Congenital Factor X Deficiency

Mendelian MONDO:0009212 Pathograph 29 Show in embeddings browser Rare bleeding disorder Vitamin K-dependent coagulation factor deficiency

An autosomal recessive bleeding disorder caused by biallelic variants in F10, the gene encoding coagulation factor X. It is among the rarest of the rare bleeding disorders, at roughly one in 500,000 to one in a million. The mechanism is short and unusually well resolved, because factor X sits at a single, non-redundant point in the coagulation cascade. Factor X is the zymogen of factor Xa, and factor Xa is the protease component of the prothrombinase complex - the assembly of factor Xa with its cofactor factor Va on an anionic phospholipid surface that converts prothrombin to thrombin some five orders of magnitude faster than factor Xa can alone. Both the tissue-factor (extrinsic) and the contact-activated (intrinsic) arms of the cascade converge on factor X activation, so a defect here is downstream of both and cannot be bypassed by either. Less functional factor X means less prothrombinase, less thrombin, less fibrin, and a bleeding tendency whose severity broadly tracks residual factor X activity. That convergence is also what makes the laboratory picture distinctive: because the lesion is in the common pathway rather than in one arm, both the prothrombin time and the activated partial thromboplastin time are prolonged, which is the finding that usually prompts factor-specific assays. Two deficiency types are recognised and are modelled here as has_subtypes rather than as separate diseases, because they converge on the same prothrombinase defect and differ only in whether the defective protein is absent or present but non-functional. Type I is cross-reactive-material-negative, with factor X activity and antigen reduced together; type II is cross-reactive-material-positive, with activity reduced against preserved antigen. Three things in this entry are deliberately hedged rather than smoothed over. First, genotype-phenotype correlation is weak: the largest cohort curated here says in terms that clinical and laboratory phenotypes are poorly correlated, and the mutation-specific associations it reports for intracranial haemorrhage are described by its own authors as tentative. That hedge is carried into the evidence rather than dropped. Second, the type I/type II split is applied inconsistently in the primary literature - at least one curated cohort reports uniformly reduced antigen and then labels the patients type II, which inverts the usual convention - so the subtype records are anchored to a variant-database definition covering 427 case reports rather than to any single cohort's labelling. Third, no pathophysiology node declares conforms_to: kb/modules/ was searched for a coagulation-cascade module and none covers a single-factor common-pathway defect. Heterozygotes are not curated as a subtype. They are usually asymptomatic, but a minority bleed, and the entry records that inside the inheritance block rather than as a distinct disease state.

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1
Inheritance
6
Pathophys.
14
Phenotypes
2
Gaps
29
Pathograph
1
Genes
5
Medical Actions
2
Subtypes
3
Models
1
Deep Research
👪

Inheritance

1
Autosomal recessive HP:0000007
Symptomatic disease requires two defective F10 alleles, homozygous or compound heterozygous. A minority of heterozygotes report bleeding symptoms, but they are not curated here as an affected state.
Autosomal recessive
Show evidence (2 references)
PMID:18403394 SUPPORT Human Clinical
"Factor X deficiency is a severe rare hemorrhagic condition inherited as an autosomal recessive trait."
States the inheritance pattern directly.
PMID:16919077 SUPPORT Human Clinical
"The manifestation of bleeding symptoms in 9 of 67 (13%) symptomatic heterozygous subjects is described."
Quantifies the minority of heterozygotes who are symptomatic, which is the qualification recorded in this block's description.
◆

Subtypes

2
Type I (cross-reactive-material-negative)
Concordant reduction of factor X activity and factor X antigen, indicating reduced synthesis or reduced stability of the protein rather than a dysfunctional circulating molecule.
Show evidence (1 reference)
PMID:35059555 SUPPORT Human Clinical
"Type-I variants involve the simultaneous reduction of FX coagulant activity (FX:C) and FX antigen levels (FX:Ag), whereas type-II variants involve a reduction in FX:C with normal FX:Ag plasma levels."
States the type I and type II definitions from a database curating 427 case reports, which is the authority this entry uses for the classification rather than any single cohort's labelling.
Type II (cross-reactive-material-positive)
Reduced factor X activity against preserved or near-preserved factor X antigen, indicating a circulating but catalytically or membrane-binding defective molecule. Gla-domain variants are a recognised structural route to this pattern, since gamma-carboxyglutamate residues mediate the calcium-dependent membrane binding that prothrombinase assembly requires.
Show evidence (3 references)
PMID:35059555 SUPPORT Human Clinical
"Type-I variants involve the simultaneous reduction of FX coagulant activity (FX:C) and FX antigen levels (FX:Ag), whereas type-II variants involve a reduction in FX:C with normal FX:Ag plasma levels."
States the type II definition, preserved antigen against reduced activity, which is what distinguishes this subtype from type I.
PMID:19490765 SUPPORT Human Clinical
"The Gla-domain of factor X (FX) is a 39 residue peptide, part of the light chain, and is characterized by the presence of 11 gamma-carboxylglutaminic acid residues interspersed among other no-Gla residues."
Describes the Gla domain whose variants give a dysfunctional but present molecule, the structural route to a type II pattern.
PMID:19490765 SUPPORT Human Clinical
"Factor X antigen varied between 16 and 55% of normal in almost all cases."
Shows antigen preserved well above the activity levels reported in the same kindreds, which is the laboratory signature of this subtype.
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Discussions and Knowledge Gaps

2
Why is residual factor X activity such a poor predictor of bleeding severity in this disease?
KNOWLEDGE GAP OPEN fx_activity_severity_discordance
Attached to
pathophysiology#Systemic Bleeding Tendency
A single non-redundant enzymatic step with a quantifiable residual activity ought to give a clean dose-response relationship with bleeding, and it does not. The largest genotyped cohort states outright that clinical and laboratory phenotypes are poorly correlated. Candidate explanations include modifying variation elsewhere in the haemostatic system, the insensitivity of one-stage clotting assays to the thrombin-generation capacity that actually matters, and the small patient numbers available in a disorder this rare. Which of these dominates is unresolved, and it bears directly on whether a one-stage laboratory value should be used to set a prophylaxis threshold.
Show evidence (1 reference)
PMID:16919077 SUPPORT Human Clinical
"The clinical and laboratory phenotypes of FXD are poorly correlated and few regional studies on the genotype and the clinical manifestations of FXD are known."
States the discordance this gap is about, and names the scarcity of regional studies as part of the problem.
Is there a consensus treatment threshold across the severity spectrum?
KNOWLEDGE GAP OPEN fx_treatment_threshold_consensus
Attached to
treatments#
A trough factor X activity above 5 IU/dL was the target in the paediatric prophylaxis study, but that figure comes from one open-label trial in nine children. The most recent comprehensive review says explicitly that consensus in treatment guidelines is still needed across the spectrum of disease severity, so the threshold used in practice is not a settled number.
Show evidence (1 reference)
PMID:34024682 SUPPORT Human Clinical
"Consensus in treatment guidelines is still urgently needed to ensure optimal management of patients with factor X deficiency across the spectrum of disease severity."
States that treatment guidance is not yet settled across severity strata.
⚙

Pathophysiology

6
Biallelic F10 Loss-of-Function Variants
Homozygous or compound heterozygous variants in F10, on chromosome 13q. Missense substitutions predominate, and the reported spectrum also includes in-frame deletions, splice-site changes and, where F7 is co-deleted, large terminal deletions of chromosome 13 that remove both loci.
hepatocyte, the site of factor X synthesis CL:0000182 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves hepatocyte, the site of factor X synthesis, annotated with hepatocyte (CL:0000182). CL:0000182 is a cell type from the Cell Ontology.
Genetic context variant_origin: GERMLINE functional_impact_category: LOSS_OF_FUNCTION
Downstream
Reduced Functional Plasma Factor X The variant protein is either not made, not secreted, or secreted in a form that cannot participate in prothrombinase assembly.
Show evidence (3 references)
PMID:16919077 SUPPORT Human Clinical
"This international study analysed the phenotype and genotype of 102 subjects from Central Europe (Germany, Poland and Slovakia) and Latin America (Costa Rica and Venezuela) with causative mutations in the F10 gene, via sequencing."
Establishes F10 as the causative locus in a large genotyped cohort.
PMID:16919077 SUPPORT Human Clinical
"Twenty-eight homozygous, seven compound-heterozygous and 67 heterozygous FXD subjects were characterized."
Documents the biallelic genotypes that produce the disease, alongside the heterozygous carrier state.
PMID:31667683 SUPPORT Human Clinical
"Genetic analysis of the proband identified two types of single-base substitutions, c.353G>A (p.Gly118Asp) and c.1303G>A (p.Gly435Ser), indicating compound heterozygous congenital FX deficiency."
A worked compound heterozygous case with both variants identified and the parental carrier states confirmed in the same study.
Reduced Functional Plasma Factor X
The functional deficit measured in plasma as factor X coagulant activity (FX:C). In type I disease the immunoreactive antigen (FX:Ag) falls with it; in type II a dysfunctional molecule is still present, so antigen is comparatively preserved. Residual activity is the quantity that grades severity.
factor X zymogen available for conversion to the active protease GO:0004252 Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves decreased factor X zymogen available for conversion to the active protease, annotated with serine-type endopeptidase activity (GO:0004252). GO:0004252 is a molecular function from the Gene Ontology. ↓ DECREASED
Downstream
Impaired Prothrombinase Complex Activity Less factor X zymogen available for activation means less factor Xa available to assemble with factor Va on the membrane surface.
Show evidence (2 references)
PMID:31667683 SUPPORT Human Clinical
"Marked declines in FX activity (< 1%) and FX antigen levels (5%) were also observed."
Directly measures the reduction in both factor X activity and antigen that defines this node in a genetically confirmed patient.
PMID:26222694 SUPPORT Human Clinical
"FX:C was <1% in 11 patients, and 4% in one."
Quantifies residual coagulant activity across a severe-deficiency cohort.
Impaired Prothrombinase Complex Activity
The non-redundant step. Factor Xa is the catalytic subunit of prothrombinase, which assembles with the cofactor factor Va on an anionic phospholipid surface supplied largely by activated platelets. The assembled complex cleaves prothrombin far faster than free factor Xa, so the amount of thrombin a patient can generate is set by how much functional prothrombinase can form. Both the extrinsic and intrinsic arms of the cascade feed into factor X activation, so neither arm can compensate for the defect.
activated platelet providing the anionic phospholipid surface CL:0000233 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves activated platelet providing the anionic phospholipid surface, annotated with platelet (CL:0000233). CL:0000233 is a cell type from the Cell Ontology.
blood coagulation, common pathway GO:0072377 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased blood coagulation, common pathway (GO:0072377). GO:0072377 is a biological process from the Gene Ontology. ↓ DECREASED
Downstream
Reduced Thrombin Generation Less assembled prothrombinase converts less prothrombin to thrombin.
Show evidence (1 reference)
PMID:25153592 SUPPORT DIRECT Computational
"Prothrombinase is composed of a protease, factor (f) Xa, and a cofactor, fVa, which interact on negatively charged phospholipid surfaces and cleave prothrombin into thrombin 300 000 times faster than fXa alone"
Gives the composition of the complex and the magnitude of the rate enhancement that makes this step non-redundant, which is why a factor X defect cannot be bypassed. Graded COMPUTATIONAL because the publication is a modelling study; see the note on the downstream edge.
Reduced Thrombin Generation
The functional common denominator of the disease. Thrombin is required both to cleave fibrinogen to fibrin and to amplify its own generation through feedback activation of factors V, VIII and XI, so a prothrombinase deficit propagates rather than being buffered.
blood coagulation GO:0007596 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased blood coagulation (GO:0007596). GO:0007596 is a biological process from the Gene Ontology. ↓ DECREASED
Downstream
Impaired Fibrin Clot Formation Insufficient thrombin to convert fibrinogen to fibrin at the rate a haemostatic plug requires.
Impaired Fibrin Clot Formation
Failure to form a stable fibrin network at sites of vascular injury. This is the step the routine coagulation screen measures, and it is the reason both the prothrombin time and the activated partial thromboplastin time are prolonged in this disease rather than only one of them.
blood coagulation, fibrin clot formation GO:0072378 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. ↓ DECREASED
Downstream
Systemic Bleeding Tendency An unstable or slowly formed clot fails to secure haemostasis, producing spontaneous and provoked bleeding.
Show evidence (2 references)
PMID:26222694 SUPPORT Human Clinical
"A total or partial deficiency of FX causes an impairment of clot formation, leading to a haemorrhagic disease, which manifests with bleeding symptoms of different severity, also unprovoked."
States the impairment of clot formation and its consequence, including that bleeding may be unprovoked.
PMID:31667683 SUPPORT Human Clinical
"Prothrombin time (> 40 s) and activated partial thromboplastin time (65.0 s) were prolonged."
Documents the simultaneous prolongation of both screening tests that a common-pathway defect predicts.
Systemic Bleeding Tendency
The clinical endpoint. Bleeding is mucocutaneous, muscular and articular, and in the most severely affected can be intracranial. Severity broadly tracks residual factor X activity, but the correlation is imperfect and this entry does not overstate it.
Animal models
F10 total knockout mouse Mouse partially recapitulates Complete absence of factor X produces fatal spontaneous bleeding at multiple sites, reproducing the bleeding tendency that is this entry's organism-level node.
f10-/- zebrafish Zebrafish partially recapitulates Loss of f10 causes an embryonic haemostatic defect with later widespread haemorrhage, reproducing the bleeding tendency in a vertebrate that tolerates the null state long enough to be studied.
Naturally occurring feline factor X deficiency Cat partially recapitulates A naturally occurring, non-engineered instance of severe factor X deficiency with a bleeding phenotype, in a species where the deficiency had not previously been reported.
Downstream
Bruising susceptibility
Subcutaneous hemorrhage
Epistaxis
Joint hemorrhage
Intracranial hemorrhage The most serious consequence, reported in about a fifth of symptomatic subjects in the largest curated cohort.
Gastrointestinal hemorrhage
Abnormal umbilical stump bleeding
Gingival bleeding
Menorrhagia The commonest bleeding manifestation for which affected women present for haemostatic treatment.
Postpartum hemorrhage
Hemoperitoneum Bleeding into the peritoneum from a normal ovulatory event, which an intact common pathway would arrest.
Show evidence (2 references)
PMID:16919077 SUPPORT Human Clinical
"Spontaneous bleeding symptoms in 42 symptomatic individuals (26 homozygous, seven compound heterozygous and nine heterozygous) comprised easy bruising (55%), haematoma (43%), epistaxis (36%), haemarthrosis (33%), intracranial haemorrhage (ICH; 21%), and gastrointestinal (GI) haemorrhage (12%)."
Quantifies the bleeding phenotype across a 102-subject genotyped cohort, and is the source for the individual phenotype frequencies below.
PMID:16919077 SUPPORT INDIRECT Human Clinical
"The clinical and laboratory phenotypes of FXD are poorly correlated and few regional studies on the genotype and the clinical manifestations of FXD are known."
Records the limit on the severity claim. Marked INDIRECT because it constrains how strongly residual activity may be read as predicting bleeding, rather than asserting the bleeding tendency itself.
⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Congenital Factor X 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

