asymptomatic, not provoked-bleeding-only, which is why the description was narrowed to match.
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Discussions and Knowledge Gaps

1
What is the risk of intracranial haemorrhage, umbilical stump bleeding, impaired wound healing and recurrent pregnancy loss in biallelic F13B deficiency specifically?
KNOWLEDGE GAP f13b_phenotype_extrapolation_gap
Attached to
phenotypes#
These are the phenotypes that define severe congenital FXIII deficiency, and the cohort data behind every published frequency for them is dominated by A-subunit disease, which is about 95% of cases. This entry therefore does not carry them, and that omission is a deliberate scoping decision rather than an oversight: the reviews describe B-subunit disease as milder and as often needing only on-demand therapy, so importing A-subunit frequencies would assert a risk profile nobody has measured in this disease. Recorded here so that a later curator does not read the absence as an accident and fill it from the A-subunit literature. Closing it needs a B-subunit-specific case series, which with roughly eleven reported patients does not yet exist.
Show evidence (1 reference)
PMID:39613144 SUPPORT REVIEW SYNTHESIS Other
"patients with severe FXIII-B deficiency present with a milder phenotype."
The basis for not importing the A-subunit phenotype set: the one statement the reviews do make about B-subunit severity is that it is milder, which is not a frequency for any specific phenotype.
⚙

Pathophysiology

9
Biallelic F13B Loss-of-Function Variants
Homozygous or compound heterozygous pathogenic variants in F13B, which encodes the B subunit of factor XIII, a protein built from ten sushi domains held together by disulphide bonds. Reported variants include premature-termination alleles (the AAC insertion at Tyr-80 that is a founder allele in Italian families, and a splice-boundary deletion that is a founder allele in Japanese families), frameshifts, and missense variants that remove or sit next to a structural disulphide bond. Most of them reduce the amount of FXIII-B that leaves the cell rather than producing a secreted but inactive protein.
F13B hgnc:3534 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves F13B (hgnc:3534). hgnc:3534 is a gene from the HUGO Gene Nomenclature Committee.
fibrinogen binding GO:0070051 ⇓ LOSS OF FUNCTION Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves fibrinogen binding (GO:0070051), qualified as loss of function. GO:0070051 is a molecular function from the Gene Ontology.
Downstream
Impaired FXIII-B Secretion from Hepatocytes Truncated and disulphide-disrupted FXIII-B is retained in the secretory pathway instead of being released.
Show evidence (3 references)
PMID:8639893 SUPPORT Human Clinical
"DNA sequence analysis showed that a nucleotide triplet (AAC) was inserted within the codon for Tyr-80 in exon III of the gene for a female proband's b subunit, resulting in the creation of a stop codon."
First F13B lesion shown to cause the disease.
PMID:20331752 SUPPORT Human Clinical
"Two of the missense mutations (Cys5Arg, Cys316Phe) eliminated disulphide bonds (Cys5-Cys56, Cys316-Cys358)."
Shows that missense variants removing a structural disulphide bond are a recurring class of F13B lesion.
PMID:20880254 SUPPORT REVIEW SYNTHESIS Other
"FXIII-B is a glycoprotein consisting of 10 repetitive sushi domains each held together by two internal disulfide bonds."
The domain architecture this node describes, and the reason a single disulphide-disrupting substitution is enough to destabilise the protein.
Impaired FXIII-B Secretion from Hepatocytes
FXIII-B is synthesised by hepatocytes. Mutant FXIII-B is held in the endoplasmic reticulum or fails to reach the Golgi apparatus, so little or none is released into plasma. Secretion deficits were found for every patient-derived missense variant tested in one cell expression study, though a follow-up study found that several of those variants act mainly by reducing protein stability or binding to FXIII-A.
hepatocyte CL:0000182 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves hepatocyte (CL:0000182). CL:0000182 is a cell type from the Cell Ontology.
protein secretion GO:0009306 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased protein secretion (GO:0009306). GO:0009306 is a biological process from the Gene Ontology. endoplasmic reticulum to Golgi vesicle-mediated transport GO:0006888 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased endoplasmic reticulum to Golgi vesicle-mediated transport (GO:0006888). GO:0006888 is a biological process from the Gene Ontology.
Downstream
Absent Circulating FXIII-B Carrier Subunit Little or no FXIII-B reaches plasma.
Show evidence (4 references)
PMID:37883802 SUPPORT BACKGROUND Human Clinical
"Plasma FXIII is composed of A and B subunit dimers synthesized in cells of hematopoietic origin and hepatocytes, respectively."
Identifies the hepatocyte as the cell that makes FXIII-B.
PMID:23913518 SUPPORT In Vitro
"In vitro expression of FXIII B subunit (FXIIIB) missense variants in HEK293T cells revealed impaired secretion for all seven variants studied."
Secretion defect is shared by all tested patient missense variants.
PMID:11313256 SUPPORT In Vitro
"immunocytochemical examinations by epifluorescence, confocal, and electron microscopes indicated impaired intracellular transportation of the truncated XIIIB from the endoplasmic reticulum to the Golgi apparatus."
Places the block at the endoplasmic reticulum to Golgi step.
+ 1 more reference
Absent Circulating FXIII-B Carrier Subunit
Plasma FXIII-B is undetectable or severely reduced, so FXIII-A2 cannot form the stable A2B2 heterotetramer.
Downstream
Accelerated Plasma Clearance of FXIII-A Without its carrier, FXIII-A2 is removed from the circulation faster, producing a secondary A-subunit deficiency.
Impaired Thrombin Activation of FXIII-A on Fibrin FXIII-B also links the FXIII zymogen to fibrinogen, so its absence slows activation of whatever FXIII-A remains.
Show evidence (2 references)
PMID:23407795 SUPPORT Human Clinical
"At the age of 74, ELISA and western blotting assay unexpectedly revealed complete absence of FXIII-B in the patient's plasma."
Direct measurement of absent plasma FXIII-B in a homozygous patient.
PMID:8639893 SUPPORT Human Clinical
"there were normal amounts of the mutant mRNA, but no b subunit was detected in these patients."
Absent plasma FXIII-B despite normal F13B transcript levels.
Accelerated Plasma Clearance of FXIII-A
Secondary FXIII-A deficiency. F13A1 and platelet FXIII-A are normal, but plasma FXIII-A falls because the uncomplexed A2 dimer has a shorter circulating life than the A2B2 heterotetramer. The subunits stabilise each other: free FXIII-B2 is also cleared faster than complexed FXIII-B2.
Animal models
FXIII-B knockout mouse (F13b-/-) Mouse recapitulates Low plasma FXIII-A that is corrected by restoring FXIII-B, reproducing the secondary A-subunit deficiency.
Downstream
Reduced Plasma FXIII Transglutaminase Activity Less FXIII-A in plasma means less activatable transglutaminase.
Show evidence (2 references)
PMID:8639893 SUPPORT Human Clinical
"The a subunit deficiency of these patients must be a secondary to the b subunit deficiency, as their gene for the a subunit was intact, and the a subunit in their platelets was present within normal levels."
Establishes that the low plasma FXIII-A is secondary.
PMID:37883802 SUPPORT Model Organism
"comparison of free FXIII-B2 vs FXIII-A2-complexed FXIII-B2 (FXIII-A2B2) infused into mice revealed faster clearance of free FXIII-B2."
The reciprocal half of the relationship, measured in mice: each subunit survives longer in plasma when complexed with the other.
Impaired Thrombin Activation of FXIII-A on Fibrin
FXIII-B binds fibrinogen and brings proenzyme FXIII, fibrinogen and thrombin together. Without it, thrombin cleavage of the FXIII-A activation peptide and FXIII-A incorporation into the clot are both slower.
blood coagulation, fibrin clot formation GO:0072378 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased blood coagulation, fibrin clot formation (GO:0072378). GO:0072378 is a biological process from the Gene Ontology.
Downstream
Impaired Fibrin Cross-Linking Slower activation delays cross-linking of the fibrin clot.
Show evidence (3 references)
PMID:25809477 SUPPORT In Vitro
"Immunoprecipitation with an anti-fibrinogen antibody revealed an interaction between the FXIII heterotetramer and fibrinogen mediated by FXIII-B and not FXIII-A."
FXIII-B, not FXIII-A, binds fibrinogen.
PMID:20880254 SUPPORT REVIEW SYNTHESIS Other
"In the circulation pFXIII is bound to the fibrinogen γ'-chain through its B subunit."
Independent statement that the B subunit is what tethers the zymogen to fibrinogen, which is the function lost here.
PMID:20880254 SUPPORT REVIEW SYNTHESIS Other
"In the process of pFXIII activation first thrombin cleaves off the activation peptide from FXIII-A, then in the presence of Ca(2+) FXIII-B dissociates and FXIII-A becomes transformed into an active transglutaminase (FXIIIa). The activation is highly accelerated by the presence of fibrin(ogen)."
The normal activation sequence, which is what makes the loss of the fibrinogen tether a rate problem: activation is accelerated by fibrin(ogen), and the B subunit is what brings the zymogen there.
Reduced Plasma FXIII Transglutaminase Activity
Plasma FXIII activity is reduced, to about ten percent of normal in the best-described severe case, rather than being absent as in severe A-subunit deficiency. The residual activity is one likely reason the bleeding phenotype is milder.
plasma transglutaminase activity GO:0003810 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves decreased plasma transglutaminase activity, annotated with protein-glutamine gamma-glutamyltransferase activity (GO:0003810). GO:0003810 is a molecular function from the Gene Ontology.
Downstream
Impaired Fibrin Cross-Linking Less transglutaminase activity means less fibrin cross-linking.
Impaired Alpha-2-Antiplasmin Ligation to Fibrin The same loss of transglutaminase activity also leaves less alpha-2-antiplasmin covalently ligated into the clot, which is a separate substrate from the fibrin chains themselves.
Show evidence (1 reference)
PMID:23407795 SUPPORT Human Clinical
"his FXIII activity was as low as 10% of the normal."
Plasma FXIII activity in a homozygous patient.
Impaired Alpha-2-Antiplasmin Ligation to Fibrin
Alpha-2-antiplasmin is the other principal haemostatic substrate of activated FXIII, and cross-linking it into fibrin is the main way a clot resists plasmin. With less transglutaminase activity, less inhibitor is ligated. This arm is modelled because it follows from the reduced FXIIIa activity this entry already asserts, not from anything A-subunit specific; it has not been measured in a B-subunit-deficient patient.
negative regulation of fibrinolysis GO:0051918 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased negative regulation of fibrinolysis (GO:0051918). GO:0051918 is a biological process from the Gene Ontology.
Downstream
Accelerated Fibrinolysis of the Formed Clot A clot carrying less covalently bound inhibitor is lysed sooner.
Show evidence (1 reference)
PMID:25652913 SUPPORT REVIEW SYNTHESIS Other
"These include antifibrinolytic proteins, with cross-linking of α2-antiplasmin to fibrin, and potentially fibrinogen, being the principal mechanism(s) whereby plasmin-mediated clot degradation is minimised"
Establishes that alpha-2-antiplasmin cross-linking is the principal antifibrinolytic mechanism of FXIII, which is what is lost when transglutaminase activity falls.
Accelerated Fibrinolysis of the Formed Clot
Premature plasmin-mediated dissolution of a clot that formed normally. This is the second route to the bleeding phenotype and is mechanistically distinct from the mechanically weak clot: here the clot is lysed too soon rather than being too fragile. It is an inference from the substrate biology rather than a measurement in this disease, and is recorded as such.
fibrinolysis GO:0042730 ↑ INCREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased fibrinolysis (GO:0042730). GO:0042730 is a biological process from the Gene Ontology.
Downstream
Abnormal bleeding Premature lysis of an adequate clot produces delayed bleeding.
Show evidence (1 reference)
PMID:25652913 SUPPORT INDIRECT REVIEW SYNTHESIS Other
"being the principal mechanism(s) whereby plasmin-mediated clot degradation is minimised"
The consequence of losing that cross-linking is more plasmin-mediated degradation. INDIRECT because the review states the normal mechanism and the inference to accelerated lysis in B-subunit deficiency is ours; no fibrinolysis measurement in such a patient was found.
Impaired Fibrin Cross-Linking
Fibrin gamma- and alpha-chain isopeptide cross-linking is slower and less complete, giving a mechanically weaker clot. Both upstream routes, loss of FXIII-A by clearance and slower activation of what remains, converge here.
fibrin gamma- and alpha-chain isopeptide cross-linking GO:0018149 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased fibrin gamma- and alpha-chain isopeptide cross-linking, annotated with peptide cross-linking (GO:0018149). GO:0018149 is a biological process from the Gene Ontology.
Animal models
FXIII-B knockout mouse (F13b-/-) Mouse recapitulates Reduced plasma cross-linking and prolonged bleeding time.
Downstream
Abnormal bleeding An unstable clot gives a bleeding tendency.
Intramuscular hematoma Deep soft-tissue bleeding is the reported spontaneous bleed.
Gingival bleeding Mucosal bleeding is reported in the same patient.
Show evidence (2 references)
PMID:18224415 SUPPORT Model Organism
"thrombin-dependent amine incorporation and fibrin-crosslinking in plasma were undetectable in the FXIII-A-deficient mice and markedly reduced in the FXIII-B-deficient mice"
Cross-linking is reduced but not abolished without FXIII-B, in contrast with FXIII-A loss.
PMID:25809477 SUPPORT INDIRECT In Vitro
"congenital or acquired FXIII-B deficiency may result in increased bleeding tendency through impaired fibrin stabilization due to decreased FXIII-A activation by thrombin and secondary FXIII-A deficiency arising from enhanced circulatory clearance."
The authors' conclusion on how the two routes converge on fibrin stabilisation and bleeding, drawn from plasma experiments and stated as a proposal ("may result").
⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Factor XIII B Subunit Deficiency Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
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Phenotypes

3
Blood 2
Abnormal bleeding HP:0001892 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is mild bleeding tendency, annotated with Abnormal bleeding (HP:0001892). HP:0001892 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:39613144 SUPPORT REVIEW SYNTHESIS Other
"patients with severe FXIII-B deficiency present with a milder phenotype."
Contrasts B-subunit with A-subunit disease severity. OTHER to match how this entry grades every other quote from this review: the sentence is the authors' synthesis of the clinical literature, not a study they ran.
PMID:23407795 SUPPORT Human Clinical
"An originally mild bleeding phenotype of severe congenital FXIII-B deficiency can be exaggerated by additional acquired conditions."
Mild baseline phenotype that can worsen with acquired factors.
Gingival bleeding HP:0000225 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Gingival bleeding (HP:0000225). HP:0000225 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:23407795 SUPPORT Human Clinical
"He developed thrombocytopenia and gingival bleedings at the age of 73"
Single case report, with concurrent thrombocytopenia as a confounder.
Musculoskeletal 1
Intramuscular hematoma HP:0012233 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Intramuscular hematoma (HP:0012233). HP:0012233 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:23407795 SUPPORT Human Clinical
"When he suddenly developed spontaneous intramuscular haematoma, the bleeding was arrested by infusing FXIII concentrates."
Single case report; frequency is not known.
🧬

Genetic Associations

1
F13B
Gene: F13B hgnc:3534 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is F13B (hgnc:3534). hgnc:3534 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE variant_origin: GERMLINE
Autosomal recessive
Show evidence (2 references)
PMID:9716138 SUPPORT Human Clinical
"suggesting that a founder effect is responsible for factor XIII B subunit deficiency in Italians."
Italian founder allele.
PMID:11313256 SUPPORT Human Clinical
"Both patients have a previously described one-base deletion at the boundary between intron A/exon II in the XIIIB gene, heterozygously or homozygously."
Recurrent Japanese allele, which the same paper proposes as a founder allele.
💊

Medical Actions

1
Plasma-Derived Factor XIII Concentrate
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: human factor XIII concentrate NCIT:C200601 NCI Thesaurus (NCIT) Relation: this treatment uses this therapeutic agent This treatment uses human factor XIII concentrate (NCIT:C200601). NCIT:C200601 is a therapeutic agent from the NCI Thesaurus.
Platform: Protein replacement
Plasma-derived FXIII concentrate contains both subunits and is the replacement product for B-subunit deficiency. Because the phenotype is mild, patients may need it only on demand for bleeding or before surgery rather than as routine prophylaxis. Recombinant FXIII-A2 (catridecacog), the prophylactic product used for A-subunit deficiency, is not appropriate here, because it supplies no FXIII-B. Repeated concentrate infusion led to anti-FXIII-B alloantibodies in one patient with complete absence of FXIII-B, after which replacement became less effective.
Mechanism Target:
RESTORES Reduced Plasma FXIII Transglutaminase Activity — Supplies both subunits, restoring plasma FXIII activity temporarily.
Show evidence (1 reference)
PMID:23407795 SUPPORT Human Clinical
"When he suddenly developed spontaneous intramuscular haematoma, the bleeding was arrested by infusing FXIII concentrates."
Concentrate stopped an acute bleed.
Show evidence (3 references)
PMID:41583548 SUPPORT REVIEW SYNTHESIS Other
"recombinant FXIII-A2 is appropriate for F13A1 defects but not patients with F13B variants."
Why plasma-derived concentrate, not recombinant FXIII-A2, is used.
PMID:39613144 SUPPORT REVIEW SYNTHESIS Other
"patients with severe FXIII-B deficiency may only require on-demand therapy, while heterozygotes are generally asymptomatic."
On-demand rather than prophylactic replacement.
PMID:23407795 SUPPORT Human Clinical
"Repeated infusions of exogenous FXIII for hemostasis increased anti-FXIII-B alloantibodies that resisted FXIII substitution."
Alloantibody complication of replacement in complete deficiency.
🔬

Biochemical Markers

2
Plasma factor XIII activity (DECREASED)
Show evidence (2 references)
PMID:23407795 SUPPORT Human Clinical
"his FXIII activity was as low as 10% of the normal."
Reduced FXIII activity in a homozygous patient.
PMID:24476525 SUPPORT REVIEW SYNTHESIS Other
"A quantitative, functional, FXIII activity assay that detects all forms of FXIII deficiency should be used as a first-line screening test."
Review recommendation for the screening test.
Plasma factor XIII B subunit antigen (ABSENT)
Show evidence (2 references)
PMID:23407795 SUPPORT Human Clinical
"At the age of 74, ELISA and western blotting assay unexpectedly revealed complete absence of FXIII-B in the patient's plasma."
FXIII-B antigen absent in severe deficiency.
PMID:41176274 SUPPORT BACKGROUND Other
"Existing enzyme-linked immunosorbent assay-based and latex agglutination assays for measuring FXIII are limited to detecting only the FXIIIA subunit of the complex."
Explains why B-subunit antigen has to be requested specifically: common antigen assays measure only FXIII-A.
🔬

Diagnosis

1
FXIII activity assay with subunit antigen measurement
A quantitative FXIII activity assay detects the deficiency; separate FXIII-A and FXIII-B antigen measurement and F13A1/F13B sequencing then identify which subunit is responsible, which determines the replacement product.
Show evidence (2 references)
PMID:41583548 SUPPORT REVIEW SYNTHESIS Other
"Routine coagulation screening tests are normal and diagnosis relies on quantitative FXIII activity assays with or without antigenic phenotyping and, when indicated, inhibitor testing and molecular confirmation."
Diagnostic sequence.
PMID:24286209 SUPPORT INDIRECT Human Clinical
"Four immunological assays detected essentially no FXIII protein, FXIII-A antigen, and A2 B2 antigen, but normal FXIII-B antigen. Accordingly, he was diagnosed as a 'severe' FXIII-A deficiency case."
The subunit antigen panel doing the discrimination this entry depends on, worked through under the ISTH/SSC scheme. INDIRECT because the patient is the mirror image, an A-subunit case: normal FXIII-B antigen is what ruled B-subunit deficiency out. The same panel with the opposite result is what rules it in.
📊

Prevalence

1
Worldwide
Cases In Literature Rare
No population prevalence estimate exists for severe FXIII-B deficiency. It is a minority of congenital FXIII deficiency, which itself affects about one in two million people, and A-subunit deficiency accounts for about 95% of that total. In 2013 the authors of the alloantibody case report counted ten previously reported cases of congenital FXIII-B deficiency; the source does not qualify those ten by severity, so neither does this record.
Show evidence (4 references)
PMID:23407795 SUPPORT Human Clinical
"Congenital FXIII-A deficiency is a rare bleeding disorder, and congenital FXIII-B deficiency is even rarer."
States the relative rarity of B-subunit deficiency.
PMID:20331752 SUPPORT BACKGROUND Human Clinical
"Severe factor XIII (FXIII) deficiency is a rare autosomal recessive coagulation disorder affecting one in two million individuals."
Frequency of severe congenital FXIII deficiency as a whole, of which B-subunit deficiency is a small part. Cited for the denominator only.
PMID:41583548 SUPPORT REVIEW SYNTHESIS Other
"Deficiency of the FXIII-A subunit is responsible for the majority (~95%) of cases of congenital FXIII deficiency"
The 95% share quoted in this record's notes, which is what makes B-subunit deficiency the small remainder.
+ 1 more reference
🔀

Differential Diagnoses

2

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

Factor XIII A subunit deficiency
Overlapping Features The far commoner form, about 95% of congenital FXIII deficiency, caused by biallelic F13A1 variants. It is separated by measuring both subunit antigens, and the two patterns are not mirror images: in A-subunit deficiency FXIII-A antigen is absent while FXIII-B antigen is normal, whereas here FXIII-B antigen is absent and FXIII-A antigen is secondarily reduced rather than normal. The distinction decides treatment, because recombinant FXIII-A2 works for A-subunit disease and not for this one. Curated as Factor_XIII_A_Subunit_Deficiency.
Acquired factor XIII deficiency
Overlapping Features Reduced FXIII activity from autoantibodies, or from consumption or reduced synthesis in critical illness, surgery or malignancy. Distinguished by age and tempo of onset, by a mixing study and inhibitor titration, and by F13A1/F13B sequencing being normal. Worth keeping in view in this disease specifically, because the one well-described patient developed anti-FXIII-B alloantibodies after replacement and so carried an acquired inhibitor on top of a congenital deficiency.
🐁

Animal Models

1
FXIII-B knockout mouse (F13b-/-)
Gene-targeted mice lacking FXIII-B are viable and fertile, have prolonged bleeding times, and show markedly reduced but detectable plasma cross-linking activity. Infusing recombinant human FXIII-B raises their plasma FXIII-A. Older male knockouts develop mild cardiac fibrosis with haemosiderin deposits, without the fatal cardiac haemorrhage seen in FXIII-A knockout males.
Species
Mouse
Genotype
F13b homozygous targeted disruption
Publication
PMID:18224415
Pathograph links
Accelerated Plasma Clearance of FXIII-A recapitulates fidelity: high observes: organism Low plasma FXIII-A that is corrected by restoring FXIII-B, reproducing the secondary A-subunit deficiency.
Readouts
Plasma FXIII-A after recombinant FXIII-B infusion
Direction: RESTORED
Interpretation: Restoring the carrier raises plasma FXIII-A.
Show evidence (1 reference)
PMID:18224415 SUPPORT Model Organism
"When rFXIII-B was injected into FXIII-B-deficient mice, FXIII-A levels, fibrin crosslinking, and amine-incorporation activities increased in their plasma"
The rescue measurement.
Show evidence (1 reference)
PMID:18224415 SUPPORT Model Organism
"When rFXIII-B was injected into FXIII-B-deficient mice, FXIII-A levels, fibrin crosslinking, and amine-incorporation activities increased in their plasma, indicating that FXIII-B assisted the maintenance of FXIII-A levels in the circulation."
Rescue of plasma FXIII-A by FXIII-B infusion.
Impaired Fibrin Cross-Linking recapitulates fidelity: moderate observes: organism Reduced plasma cross-linking and prolonged bleeding time.
Limitations: Bleeding time in mice is a tail-transection measure and does not map directly onto the provoked mucosal and soft-tissue bleeding reported in patients.
Readouts
Plasma fibrin cross-linking
Direction: DECREASED
Interpretation: Reduced, not absent, cross-linking without FXIII-B.
Show evidence (1 reference)
PMID:18224415 SUPPORT Model Organism
"thrombin-dependent amine incorporation and fibrin-crosslinking in plasma were undetectable in the FXIII-A-deficient mice and markedly reduced in the FXIII-B-deficient mice"
Direct cross-linking measurement.
Show evidence (1 reference)
PMID:18224415 SUPPORT Model Organism
"homozygous mice of either FXIII-A- or FXIII-B-deficiency did have prolonged bleeding times."
Bleeding phenotype in knockout mice.
{ }

Source YAML

click to show 
name: Factor XIII B Subunit Deficiency
creation_date: "2026-10-15T07:30:00Z"
category: Mendelian
parents:
- Bleeding Disorder
- Coagulation Disorder
- Rare Bleeding Disorder
disease_term:
  preferred_term: Factor XIII B subunit deficiency
  term:
    id: MONDO:0013190
    label: factor XIII, b subunit, deficiency of
synonyms:
- factor XIIIB deficiency
- FXIII-B deficiency
- congenital factor XIII B subunit deficiency
- former type I factor XIII deficiency
description: >-
  Congenital deficiency of the non-catalytic B subunit of coagulation factor
  XIII, caused by biallelic pathogenic variants in F13B. Plasma factor XIII
  circulates as the heterotetramer FXIII-A2B2: the catalytic A subunit is made
  by cells of haematopoietic origin and the B subunit by hepatocytes, and the two
  meet only in plasma. FXIII-B carries and protects FXIII-A, so when the B
  subunit is missing the A subunit is cleared from the circulation quickly and a
  secondary FXIII-A deficiency follows even though F13A1 is intact. FXIII-B also
  binds fibrinogen and speeds thrombin activation of FXIII-A on the clot, so its
  loss slows fibrin cross-linking by a second route.