14
Blood 13
Bruising susceptibility HP:0000978 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Easy bruising, annotated with Bruising susceptibility (HP:0000978). HP:0000978 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:16919077 SUPPORT Human Clinical
"Spontaneous bleeding symptoms in 42 symptomatic individuals (26 homozygous, seven compound heterozygous and nine heterozygous) comprised easy bruising (55%), haematoma (43%), epistaxis (36%), haemarthrosis (33%), intracranial haemorrhage (ICH; 21%), and gastrointestinal (GI) haemorrhage (12%)."
Reports the frequency of easy bruising among symptomatic subjects.
PMID:31667683 SUPPORT Human Clinical
"The proband, a 2-year-old girl, exhibited easy bruising and a history of umbilical cord bleeding at birth."
A genetically confirmed case presenting with easy bruising.
Subcutaneous hemorrhage HP:0001933 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Haematoma, annotated with Subcutaneous hemorrhage (HP:0001933). HP:0001933 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:16919077 SUPPORT Human Clinical
"Spontaneous bleeding symptoms in 42 symptomatic individuals (26 homozygous, seven compound heterozygous and nine heterozygous) comprised easy bruising (55%), haematoma (43%), epistaxis (36%), haemarthrosis (33%), intracranial haemorrhage (ICH; 21%), and gastrointestinal (GI) haemorrhage (12%)."
Reports haematoma frequency among symptomatic subjects.
PMID:18403394 SUPPORT Human Clinical
"The most frequent bleeding episodes were hematomas (70%) and gum bleeding (60%)."
An independent cohort in which haematoma was the commonest bleeding episode, at a higher frequency than the European and Latin American series.
Epistaxis HP:0000421 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Epistaxis (HP:0000421). HP:0000421 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:16919077 SUPPORT Human Clinical
"Spontaneous bleeding symptoms in 42 symptomatic individuals (26 homozygous, seven compound heterozygous and nine heterozygous) comprised easy bruising (55%), haematoma (43%), epistaxis (36%), haemarthrosis (33%), intracranial haemorrhage (ICH; 21%), and gastrointestinal (GI) haemorrhage (12%)."
Reports epistaxis frequency among symptomatic subjects.
PMID:26222694 SUPPORT Human Clinical
"The most frequent bleeding episodes in patients were epistaxis and easy bruising (11/12, 91%), followed by haemarthroses (10/12, 83%)."
In a severe-deficiency cohort, epistaxis was among the most frequent symptoms.
Joint hemorrhage HP:0005261 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Haemarthrosis, annotated with Joint hemorrhage (HP:0005261). HP:0005261 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:16919077 SUPPORT Human Clinical
"Spontaneous bleeding symptoms in 42 symptomatic individuals (26 homozygous, seven compound heterozygous and nine heterozygous) comprised easy bruising (55%), haematoma (43%), epistaxis (36%), haemarthrosis (33%), intracranial haemorrhage (ICH; 21%), and gastrointestinal (GI) haemorrhage (12%)."
Reports haemarthrosis frequency among symptomatic subjects.
PMID:26222694 SUPPORT Human Clinical
"followed by haemarthroses (10/12, 83%)"
A severe-deficiency cohort in which most patients had haemarthrosis.
Intracranial hemorrhage HP:0002170 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Intracranial haemorrhage, annotated with Intracranial hemorrhage (HP:0002170). HP:0002170 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:16919077 SUPPORT Human Clinical
"Spontaneous bleeding symptoms in 42 symptomatic individuals (26 homozygous, seven compound heterozygous and nine heterozygous) comprised easy bruising (55%), haematoma (43%), epistaxis (36%), haemarthrosis (33%), intracranial haemorrhage (ICH; 21%), and gastrointestinal (GI) haemorrhage (12%)."
Reports intracranial haemorrhage frequency among symptomatic subjects.
PMID:16919077 SUPPORT INDIRECT Human Clinical
"The results suggested that ICH seems to be associated with the F10 mutation Gly380Arg, and possibly with the mutations IVS7-1G>A and Tyr163delAT."
A hedged genotype association. Marked INDIRECT because the authors' own wording does not assert the association outright.
Gastrointestinal hemorrhage HP:0002239 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Gastrointestinal haemorrhage, annotated with Gastrointestinal hemorrhage (HP:0002239). HP:0002239 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:16919077 SUPPORT Human Clinical
"Spontaneous bleeding symptoms in 42 symptomatic individuals (26 homozygous, seven compound heterozygous and nine heterozygous) comprised easy bruising (55%), haematoma (43%), epistaxis (36%), haemarthrosis (33%), intracranial haemorrhage (ICH; 21%), and gastrointestinal (GI) haemorrhage (12%)."
Reports gastrointestinal haemorrhage frequency among symptomatic subjects.
Abnormal umbilical stump bleeding HP:0011884 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Umbilical cord bleeding at birth, annotated with Abnormal umbilical stump bleeding (HP:0011884). HP:0011884 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:31667683 SUPPORT Human Clinical
"a history of umbilical cord bleeding at birth"
Documents umbilical cord bleeding at birth in a genetically confirmed severe case.
Gingival bleeding HP:0000225 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Gum bleeding, annotated with Gingival bleeding (HP:0000225). HP:0000225 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:18403394 SUPPORT Human Clinical
"The most frequent bleeding episodes were hematomas (70%) and gum bleeding (60%)."
Reports gum bleeding frequency in a severe-deficiency cohort.
Menorrhagia OCCASIONAL HP:0000132 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Heavy menstrual bleeding, annotated with Menorrhagia (HP:0000132). HP:0000132 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:30901144 SUPPORT Human Clinical
"Heavy menstrual bleeding was reported in 72/284 (25%) women in total, 14/30 (47%) in case reports and 58/254 (23%) in 11 case series, 64% and 10% required blood products and blood transfusion, respectively."
Quantifies heavy menstrual bleeding across the largest assembled series of women with this disorder, and is the source for the OCCASIONAL band: the pooled figure is 25%, which falls in OCCASIONAL (5-29%). The 47% case-report subset would reach FREQUENT on its own, but it is the ascertainment-biased half of the same pooled estimate and is not what this band reports.
PMID:30901144 SUPPORT Human Clinical
"In conclusion, women with FXD are at an increased risk of heavy bleeding during menstruation and ovulation as well as adverse pregnancy outcome and postpartum haemorrhage."
The review's own conclusion, stating the menstrual bleeding risk as a property of the disorder rather than of one cohort.
Postpartum hemorrhage OCCASIONAL HP:0011891 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Postpartum haemorrhage, annotated with Post-partum hemorrhage (HP:0011891). HP:0011891 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:30901144 SUPPORT Human Clinical
"Postpartum haemorrhage (PPH) occurred in six (22%) of deliveries, one requiring hysterectomy."
Quantifies postpartum haemorrhage as a fraction of deliveries, which is the denominator this phenotype is banded against.
Reduced factor X activity HP:0008321 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Reduced factor X coagulant activity, annotated with Reduced factor X activity (HP:0008321). HP:0008321 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:26222694 SUPPORT Human Clinical
"FX:C was <1% in 11 patients, and 4% in one."
Quantifies residual factor X coagulant activity in a severe-deficiency cohort.
Prolonged prothrombin time HP:0008151 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Prolonged prothrombin time (HP:0008151). HP:0008151 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:31667683 SUPPORT Human Clinical
"Prothrombin time (> 40 s) and activated partial thromboplastin time (65.0 s) were prolonged."
Documents a markedly prolonged prothrombin time in a confirmed case.
Prolonged partial thromboplastin time HP:0003645 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Prolonged activated partial thromboplastin time, annotated with Prolonged partial thromboplastin time (HP:0003645). HP:0003645 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:31667683 SUPPORT Human Clinical
"activated partial thromboplastin time (65.0 s) were prolonged"
Documents a prolonged activated partial thromboplastin time in the same confirmed case.
Digestive 1
Hemoperitoneum VERY_RARE HP:0011854 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Haemoperitoneum from ovulation bleeding, annotated with Hemoperitoneum (HP:0011854). HP:0011854 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:30901144 SUPPORT Human Clinical
"Haemoperitoneum from ovulation bleeding or ruptured haemorrhagic ovarian cyst requiring blood transfusion occurred in 8/322 (2.4%) women, six required surgical intervention, including oophorectomy in two."
Source for both the 2.4% frequency, which is the VERY_RARE band (<5%), and for the severity of the episodes that do occur.
🧬