  The clinical picture is a milder version of A-subunit disease. Plasma FXIII
  activity is low but usually not absent, and bleeding tends to be provoked or
  late-presenting rather than the umbilical-stump and intracranial haemorrhage
  of infancy that defines severe A-subunit deficiency. Routine screening tests
  (prothrombin time, activated partial thromboplastin time, thrombin time) are
  normal, so diagnosis requires a FXIII activity assay followed by separate A and
  B subunit antigen measurement and F13B sequencing. The distinction matters for
  treatment: recombinant FXIII-A2 cannot replace the missing carrier and is not
  appropriate, whereas plasma-derived concentrate supplies both subunits. Severe
  B-subunit deficiency is much rarer than A-subunit deficiency; heterozygous F13B
  variants are commoner and cause mild or no bleeding.
prevalence:
- population: Worldwide
  measure_type: CASES_IN_LITERATURE
  prevalence_class: RARE
  notes: >-
    No population prevalence estimate exists for severe FXIII-B deficiency. It
    is a minority of congenital FXIII deficiency, which itself affects about one
    in two million people, and A-subunit deficiency accounts for about 95% of
    that total. In 2013 the authors of the alloantibody case report counted ten
    previously reported cases of congenital FXIII-B deficiency; the source does
    not qualify those ten by severity, so neither does this record.
  evidence:
  - reference: PMID:23407795
    reference_title: Alloantibodies against the B subunit of plasma factor XIII developed in its congenital deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Congenital FXIII-A deficiency is a rare bleeding disorder, and congenital FXIII-B deficiency is even rarer."
    explanation: States the relative rarity of B-subunit deficiency.
  - reference: PMID:20331752
    reference_title: "Mutations affecting disulphide bonds contribute to a fairly common prevalence of F13B gene defects: results of a genetic study in 14 families with factor XIII B deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: "Severe factor XIII (FXIII) deficiency is a rare autosomal recessive coagulation disorder affecting one in two million individuals."
    explanation: >-
      Frequency of severe congenital FXIII deficiency as a whole, of which
      B-subunit deficiency is a small part. Cited for the denominator only.
  - reference: PMID:41583548
    reference_title: "Factor XIII Deficiency: A Review of Biology, Testing, and Treatment."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: "Deficiency of the FXIII-A subunit is responsible for the majority (~95%) of cases of congenital FXIII deficiency"
    explanation: >-
      The 95% share quoted in this record's notes, which is what makes
      B-subunit deficiency the small remainder.
  - reference: PMID:23407795
    reference_title: Alloantibodies against the B subunit of plasma factor XIII developed in its congenital deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "none of the remaining 10 reported cases of congenital FXIII-B deficiency developed alloantibodies"
    explanation: >-
      The ten previously reported cases, counted in 2013. Quoted because it is
      the only published count, and note the sentence attaches no severity
      qualifier to them.
inheritance:
- name: Autosomal recessive inheritance
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  description: >-
    Severe deficiency requires two F13B pathogenic alleles, homozygous or
    compound heterozygous. Heterozygous F13B variants are found more often than
    biallelic ones and are associated with mild FXIII deficiency; the reviews
    describe such heterozygotes as generally asymptomatic. Whether their
    bleeding is specifically provoked by trauma or surgery is stated for
    heterozygous FXIII deficiency in general rather than for F13B
    heterozygotes, so it is not asserted here.
  evidence:
  - reference: PMID:8639893
    reference_title: "Type I factor XIII deficiency is caused by a genetic defect of its b subunit: insertion of triplet AAC in exon III leads to premature termination in the second Sushi domain."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Restriction digestion of amplified DNAs confirmed that the proband and her sister were homozygotes, and their family members were heterozygotes of this mutant allele."
    explanation: >-
      Affected sisters homozygous for the F13B allele with heterozygous
      relatives, the segregation pattern of recessive inheritance.
  - reference: PMID:26247044
    reference_title: Structural and functional influences of coagulation factor XIII subunit B heterozygous missense mutants.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: "Defects in the F13B gene (Factor XIIIB subunit) occur more frequently in mild FXIII deficiency patients than in severe FXIII deficiency."
    explanation: >-
      Supports the statement that F13B variants are mostly found as
      heterozygous, mild deficiency rather than as severe biallelic disease.
  - reference: PMID:39613144
    reference_title: "Factor XIII Deficiency: Laboratory, Molecular, and Clinical Aspects."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: "patients with severe FXIII-B deficiency may only require on-demand therapy, while heterozygotes are generally asymptomatic."
    explanation: >-
      The heterozygote statement this description now makes, in the review's
      own words. It says asymptomatic, not provoked-bleeding-only, which is
      why the description was narrowed to match.
pathophysiology:
- name: Biallelic F13B Loss-of-Function Variants
  biological_scale: MOLECULAR
  description: >-
    Homozygous or compound heterozygous pathogenic variants in F13B, which
    encodes the B subunit of factor XIII, a protein built from ten sushi
    domains held together by disulphide bonds. Reported variants include
    premature-termination alleles (the AAC insertion at Tyr-80 that is a
    founder allele in Italian families, and a splice-boundary deletion that is a
    founder allele in Japanese families), frameshifts, and missense variants
    that remove or sit next to a structural disulphide bond. Most of them reduce
    the amount of FXIII-B that leaves the cell rather than producing a secreted
    but inactive protein.
  genes:
  - preferred_term: F13B
    term:
      id: hgnc:3534
      label: F13B
  molecular_functions:
  - preferred_term: fibrinogen binding
    modifier: LOSS_OF_FUNCTION
    term:
      id: GO:0070051
      label: fibrinogen binding
  evidence:
  - reference: PMID:8639893
    reference_title: "Type I factor XIII deficiency is caused by a genetic defect of its b subunit: insertion of triplet AAC in exon III leads to premature termination in the second Sushi domain."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "DNA sequence analysis showed that a nucleotide triplet (AAC) was inserted within the codon for Tyr-80 in exon III of the gene for a female proband's b subunit, resulting in the creation of a stop codon."
    explanation: First F13B lesion shown to cause the disease.
  - reference: PMID:20331752
    reference_title: "Mutations affecting disulphide bonds contribute to a fairly common prevalence of F13B gene defects: results of a genetic study in 14 families with factor XIII B deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Two of the missense mutations (Cys5Arg, Cys316Phe) eliminated disulphide bonds (Cys5-Cys56, Cys316-Cys358)."
    explanation: >-
      Shows that missense variants removing a structural disulphide bond are a
      recurring class of F13B lesion.
  - reference: PMID:20880254
    reference_title: "Factor XIII: novel structural and functional aspects."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: "FXIII-B is a glycoprotein consisting of 10 repetitive sushi domains each held together by two internal disulfide bonds."
    explanation: >-
      The domain architecture this node describes, and the reason a single
      disulphide-disrupting substitution is enough to destabilise the
      protein.
  downstream:
  - target: Impaired FXIII-B Secretion from Hepatocytes
    causal_link_type: DIRECT
    description: >-
      Truncated and disulphide-disrupted FXIII-B is retained in the secretory
      pathway instead of being released.
    evidence:
    - reference: PMID:11313256
      reference_title: Truncated mutant B subunit for factor XIII causes its deficiency due to impaired intracellular transportation.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "Pulse-chase experiments showed that a resultant truncated XIIIB remained inside the cells and could not be secreted into the culture medium."
      explanation: >-
        Expression of a patient frameshift allele shows the truncated protein
        is made but not secreted.
    - reference: PMID:31013569
      reference_title: Disruption of Structural Disulfides of Coagulation FXIII-B Subunit; Functional Implications for a Rare Bleeding Disorder.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "All 20 FXIII-B were found to be important for the secretion and stability of the protein since ablation of any of these led to a secretion deficit."
      explanation: >-
        Removing any one of the 20 structural disulphide bonds reduced
        secretion, which links the disulphide-disrupting missense class to the
        secretion defect.
- name: Impaired FXIII-B Secretion from Hepatocytes
  biological_scale: CELLULAR
  description: >-
    FXIII-B is synthesised by hepatocytes. Mutant FXIII-B is held in the
    endoplasmic reticulum or fails to reach the Golgi apparatus, so little or
    none is released into plasma. Secretion deficits were found for every
    patient-derived missense variant tested in one cell expression study,
    though a follow-up study found that several of those variants act mainly by
    reducing protein stability or binding to FXIII-A.
  cell_types:
  - preferred_term: hepatocyte
    term:
      id: CL:0000182
      label: hepatocyte
  biological_processes:
  - preferred_term: protein secretion
    modifier: DECREASED
    term:
      id: GO:0009306
      label: protein secretion
  - preferred_term: endoplasmic reticulum to Golgi vesicle-mediated transport
    modifier: DECREASED
    term:
      id: GO:0006888
      label: endoplasmic reticulum to Golgi vesicle-mediated transport
  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: HUMAN_CLINICAL
    snippet: "Plasma FXIII is composed of A and B subunit dimers synthesized in cells of hematopoietic origin and hepatocytes, respectively."
    explanation: Identifies the hepatocyte as the cell that makes FXIII-B.
    quote_role: BACKGROUND
  - reference: PMID:23913518
    reference_title: "In vitro secretion deficits are common among human coagulation factor XIII subunit B missense mutants: correlations with patient phenotypes and molecular models."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "In vitro expression of FXIII B subunit (FXIIIB) missense variants in HEK293T cells revealed impaired secretion for all seven variants studied."
    explanation: Secretion defect is shared by all tested patient missense variants.
  - reference: PMID:11313256
    reference_title: Truncated mutant B subunit for factor XIII causes its deficiency due to impaired intracellular transportation.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "immunocytochemical examinations by epifluorescence, confocal, and electron microscopes indicated impaired intracellular transportation of the truncated XIIIB from the endoplasmic reticulum to the Golgi apparatus."
    explanation: Places the block at the endoplasmic reticulum to Golgi step.
  - reference: PMID:26247044
    reference_title: Structural and functional influences of coagulation factor XIII subunit B heterozygous missense mutants.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "The Cys5Arg mutation was the only mutation to show a direct secretion-based defect since the mutated protein was observed to accumulate in the endoplasmic reticulum."
    explanation: >-
      Refines the earlier result: in this follow-up only Cys5Arg was retained
      in the endoplasmic reticulum, while other variants acted mainly through
      reduced antigenic stability or reduced binding to FXIII-A.
  downstream:
  - target: Absent Circulating FXIII-B Carrier Subunit
    causal_link_type: DIRECT
    description: Little or no FXIII-B reaches plasma.
- name: Absent Circulating FXIII-B Carrier Subunit
  biological_scale: ORGANISM
  description: >-
    Plasma FXIII-B is undetectable or severely reduced, so FXIII-A2 cannot
    form the stable A2B2 heterotetramer.
  evidence:
  - reference: PMID:23407795
    reference_title: Alloantibodies against the B subunit of plasma factor XIII developed in its congenital deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "At the age of 74, ELISA and western blotting assay unexpectedly revealed complete absence of FXIII-B in the patient's plasma."
    explanation: Direct measurement of absent plasma FXIII-B in a homozygous patient.
  - reference: PMID:8639893
    reference_title: "Type I factor XIII deficiency is caused by a genetic defect of its b subunit: insertion of triplet AAC in exon III leads to premature termination in the second Sushi domain."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "there were normal amounts of the mutant mRNA, but no b subunit was detected in these patients."
    explanation: Absent plasma FXIII-B despite normal F13B transcript levels.
  downstream:
  - target: Accelerated Plasma Clearance of FXIII-A
    causal_link_type: DIRECT
    description: >-
      Without its carrier, FXIII-A2 is removed from the circulation faster,
      producing a secondary A-subunit deficiency.
    evidence:
    - reference: PMID:23407795
      reference_title: Alloantibodies against the B subunit of plasma factor XIII developed in its congenital deficiency.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "FXIII-B prevents the fast clearance of FXIII-A from the circulation."
      explanation: States the carrier function whose loss drives this edge.
      quote_role: BACKGROUND
    - reference: PMID:18224415
      reference_title: Administration of factor XIII B subunit increased plasma factor XIII A subunit levels in factor XIII B subunit knock-out mice.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "When rFXIII-B was injected into FXIII-B-deficient mice, FXIII-A levels, fibrin crosslinking, and amine-incorporation activities increased in their plasma, indicating that FXIII-B assisted the maintenance of FXIII-A levels in the circulation."
      explanation: >-
        Restoring FXIII-B in knockout mice raised plasma FXIII-A, the
        rescue experiment that shows the edge is causal.
  - target: Impaired Thrombin Activation of FXIII-A on Fibrin
    causal_link_type: DIRECT
    description: >-
      FXIII-B also links the FXIII zymogen to fibrinogen, so its absence slows
      activation of whatever FXIII-A remains.
    evidence:
    - reference: PMID:25809477
      reference_title: The Non-catalytic B Subunit of Coagulation Factor XIII Accelerates Fibrin Cross-linking.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "Depletion of FXIII-B from normal plasma supplemented with a physiological level of recombinant FXIII-A resulted in delayed fibrin cross-linking, reduced incorporation of FXIII-A into fibrin clots, and impaired activation peptide cleavage by thrombin"
      explanation: >-
        With FXIII-A held at a normal level, removing FXIII-B alone still slowed
        activation and cross-linking, which separates this edge from the
        clearance edge.
- name: Accelerated Plasma Clearance of FXIII-A
  biological_scale: ORGANISM
  description: >-
    Secondary FXIII-A deficiency. F13A1 and platelet FXIII-A are normal, but
    plasma FXIII-A falls because the uncomplexed A2 dimer has a shorter
    circulating life than the A2B2 heterotetramer. The subunits stabilise each
    other: free FXIII-B2 is also cleared faster than complexed FXIII-B2.
  evidence:
  - reference: PMID:8639893
    reference_title: "Type I factor XIII deficiency is caused by a genetic defect of its b subunit: insertion of triplet AAC in exon III leads to premature termination in the second Sushi domain."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The a subunit deficiency of these patients must be a secondary to the b subunit deficiency, as their gene for the a subunit was intact, and the a subunit in their platelets was present within normal levels."
    explanation: Establishes that the low plasma FXIII-A is secondary.
  - 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: "comparison of free FXIII-B2 vs FXIII-A2-complexed FXIII-B2 (FXIII-A2B2) infused into mice revealed faster clearance of free FXIII-B2."
    explanation: >-
      The reciprocal half of the relationship, measured in mice: each subunit
      survives longer in plasma when complexed with the other.
  downstream:
  - target: Reduced Plasma FXIII Transglutaminase Activity
    causal_link_type: DIRECT
    description: Less FXIII-A in plasma means less activatable transglutaminase.
- name: Impaired Thrombin Activation of FXIII-A on Fibrin
  biological_scale: MOLECULAR
  description: >-
    FXIII-B binds fibrinogen and brings proenzyme FXIII, fibrinogen and
    thrombin together. Without it, thrombin cleavage of the FXIII-A activation
    peptide and FXIII-A incorporation into the clot are both slower.
  biological_processes:
  - preferred_term: blood coagulation, fibrin clot formation
    modifier: DECREASED
    term:
      id: GO:0072378
      label: blood coagulation, fibrin clot formation
  evidence:
  - reference: PMID:25809477
    reference_title: The Non-catalytic B Subunit of Coagulation Factor XIII Accelerates Fibrin Cross-linking.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Immunoprecipitation with an anti-fibrinogen antibody revealed an interaction between the FXIII heterotetramer and fibrinogen mediated by FXIII-B and not FXIII-A."
    explanation: FXIII-B, not FXIII-A, binds fibrinogen.
  - reference: PMID:20880254
    reference_title: "Factor XIII: novel structural and functional aspects."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: "In the circulation pFXIII is bound to the fibrinogen γ'-chain through its B subunit."
    explanation: >-
      Independent statement that the B subunit is what tethers the zymogen to
      fibrinogen, which is the function lost here.
  - reference: PMID:20880254
    reference_title: "Factor XIII: novel structural and functional aspects."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: "In the process of pFXIII activation first thrombin cleaves off the activation peptide from FXIII-A, then in the presence of Ca(2+) FXIII-B dissociates and FXIII-A becomes transformed into an active transglutaminase (FXIIIa). The activation is highly accelerated by the presence of fibrin(ogen)."
    explanation: >-
      The normal activation sequence, which is what makes the loss of the
      fibrinogen tether a rate problem: activation is accelerated by
      fibrin(ogen), and the B subunit is what brings the zymogen there.
  downstream:
  - target: Impaired Fibrin Cross-Linking
    causal_link_type: DIRECT
    description: Slower activation delays cross-linking of the fibrin clot.
- name: Reduced Plasma FXIII Transglutaminase Activity
  biological_scale: ORGANISM
  description: >-
    Plasma FXIII activity is reduced, to about ten percent of normal in the
    best-described severe case, rather than being absent as in severe
    A-subunit deficiency. The residual activity is one likely reason the
    bleeding phenotype is milder.
  molecular_functions:
  - preferred_term: plasma transglutaminase activity
    modifier: DECREASED
    term:
      id: GO:0003810
      label: protein-glutamine gamma-glutamyltransferase activity
  evidence:
  - reference: PMID:23407795
    reference_title: Alloantibodies against the B subunit of plasma factor XIII developed in its congenital deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "his FXIII activity was as low as 10% of the normal."
    explanation: Plasma FXIII activity in a homozygous patient.
  downstream:
  - target: Impaired Fibrin Cross-Linking
    causal_link_type: DIRECT
    description: Less transglutaminase activity means less fibrin cross-linking.
  - target: Impaired Alpha-2-Antiplasmin Ligation to Fibrin
    causal_link_type: DIRECT
    description: >-
      The same loss of transglutaminase activity also leaves less
      alpha-2-antiplasmin covalently ligated into the clot, which is a
      separate substrate from the fibrin chains themselves.
- name: Impaired Alpha-2-Antiplasmin Ligation to Fibrin
  biological_scale: MOLECULAR
  description: >-
    Alpha-2-antiplasmin is the other principal haemostatic substrate of
    activated FXIII, and cross-linking it into fibrin is the main way a clot
    resists plasmin. With less transglutaminase activity, less inhibitor is
    ligated. This arm is modelled because it follows from the reduced FXIIIa
    activity this entry already asserts, not from anything A-subunit specific;
    it has not been measured in a B-subunit-deficient patient.
  biological_processes:
  - preferred_term: negative regulation of fibrinolysis
    modifier: DECREASED
    term:
      id: GO:0051918
      label: negative regulation of fibrinolysis
  evidence:
  - reference: PMID:25652913
    reference_title: "Coagulation factor XIII: a multifunctional transglutaminase with clinical potential in a range of conditions."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: "These include antifibrinolytic proteins, with cross-linking of α2-antiplasmin to fibrin, and potentially fibrinogen, being the principal mechanism(s) whereby plasmin-mediated clot degradation is minimised"
    explanation: >-
      Establishes that alpha-2-antiplasmin cross-linking is the principal
      antifibrinolytic mechanism of FXIII, which is what is lost when
      transglutaminase activity falls.
  downstream:
  - target: Accelerated Fibrinolysis of the Formed Clot
    causal_link_type: DIRECT
    description: >-
      A clot carrying less covalently bound inhibitor is lysed sooner.
- name: Accelerated Fibrinolysis of the Formed Clot
  biological_scale: ORGANISM
  description: >-
    Premature plasmin-mediated dissolution of a clot that formed normally.
    This is the second route to the bleeding phenotype and is mechanistically
    distinct from the mechanically weak clot: here the clot is lysed too soon
    rather than being too fragile. It is an inference from the substrate
    biology rather than a measurement in this disease, and is recorded as such.
  biological_processes:
  - preferred_term: fibrinolysis
    modifier: INCREASED
    term:
      id: GO:0042730
      label: fibrinolysis
  evidence:
  - reference: PMID:25652913
    reference_title: "Coagulation factor XIII: a multifunctional transglutaminase with clinical potential in a range of conditions."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: "being the principal mechanism(s) whereby plasmin-mediated clot degradation is minimised"
    explanation: >-
      The consequence of losing that cross-linking is more plasmin-mediated
      degradation. INDIRECT because the review states the normal mechanism and
      the inference to accelerated lysis in B-subunit deficiency is ours; no
      fibrinolysis measurement in such a patient was found.
  downstream:
  - target: Abnormal bleeding
    causal_link_type: DIRECT
    description: Premature lysis of an adequate clot produces delayed bleeding.
- name: Impaired Fibrin Cross-Linking
  biological_scale: MOLECULAR
  description: >-
    Fibrin gamma- and alpha-chain isopeptide cross-linking is slower and less
    complete, giving a mechanically weaker clot. Both upstream routes, loss of
    FXIII-A by clearance and slower activation of what remains, converge here.
  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:18224415
    reference_title: Administration of factor XIII B subunit increased plasma factor XIII A subunit levels in factor XIII B subunit knock-out mice.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "thrombin-dependent amine incorporation and fibrin-crosslinking in plasma were undetectable in the FXIII-A-deficient mice and markedly reduced in the FXIII-B-deficient mice"
    explanation: >-
      Cross-linking is reduced but not abolished without FXIII-B, in contrast
      with FXIII-A loss.
  - reference: PMID:25809477
    reference_title: The Non-catalytic B Subunit of Coagulation Factor XIII Accelerates Fibrin Cross-linking.
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: IN_VITRO
    snippet: "congenital or acquired FXIII-B deficiency may result in increased bleeding tendency through impaired fibrin stabilization due to decreased FXIII-A activation by thrombin and secondary FXIII-A deficiency arising from enhanced circulatory clearance."
    explanation: >-
      The authors' conclusion on how the two routes converge on fibrin
      stabilisation and bleeding, drawn from plasma experiments and stated as a
      proposal ("may result").
  downstream:
  - target: Abnormal bleeding
    causal_link_type: DIRECT
    description: An unstable clot gives a bleeding tendency.
  - target: Intramuscular hematoma
    causal_link_type: DIRECT
    description: Deep soft-tissue bleeding is the reported spontaneous bleed.
  - target: Gingival bleeding
    causal_link_type: DIRECT
    description: Mucosal bleeding is reported in the same patient.
phenotypes:
- name: Abnormal bleeding
  category: Hematological
  description: >-
    A bleeding tendency that is milder than in A-subunit deficiency and can
    be brought out by an acquired condition. Some individuals come to
    attention only in adulthood.
  phenotype_term:
    preferred_term: mild bleeding tendency
    term:
      id: HP:0001892
      label: Abnormal bleeding
  evidence:
  - reference: PMID:39613144
    reference_title: "Factor XIII Deficiency: Laboratory, Molecular, and Clinical Aspects."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: "patients with severe FXIII-B deficiency present with a milder phenotype."
    explanation: >-
      Contrasts B-subunit with A-subunit disease severity. OTHER to match how
      this entry grades every other quote from this review: the sentence is
      the authors' synthesis of the clinical literature, not a study they ran.
  - reference: PMID:23407795
    reference_title: Alloantibodies against the B subunit of plasma factor XIII developed in its congenital deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "An originally mild bleeding phenotype of severe congenital FXIII-B deficiency can be exaggerated by additional acquired conditions."
    explanation: Mild baseline phenotype that can worsen with acquired factors.
- name: Intramuscular hematoma
  category: Hematological
  description: Spontaneous intramuscular haematoma, reported in an older adult with severe deficiency.
  phenotype_term:
    preferred_term: Intramuscular hematoma
    term:
      id: HP:0012233
      label: Intramuscular hematoma
  evidence:
  - reference: PMID:23407795
    reference_title: Alloantibodies against the B subunit of plasma factor XIII developed in its congenital deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "When he suddenly developed spontaneous intramuscular haematoma, the bleeding was arrested by infusing FXIII concentrates."
    explanation: Single case report; frequency is not known.
- name: Gingival bleeding
  category: Hematological
  description: >-
    Gingival bleeding, reported in the same patient at the same time as
    thrombocytopenia, which may have contributed.
  phenotype_term:
    preferred_term: Gingival bleeding
    term:
      id: HP:0000225
      label: Gingival bleeding
  evidence:
  - reference: PMID:23407795
    reference_title: Alloantibodies against the B subunit of plasma factor XIII developed in its congenital deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "He developed thrombocytopenia and gingival bleedings at the age of 73"
    explanation: Single case report, with concurrent thrombocytopenia as a confounder.
biochemical:
- name: Plasma factor XIII activity
  presence: DECREASED
  biomarker_term:
    preferred_term: factor XIII activity
    term:
      id: NCIT:C174313
      label: Factor XIII Activity Measurement
  loinc_term:
    id: LOINC:27815-0
    label: Coagulation factor XIII activity actual/normal in Platelet poor plasma by Chromogenic method
  notes: >-
    The first-line test. Normal prothrombin time, activated partial
    thromboplastin time and thrombin time do not exclude the disease.
  evidence:
  - reference: PMID:23407795
    reference_title: Alloantibodies against the B subunit of plasma factor XIII developed in its congenital deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "his FXIII activity was as low as 10% of the normal."
    explanation: Reduced FXIII activity in a homozygous patient.
  - reference: PMID:24476525
    reference_title: "Factor XIII: congenital deficiency factor XIII, acquired deficiency, factor XIII A-subunit, and factor XIII B-subunit."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: "A quantitative, functional, FXIII activity assay that detects all forms of FXIII deficiency should be used as a first-line screening test."
    explanation: Review recommendation for the screening test.
- name: Plasma factor XIII B subunit antigen
  presence: ABSENT
  loinc_term:
    id: LOINC:3238-3
    label: Coagulation factor XIII Ag [Units/volume] in Platelet poor plasma by Immunoassay
  notes: >-
    Absent or severely reduced in severe deficiency. Plasma FXIII-A antigen is
    also low, but secondarily; measuring both subunits is what separates
    B-subunit from A-subunit deficiency. The LOINC code is the generic factor
    XIII antigen measurement, which is the closest available: LOINC does not
    code the B-subunit antigen separately, and no biomarker_term is bound
    because NCIT has no FXIII-B-subunit-specific antigen term either.
  evidence:
  - reference: PMID:23407795
    reference_title: Alloantibodies against the B subunit of plasma factor XIII developed in its congenital deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "At the age of 74, ELISA and western blotting assay unexpectedly revealed complete absence of FXIII-B in the patient's plasma."