Genetic Associations

1
F10
Gene: F10 hgnc:3528 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is F10 (hgnc:3528). hgnc:3528 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE
Show evidence (7 references)
PMID:16919077 SUPPORT Human Clinical
"Twenty-nine different causative mutations, including 15 novel mutations, were analysed."
Establishes allelic heterogeneity at the causative locus.
PMID:25582404 SUPPORT Human Clinical
"The F7 and F10 genes are located on the long arm of chromosome 13."
Supports the locus assignment and the adjacency to F7 described in the notes.
PMID:25582404 SUPPORT Human Clinical
"In four patients, the combined deficiency was due to a large deletion within the terminal end of chromosome 13."
Documents the contiguous-deletion mechanism that produces combined FVII/FX deficiency rather than isolated factor X deficiency.
+ 4 more references
💊

Medical Actions

5
Plasma-derived factor X concentrate
Action: factor X replacement therapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is factor X replacement therapy, annotated with Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. Ontology label: Pharmacotherapy NCIT:C15986
Agent: human coagulation factor X NCIT:C82272 NCI Thesaurus (NCIT) Relation: this treatment uses this therapeutic agent This treatment uses human coagulation factor X, annotated with Coagulation Factor X Human (NCIT:C82272). NCIT:C82272 is a therapeutic agent from the NCI Thesaurus.
Platform: Protein replacement
High-purity human plasma-derived factor X concentrate, the first single-factor replacement therapy licensed specifically for hereditary factor X deficiency. It is the preferred replacement product because, unlike plasma or prothrombin complex concentrate, its factor X content is specified.
Mechanism Target:
Reduced Functional Plasma Factor X — Replacement restores circulating functional factor X, and so restores the substrate for prothrombinase assembly. The treatment acts at the node immediately downstream of the genetic lesion, not on the lesion itself.
Show evidence (3 references)
PMID:27797267 SUPPORT Human Clinical
"To meet the need for a single-factor replacement therapy specifically for use in FX-deficient patients, a high-purity, high-potency, human plasma-derived FX concentrate (pdFX; Coagadex®; Bio Products Laboratory, Elstree, UK) has been developed and approved for treatment of perioperative bleeding..."
Establishes the agent, its indication and its regulatory approval.
PMID:29707881 SUPPORT Human Clinical
"At end of study, investigators rated pdFX efficacy excellent for all subjects."
Prospective phase 3 efficacy result in children under 12, the age group for which data were previously lacking. Investigator-rated rather than blinded, in nine subjects.
PMID:34024682 SUPPORT Human Clinical
"Current recommendations advise clinicians to use single-factor replacement therapy for hereditary disease rather than multifactor therapies such as fresh frozen plasma, cryoprecipitate, and prothrombin complex concentrates."
Supports the preference for single-factor replacement over the multifactor alternatives recorded below.
Prophylactic factor X replacement
Action: prophylactic factor X replacement therapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is prophylactic factor X replacement therapy, annotated with Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. Ontology label: Pharmacotherapy NCIT:C15986
Agent: human coagulation factor X NCIT:C82272 NCI Thesaurus (NCIT) Relation: this treatment uses this therapeutic agent This treatment uses human coagulation factor X, annotated with Coagulation Factor X Human (NCIT:C82272). NCIT:C82272 is a therapeutic agent from the NCI Thesaurus.
Platform: Protein replacement
Regular replacement dosed to keep trough factor X activity above a threshold, rather than treating bleeds as they occur. In the paediatric phase 3 study doses were adjusted to maintain trough activity above 5 IU/dL.
Mechanism Target:
Systemic Bleeding Tendency — Maintaining a trough activity level above the bleeding threshold prevents bleeding episodes rather than treating them.
Show evidence (2 references)
PMID:29707881 SUPPORT Human Clinical
"Subjects aged <12 years with basal plasma FX activity (FX:C) <5 IU/dL received pdFX as prophylactic and on-demand treatment, with doses adjusted to maintain FX:C > 5 IU/dL."
States the prophylactic regimen and the trough target it is dosed to.
PMID:29707881 SUPPORT Human Clinical
"Trough FX:C levels remained >5 IU/dL for all subjects after the last dose adjustment study visit."
Reports that the trough target was achieved in every subject.
Prothrombin complex concentrate
Action: prothrombin complex concentrate therapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is prothrombin complex concentrate therapy, annotated with Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. Ontology label: Pharmacotherapy NCIT:C15986
Agent: four-factor prothrombin complex concentrate NCIT:C208347 NCI Thesaurus (NCIT) Relation: this treatment uses this therapeutic agent This treatment uses four-factor prothrombin complex concentrate (NCIT:C208347). NCIT:C208347 is a therapeutic agent from the NCI Thesaurus.
Platform: Protein replacement
A multifactor product containing factor X alongside the other vitamin K-dependent factors. Current guidance prefers single-factor replacement where it is available, but prothrombin complex concentrate remains in use, including as regular replacement where it is the accessible option.
Mechanism Target:
Reduced Functional Plasma Factor X — Supplies factor X, though at a concentration the product specification may not state.
Show evidence (2 references)
PMID:31667683 SUPPORT Human Clinical
"Following continued regular replacement of 500 units of PPSB-HT once per week, the proband has exhibited no bleeding tendencies and no new bruises have been observed."
A single-patient outcome under regular prothrombin complex concentrate replacement. This is one uncontrolled case, and the authors present it as a first report rather than as established practice.
PMID:27797267 REFUTE Human Clinical
"Previously, treatment options for hereditary FX deficiency were limited mostly to products that may not specify FX content (i.e. fresh frozen plasma and prothrombin complex concentrates) and that have associated safety concerns."
Cuts against prothrombin complex concentrate as a preferred option, on the grounds of unspecified factor X content and safety concerns. Recorded as REFUTE against this treatment rather than dropped, because the same sentence is the reason single-factor replacement is now recommended.
Fresh frozen plasma
Action: fresh frozen plasma transfusionNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is fresh frozen plasma transfusion, annotated with Blood Transfusion (NCIT:C15192). NCIT:C15192 is a clinical intervention from the NCI Thesaurus. Ontology label: Blood Transfusion NCIT:C15192
Platform: Other
The historical option, still used where no concentrate is available. It carries the same unspecified-content problem as prothrombin complex concentrate, plus volume load and transfusion reaction risk.
Mechanism Target:
Reduced Functional Plasma Factor X — Supplies factor X in unpurified form along with all other plasma proteins.
Show evidence (3 references)
PMID:35958882 SUPPORT INDIRECT Human Clinical
"The patient was re-hospitalized to remove a wisdom tooth, during which fresh frozen plasma was administered."
Documents fresh frozen plasma used as perioperative cover where concentrate was unavailable. Marked INDIRECT because the case reports the practice, not a measured haemostatic benefit.
PMID:35958882 REFUTE Human Clinical
"An allergic reaction complicated this procedure in the form of a rash on the body."
Records a transfusion reaction in the same patient, which is part of why plasma is no longer the preferred option.
PMID:34024682 REFUTE Human Clinical
"Current recommendations advise clinicians to use single-factor replacement therapy for hereditary disease rather than multifactor therapies such as fresh frozen plasma, cryoprecipitate, and prothrombin complex concentrates."
Current guidance recommends against fresh frozen plasma where single-factor replacement is available.
Antifibrinolytic therapy
Action: antifibrinolytic therapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is antifibrinolytic therapy, annotated with Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. Ontology label: Pharmacotherapy NCIT:C15986
Agent: tranexamic acid CHEBI:48669 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses tranexamic acid (CHEBI:48669). CHEBI:48669 is a therapeutic agent from Chemical Entities of Biological Interest.
Platform: Small molecule
Tranexamic acid or epsilon-aminocaproic acid, used for minor and mucosal bleeding, often alongside or instead of factor replacement. Antifibrinolytics do not correct the factor X defect; they stabilise the clot that the reduced thrombin generation does manage to form, by inhibiting its fibrinolytic breakdown. Fibrin glue is used in the same setting.
Mechanism Target:
Impaired Fibrin Clot Formation — Acts at the fibrin node rather than upstream of it: the clot formed under reduced thrombin generation is preserved by blocking plasmin-mediated lysis. This is why antifibrinolytics help in mucosal bleeding without raising factor X activity.
Show evidence (2 references)
PMID:35059555 SUPPORT Human Clinical
"The predominant treatments for FX deficiency include FX replacement and the use of antifibrinolytics."
Places antifibrinolytics alongside replacement as one of the two mainstay treatment classes for this disorder.
PMID:35059555 SUPPORT Human Clinical
"Antifibrinolytics such as ε-aminocaproic and tranexamic acid or fibrin glue are often used for the treatment of minor bleeds."
Names the specific agents and the clinical setting (minor bleeds) that this treatment record describes.
🔬

Biochemical Markers

1
Factor X coagulant activity (FX:C) (DECREASED)
Pathograph Readouts
Readout Of Reduced Functional Plasma Factor X
FX:C measures the functional consequence of the genetic lesion at the level of circulating protein activity.
Reference Ranges
50.0–150.0 IU/dL (healthy adults)
Severe deficiency (–1.0 % of normal FX:C) Moderate deficiency (1.0–6.0 % of normal FX:C) Mild deficiency (6.0–10.0 % of normal FX:C)
Two things are recorded deliberately. First, the normal interval is quoted in IU/dL while the source states the severity strata as a percentage of normal FX:C, so the bands carry their own unit rather than being silently converted. Second, the source states the moderate stratum as the integers 1 to 5, which is encoded here as the half-open interval [1, 6) so that a fractional value between 5% and 6% is assigned to moderate rather than falling in no band.
Show evidence (2 references)
PMID:35059555 SUPPORT Human Clinical
"FX:C in healthy human plasma ranges from 50 to 150 IU/dL."
Source for the normal reference interval.
PMID:35059555 SUPPORT Human Clinical
"Mildly deficient patients have 6 to 10% of normal FX:C, moderately deficient patients 1 to 5% and severely deficient patients"
Source for the three severity bands. The quote stops where the cached extraction breaks the sentence: the trailing "<1%." for the severe stratum sits on the following line of the cache file, so quoting further would not be an exact substring.
Show evidence (1 reference)
PMID:34024682 SUPPORT Human Clinical
"The typology and severity of the associated bleeding symptoms are highly heterogeneous, adding to the difficulties of diagnosis and management."
Records why the severity strata above matter clinically and why they are not a reliable predictor of bleeding on their own, which is the point the fx_activity_severity_discordance knowledge gap makes.
🔬