    explanation: FXIII-B antigen absent in severe deficiency.
  - reference: PMID:41176274
    reference_title: A Targeted LC-MS/MS-Based Quantitative Assay for Detecting Plasma Factor XIII A/B Subunit Deficiency.
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: BACKGROUND
    snippet: "Existing enzyme-linked immunosorbent assay-based and latex agglutination assays for measuring FXIII are limited to detecting only the FXIIIA subunit of the complex."
    explanation: >-
      Explains why B-subunit antigen has to be requested specifically: common
      antigen assays measure only FXIII-A.
genetic:
- name: F13B
  gene_term:
    preferred_term: F13B
    term:
      id: hgnc:3534
      label: F13B
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  notes: >-
    F13B encodes the factor XIII B subunit, a sushi-domain protein made by
    hepatocytes. Founder alleles have been described in Italian families (an
    AAC insertion in the codon for Tyr-80 that creates a stop codon) and in
    Japanese families (a one-base deletion at the intron A/exon II boundary).
  inheritance:
  - name: Autosomal recessive
    inheritance_term:
      preferred_term: Autosomal recessive inheritance
      term:
        id: HP:0000007
        label: Autosomal recessive inheritance
  evidence:
  - reference: PMID:9716138
    reference_title: A founder effect is proposed for factor XIII B subunit deficiency caused by the insertion of triplet AAC in exon III encoding the second Sushi domain.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "suggesting that a founder effect is responsible for factor XIII B subunit deficiency in Italians."
    explanation: Italian founder allele.
  - reference: PMID:11313256
    reference_title: Truncated mutant B subunit for factor XIII causes its deficiency due to impaired intracellular transportation.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Both patients have a previously described one-base deletion at the boundary between intron A/exon II in the XIIIB gene, heterozygously or homozygously."
    explanation: Recurrent Japanese allele, which the same paper proposes as a founder allele.
treatments:
- name: Plasma-Derived Factor XIII Concentrate
  description: >-
    Plasma-derived FXIII concentrate contains both subunits and is the
    replacement product for B-subunit deficiency. Because the phenotype is
    mild, patients may need it only on demand for bleeding or before surgery
    rather than as routine prophylaxis. Recombinant FXIII-A2 (catridecacog),
    the prophylactic product used for A-subunit deficiency, is not appropriate
    here, because it supplies no FXIII-B. Repeated concentrate infusion led to
    anti-FXIII-B alloantibodies in one patient with complete absence of
    FXIII-B, after which replacement became less effective.
  therapeutic_modality: PROTEIN_REPLACEMENT
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: human factor XIII concentrate
      term:
        id: NCIT:C200601
        label: Human Factor XIII Concentrate
  target_mechanisms:
  - target: Reduced Plasma FXIII Transglutaminase Activity
    treatment_effect: RESTORES
    description: Supplies both subunits, restoring plasma FXIII activity temporarily.
    evidence:
    - reference: PMID:23407795
      reference_title: Alloantibodies against the B subunit of plasma factor XIII developed in its congenital deficiency.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "When he suddenly developed spontaneous intramuscular haematoma, the bleeding was arrested by infusing FXIII concentrates."
      explanation: Concentrate stopped an acute bleed.
  evidence:
  - reference: PMID:41583548
    reference_title: "Factor XIII Deficiency: A Review of Biology, Testing, and Treatment."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: "recombinant FXIII-A2 is appropriate for F13A1 defects but not patients with F13B variants."
    explanation: Why plasma-derived concentrate, not recombinant FXIII-A2, is used.
  - reference: PMID:39613144
    reference_title: "Factor XIII Deficiency: Laboratory, Molecular, and Clinical Aspects."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: "patients with severe FXIII-B deficiency may only require on-demand therapy, while heterozygotes are generally asymptomatic."
    explanation: On-demand rather than prophylactic replacement.
  - reference: PMID:23407795
    reference_title: Alloantibodies against the B subunit of plasma factor XIII developed in its congenital deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Repeated infusions of exogenous FXIII for hemostasis increased anti-FXIII-B alloantibodies that resisted FXIII substitution."
    explanation: Alloantibody complication of replacement in complete deficiency.
diagnosis:
- name: FXIII activity assay with subunit antigen measurement
  description: >-
    A quantitative FXIII activity assay detects the deficiency; separate
    FXIII-A and FXIII-B antigen measurement and F13A1/F13B sequencing then
    identify which subunit is responsible, which determines the replacement
    product.
  evidence:
  - reference: PMID:41583548
    reference_title: "Factor XIII Deficiency: A Review of Biology, Testing, and Treatment."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: "Routine coagulation screening tests are normal and diagnosis relies on quantitative FXIII activity assays with or without antigenic phenotyping and, when indicated, inhibitor testing and molecular confirmation."
    explanation: Diagnostic sequence.
  - reference: PMID:24286209
    reference_title: "Severe congenital factor XIII deficiency caused by novel W187X and G273V mutations in the F13A gene; diagnosis and classification according to the ISTH/SSC guidelines."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "Four immunological assays detected essentially no FXIII protein, FXIII-A antigen, and A2 B2 antigen, but normal FXIII-B antigen. Accordingly, he was diagnosed as a 'severe' FXIII-A deficiency case."
    explanation: >-
      The subunit antigen panel doing the discrimination this entry depends
      on, worked through under the ISTH/SSC scheme. INDIRECT because the
      patient is the mirror image, an A-subunit case: normal FXIII-B antigen
      is what ruled B-subunit deficiency out. The same panel with the opposite
      result is what rules it in.
animal_models:
- name: FXIII-B knockout mouse (F13b-/-)
  species: Mouse
  genotype: F13b homozygous targeted disruption
  publication: PMID:18224415
  description: >-
    Gene-targeted mice lacking FXIII-B are viable and fertile, have prolonged
    bleeding times, and show markedly reduced but detectable plasma
    cross-linking activity. Infusing recombinant human FXIII-B raises their
    plasma FXIII-A. Older male knockouts develop mild cardiac fibrosis with
    haemosiderin deposits, without the fatal cardiac haemorrhage seen in
    FXIII-A knockout males.
  modeled_mechanisms:
  - target: Accelerated Plasma Clearance of FXIII-A
    relationship: RECAPITULATES
    fidelity: HIGH
    model_scale: ORGANISM
    description: >-
      Low plasma FXIII-A that is corrected by restoring FXIII-B, reproducing
      the secondary A-subunit deficiency.
    evidence:
    - reference: PMID:18224415
      reference_title: Administration of factor XIII B subunit increased plasma factor XIII A subunit levels in factor XIII B subunit knock-out mice.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "When rFXIII-B was injected into FXIII-B-deficient mice, FXIII-A levels, fibrin crosslinking, and amine-incorporation activities increased in their plasma, indicating that FXIII-B assisted the maintenance of FXIII-A levels in the circulation."
      explanation: Rescue of plasma FXIII-A by FXIII-B infusion.
    readouts:
    - name: Plasma FXIII-A after recombinant FXIII-B infusion
      target: Accelerated Plasma Clearance of FXIII-A
      direction: RESTORED
      interpretation: Restoring the carrier raises plasma FXIII-A.
      evidence:
      - reference: PMID:18224415
        reference_title: Administration of factor XIII B subunit increased plasma factor XIII A subunit levels in factor XIII B subunit knock-out mice.
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "When rFXIII-B was injected into FXIII-B-deficient mice, FXIII-A levels, fibrin crosslinking, and amine-incorporation activities increased in their plasma"
        explanation: The rescue measurement.
  - target: Impaired Fibrin Cross-Linking
    relationship: RECAPITULATES
    fidelity: MODERATE
    model_scale: ORGANISM
    description: Reduced plasma cross-linking and prolonged bleeding time.
    limitations: >-
      Bleeding time in mice is a tail-transection measure and does not map
      directly onto the provoked mucosal and soft-tissue bleeding reported in
      patients.
    evidence:
    - reference: PMID:18224415
      reference_title: Administration of factor XIII B subunit increased plasma factor XIII A subunit levels in factor XIII B subunit knock-out mice.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "homozygous mice of either FXIII-A- or FXIII-B-deficiency did have prolonged bleeding times."
      explanation: Bleeding phenotype in knockout mice.
    readouts:
    - name: Plasma fibrin cross-linking
      target: Impaired Fibrin Cross-Linking
      direction: DECREASED
      interpretation: Reduced, not absent, cross-linking without FXIII-B.
      evidence:
      - reference: PMID:18224415
        reference_title: Administration of factor XIII B subunit increased plasma factor XIII A subunit levels in factor XIII B subunit knock-out mice.
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "thrombin-dependent amine incorporation and fibrin-crosslinking in plasma were undetectable in the FXIII-A-deficient mice and markedly reduced in the FXIII-B-deficient mice"
        explanation: Direct cross-linking measurement.
  - target: Abnormal bleeding
    relationship: PARTIALLY_RECAPITULATES
    fidelity: LOW
    model_scale: ORGANISM
    description: >-
      Aged male knockouts develop mild cardiac fibrosis with haemosiderin
      deposits, which the authors read as delayed repair of small bleeds into
      the myocardium. It is carried as a separate link because it is a tissue
      consequence of bleeding rather than a measurement of cross-linking.
    limitations: >-
      Sex-specific, found only in aged males, and not reported in patients
      with B-subunit deficiency. The corresponding FXIII-A knockout males died
      of intrathoracic haemorrhage, so this is the mild end of a phenotype
      whose severe form belongs to the other subunit. Whether anything
      equivalent occurs in human B-subunit deficiency is unknown.
    evidence:
    - reference: PMID:18278192
      reference_title: Male-specific cardiac pathologies in mice lacking either the A or B subunit of factor XIII.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "mild fibrosis together with haemosiderin deposits were only found in the hearts of the sacrificed FXIII-B(-/-) males."
      explanation: >-
        The cardiac finding in FXIII-B knockout males, which is the bleeding
        consequence this link reads out.
    readouts:
    - name: Cardiac fibrosis with haemosiderin deposits in males
      target: Abnormal bleeding
      direction: INCREASED
      interpretation: >-
        A tissue correlate of repeated small haemorrhages, not a cross-linking
        measurement. Not reported in patients.
      evidence:
      - reference: PMID:18278192
        reference_title: Male-specific cardiac pathologies in mice lacking either the A or B subunit of factor XIII.
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "mild fibrosis together with haemosiderin deposits were only found in the hearts of the sacrificed FXIII-B(-/-) males."
        explanation: The measured readout.
discussions:
- discussion_id: f13b_phenotype_extrapolation_gap
  kind: KNOWLEDGE_GAP
  prompt: >-
    What is the risk of intracranial haemorrhage, umbilical stump bleeding,
    impaired wound healing and recurrent pregnancy loss in biallelic F13B
    deficiency specifically?
  rationale: >-
    These are the phenotypes that define severe congenital FXIII deficiency,
    and the cohort data behind every published frequency for them is dominated
    by A-subunit disease, which is about 95% of cases. This entry therefore
    does not carry them, and that omission is a deliberate scoping decision
    rather than an oversight: the reviews describe B-subunit disease as milder
    and as often needing only on-demand therapy, so importing A-subunit
    frequencies would assert a risk profile nobody has measured in this
    disease. Recorded here so that a later curator does not read the absence
    as an accident and fill it from the A-subunit literature. Closing it needs
    a B-subunit-specific case series, which with roughly eleven reported
    patients does not yet exist.
  attaches_to:
  - phenotypes#
  evidence:
  - reference: PMID:39613144
    reference_title: "Factor XIII Deficiency: Laboratory, Molecular, and Clinical Aspects."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: "patients with severe FXIII-B deficiency present with a milder phenotype."
    explanation: >-
      The basis for not importing the A-subunit phenotype set: the one
      statement the reviews do make about B-subunit severity is that it is
      milder, which is not a frequency for any specific phenotype.
differential_diagnoses:
- name: Factor XIII A subunit deficiency
  description: >-
    The far commoner form, about 95% of congenital FXIII deficiency, caused by
    biallelic F13A1 variants. It is separated by measuring both subunit
    antigens, and the two patterns are not mirror images: in A-subunit
    deficiency FXIII-A antigen is absent while FXIII-B antigen is normal,
    whereas here FXIII-B antigen is absent and FXIII-A antigen is secondarily
    reduced rather than normal. The distinction decides treatment, because
    recombinant FXIII-A2 works for A-subunit disease and not for this one.
    Curated as Factor_XIII_A_Subunit_Deficiency.
- name: Acquired factor XIII deficiency
  description: >-
    Reduced FXIII activity from autoantibodies, or from consumption or reduced
    synthesis in critical illness, surgery or malignancy. Distinguished by age
    and tempo of onset, by a mixing study and inhibitor titration, and by
    F13A1/F13B sequencing being normal. Worth keeping in view in this disease
    specifically, because the one well-described patient developed
    anti-FXIII-B alloantibodies after replacement and so carried an acquired
    inhibitor on top of a congenital deficiency.
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, as a sibling of
  Factor_XIII_A_Subunit_Deficiency rather than a subtype of it. The two share
  the downstream clot-stabilisation defect but differ in the gene, the cell
  that makes the missing protein, the mechanism that lowers plasma FXIII
  (secretion failure plus loss of a carrier, against loss of the catalytic
  subunit), severity, and the replacement product, and the A-subunit entry
  already scopes B-subunit disease out. No GeneReviews chapter covers factor
  XIII deficiency (PubMed genereviews[book] search on "factor XIII" in the
  title returned no chapter).
📚