Diagnosis

2
Coagulation screen with factor-specific assay
Simultaneous prolongation of the prothrombin time and the activated partial thromboplastin time prompts single-factor assays. Factor X coagulant activity establishes the diagnosis; factor X antigen measured alongside it separates type I from type II. Because a prolonged prothrombin time with a normal activated partial thromboplastin time can still conceal combined FVII/FX deficiency, single-factor activities should be measured in any case with a prolonged prothrombin time.
Show evidence (1 reference)
PMID:25582404 SUPPORT Human Clinical
"To avoid a misdiagnosis of combined FVII/FX deficiency, analyses of single factor activities have to be performed in all cases with prolonged PT even if aPTT is normal."
States the diagnostic rule this record recommends, and the misdiagnosis it is designed to prevent.
F10 sequencing
Confirms the diagnosis, establishes the inheritance pattern for counselling, and distinguishes isolated factor X deficiency from a contiguous 13q deletion involving F7. Multiplex ligation-dependent probe amplification is needed alongside sequencing to detect large heterozygous deletions.
Show evidence (2 references)
PMID:25582404 SUPPORT Human Clinical
"Genetic analyses included direct sequencing of the F7 and F10 genes and MLPA (multiplex ligation-dependent probe amplification) for detection of heterozygous large deletions."
States the two assays needed, and why sequencing alone is not sufficient.
PMID:25582404 SUPPORT Human Clinical
"Genetic analyses are substantial for correct prediction of an inheritance pattern and a proper genetic counselling."
States the role of genetic analysis in establishing inheritance and counselling.
📊

Prevalence

1
Worldwide
Point Prevalence 0.15 per 100,000 (0.1–0.2) 1–9 per 1,000,000
Reported as 1 in 500,000 to 1 in 1,000,000, which normalises to 0.1-0.2 per 100,000. The point estimate recorded here is the midpoint of that range; the range itself is carried in rate_low and rate_high.
Show evidence (2 references)
PMID:29707881 SUPPORT Human Clinical
"Hereditary factor X (FX) deficiency (FXD) affects 1:500 000-1:1 000 000 people worldwide."
States the worldwide frequency range normalised in this record.
PMID:16919077 SUPPORT Human Clinical
"Inherited factor X deficiency (FXD) is a rare (1:1,000,000) recessive bleeding disorder."
An independent statement of frequency at the lower-frequency end of the range.
🐁

Animal Models

3
F10 total knockout mouse
Mice carrying a targeted deletion of every exon encoding mature factor X. Homozygotes are partially lost in utero around E11.5-12.5 with massive bleeding and no vascular malformation; most survivors die within five days, usually of intraabdominal bleeding, and the rest between P5 and P20. The model establishes that factor X is required for embryonic and postnatal survival.
Species
Mouse
Genotype
F10-/- (targeted deletion of all exons encoding the mature FX protein)
Publication
PMID:12161341
Pathograph links
Systemic Bleeding Tendency partially recapitulates fidelity: moderate observes: organism Complete absence of factor X produces fatal spontaneous bleeding at multiple sites, reproducing the bleeding tendency that is this entry's organism-level node.
Limitations: The match is to severity rather than to course. Total factor X deficiency is embryonic or perinatally lethal in the mouse, whereas the human disorder is a survivable chronic bleeding diathesis in which some residual factor X activity is essentially always present. The model therefore cannot report on the human disease's natural history, its genotype-phenotype relationship, or long-term treatment, and its lethality is what prevented further study.
Show evidence (1 reference)
PMID:12161341 SUPPORT Model Organism
"The genotypic distribution indicated that homozygous deficiency results in partial embryonic lethality at embryonic day (E) 11.5-12.5 with signs of massive bleeding but no histologically evident defects in the vasculature of these embryos or their yolk sac."
Reports the bleeding phenotype and, importantly, its absence of a vascular malformation, so the haemorrhage is attributable to the coagulation defect itself.
Show evidence (1 reference)
PMID:12161341 SUPPORT Model Organism
"These observations underline the importance of FX function in embryonic and postnatal survival and confirm that these mice serve as effective models of the bleeding disorders observed in human FX deficiency."
The authors' own statement that the knockout is a model of the human bleeding disorder, which is what licenses the link below.
f10-/- zebrafish
TALEN-generated factor X null zebrafish. They show a major embryonic haemostatic defect but, unlike the mouse, survive well beyond the equivalent stage, which makes them usable for functional testing of human F10 variants.
Species
Zebrafish
Genotype
f10-/- (TALEN-mediated ablation)
Publication
PMID:28576875
Pathograph links
Systemic Bleeding Tendency partially recapitulates fidelity: moderate observes: organism Loss of f10 causes an embryonic haemostatic defect with later widespread haemorrhage, reproducing the bleeding tendency in a vertebrate that tolerates the null state long enough to be studied.
Limitations: The paper's own finding is that fish tolerate what is an early lethal defect in mammals, so the timing and severity of the zebrafish course cannot be transferred to human disease. Vascular development is unaffected, which is informative, but the model is best read as a variant-pathogenicity assay rather than as a model of the human clinical phenotype.
Show evidence (1 reference)
PMID:28576875 SUPPORT Model Organism
"However, widespread hemorrhage and subsequent lethality does not occur until later stages, with absence of any detectable defect in vascular development."
States both the bleeding phenotype and the divergence in timing that the limitations field records.
Show evidence (1 reference)
PMID:28576875 SUPPORT Model Organism
"We also use f10-/- zebrafish to confirm 5 novel human F10 variants as causative mutations in affected patients, providing a rapid and reliable in vivo model for testing the severity of F10 variants."
Establishes the model's actual utility for this disorder: assigning pathogenicity to human F10 variants.
Naturally occurring feline factor X deficiency
A spontaneous, apparently heritable severe factor X deficiency in a domestic shorthair cat, presenting with prolonged bleeding after venipuncture and generalized seizures. Reduced factor X activity in the dam and a sibling supported heritability.
Species
Cat
Genotype
Presumed inherited factor X deficiency (reduced FX activity in dam and one sibling)
Publication
PMID:9290823
Pathograph links
Systemic Bleeding Tendency partially recapitulates fidelity: low observes: organism A naturally occurring, non-engineered instance of severe factor X deficiency with a bleeding phenotype, in a species where the deficiency had not previously been reported.
Limitations: A single animal, with no molecular characterisation of the underlying defect and no formal inheritance study, so heritability is suspected rather than established. The seizures were not shown to be haemorrhagic in origin and are not curated here as a phenotype of this disorder.
Kept because it is the only spontaneous animal occurrence of this deficiency in the cited literature, not because it carries weight comparable to the engineered models above.
Show evidence (1 reference)
PMID:9290823 SUPPORT Model Organism
"Severe congenital deficiency of factor X was diagnosed in a 3-year-old castrated male domestic shorthair cat with clinical signs of generalized seizures and prolonged bleeding after venipuncture."
Records a spontaneous non-human occurrence of the same deficiency with a bleeding phenotype. Graded MODEL_ORGANISM per the convention that veterinary observations in non-human animals are model-organism evidence.
{ }

Source YAML

click to show 
name: Congenital Factor X Deficiency
creation_date: "2026-09-12T12:52:00Z"
category: Mendelian
synonyms:
- factor X deficiency
- hereditary factor X deficiency
- inherited factor X deficiency
- Stuart-Prower factor deficiency
- FX deficiency
- FXD
description: >-
  An autosomal recessive bleeding disorder caused by biallelic variants in F10,
  the gene encoding coagulation factor X. It is among the rarest of the rare
  bleeding disorders, at roughly one in 500,000 to one in a million.

  The mechanism is short and unusually well resolved, because factor X sits at a
  single, non-redundant point in the coagulation cascade. Factor X is the zymogen
  of factor Xa, and factor Xa is the protease component of the prothrombinase
  complex - the assembly of factor Xa with its cofactor factor Va on an anionic
  phospholipid surface that converts prothrombin to thrombin some five orders of
  magnitude faster than factor Xa can alone. Both the tissue-factor (extrinsic)
  and the contact-activated (intrinsic) arms of the cascade converge on factor X
  activation, so a defect here is downstream of both and cannot be bypassed by
  either. Less functional factor X means less prothrombinase, less thrombin, less
  fibrin, and a bleeding tendency whose severity broadly tracks residual factor X
  activity.

  That convergence is also what makes the laboratory picture distinctive: because
  the lesion is in the common pathway rather than in one arm, both the prothrombin
  time and the activated partial thromboplastin time are prolonged, which is the
  finding that usually prompts factor-specific assays.

  Two deficiency types are recognised and are modelled here as has_subtypes rather
  than as separate diseases, because they converge on the same prothrombinase
  defect and differ only in whether the defective protein is absent or present but
  non-functional. Type I is cross-reactive-material-negative, with factor X
  activity and antigen reduced together; type II is
  cross-reactive-material-positive, with activity reduced against preserved
  antigen.

  Three things in this entry are deliberately hedged rather than smoothed over.
  First, genotype-phenotype correlation is weak: the largest cohort curated here
  says in terms that clinical and laboratory phenotypes are poorly correlated, and
  the mutation-specific associations it reports for intracranial haemorrhage are
  described by its own authors as tentative. That hedge is carried into the
  evidence rather than dropped. Second, the type I/type II split is applied
  inconsistently in the primary literature - at least one curated cohort reports
  uniformly reduced antigen and then labels the patients type II, which inverts the
  usual convention - so the subtype records are anchored to a variant-database
  definition covering 427 case reports rather than to any single cohort's
  labelling. Third, no
  pathophysiology node declares conforms_to: kb/modules/ was searched for a
  coagulation-cascade module and none covers a single-factor common-pathway defect.