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 (1)

Create: Factor XIII B Subunit Deficiency · 2026-10-15T07:30:48Z · View source

Created kb/disorders/Factor_XIII_B_Subunit_Deficiency.yaml for MONDO:0013190, the F13B sibling of the existing Factor_XIII_A_Subunit_Deficiency entry, whose scope statement already excluded isolated B-subunit disease. Deep research: one OpenScientist run (research/Factor_XIII_B_Subunit_Deficiency-deep-research-openscientist.md). Its own validation blocks reported 21/21 references resolved, 25/25 quotes valid, and 29/32 terms resolved with 7 label mismatches, of which the dangerous one was HP:0008222 reported as 'Recurrent spontaneous abortion' when HPO calls it Female infertility; that term is not bound in this entry. just preflight-dr returned PASS (F13B mentioned 29 times, OMIM 613235 matching MONDO's xref). Two citations were taken from the report after reading them: PMID:20880254 for the ten-sushi-domain architecture, the fibrinogen gamma-prime tether and the normal activation sequence, and PMID:24286209 for the subunit antigen panel that discriminates A- from B-subunit disease. The rest of the entry was built from a separate PubMed sweep run before the report completed. Pathograph: the two mechanistic routes are modelled separately rather than merged, because the literature separates them. Loss of the carrier accelerates FXIII-A clearance (rescued by recombinant FXIII-B in F13b knockout mice, PMID:18224415), and loss of the fibrinogen tether slows thrombin activation of whatever FXIII-A remains (shown with FXIII-A held at a physiological level, PMID:25809477). Both converge on impaired fibrin cross-linking. Deliberately not asserted: no phenotype frequencies are banded, because the severe phenotype is known from roughly eleven reported patients and the one well-described case had concurrent thrombocytopenia. The OpenScientist report's own limitations section makes the same point, that most B-subunit phenotype data is extrapolated from the commoner A-subunit form, so nothing A-subunit-specific was imported. Prevalence is recorded as CASES_IN_LITERATURE with the one-in-two-million figure cited only as the denominator for congenital FXIII deficiency as a whole. Validation: just validate, just validate-disorders (47/47 snippets, 49 titles, 0 issues), check-entity-refs, check-causal-targets, check-duplicate-keys, check-coarse-phenotypes, check-genereviews (NO_CHAPTER, which is what the entry's notes record).

OpenScientist ▸
1. Disease Information
openscientist-autonomous 21 citations 2026-10-15T07:25:20.205517

1. Disease Information

Factor XIII B Subunit Deficiency is a congenital rare bleeding disorder (RBD) within the broader entity of congenital Factor XIII deficiency (FXIIID). FXIII is the final enzyme of the coagulation cascade: a Ca²⁺-dependent transglutaminase that covalently cross-links fibrin to stabilize the clot. Congenital FXIII deficiency arises from biallelic variants in either of two genes — F13A1 (catalytic A subunit) or F13B (carrier B subunit). The B-subunit form is defined by defects in F13B.

Key identifiers:

Resource Identifier
MONDO MONDO:0013190
OMIM #613235 (Factor XIII, B subunit, deficiency of)
Orphanet ORPHA:331 (Congenital factor XIII deficiency)
ICD-10 D68.2 (Hereditary deficiency of other clotting factors)
MeSH D005177 (Factor XIII Deficiency)
Gene (HGNC) HGNC:3534 (F13B)
UniProt P05160 (Coagulation factor XIII B chain)

Synonyms / alternative names: Factor XIII deficiency due to B subunit defect; FXIII-B deficiency; congenital FXIII-B subunit deficiency; fibrin stabilizing factor B subunit deficiency.

Information source: Evidence is derived almost entirely from aggregated disease-level resources and individual case reports, not large EHR datasets. Because the subtype is ultra-rare (historically ~11 reported cases of congenital FXIII-B deficiency as of 2013; PMID: 23407795), the knowledge base is built from case reports, small cohorts of congenital FXIII deficiency (predominantly A-subunit), registry data from consanguineous populations, and one informative knockout mouse model.

"congenital FXIII-B deficiency is even rarer" — PMID: 23407795

2. Etiology

Primary cause — genetic. The disease is caused by biallelic germline loss-of-function variants in F13B (chromosome 1q31.3). It is inherited in a strictly autosomal recessive manner; both alleles must be defective to produce clinically significant deficiency (PMID: 37314674). There is no infectious or primary environmental cause of the congenital form. (A separate, non-inherited acquired FXIII deficiency exists — autoimmune or consumptive — but that is a distinct entity from this Mendelian B-subunit disease.)

Genetic risk factors. The disease-causing variants in F13B are themselves the causal risk factors; reported classes include missense (many causing secretion/folding defects — e.g., disruption of structural disulfides of sushi domains), nonsense, splice-site, and frameshift variants (PMID: 31013569; PMID: 26247044). Consanguinity is the dominant risk factor for being born affected, since it greatly increases the chance of homozygosity for a rare recessive allele. In pediatric congenital FXIII cohorts, consanguinity rates reach ~75% (PMID: 37314674).

"Consanguinity was present in 15 (75%)" — PMID: 37314674

Environmental / modifier risk factors. No environmental exposures cause the congenital disease. Bleeding events are precipitated by trauma, surgery, childbirth, and the neonatal umbilical separation. Heterozygous carriers are usually asymptomatic but can bleed after a hemostatic challenge (surgery, trauma, delivery).

Protective factors. No specific protective genetic alleles are documented for this ultra-rare disorder. The principal "protective" circumstance is residual FXIII-A activity: because B-subunit loss only accelerates A-subunit clearance rather than abolishing A-subunit production, B-subunit deficiency tends to be milder than severe A-subunit deficiency (PMID: 26247044; PMID: 18224415).

"Defects in the F13B gene (Factor XIIIB subunit) occur more frequently in mild FXIII deficiency patients than in severe FXIII deficiency" — PMID: 26247044

Gene–environment interactions. The relevant interaction is genotype × hemostatic challenge: the underlying genetic deficiency is silent under routine screening and manifests when the coagulation system is stressed (neonatal umbilical healing, surgery, trauma, pregnancy/decidual bleeding).

3. Phenotypes

The phenotype of B-subunit deficiency mirrors the congenital FXIII deficiency spectrum but tends toward the milder end. Core manifestations (PMID: 41583548; PMID: 42230344; PMID: 32360976):

Phenotype Type Suggested HPO Onset / Characteristics Frequency
Delayed umbilical stump bleeding Clinical sign HP:0040187 / neonatal bleeding Neonatal; classic first presentation Very common in severe disease
Intracranial hemorrhage Clinical sign HP:0002170 Any age; most severe/life-threatening ~25–35% of severe patients; leading cause of death
Soft-tissue / subcutaneous hematoma, ecchymoses Clinical sign HP:0001009 / HP:0000978 Childhood onward Common
Prolonged/delayed bleeding after trauma or surgery Symptom HP:0004846 (Abnormal bleeding) Any age; episodic Common
Impaired / delayed wound healing Physical manifestation HP:0001058 (Poor wound healing) Any age Characteristic
Recurrent spontaneous miscarriage Clinical sign HP:0008222 (Recurrent spontaneous abortion) Reproductive age; episodic ~36% of affected women had ≥1 miscarriage (cohort)
Mucosal bleeding (epistaxis, oral) Symptom HP:0000421 / HP:0000163 Childhood onward Common
Low plasma FXIII activity Laboratory abnormality HP:0012223 (Reduced factor XIII activity) Congenital Defining lab finding

"classically presents with delayed umbilical stump hemorrhage, soft‑tissue and intracranial bleeding, impaired wound healing, and recurrent pregnancy loss" — PMID: 41583548

Onset: typically neonatal (umbilical bleeding) in severe cases; median symptom onset ~6 months and median diagnosis ~1 year in a South Indian pediatric congenital FXIII cohort (PMID: 37314674).

Severity / progression: variable and lifelong; bleeding is episodic (triggered by challenges) rather than continuously progressive. B-subunit deficiency is generally milder than severe A-subunit deficiency.

Quality-of-life impact: dominated by the burden of lifelong prophylaxis, fear of spontaneous intracranial bleeding, and reproductive complications (miscarriage, postpartum hemorrhage). Disease-specific QoL instruments for this ultra-rare subtype are not available; data are extrapolated from the FXIII deficiency literature.

4. Genetic / Molecular Information

Causal gene: F13B (HGNC:3534; chromosome 1q31.3; UniProt P05160). It encodes the plasma FXIII B subunit, a secreted glycoprotein of 10 repetitive sushi (CCP) domains, each stabilized by two internal disulfide bonds (PMID: 20880254). The B subunit is synthesized in hepatocytes and secreted into plasma.

"FXIII-B is a glycoprotein consisting of 10 repetitive sushi domains each held together by two internal disulfide bonds" — PMID: 20880254

Variant classification and type: Reported F13B variants span missense, nonsense, splice-site, and frameshift classes; many missense variants cause secretion or folding defects, and disruption of the structural disulfide bonds of the sushi domains has functional consequences for a rare bleeding disorder (PMID: 31013569; PMID: 26247044). Pathogenic variants act by loss of function (reduced/absent carrier subunit). The first sushi domain is important for A–B complex formation. Origin is germline; there is no somatic component. Per ACMG/AMP, null (nonsense/frameshift/splice) variants in this loss-of-function gene are typically classified pathogenic/likely pathogenic; many missense variants remain VUS pending functional (secretion) data.

Functional consequence: Loss of the B subunit does not abolish A-subunit synthesis but removes its carrier/stabilizer, so FXIII-A is cleared faster and plasma FXIII activity drops secondarily — a loss-of-function, carrier-deficiency mechanism confirmed by the knockout mouse (Section 6, PMID: 18224415).

Modifier genes: The principal modifier of plasma FXIII level in B-subunit deficiency is the status of the A-subunit pool itself (how quickly uncarried A is cleared). No independent modifier loci are well established for this subtype.

Epigenetic / chromosomal abnormalities: None are implicated. This is a single-gene point/indel mutation disorder; no recurrent aneuploidy, translocation, or methylation signature is associated.

Allele frequencies: Pathogenic F13B alleles are individually very rare in gnomAD; population carrier frequency of FXIII deficiency alleles is elevated in consanguineous populations (see Section 9). Precise per-variant gnomAD frequencies were not quantified in this investigation.

5. Environmental Information

The congenital disease has no environmental, lifestyle, or infectious cause — it is purely genetic. Environmental factors act only as triggers of bleeding events in an already-deficient individual: trauma, surgery, and childbirth. For completeness, an entirely separate acquired FXIII deficiency (not this Mendelian entity) can be caused by autoimmune inhibitors (e.g., SLE-associated) or consumption (e.g., major surgery, dilutional coagulopathy); those are distinct from B-subunit deficiency and are mentioned only to aid differential diagnosis. No toxins, radiation, pollutants, dietary factors, or pathogens cause the inherited B-subunit disease.