  Heterozygotes are not curated as a subtype. They are usually asymptomatic, but a
  minority bleed, and the entry records that inside the inheritance block rather
  than as a distinct disease state.
disease_term:
  preferred_term: congenital factor X deficiency
  term:
    id: MONDO:0009212
    label: congenital factor X deficiency
parents:
- Rare bleeding disorder
- Vitamin K-dependent coagulation factor deficiency
inheritance:
- name: Autosomal recessive
  inheritance_term:
    preferred_term: Autosomal recessive
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  description: >-
    Symptomatic disease requires two defective F10 alleles, homozygous or compound
    heterozygous. A minority of heterozygotes report bleeding symptoms, but they
    are not curated here as an affected state.
  evidence:
  - reference: PMID:18403394
    reference_title: "Phenotype and genotype report on homozygous and heterozygous patients with congenital factor X deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Factor X deficiency is a severe rare hemorrhagic condition inherited as an autosomal recessive trait."
    explanation: >-
      States the inheritance pattern directly.
  - reference: PMID:16919077
    reference_title: "Factor X deficiency: clinical manifestation of 102 subjects from Europe and Latin America with mutations in the factor 10 gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The manifestation of bleeding symptoms in 9 of 67 (13%) symptomatic heterozygous subjects is described."
    explanation: >-
      Quantifies the minority of heterozygotes who are symptomatic, which is the
      qualification recorded in this block's description.
has_subtypes:
- name: Type I
  display_name: Type I (cross-reactive-material-negative)
  description: >-
    Concordant reduction of factor X activity and factor X antigen, indicating
    reduced synthesis or reduced stability of the protein rather than a
    dysfunctional circulating molecule.
  evidence:
  - reference: PMID:35059555
    reference_title: "Analysis of 180 Genetic Variants in a New Interactive FX Variant Database Reveals Novel Insights into FX Deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Type-I variants involve the simultaneous reduction of FX coagulant activity (FX:C) and FX antigen levels (FX:Ag), whereas type-II variants involve a reduction in FX:C with normal FX:Ag plasma levels."
    explanation: >-
      States the type I and type II definitions from a database curating 427 case
      reports, which is the authority this entry uses for the classification
      rather than any single cohort's labelling.
- name: Type II
  display_name: Type II (cross-reactive-material-positive)
  description: >-
    Reduced factor X activity against preserved or near-preserved factor X
    antigen, indicating a circulating but catalytically or membrane-binding
    defective molecule. Gla-domain variants are a recognised structural route to
    this pattern, since gamma-carboxyglutamate residues mediate the
    calcium-dependent membrane binding that prothrombinase assembly requires.
  evidence:
  - reference: PMID:35059555
    reference_title: "Analysis of 180 Genetic Variants in a New Interactive FX Variant Database Reveals Novel Insights into FX Deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Type-I variants involve the simultaneous reduction of FX coagulant activity (FX:C) and FX antigen levels (FX:Ag), whereas type-II variants involve a reduction in FX:C with normal FX:Ag plasma levels."
    explanation: >-
      States the type II definition, preserved antigen against reduced activity,
      which is what distinguishes this subtype from type I.
  - reference: PMID:19490765
    reference_title: "The clinical and laboratory significance of cases of congenital FX deficiency due to defects in the Gla-domain."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The Gla-domain of factor X (FX) is a 39 residue peptide, part of the light chain, and is characterized by the presence of 11 gamma-carboxylglutaminic acid residues interspersed among other no-Gla residues."
    explanation: >-
      Describes the Gla domain whose variants give a dysfunctional but present
      molecule, the structural route to a type II pattern.
  - reference: PMID:19490765
    reference_title: "The clinical and laboratory significance of cases of congenital FX deficiency due to defects in the Gla-domain."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Factor X antigen varied between 16 and 55% of normal in almost all cases."
    explanation: >-
      Shows antigen preserved well above the activity levels reported in the same
      kindreds, which is the laboratory signature of this subtype.
pathophysiology:
- name: Biallelic F10 Loss-of-Function Variants
  biological_scale: MOLECULAR
  description: >-
    Homozygous or compound heterozygous variants in F10, on chromosome 13q.
    Missense substitutions predominate, and the reported spectrum also includes
    in-frame deletions, splice-site changes and, where F7 is co-deleted, large
    terminal deletions of chromosome 13 that remove both loci.
  genetic_context:
    variant_origin: GERMLINE
    functional_impact_category: LOSS_OF_FUNCTION
  cell_types:
  - preferred_term: hepatocyte, the site of factor X synthesis
    term:
      id: CL:0000182
      label: hepatocyte
  downstream:
  - target: Reduced Functional Plasma Factor X
    description: >-
      The variant protein is either not made, not secreted, or secreted in a form
      that cannot participate in prothrombinase assembly.
  evidence:
  - reference: PMID:16919077
    reference_title: "Factor X deficiency: clinical manifestation of 102 subjects from Europe and Latin America with mutations in the factor 10 gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This international study analysed the phenotype and genotype of 102 subjects from Central Europe (Germany, Poland and Slovakia) and Latin America (Costa Rica and Venezuela) with causative mutations in the F10 gene, via sequencing."
    explanation: >-
      Establishes F10 as the causative locus in a large genotyped cohort.
  - reference: PMID:16919077
    reference_title: "Factor X deficiency: clinical manifestation of 102 subjects from Europe and Latin America with mutations in the factor 10 gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Twenty-eight homozygous, seven compound-heterozygous and 67 heterozygous FXD subjects were characterized."
    explanation: >-
      Documents the biallelic genotypes that produce the disease, alongside the
      heterozygous carrier state.
  - reference: PMID:31667683
    reference_title: "Genetic analysis of a compound heterozygous patient with congenital factor X deficiency and regular replacement therapy with a prothrombin complex concentrate."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Genetic analysis of the proband identified two types of single-base substitutions, c.353G>A (p.Gly118Asp) and c.1303G>A (p.Gly435Ser), indicating compound heterozygous congenital FX deficiency."
    explanation: >-
      A worked compound heterozygous case with both variants identified and the
      parental carrier states confirmed in the same study.
- name: Reduced Functional Plasma Factor X
  biological_scale: MOLECULAR
  description: >-
    The functional deficit measured in plasma as factor X coagulant activity
    (FX:C). In type I disease the immunoreactive antigen (FX:Ag) falls with it; in
    type II a dysfunctional molecule is still present, so antigen is comparatively
    preserved. Residual activity is the quantity that grades severity.
  molecular_functions:
  - preferred_term: factor X zymogen available for conversion to the active protease
    modifier: DECREASED
    term:
      id: GO:0004252
      label: serine-type endopeptidase activity
  downstream:
  - target: Impaired Prothrombinase Complex Activity
    description: >-
      Less factor X zymogen available for activation means less factor Xa
      available to assemble with factor Va on the membrane surface.
  evidence:
  - reference: PMID:31667683
    reference_title: "Genetic analysis of a compound heterozygous patient with congenital factor X deficiency and regular replacement therapy with a prothrombin complex concentrate."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Marked declines in FX activity (< 1%) and FX antigen levels (5%) were also observed."
    explanation: >-
      Directly measures the reduction in both factor X activity and antigen that
      defines this node in a genetically confirmed patient.
  - reference: PMID:26222694
    reference_title: "Frequency of the p.Gly262Asp mutation in congenital Factor X deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "FX:C was <1% in 11 patients, and 4% in one."
    explanation: >-
      Quantifies residual coagulant activity across a severe-deficiency cohort.
- name: Impaired Prothrombinase Complex Activity
  biological_scale: MOLECULAR
  description: >-
    The non-redundant step. Factor Xa is the catalytic subunit of prothrombinase,
    which assembles with the cofactor factor Va on an anionic phospholipid surface
    supplied largely by activated platelets. The assembled complex cleaves
    prothrombin far faster than free factor Xa, so the amount of thrombin a patient
    can generate is set by how much functional prothrombinase can form. Both the
    extrinsic and intrinsic arms of the cascade feed into factor X activation, so
    neither arm can compensate for the defect.
  biological_processes:
  - preferred_term: blood coagulation, common pathway
    modifier: DECREASED
    term:
      id: GO:0072377
      label: blood coagulation, common pathway
  cell_types:
  - preferred_term: activated platelet providing the anionic phospholipid surface
    term:
      id: CL:0000233
      label: platelet
  downstream:
  - target: Reduced Thrombin Generation
    description: >-
      Less assembled prothrombinase converts less prothrombin to thrombin.
    evidence:
    - reference: PMID:25153592
      reference_title: "Homology model of human prothrombinase based on the crystal structure of Pseutarin C."
      supports: SUPPORT
      directness: DIRECT
      evidence_source: COMPUTATIONAL
      snippet: "The balance between bleeding and thrombosis depends on the amount of thrombin produced, and this in turn depends on the function of the prothrombinase complex."
      explanation: >-
        States the dependency this edge asserts, that thrombin output is set by
        prothrombinase function. Graded COMPUTATIONAL because the cited
        publication is a homology-modelling study, even though the quoted
        sentence is the paper's statement of established biochemistry rather than
        a result of its own model.
  evidence:
  - reference: PMID:25153592
    reference_title: "Homology model of human prothrombinase based on the crystal structure of Pseutarin C."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: COMPUTATIONAL
    snippet: "Prothrombinase is composed of a protease, factor (f) Xa, and a cofactor, fVa, which interact on negatively charged phospholipid surfaces and cleave prothrombin into thrombin 300 000 times faster than fXa alone"
    explanation: >-
      Gives the composition of the complex and the magnitude of the rate
      enhancement that makes this step non-redundant, which is why a factor X
      defect cannot be bypassed. Graded COMPUTATIONAL because the publication is a
      modelling study; see the note on the downstream edge.
- name: Reduced Thrombin Generation
  biological_scale: MOLECULAR
  description: >-
    The functional common denominator of the disease. Thrombin is required both to
    cleave fibrinogen to fibrin and to amplify its own generation through feedback
    activation of factors V, VIII and XI, so a prothrombinase deficit propagates
    rather than being buffered.
  biological_processes:
  - preferred_term: blood coagulation
    modifier: DECREASED
    term:
      id: GO:0007596
      label: blood coagulation
  downstream:
  - target: Impaired Fibrin Clot Formation
    description: >-
      Insufficient thrombin to convert fibrinogen to fibrin at the rate a
      haemostatic plug requires.
- name: Impaired Fibrin Clot Formation
  biological_scale: TISSUE
  description: >-
    Failure to form a stable fibrin network at sites of vascular injury. This is
    the step the routine coagulation screen measures, and it is the reason both the
    prothrombin time and the activated partial thromboplastin time are prolonged in
    this disease rather than only one of them.
  biological_processes:
  - preferred_term: blood coagulation, fibrin clot formation
    modifier: DECREASED
    term:
      id: GO:0072378
      label: blood coagulation, fibrin clot formation
  downstream:
  - target: Systemic Bleeding Tendency
    description: >-
      An unstable or slowly formed clot fails to secure haemostasis, producing
      spontaneous and provoked bleeding.
  evidence:
  - reference: PMID:26222694
    reference_title: "Frequency of the p.Gly262Asp mutation in congenital Factor X deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A total or partial deficiency of FX causes an impairment of clot formation, leading to a haemorrhagic disease, which manifests with bleeding symptoms of different severity, also unprovoked."
    explanation: >-
      States the impairment of clot formation and its consequence, including that
      bleeding may be unprovoked.
  - reference: PMID:31667683
    reference_title: "Genetic analysis of a compound heterozygous patient with congenital factor X deficiency and regular replacement therapy with a prothrombin complex concentrate."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Prothrombin time (> 40 s) and activated partial thromboplastin time (65.0 s) were prolonged."
    explanation: >-
      Documents the simultaneous prolongation of both screening tests that a
      common-pathway defect predicts.
- name: Systemic Bleeding Tendency
  biological_scale: ORGANISM
  description: >-
    The clinical endpoint. Bleeding is mucocutaneous, muscular and articular, and
    in the most severely affected can be intracranial. Severity broadly tracks
    residual factor X activity, but the correlation is imperfect and this entry
    does not overstate it.
  downstream:
  - target: Bruising susceptibility
  - target: Subcutaneous hemorrhage
  - target: Epistaxis
  - target: Joint hemorrhage
  - target: Intracranial hemorrhage
    description: >-
      The most serious consequence, reported in about a fifth of symptomatic
      subjects in the largest curated cohort.
  - target: Gastrointestinal hemorrhage
  - target: Abnormal umbilical stump bleeding
  - target: Gingival bleeding
  - target: Menorrhagia
    description: >-
      The commonest bleeding manifestation for which affected women present for
      haemostatic treatment.
  - target: Postpartum hemorrhage
  - target: Hemoperitoneum
    description: >-
      Bleeding into the peritoneum from a normal ovulatory event, which an intact
      common pathway would arrest.
  evidence:
  - reference: PMID:16919077
    reference_title: "Factor X deficiency: clinical manifestation of 102 subjects from Europe and Latin America with mutations in the factor 10 gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Spontaneous bleeding symptoms in 42 symptomatic individuals (26 homozygous, seven compound heterozygous and nine heterozygous) comprised easy bruising (55%), haematoma (43%), epistaxis (36%), haemarthrosis (33%), intracranial haemorrhage (ICH; 21%), and gastrointestinal (GI) haemorrhage (12%)."
    explanation: >-
      Quantifies the bleeding phenotype across a 102-subject genotyped cohort, and
      is the source for the individual phenotype frequencies below.
  - reference: PMID:16919077
    reference_title: "Factor X deficiency: clinical manifestation of 102 subjects from Europe and Latin America with mutations in the factor 10 gene."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "The clinical and laboratory phenotypes of FXD are poorly correlated and few regional studies on the genotype and the clinical manifestations of FXD are known."
    explanation: >-
      Records the limit on the severity claim. Marked INDIRECT because it
      constrains how strongly residual activity may be read as predicting
      bleeding, rather than asserting the bleeding tendency itself.
phenotypes:
- category: Hematologic
  name: Bruising susceptibility
  description: >-
    The most frequent spontaneous bleeding symptom, reported in 55% of symptomatic
    subjects in the largest genotyped cohort.
  phenotype_term:
    preferred_term: Easy bruising
    term:
      id: HP:0000978
      label: Bruising susceptibility
  evidence:
  - reference: PMID:16919077
    reference_title: "Factor X deficiency: clinical manifestation of 102 subjects from Europe and Latin America with mutations in the factor 10 gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Spontaneous bleeding symptoms in 42 symptomatic individuals (26 homozygous, seven compound heterozygous and nine heterozygous) comprised easy bruising (55%), haematoma (43%), epistaxis (36%), haemarthrosis (33%), intracranial haemorrhage (ICH; 21%), and gastrointestinal (GI) haemorrhage (12%)."
    explanation: >-
      Reports the frequency of easy bruising among symptomatic subjects.
  - reference: PMID:31667683
    reference_title: "Genetic analysis of a compound heterozygous patient with congenital factor X deficiency and regular replacement therapy with a prothrombin complex concentrate."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The proband, a 2-year-old girl, exhibited easy bruising and a history of umbilical cord bleeding at birth."
    explanation: >-
      A genetically confirmed case presenting with easy bruising.
- category: Hematologic
  name: Subcutaneous hemorrhage
  description: >-
    Haematoma formation, reported in 43% of symptomatic subjects in one cohort and
    as the commonest bleeding episode at 70% in another.
  phenotype_term:
    preferred_term: Haematoma
    term:
      id: HP:0001933
      label: Subcutaneous hemorrhage
  evidence:
  - reference: PMID:16919077
    reference_title: "Factor X deficiency: clinical manifestation of 102 subjects from Europe and Latin America with mutations in the factor 10 gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Spontaneous bleeding symptoms in 42 symptomatic individuals (26 homozygous, seven compound heterozygous and nine heterozygous) comprised easy bruising (55%), haematoma (43%), epistaxis (36%), haemarthrosis (33%), intracranial haemorrhage (ICH; 21%), and gastrointestinal (GI) haemorrhage (12%)."
    explanation: >-
      Reports haematoma frequency among symptomatic subjects.
  - reference: PMID:18403394
    reference_title: "Phenotype and genotype report on homozygous and heterozygous patients with congenital factor X deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The most frequent bleeding episodes were hematomas (70%) and gum bleeding (60%)."
    explanation: >-
      An independent cohort in which haematoma was the commonest bleeding episode,
      at a higher frequency than the European and Latin American series.
- category: Hematologic
  name: Epistaxis
  description: >-
    Nosebleed, reported in 36% of symptomatic subjects, and one of the two
    commonest symptoms in a separate severe-deficiency series.
  phenotype_term:
    preferred_term: Epistaxis
    term:
      id: HP:0000421
      label: Epistaxis
  evidence:
  - reference: PMID:16919077
    reference_title: "Factor X deficiency: clinical manifestation of 102 subjects from Europe and Latin America with mutations in the factor 10 gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Spontaneous bleeding symptoms in 42 symptomatic individuals (26 homozygous, seven compound heterozygous and nine heterozygous) comprised easy bruising (55%), haematoma (43%), epistaxis (36%), haemarthrosis (33%), intracranial haemorrhage (ICH; 21%), and gastrointestinal (GI) haemorrhage (12%)."
    explanation: >-
      Reports epistaxis frequency among symptomatic subjects.
  - reference: PMID:26222694
    reference_title: "Frequency of the p.Gly262Asp mutation in congenital Factor X deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The most frequent bleeding episodes in patients were epistaxis and easy bruising (11/12, 91%), followed by haemarthroses (10/12, 83%)."
    explanation: >-
      In a severe-deficiency cohort, epistaxis was among the most frequent
      symptoms.
- category: Musculoskeletal
  name: Joint hemorrhage
  description: >-
    Haemarthrosis, reported in 33% of symptomatic subjects and in 83% of a severely
    affected cohort. Its presence places factor X deficiency among the rare
    bleeding disorders with a haemophilia-like joint phenotype.
  phenotype_term:
    preferred_term: Haemarthrosis
    term:
      id: HP:0005261
      label: Joint hemorrhage
  evidence:
  - reference: PMID:16919077
    reference_title: "Factor X deficiency: clinical manifestation of 102 subjects from Europe and Latin America with mutations in the factor 10 gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Spontaneous bleeding symptoms in 42 symptomatic individuals (26 homozygous, seven compound heterozygous and nine heterozygous) comprised easy bruising (55%), haematoma (43%), epistaxis (36%), haemarthrosis (33%), intracranial haemorrhage (ICH; 21%), and gastrointestinal (GI) haemorrhage (12%)."
    explanation: >-
      Reports haemarthrosis frequency among symptomatic subjects.
  - reference: PMID:26222694
    reference_title: "Frequency of the p.Gly262Asp mutation in congenital Factor X deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "followed by haemarthroses (10/12, 83%)"
    explanation: >-
      A severe-deficiency cohort in which most patients had haemarthrosis.
- category: Neurologic
  name: Intracranial hemorrhage
  description: >-
    The most serious manifestation, reported in 21% of symptomatic subjects. The
    cohort reporting it proposes an association with particular F10 genotypes but
    describes that association as tentative.
  phenotype_term:
    preferred_term: Intracranial haemorrhage
    term:
      id: HP:0002170
      label: Intracranial hemorrhage
  evidence:
  - reference: PMID:16919077
    reference_title: "Factor X deficiency: clinical manifestation of 102 subjects from Europe and Latin America with mutations in the factor 10 gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Spontaneous bleeding symptoms in 42 symptomatic individuals (26 homozygous, seven compound heterozygous and nine heterozygous) comprised easy bruising (55%), haematoma (43%), epistaxis (36%), haemarthrosis (33%), intracranial haemorrhage (ICH; 21%), and gastrointestinal (GI) haemorrhage (12%)."
    explanation: >-
      Reports intracranial haemorrhage frequency among symptomatic subjects.
  - reference: PMID:16919077
    reference_title: "Factor X deficiency: clinical manifestation of 102 subjects from Europe and Latin America with mutations in the factor 10 gene."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "The results suggested that ICH seems to be associated with the F10 mutation Gly380Arg, and possibly with the mutations IVS7-1G>A and Tyr163delAT."
    explanation: >-
      A hedged genotype association. Marked INDIRECT because the authors' own
      wording does not assert the association outright.
- category: Gastrointestinal
  name: Gastrointestinal hemorrhage
  description: >-
    Reported in 12% of symptomatic subjects, the least frequent of the spontaneous
    bleeding symptoms recorded in that cohort.
  phenotype_term:
    preferred_term: Gastrointestinal haemorrhage
    term:
      id: HP:0002239
      label: Gastrointestinal hemorrhage
  evidence:
  - reference: PMID:16919077
    reference_title: "Factor X deficiency: clinical manifestation of 102 subjects from Europe and Latin America with mutations in the factor 10 gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Spontaneous bleeding symptoms in 42 symptomatic individuals (26 homozygous, seven compound heterozygous and nine heterozygous) comprised easy bruising (55%), haematoma (43%), epistaxis (36%), haemarthrosis (33%), intracranial haemorrhage (ICH; 21%), and gastrointestinal (GI) haemorrhage (12%)."
    explanation: >-
      Reports gastrointestinal haemorrhage frequency among symptomatic subjects.
- category: Hematologic
  name: Abnormal umbilical stump bleeding
  description: >-
    Umbilical cord bleeding at birth is a classic neonatal presentation of severe
    deficiency and is often the finding that prompts investigation.
  phenotype_term:
    preferred_term: Umbilical cord bleeding at birth
    term:
      id: HP:0011884
      label: Abnormal umbilical stump bleeding
  evidence:
  - reference: PMID:31667683
    reference_title: "Genetic analysis of a compound heterozygous patient with congenital factor X deficiency and regular replacement therapy with a prothrombin complex concentrate."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "a history of umbilical cord bleeding at birth"
    explanation: >-
      Documents umbilical cord bleeding at birth in a genetically confirmed severe
      case.
- category: Hematologic
  name: Gingival bleeding
  description: >-
    Gum bleeding, the second commonest bleeding episode at 60% in a cohort of
    severely affected patients.
  phenotype_term:
    preferred_term: Gum bleeding
    term:
      id: HP:0000225
      label: Gingival bleeding
  evidence:
  - reference: PMID:18403394
    reference_title: "Phenotype and genotype report on homozygous and heterozygous patients with congenital factor X deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The most frequent bleeding episodes were hematomas (70%) and gum bleeding (60%)."
    explanation: >-
      Reports gum bleeding frequency in a severe-deficiency cohort.
- category: Hematologic
  name: Menorrhagia
  description: >-
    Heavy menstrual bleeding, reported in 25% of women in a systematic review of
    332 women with congenital factor X deficiency. Where it occurs it is a
    substantial clinical problem: 64% of affected women required blood products.
  phenotype_term:
    preferred_term: Heavy menstrual bleeding
    term:
      id: HP:0000132
      label: Menorrhagia
  frequency: OCCASIONAL
  evidence:
  - reference: PMID:30901144
    reference_title: "Congenital Factor X deficiency in women: A systematic review of the literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Heavy menstrual bleeding was reported in 72/284 (25%) women in total, 14/30 (47%) in case reports and 58/254 (23%) in 11 case series, 64% and 10% required blood products and blood transfusion, respectively."
    explanation: >-
      Quantifies heavy menstrual bleeding across the largest assembled series of