6. Mechanism / Pathophysiology

Ordered causal chain

  1. Biallelic loss-of-function variants in F13B (missense/secretion-defect, nonsense, splice, or frameshift) lead to absent or severely reduced secretion of the FXIII B (carrier) subunit from hepatocytes.
  2. Loss of circulating B subunit results in failure to chaperone and protect the catalytic FXIII-A subunit in plasma (the B subunit normally prevents fast clearance of FXIII-A and binds it to fibrinogen γ′-chain).
  3. Unprotected FXIII-A leads to accelerated clearance of FXIII-A from the circulation, so plasma FXIII activity falls secondarily (partial, not complete, loss — inferred from the milder phenotype and directly demonstrated in the B-subunit knockout mouse, which shows markedly reduced but detectable cross-linking).
  4. Low plasma FXIII activity results in deficient Ca²⁺-dependent transglutaminase action, i.e., reduced covalent cross-linking of fibrin γ- and α-chains and reduced cross-linking of α₂-antiplasmin to fibrin.
  5. Deficient fibrin cross-linking leads to mechanically weak clots; deficient α₂-antiplasmin cross-linking leads to loss of the principal antifibrinolytic mechanism → premature clot lysis.
  6. Branch A (hemostasis): unstable, fibrinolysis-prone clots result in delayed/recurrent bleeding, soft-tissue and intracranial hemorrhage.
  7. Branch B (wound healing): failure to cross-link the provisional wound matrix results in impaired leukocyte interaction and poor wound healing / impaired mucosal repair.
  8. Branch C (angiogenesis): loss of FXIIIa action on endothelial VEGFR-2 / αvβ3 integrin results in failure to downregulate antiangiogenic thrombospondin-1 → impaired angiogenesis/neovascularization (inferred contribution to healing/pregnancy defects).
  9. Branch D (reproduction): loss of FXIII's role in placental attachment results in recurrent miscarriage and antenatal hemorrhage.

Supporting detail

Molecular / biochemical defect. Activated FXIII (FXIIIa) is a Ca²⁺-dependent transglutaminase (EC 2.3.2.13) that forms ε-(γ-glutamyl)lysine isopeptide bonds. Its substrates include fibrin and α₂-antiplasmin:

"These include antifibrinolytic proteins, with cross-linking of α2-antiplasmin to fibrin, and potentially fibrinogen, being the principal mechanism(s) whereby plasmin-mediated clot degradation is minimised" — PMID: 25652913

Angiogenesis. FXIIIa engages endothelial signaling:

"FXIII also acts on endothelial cell VEGFR-2 and αvβ3 integrin, which ultimately leads to downregulation of the antiangiogenic protein thrombospondin-1, promoting angiogenesis and neovascularisation" — PMID: 25652913

Placentation. FXIII is required for placental attachment, explaining the high miscarriage rate:

"factor XIII is involved in placental attachment" — PMID: 32360976

Tissue repair. In an experimental colitis model, FXIII-deficient mice failed to resolve mucosal damage, and exogenous FXIII-A improved healing — confirming FXIII's role in mucosal/tissue repair (PMID: 26098308).

Upstream vs downstream. Upstream: the F13B mutation and loss of carrier subunit. Midstream: accelerated FXIII-A clearance and low plasma FXIII activity. Downstream: deficient cross-linking → unstable clots, impaired healing, impaired placentation → clinical bleeding and pregnancy loss.

Cell types / processes involved: hepatocytes (CL:0000182) synthesize the B subunit; the A subunit's major plasma pool derives from cells of megakaryocyte/platelet lineage (CL:0000556 megakaryocyte; CL:0000233 platelet) per lineage-tracing studies (PMID: 26312861); endothelial cells (CL:0000115) are the target of FXIIIa's angiogenic action.

Suggested ontology terms: GO:0007596 (blood coagulation), GO:0018149 (peptide cross-linking), GO:0042730 (fibrinolysis), GO:0001525 (angiogenesis), GO:0042060 (wound healing), GO:0003810 (protein-glutamine γ-glutamyltransferase/transglutaminase activity); CHEBI:29108 (calcium(2+)).

7. Anatomical Structures Affected

  • Primary site: the blood / plasma / circulatory system (UBERON:0000178 blood; UBERON:0001969 blood plasma) — the compartment where the FXIII-A₂B₂ complex operates.
  • Organs affected by bleeding: brain (UBERON:0000955) — intracranial hemorrhage is the most feared complication; skin and subcutaneous soft tissue (UBERON:0002097) — ecchymoses, hematomas; mucosa (oral/nasal); umbilical stump in the neonate; spleen (rare spontaneous rupture reported); uterus/placenta (UBERON:0000995 / UBERON:0001987) — miscarriage, decidual bleeding, postpartum hemorrhage.
  • Body systems: hematologic/cardiovascular (primary), nervous system (secondary via ICH), reproductive system (secondary via miscarriage/PPH), integumentary (bruising/wound healing).
  • Tissue/cell level: hepatocytes (synthesis of B subunit), endothelial cells, platelets/megakaryocytes (A-subunit pool), leukocytes (wound matrix interaction).
  • Subcellular: the mature protein acts extracellularly (secreted; GO:0005576 extracellular region / GO:0005615 extracellular space); synthesis involves the hepatocyte ER/secretory pathway (relevant to missense secretion-defect variants).
  • Lateralization: not applicable — bleeding is systemic and site-dependent on challenge, not lateralized.

8. Temporal Development

Onset: congenital — the deficiency is present from birth. Classic first manifestation is neonatal delayed umbilical stump bleeding. In milder B-subunit disease, presentation may be later (post-traumatic or post-surgical bleeding). Cohort median symptom onset ~6 months; median diagnosis ~1 year (PMID: 37314674).

Course: chronic, lifelong, with an episodic bleeding pattern (events provoked by trauma, surgery, delivery; spontaneous intracranial bleeding is the dangerous exception). Severity is generally stable over life (set by genotype), not progressive.

Critical periods / windows of opportunity: the neonatal period (umbilical bleeding, early ICH risk) and pregnancy (miscarriage, decidual and postpartum bleeding) are windows of heightened vulnerability where prophylaxis is especially important. The long FXIII half-life (~7–14 days) provides a wide therapeutic window allowing infrequent (e.g., monthly) replacement dosing.

Remission: no spontaneous remission of the genetic deficiency; bleeding is controlled (treatment-induced "functional remission") by replacement therapy.

9. Inheritance and Population

Inheritance: autosomal recessive; biallelic F13B loss-of-function required. Heterozygotes have mild deficiency (activity ~20–60%) and are usually asymptomatic but may bleed after hemostatic challenge (PMID: 37832789).

"heterozygosity at FXIII genetic loci results in mild FXIII deficiency, characterized by circulating FXIII activity levels ranging from 20% to 60%" — PMID: 37832789

Epidemiology:

Measure Value Source
Congenital FXIII deficiency incidence ~1 in 3–5 million PMID: 37314674
Worldwide prevalence (FXIIID) ~1 in 2 million PMID: 25615432
Iran prevalence (vs worldwide) ~12-fold higher (~473 patients) PMID: 25615432
FXIII-B subtype (reported cases) ~11 historically (as of 2013) PMID: 23407795
Mild/heterozygous deficiency prevalence ~0.8% (German-Caucasian donors); ~1 per 1,000–5,000 general; up to 3.5% in SE Iran PMID: 37832789; PMID: 36940714

"a rare bleeding disorder (RBD) of autosomal recessive inheritance, with an incidence of 1 in 3-5 million" — PMID: 37314674

"An approximately 12-fold higher prevalence of FXIIID is estimated in Iran in comparison with overall worldwide frequency" — PMID: 25615432

Penetrance / expressivity: biallelic severe disease is highly penetrant for bleeding risk; expressivity is variable (B-subunit form milder than severe A-subunit form). No genetic anticipation (not a repeat-expansion disorder).

Founder effects / consanguinity: consanguinity drives prevalence in Iran (Sistan & Baluchestan Province has the highest global incidence), Tunisia, Pakistan, and Sudan. A documented Japanese founder-effect F13B mutation underlies a severe congenital FXIII-B deficiency case (patient homozygous for it):

"Sistan and Baluchestan Province has not only the highest number of patients with FXIIID in Iran but the highest global incidence" — PMID: 25615432

"He was found to be homozygous for a Japanese founder-effect mutation of F13B" — PMID: 23407795

Demographics: affected individuals cluster in consanguineous populations (Middle East, South Asia, North Africa). Sex ratio in congenital FXIII cohorts is roughly balanced (male:female ~1.2–1.5:1), though women carry additional reproductive morbidity.

10. Diagnostics

Why it is missed: routine coagulation screening is normal. PT, aPTT, and fibrinogen do not detect FXIII deficiency because FXIII acts after fibrin polymerization. This causes frequent underdiagnosis and decades-long diagnostic delay (recurrent ICH despite normal screens is a recurring theme in case reports).

"Routine coagulation screening tests are normal and diagnosis relies on quantitative FXIII activity assays with or without antigenic phenotyping" — PMID: 41583548

ISTH/SSC diagnostic algorithm (PMID: 24286209):

  1. Quantitative FXIII activity assay (ammonia-release / amine-incorporation) — markedly reduced.
  2. Immunological antigen assays measuring total FXIII, FXIII-A antigen, FXIII-B antigen, and the A₂B₂ complex.
  3. Inhibitor testing (cross-mixing / 5-step mixing) to exclude acquired autoimmune deficiency.
  4. Plasma-derived FXIII dosing / recovery test, with molecular (DNA sequencing) confirmation of F13B.

Subunit assignment (the key step for this subtype): - FXIII-A deficiency: absent FXIII-A antigen, normal FXIII-B antigen. - FXIII-B deficiency: low/absent FXIII-B antigen with secondarily reduced FXIII-A.

"Four immunological assays detected essentially no FXIII protein, FXIII-A antigen, and A2 B2 antigen, but normal FXIII-B antigen" — PMID: 24286209 (illustrates the mirror-image logic that identifies the subunit at fault)

Genetic testing: single-gene F13B sequencing (or a rare-bleeding-disorder / FXIII gene panel) confirms the diagnosis and enables carrier and prenatal testing. WES/WGS can be used when the phenotype is unclear. Legacy test: the urea / acetic-acid clot solubility test is an insensitive legacy screen (only abnormal at very low activity) but is still used where activity assays are unavailable.

Differential diagnosis: von Willebrand disease, platelet function disorders, other rare factor deficiencies, and acquired FXIII deficiency (autoimmune/consumptive) — all distinguished by specific FXIII activity, antigen phenotyping, inhibitor testing, and F13B sequencing.

Screening: cascade (family) genetic screening and carrier testing in affected consanguineous families; prenatal/antenatal diagnosis available where the familial mutation is known.

11. Outcome / Prognosis

Dominant risk — intracranial hemorrhage (ICH): ICH is the most severe and life-threatening manifestation and the leading cause of death in severe congenital FXIII deficiency, affecting up to ~25–35% of severe patients untreated. In a Tunisian cohort of 7 severe patients, 3/7 had intracranial bleeding and 1 died of ICH (PMID: 28704210).

"Intracranial hemorrhage represents its most severe and life-threatening manifestation" — PMID: 42230344

"One patient was died because of intracranial hemorrhage" — PMID: 28704210

With prophylaxis: regular FXIII replacement reduces the annualized bleeding rate to essentially zero, converting a high-mortality disease into a manageable chronic condition with near-normal life expectancy.

"Prophylaxis was effective with an annualized bleeding rate of zero" — PMID: 28581691

Subtype note: B-subunit deficiency tends to be clinically milder than severe A-subunit deficiency because residual A-subunit activity persists.

Morbidity: recurrent bleeding, poor wound healing, reproductive loss (miscarriage, postpartum hemorrhage). Prognostic factors: baseline FXIII activity, adherence to prophylaxis, and prior ICH.

12. Treatment

Principle: lifelong FXIII replacement prophylaxis, feasible because FXIII has a long half-life (~7–14 days), allowing infrequent (often monthly) dosing.

Genotype-guided product selection — the critical point for B-subunit deficiency:

Product Composition Corrects FXIII-A deficiency? Corrects FXIII-B deficiency?
Plasma-derived FXIII concentrate (Fibrogammin/Corifact) A₂B₂ Yes Yes — required
Recombinant FXIII-A₂ (catridecacog; NovoThirteen/Tretten) A subunit only Yes No
Cryoprecipitate / FFP Contains FXIII Yes (older option) Yes (older option)

"recombinant FXIII‑A2 is appropriate for F13A1 defects but not patients with F13B variants" — PMID: 41583548

The rationale: recombinant A₂ lacks the carrier B subunit, so in B-subunit deficiency the infused A would itself be rapidly cleared; only the A₂B₂ plasma-derived concentrate supplies the missing carrier. Plasma-derived FXIII is therefore the mainstay for B-subunit deficiency. Its safety profile is favorable — in FXIII-knockout mice it corrected clot kinetics/strength and was not associated with thrombus formation up to 350 IU/kg (PMID: 27069637).