      women with this disorder, and is the source for the OCCASIONAL band: the
      pooled figure is 25%, which falls in OCCASIONAL (5-29%). The 47% case-report
      subset would reach FREQUENT on its own, but it is the ascertainment-biased
      half of the same pooled estimate and is not what this band reports.
  - reference: PMID:30901144
    reference_title: "Congenital Factor X deficiency in women: A systematic review of the literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In conclusion, women with FXD are at an increased risk of heavy bleeding during menstruation and ovulation as well as adverse pregnancy outcome and postpartum haemorrhage."
    explanation: >-
      The review's own conclusion, stating the menstrual bleeding risk as a
      property of the disorder rather than of one cohort.
- category: Hematologic
  name: Postpartum hemorrhage
  description: >-
    Excessive bleeding after delivery, reported in 22% of deliveries in the
    systematic review of women with congenital factor X deficiency, one of which
    required hysterectomy.
  phenotype_term:
    preferred_term: Postpartum haemorrhage
    term:
      id: HP:0011891
      label: Post-partum hemorrhage
  frequency: OCCASIONAL
  evidence:
  - reference: PMID:30901144
    reference_title: "Congenital Factor X deficiency in women: A systematic review of the literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Postpartum haemorrhage (PPH) occurred in six (22%) of deliveries, one requiring hysterectomy."
    explanation: >-
      Quantifies postpartum haemorrhage as a fraction of deliveries, which is the
      denominator this phenotype is banded against.
- category: Hematologic
  name: Hemoperitoneum
  description: >-
    Intraperitoneal bleeding from ovulation or a ruptured haemorrhagic ovarian
    cyst. Uncommon, but closer to distinctive of this disorder than the generic
    mucocutaneous bleeding, and disproportionately consequential: of eight
    affected women, six needed surgery and two underwent oophorectomy.
  phenotype_term:
    preferred_term: Haemoperitoneum from ovulation bleeding
    term:
      id: HP:0011854
      label: Hemoperitoneum
  frequency: VERY_RARE
  evidence:
  - reference: PMID:30901144
    reference_title: "Congenital Factor X deficiency in women: A systematic review of the literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Haemoperitoneum from ovulation bleeding or ruptured haemorrhagic ovarian cyst requiring blood transfusion occurred in 8/322 (2.4%) women, six required surgical intervention, including oophorectomy in two."
    explanation: >-
      Source for both the 2.4% frequency, which is the VERY_RARE band (<5%), and
      for the severity of the episodes that do occur.
- category: Laboratory
  name: Reduced factor X activity
  description: >-
    The defining laboratory abnormality. Severe disease is conventionally taken as
    activity below 1%, and the curated cohorts report values in that range.
  phenotype_term:
    preferred_term: Reduced factor X coagulant activity
    term:
      id: HP:0008321
      label: Reduced factor X activity
  reports_on:
  - target: Reduced Functional Plasma Factor X
    relationship: READOUT_OF
    description: >-
      The factor X coagulant activity assay is the direct laboratory measurement
      of this node.
  evidence:
  - reference: PMID:26222694
    reference_title: "Frequency of the p.Gly262Asp mutation in congenital Factor X deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "FX:C was <1% in 11 patients, and 4% in one."
    explanation: >-
      Quantifies residual factor X coagulant activity in a severe-deficiency
      cohort.
- category: Laboratory
  name: Prolonged prothrombin time
  description: >-
    Prolonged because the lesion is in the common pathway, downstream of the
    tissue-factor arm that this test interrogates.
  phenotype_term:
    preferred_term: Prolonged prothrombin time
    term:
      id: HP:0008151
      label: Prolonged prothrombin time
  reports_on:
  - target: Impaired Fibrin Clot Formation
    relationship: READOUT_OF
    description: >-
      The prothrombin time is a functional readout of fibrin formation through the
      tissue-factor and common pathways.
  evidence:
  - reference: PMID:31667683
    reference_title: "Genetic analysis of a compound heterozygous patient with congenital factor X deficiency and regular replacement therapy with a prothrombin complex concentrate."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Prothrombin time (> 40 s) and activated partial thromboplastin time (65.0 s) were prolonged."
    explanation: >-
      Documents a markedly prolonged prothrombin time in a confirmed case.
- category: Laboratory
  name: Prolonged partial thromboplastin time
  description: >-
    Prolonged alongside the prothrombin time. Simultaneous prolongation of both
    screening tests is what distinguishes a common-pathway factor defect from an
    isolated extrinsic or intrinsic pathway defect.
  phenotype_term:
    preferred_term: Prolonged activated partial thromboplastin time
    term:
      id: HP:0003645
      label: Prolonged partial thromboplastin time
  reports_on:
  - target: Impaired Fibrin Clot Formation
    relationship: READOUT_OF
    description: >-
      The activated partial thromboplastin time is a functional readout of fibrin
      formation through the contact-activated and common pathways.
  evidence:
  - reference: PMID:31667683
    reference_title: "Genetic analysis of a compound heterozygous patient with congenital factor X deficiency and regular replacement therapy with a prothrombin complex concentrate."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "activated partial thromboplastin time (65.0 s) were prolonged"
    explanation: >-
      Documents a prolonged activated partial thromboplastin time in the same
      confirmed case.
genetic:
- name: F10
  gene_term:
    preferred_term: F10
    term:
      id: hgnc:3528
      label: F10
  relationship_type: CAUSATIVE
  notes: >-
    F10 lies at the telomeric end of chromosome 13q, immediately adjacent to F7.
    That adjacency is clinically relevant: a large terminal deletion can remove
    both loci and produce combined factor VII and factor X deficiency, which is a
    different entity from isolated factor X deficiency and is reached by a
    different genetic mechanism. Allelic heterogeneity is high and no single
    founder variant dominates worldwide, though regional recurrence is reported.
    The protein has four domains - a Gla domain, two EGF-like domains and a serine
    protease domain - and pathogenic variants are distributed across all of them,
    which is part of why domain location alone does not predict severity.
  evidence:
  - reference: PMID:16919077
    reference_title: "Factor X deficiency: clinical manifestation of 102 subjects from Europe and Latin America with mutations in the factor 10 gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Twenty-nine different causative mutations, including 15 novel mutations, were analysed."
    explanation: >-
      Establishes allelic heterogeneity at the causative locus.
  - reference: PMID:25582404
    reference_title: "Congenital combined deficiency of coagulation factors VII and X--different genetic mechanisms."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The F7 and F10 genes are located on the long arm of chromosome 13."
    explanation: >-
      Supports the locus assignment and the adjacency to F7 described in the
      notes.
  - reference: PMID:25582404
    reference_title: "Congenital combined deficiency of coagulation factors VII and X--different genetic mechanisms."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In four patients, the combined deficiency was due to a large deletion within the terminal end of chromosome 13."
    explanation: >-
      Documents the contiguous-deletion mechanism that produces combined FVII/FX
      deficiency rather than isolated factor X deficiency.
  - reference: PMID:26222694
    reference_title: "Frequency of the p.Gly262Asp mutation in congenital Factor X deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The p.Gly262Asp missense mutation was identified in 11 of the 12 patients in this study."
    explanation: >-
      A regional recurrent variant, which is the qualification to the allelic
      heterogeneity recorded in the notes.
  - reference: PMID:35059555
    reference_title: "Analysis of 180 Genetic Variants in a New Interactive FX Variant Database Reveals Novel Insights into FX Deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Coagulation factor X (FX), often termed as Stuart-Prower factor, is a plasma glycoprotein composed of the \u03b3-carboxyglutamic acid (GLA) domain, two epidermal growth factor domains (EGF-1 and EGF-2), and the serine protease (SP) domain."
    explanation: >-
      States the four-domain architecture described in the notes.
  - reference: PMID:35059555
    reference_title: "Analysis of 180 Genetic Variants in a New Interactive FX Variant Database Reveals Novel Insights into FX Deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Of these, 149 are point variants (of which 128 are missense), 22 are deletions, 3 are insertions, and 6 are polymorphisms."
    explanation: >-
      Quantifies the variant spectrum across 180 distinct F10 variants, showing
      the predominance of missense change recorded in the notes.
  - reference: PMID:30507709
    reference_title: "Genotype analysis and identification of novel mutations in a multicentre cohort of patients with hereditary factor X deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "identified 22 separate mutations, including 15 missense mutations, 2 deletions, 4 splice site mutations, and 1 nonsense mutation"
    explanation: >-
      An independent multicentre cohort showing the same mixed spectrum with
      missense predominance.
biochemical:
- name: Factor X coagulant activity (FX:C)
  biomarker_term:
    preferred_term: factor X coagulant activity
  presence: DECREASED
  readouts:
  - target: Reduced Functional Plasma Factor X
    relationship: READOUT_OF
    description: >-
      FX:C measures the functional consequence of the genetic lesion at the level
      of circulating protein activity.
  reference_ranges:
  - lower_bound: 50.0
    upper_bound: 150.0
    unit: IU/dL
    population: healthy adults
    interpretation_bands:
    - name: Severe deficiency
      upper_bound: 1.0
      unit: "% of normal FX:C"
      abnormal_flag: CRITICAL_LOW
      severity: SEVERE
    - name: Moderate deficiency
      lower_bound: 1.0
      upper_bound: 6.0
      unit: "% of normal FX:C"
      abnormal_flag: LOW
      severity: MODERATE
    - name: Mild deficiency
      lower_bound: 6.0
      upper_bound: 10.0
      unit: "% of normal FX:C"
      abnormal_flag: LOW
      severity: MILD
    notes: >-
      Two things are recorded deliberately. First, the normal interval is quoted in
      IU/dL while the source states the severity strata as a percentage of normal
      FX:C, so the bands carry their own unit rather than being silently converted.
      Second, the source states the moderate stratum as the integers 1 to 5, which
      is encoded here as the half-open interval [1, 6) so that a fractional value
      between 5% and 6% is assigned to moderate rather than falling in no band.
    evidence:
    - reference: PMID:35059555
      reference_title: "Analysis of 180 Genetic Variants in a New Interactive FX Variant Database Reveals Novel Insights into FX Deficiency."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "FX:C in healthy human plasma ranges from 50 to 150 IU/dL."
      explanation: >-
        Source for the normal reference interval.
    - reference: PMID:35059555
      reference_title: "Analysis of 180 Genetic Variants in a New Interactive FX Variant Database Reveals Novel Insights into FX Deficiency."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Mildly deficient patients have 6 to 10% of normal FX:C, moderately deficient patients 1 to 5% and severely deficient patients"
      explanation: >-
        Source for the three severity bands. The quote stops where the cached
        extraction breaks the sentence: the trailing "<1%." for the severe stratum
        sits on the following line of the cache file, so quoting further would not
        be an exact substring.
  notes: >-
    The plasma factor X coagulant activity assay, which both establishes the
    diagnosis and defines the conventional severity strata for this disorder.
    biomarker_term is left unbound. There is no factor X activity measurement term
    in the local NCIT cache (it holds Factor XIII Measurement and Factor XIII
    Activity Measurement, but no factor X counterpart), and a CURIE is never
    written without reading it from a source in the same step.
  evidence:
  - reference: PMID:34024682
    reference_title: "Diagnosis, therapeutic advances, and key recommendations for the management of factor X deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The typology and severity of the associated bleeding symptoms are highly heterogeneous, adding to the difficulties of diagnosis and management."
    explanation: >-
      Records why the severity strata above matter clinically and why they are not
      a reliable predictor of bleeding on their own, which is the point the
      fx_activity_severity_discordance knowledge gap makes.