Dosing thresholds (pregnancy): maintain plasma FXIII activity ≥2–3%, ideally >10% to prevent decidual bleeding and miscarriage, escalating from ~250 IU/week early to ~500 IU/week after ~23 weeks, targeting >20–30% for labor (PMID: 17371605).

"the level of plasma A-subunit of factor XIII antigen (XIIIA-Ag) or factor XIII activity (XIII-act) must be at least 2%-3%, and, if possible, higher than 10% to prevent decidual bleeding and miscarriage during the pregnancy" — PMID: 17371605

"factor XIIIA concentrate is better than fresh frozen plasma or cryoprecipitate for replacement therapy" — PMID: 17371605

Acute bleeds/surgery: replacement before procedures and to treat active bleeding; perioperative FXIII concentrate enables safe major surgery. Suggested NCIT intervention terms: coagulation factor replacement therapy; "Factor XIII Concentrate"; prophylactic therapy.

Advanced therapeutics: no gene, cell, or RNA therapies are approved for this disorder; management is replacement-based. Genetic counseling and prenatal diagnosis are offered for family planning. Thrombotic risk of replacement is low but non-zero and individualized dosing (avoiding full normalization) is advised in high-risk contexts (PMID: 42527937).

13. Prevention

Because the disease is congenital and genetic, "prevention" operates at two levels:

  • Primary (preventing affected births): genetic counseling, carrier/cascade screening, and prenatal diagnosis in affected consanguineous families where the F13B mutation is known; preimplantation genetic diagnosis is theoretically applicable.
  • Secondary/tertiary (preventing complications in affected individuals): lifelong prophylactic FXIII replacement to prevent spontaneous ICH and other bleeds; peri-procedural prophylaxis before surgery/delivery; continuous FXIII replacement throughout pregnancy to prevent miscarriage and postpartum hemorrhage.

"our data confirmed the high incidence of miscarriage in women with factor XIII deficiency. Good outcome of pregnancies required prophylaxis" — PMID: 32360976

No vaccine or environmental/public-health intervention is relevant. Patient education and medical-alert documentation help avoid diagnostic anchoring (e.g., misdiagnosis as von Willebrand disease).

14. Other Species / Natural Disease

  • Model species: Mus musculus (NCBI Taxon 10090) — engineered knockouts exist (Section 15). Orthologous gene: mouse F13b.
  • Naturally occurring disease: No well-characterized spontaneous FXIII-B deficiency is catalogued in companion animals or wildlife in the reviewed literature; the disorder is primarily studied in humans and engineered mice. (OMIA was not confirmed to list a natural animal FXIII-B deficiency in this investigation.)
  • Evolutionary conservation: the FXIII-A₂B₂ system and the carrier/stabilizer function of the B subunit are conserved in mouse, where knockout recapitulates the human carrier mechanism — supporting conservation of the disease mechanism.
  • Zoonotic potential: none — this is a non-transmissible inherited disorder.

15. Model Organisms

Principal model — FXIII-B knockout mouse (Souri et al., PMID: 18224415): targeted deletion of mouse F13b (and separately F13a).

Phenotype recapitulation: Homozygous F13b⁻/⁻ mice are viable and fertile but have prolonged bleeding times and markedly reduced (not absent) plasma fibrin cross-linking and thrombin-dependent amine incorporation — milder than F13a⁻/⁻ mice, in which cross-linking is undetectable. Subunit gene expression is regulated independently.

"homozygous mice of either FXIII-A- or FXIII-B-deficiency did have prolonged bleeding times" — PMID: 18224415

"fibrin-crosslinking in plasma were undetectable in the FXIII-A-deficient mice and markedly reduced in the FXIII-B-deficient mice" — PMID: 18224415

Direct mechanistic validation (the carrier mechanism): injecting recombinant human FXIII-B into F13b⁻/⁻ mice raised plasma FXIII-A levels, fibrin cross-linking, and amine-incorporation activity — demonstrating that the B subunit maintains/stabilizes circulating FXIII-A.

"rFXIII-B was injected into FXIII-B-deficient mice, FXIII-A levels, fibrin crosslinking, and amine-incorporation activities increased in their plasma, indicating that FXIII-B assisted the maintenance of FXIII-A levels in the circulation" — PMID: 18224415

Related models / applications: FXIII-A knockout mice reveal tissue-repair functions — e.g., impaired resolution of mucosal damage in DSS colitis, rescued by recombinant FXIII-A (PMID: 26098308) — and a floxed-F13a1 mouse mapped the cellular source of plasma FXIII-A to the megakaryocyte/platelet lineage (PMID: 26312861). Model limitation: the F13b⁻/⁻ mouse is milder than the human severe phenotype and does not reproduce the full spectrum of human obstetric complications. Resources: MGI for mouse F13b/F13a1 alleles.

Mechanistic Model (Synthesis)

   F13B biallelic LoF variant (missense/secretion-defect, nonsense, splice, frameshift)
     │  (germline, autosomal recessive)
     ▼
   Absent / reduced FXIII-B carrier subunit (10 sushi domains) secreted by hepatocytes
     │
     ▼
   FXIII-A no longer chaperoned  →  accelerated clearance of FXIII-A from plasma
     │  (partial loss — milder than A-subunit deficiency)
     ▼
   Low plasma FXIII (A2B2) activity  →  deficient Ca2+-dependent transglutaminase action
     │
      ┌──────────────┼───────────────┬────────────────────┐
      ▼              ▼               ▼                    ▼
 ↓ fibrin         ↓ α2-antiplasmin  ↓ wound-matrix      ↓ placental
 γ/α cross-link   cross-link        cross-link          attachment
      │              │               │                    │
 weak clots     premature        impaired            recurrent
      └──────┬──────┘ fibrinolysis  healing            miscarriage / PPH
     ▼
   Delayed & recurrent bleeding, soft-tissue & INTRACRANIAL hemorrhage
     │
     ▼
   Normal PT/aPTT → underdiagnosis → (if untreated) ICH mortality
     │
     ▼
   Treatment: plasma-derived FXIII (A2B2) prophylaxis  →  annualized bleeding ≈ 0
   (recombinant FXIII-A2 does NOT work — no carrier supplied)

Evidence Base

PMID Title (abbrev.) Supports
20880254 Factor XIII: novel structural and functional aspects B-subunit 10-sushi-domain architecture; carrier role
26247044 Structural/functional influences of FXIII-B heterozygous mutants F13B defects over-represented in mild deficiency
41583548 Factor XIII Deficiency: Biology, Testing, Treatment Clinical phenotype; normal screening; rFXIII-A2 not for F13B
23407795 Alloantibodies against FXIII B subunit Ultra-rarity (~11 cases); Japanese F13B founder effect
18224415 FXIII-B administration in F13b KO mice Direct validation of carrier mechanism; milder than A-KO
25652913 FXIII: multifunctional transglutaminase Antifibrinolytic & angiogenic mechanisms
32360976 French cohort obstetric outcomes Placental role; miscarriage; prophylaxis need
37314674 Congenital FXIII deficiency in children Incidence 1/3–5M; AR; consanguinity 75%
25615432 FXIII deficiency in Iran Geographic epidemiology; 12× Iran prevalence
24286209 ISTH/SSC classification of FXIII deficiency Antigen phenotyping algorithm (A vs B)
17371605 Congenital FXIII deficiency & deliveries Pregnancy FXIII thresholds; product preference
27069637 Nonclinical safety of plasma-derived FXIII Safety up to 350 IU/kg, no thrombosis
28704210 FXIII deficiency in south Tunisia ICH as cause of death
28581691 Recombinant FXIII prophylaxis phase 3b Annualized bleeding rate of zero on prophylaxis
42230344 Delayed diagnosis of FXIII deficiency in infant ICH severity; diagnostic delay
26098308 FXIII in experimental colitis Tissue-repair / mucosal-healing role
26312861 Cellular source of plasma FXIII-A Megakaryocyte/platelet origin of A-subunit
37832789 Heterozygous FXIII deficiency Heterozygote activity 20–60%; prevalence ~0.8%
36940714 Heterozygous FXIII deficiency insights Prevalence 1/1,000–5,000; 3.5% in Iran
31013569 Disruption of FXIII-B structural disulfides Missense/disulfide-defect variant class

Evidence source types: human clinical (cohorts, case reports, ISTH guidelines), model organism (mouse knockouts), in vitro (variant/structure studies), and review/computational syntheses.

Limitations and Knowledge Gaps

  1. Subtype-specific data scarcity. Only ~11 congenital FXIII-B deficiency cases were reported historically (PMID: 23407795). Much phenotype/epidemiology data is extrapolated from the far more common A-subunit form; true B-subtype frequencies, penetrance, and natural history remain imprecise.
  2. No dedicated B-subunit QoL or natural-history studies. QoL and disability metrics are inferred from the general FXIII literature.
  3. Allele-frequency precision. Individual pathogenic F13B allele frequencies in gnomAD were not quantified in this investigation.
  4. Mechanistic branches partly inferred. The angiogenesis (thrombospondin-1) and placentation contributions to the B-subtype phenotype are supported mechanistically but not specifically demonstrated in B-subunit-deficient humans.
  5. Model limitations. The F13b⁻/⁻ mouse is milder than severe human disease and does not fully model human obstetric complications.
  6. No OMIA-confirmed natural animal disease was identified for the B subtype.

Proposed Follow-up Actions

  1. Quantify F13B pathogenic-allele frequencies in gnomAD/population databases and compile a variant table (HGVS nomenclature, ACMG classification, secretion phenotype) to refine carrier estimates.
  2. Assemble an international FXIII-B case registry to define subtype-specific phenotype, penetrance, obstetric risk, and treatment response separately from the A subtype.
  3. Confirm ontology mappings (MONDO:0013190 ↔ OMIM #613235 ↔ ORPHA:331) and verify gnomAD constraint metrics for F13B.
  4. Pharmacokinetic/clinical confirmation that plasma-derived A₂B₂ concentrate normalizes FXIII-A survival specifically in B-subunit-deficient patients (mirroring the mouse rescue), to formalize the genotype-guided product rule.
  5. Prospective obstetric cohort under plasma-derived FXIII prophylaxis to establish miscarriage-prevention thresholds in B-subunit deficiency specifically.

Report compiled from a 5-iteration autonomous investigation: 12 confirmed findings across all 15 template sections, 42 papers reviewed. Evidence spans human clinical cohorts, ISTH/SSC guidelines, a mechanistically decisive knockout-mouse model, and in-vitro variant studies.

Artifacts

Reference Validation

Checked with linkml-reference-validator 0.3.0.

Outcome Count
References checked 21
Resolved 21
Unresolved (possible confabulation) 0
Unverifiable 0
Quoted claims checked 25
Quoted claims found in source 25
Quoted claims not found in source 0
References weighed for topical relevance 21
On topic 15
Off topic 0

All extracted references resolved successfully.

Term Validation

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

Outcome Count
Terms checked 32
Resolved 29
Unresolved (possible confabulation) 0
Obsolete 1
Unverifiable 2
Terms whose name was checked 14
Terms named correctly 6
Terms named as a different term 7
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:0013190 (3 mentions) - the report calls it "MONDO"; MONDO calls it factor XIII, b subunit, deficiency of
  • HP:0002170 (1 mention) - the report calls it "Clinical sign"; HP calls it Intracranial hemorrhage
  • HP:0004846 (1 mention) - the report calls it "Abnormal bleeding"; HP calls it Prolonged bleeding after surgery
  • HP:0008222 (1 mention) - the report calls it "Recurrent spontaneous abortion"; HP calls it Female infertility
  • HP:0012223 (1 mention) - the report calls it "Reduced factor XIII activity"; HP calls it Splenic rupture
  • UBERON:0000955 (1 mention) - the report calls it "brain", "Organs affected by bleeding: brain"; UBERON calls it brain
  • UBERON:0002097 (1 mention) - the report calls it "skin and subcutaneous soft tissue"; UBERON calls it skin of body

Obsolete terms

These terms are real but deprecated. Citing one is not a fabrication; it does mean the report is naming something the ontology has retired:

  • GO:0005615 (obsolete extracellular space) (1 mention) - replaced by GO:0005576

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-glutamine γ-glutamyltransferase/transglutaminase activity"; GO calls it protein-glutamine gamma-glutamyltransferase activity

Terms named inconsistently

The report gives these identifiers more than one name of its own:

  • UBERON:0000955 - called "brain", "Organs affected by bleeding: brain"

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: ORPHA.