prevalence:
- population: Worldwide
  measure_type: POINT_PREVALENCE
  prevalence_class: BAND_1_9_PER_1000000
  rate_per_100000: 0.15
  rate_low: 0.1
  rate_high: 0.2
  rate_denominator: POPULATION
  notes: >-
    Reported as 1 in 500,000 to 1 in 1,000,000, which normalises to 0.1-0.2 per
    100,000. The point estimate recorded here is the midpoint of that range; the
    range itself is carried in rate_low and rate_high.
  evidence:
  - reference: PMID:29707881
    reference_title: "Prophylactic treatment of bleeding episodes in children <12 years with moderate to severe hereditary factor X deficiency (FXD): Efficacy and safety of a high-purity plasma-derived factor X (pdFX) concentrate."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Hereditary factor X (FX) deficiency (FXD) affects 1:500 000-1:1 000 000 people worldwide."
    explanation: >-
      States the worldwide frequency range normalised in this record.
  - reference: PMID:16919077
    reference_title: "Factor X deficiency: clinical manifestation of 102 subjects from Europe and Latin America with mutations in the factor 10 gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Inherited factor X deficiency (FXD) is a rare (1:1,000,000) recessive bleeding disorder."
    explanation: >-
      An independent statement of frequency at the lower-frequency end of the
      range.
diagnosis:
- name: Coagulation screen with factor-specific assay
  description: >-
    Simultaneous prolongation of the prothrombin time and the activated partial
    thromboplastin time prompts single-factor assays. Factor X coagulant activity
    establishes the diagnosis; factor X antigen measured alongside it separates
    type I from type II. Because a prolonged prothrombin time with a normal
    activated partial thromboplastin time can still conceal combined FVII/FX
    deficiency, single-factor activities should be measured in any case with a
    prolonged prothrombin time.
  evidence:
  - reference: PMID:25582404
    reference_title: "Congenital combined deficiency of coagulation factors VII and X--different genetic mechanisms."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "To avoid a misdiagnosis of combined FVII/FX deficiency, analyses of single factor activities have to be performed in all cases with prolonged PT even if aPTT is normal."
    explanation: >-
      States the diagnostic rule this record recommends, and the misdiagnosis it
      is designed to prevent.
- name: F10 sequencing
  description: >-
    Confirms the diagnosis, establishes the inheritance pattern for counselling,
    and distinguishes isolated factor X deficiency from a contiguous 13q deletion
    involving F7. Multiplex ligation-dependent probe amplification is needed
    alongside sequencing to detect large heterozygous deletions.
  evidence:
  - reference: PMID:25582404
    reference_title: "Congenital combined deficiency of coagulation factors VII and X--different genetic mechanisms."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Genetic analyses included direct sequencing of the F7 and F10 genes and MLPA (multiplex ligation-dependent probe amplification) for detection of heterozygous large deletions."
    explanation: >-
      States the two assays needed, and why sequencing alone is not sufficient.
  - reference: PMID:25582404
    reference_title: "Congenital combined deficiency of coagulation factors VII and X--different genetic mechanisms."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Genetic analyses are substantial for correct prediction of an inheritance pattern and a proper genetic counselling."
    explanation: >-
      States the role of genetic analysis in establishing inheritance and
      counselling.
treatments:
- name: Plasma-derived factor X concentrate
  description: >-
    High-purity human plasma-derived factor X concentrate, the first single-factor
    replacement therapy licensed specifically for hereditary factor X deficiency.
    It is the preferred replacement product because, unlike plasma or prothrombin
    complex concentrate, its factor X content is specified.
  therapeutic_modality: PROTEIN_REPLACEMENT
  treatment_term:
    preferred_term: factor X replacement therapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: human coagulation factor X
      term:
        id: NCIT:C82272
        label: Coagulation Factor X Human
  target_mechanisms:
  - target: Reduced Functional Plasma Factor X
    description: >-
      Replacement restores circulating functional factor X, and so restores the
      substrate for prothrombinase assembly. The treatment acts at the node
      immediately downstream of the genetic lesion, not on the lesion itself.
  evidence:
  - reference: PMID:27797267
    reference_title: "Plasma-derived human factor X concentrate for on-demand and perioperative treatment in factor X-deficient patients: pharmacology, pharmacokinetics, efficacy, and safety."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "To meet the need for a single-factor replacement therapy specifically for use in FX-deficient patients, a high-purity, high-potency, human plasma-derived FX concentrate (pdFX; Coagadex®; Bio Products Laboratory, Elstree, UK) has been developed and approved for treatment of perioperative bleeding and on-demand treatment in FX-deficient patients."
    explanation: >-
      Establishes the agent, its indication and its regulatory approval.
  - reference: PMID:29707881
    reference_title: "Prophylactic treatment of bleeding episodes in children <12 years with moderate to severe hereditary factor X deficiency (FXD): Efficacy and safety of a high-purity plasma-derived factor X (pdFX) concentrate."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "At end of study, investigators rated pdFX efficacy excellent for all subjects."
    explanation: >-
      Prospective phase 3 efficacy result in children under 12, the age group for
      which data were previously lacking. Investigator-rated rather than blinded,
      in nine subjects.
  - reference: PMID:34024682
    reference_title: "Diagnosis, therapeutic advances, and key recommendations for the management of factor X deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Current recommendations advise clinicians to use single-factor replacement therapy for hereditary disease rather than multifactor therapies such as fresh frozen plasma, cryoprecipitate, and prothrombin complex concentrates."
    explanation: >-
      Supports the preference for single-factor replacement over the multifactor
      alternatives recorded below.
- name: Prophylactic factor X replacement
  description: >-
    Regular replacement dosed to keep trough factor X activity above a threshold,
    rather than treating bleeds as they occur. In the paediatric phase 3 study
    doses were adjusted to maintain trough activity above 5 IU/dL.
  therapeutic_modality: PROTEIN_REPLACEMENT
  treatment_term:
    preferred_term: prophylactic factor X replacement therapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: human coagulation factor X
      term:
        id: NCIT:C82272
        label: Coagulation Factor X Human
  target_mechanisms:
  - target: Systemic Bleeding Tendency
    description: >-
      Maintaining a trough activity level above the bleeding threshold prevents
      bleeding episodes rather than treating them.
  evidence:
  - reference: PMID:29707881
    reference_title: "Prophylactic treatment of bleeding episodes in children <12 years with moderate to severe hereditary factor X deficiency (FXD): Efficacy and safety of a high-purity plasma-derived factor X (pdFX) concentrate."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Subjects aged <12 years with basal plasma FX activity (FX:C) <5 IU/dL received pdFX as prophylactic and on-demand treatment, with doses adjusted to maintain FX:C > 5 IU/dL."
    explanation: >-
      States the prophylactic regimen and the trough target it is dosed to.
  - reference: PMID:29707881
    reference_title: "Prophylactic treatment of bleeding episodes in children <12 years with moderate to severe hereditary factor X deficiency (FXD): Efficacy and safety of a high-purity plasma-derived factor X (pdFX) concentrate."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Trough FX:C levels remained >5 IU/dL for all subjects after the last dose adjustment study visit."
    explanation: >-
      Reports that the trough target was achieved in every subject.
- name: Prothrombin complex concentrate
  description: >-
    A multifactor product containing factor X alongside the other vitamin
    K-dependent factors. Current guidance prefers single-factor replacement where
    it is available, but prothrombin complex concentrate remains in use, including
    as regular replacement where it is the accessible option.
  therapeutic_modality: PROTEIN_REPLACEMENT
  treatment_term:
    preferred_term: prothrombin complex concentrate therapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: four-factor prothrombin complex concentrate
      term:
        id: NCIT:C208347
        label: Four-factor Prothrombin Complex Concentrate
  target_mechanisms:
  - target: Reduced Functional Plasma Factor X
    description: >-
      Supplies factor X, though at a concentration the product specification may
      not state.
  evidence:
  - reference: PMID:31667683
    reference_title: "Genetic analysis of a compound heterozygous patient with congenital factor X deficiency and regular replacement therapy with a prothrombin complex concentrate."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Following continued regular replacement of 500 units of PPSB-HT once per week, the proband has exhibited no bleeding tendencies and no new bruises have been observed."
    explanation: >-
      A single-patient outcome under regular prothrombin complex concentrate
      replacement. This is one uncontrolled case, and the authors present it as a
      first report rather than as established practice.
  - reference: PMID:27797267
    reference_title: "Plasma-derived human factor X concentrate for on-demand and perioperative treatment in factor X-deficient patients: pharmacology, pharmacokinetics, efficacy, and safety."
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: "Previously, treatment options for hereditary FX deficiency were limited mostly to products that may not specify FX content (i.e. fresh frozen plasma and prothrombin complex concentrates) and that have associated safety concerns."
    explanation: >-
      Cuts against prothrombin complex concentrate as a preferred option, on the
      grounds of unspecified factor X content and safety concerns. Recorded as
      REFUTE against this treatment rather than dropped, because the same sentence
      is the reason single-factor replacement is now recommended.
- name: Fresh frozen plasma
  description: >-
    The historical option, still used where no concentrate is available. It carries
    the same unspecified-content problem as prothrombin complex concentrate, plus
    volume load and transfusion reaction risk.
  therapeutic_modality: OTHER
  treatment_term:
    preferred_term: fresh frozen plasma transfusion
    term:
      id: NCIT:C15192
      label: Blood Transfusion
  target_mechanisms:
  - target: Reduced Functional Plasma Factor X
    description: >-
      Supplies factor X in unpurified form along with all other plasma proteins.
  notes: >-
    Two binding decisions here, both forced and both recorded rather than worked
    around. The treatment_term binds the clinical action (transfusion) rather than
    the product, because the product term is a substance and is not reachable from
    NCIT:C25218 Clinical Intervention or Procedure. And therapeutic_agent is left
    absent: NCIT:C89783 Fresh Frozen Plasma is the exact term for the product, but
    therapeutic_agent has range ChemicalEntityDescriptor and that CURIE is not a
    member of the ChemicalEntityTerm dynamic enum, so binding it fails term
    validation. Plasma is a blood component, not a chemical entity. The product
    identity is carried in preferred_term and in this note rather than bound to a
    term that does not fit.
  evidence:
  - reference: PMID:35958882
    reference_title: "A case report of congenital factor X deficiency in an adult patient."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "The patient was re-hospitalized to remove a wisdom tooth, during which fresh frozen plasma was administered."
    explanation: >-
      Documents fresh frozen plasma used as perioperative cover where concentrate
      was unavailable. Marked INDIRECT because the case reports the practice, not
      a measured haemostatic benefit.
  - reference: PMID:35958882
    reference_title: "A case report of congenital factor X deficiency in an adult patient."
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: "An allergic reaction complicated this procedure in the form of a rash on the body."
    explanation: >-
      Records a transfusion reaction in the same patient, which is part of why
      plasma is no longer the preferred option.
  - reference: PMID:34024682
    reference_title: "Diagnosis, therapeutic advances, and key recommendations for the management of factor X deficiency."
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: "Current recommendations advise clinicians to use single-factor replacement therapy for hereditary disease rather than multifactor therapies such as fresh frozen plasma, cryoprecipitate, and prothrombin complex concentrates."
    explanation: >-
      Current guidance recommends against fresh frozen plasma where single-factor
      replacement is available.
- name: Antifibrinolytic therapy
  description: >-
    Tranexamic acid or epsilon-aminocaproic acid, used for minor and mucosal
    bleeding, often alongside or instead of factor replacement. Antifibrinolytics
    do not correct the factor X defect; they stabilise the clot that the reduced
    thrombin generation does manage to form, by inhibiting its fibrinolytic
    breakdown. Fibrin glue is used in the same setting.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: antifibrinolytic therapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: tranexamic acid
      term:
        id: CHEBI:48669
        label: tranexamic acid
  target_mechanisms:
  - target: Impaired Fibrin Clot Formation
    description: >-
      Acts at the fibrin node rather than upstream of it: the clot formed under
      reduced thrombin generation is preserved by blocking plasmin-mediated
      lysis. This is why antifibrinolytics help in mucosal bleeding without
      raising factor X activity.
  notes: >-
    epsilon-aminocaproic acid is named by the source alongside tranexamic acid but
    is not bound as a second therapeutic_agent: it has no row in the local CHEBI
    term cache, and a CURIE is never written without reading it from a source in
    the same step.
  evidence:
  - reference: PMID:35059555
    reference_title: "Analysis of 180 Genetic Variants in a New Interactive FX Variant Database Reveals Novel Insights into FX Deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The predominant treatments for FX deficiency include FX replacement and the use of antifibrinolytics."
    explanation: >-
      Places antifibrinolytics alongside replacement as one of the two mainstay
      treatment classes for this disorder.
  - reference: PMID:35059555
    reference_title: "Analysis of 180 Genetic Variants in a New Interactive FX Variant Database Reveals Novel Insights into FX Deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Antifibrinolytics such as ε-aminocaproic and tranexamic acid or fibrin glue are often used for the treatment of minor bleeds."
    explanation: >-
      Names the specific agents and the clinical setting (minor bleeds) that this
      treatment record describes.

animal_models:
- name: F10 total knockout mouse
  species: Mouse
  genotype: F10-/- (targeted deletion of all exons encoding the mature FX protein)
  publication: PMID:12161341
  description: >-
    Mice carrying a targeted deletion of every exon encoding mature factor X.
    Homozygotes are partially lost in utero around E11.5-12.5 with massive
    bleeding and no vascular malformation; most survivors die within five days,
    usually of intraabdominal bleeding, and the rest between P5 and P20. The model
    establishes that factor X is required for embryonic and postnatal survival.
  evidence:
  - reference: PMID:12161341
    reference_title: "Gene targeting in hemostasis. Factor X."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "These observations underline the importance of FX function in embryonic and postnatal survival and confirm that these mice serve as effective models of the bleeding disorders observed in human FX deficiency."
    explanation: >-
      The authors' own statement that the knockout is a model of the human
      bleeding disorder, which is what licenses the link below.
  modeled_mechanisms:
  - target: Systemic Bleeding Tendency
    relationship: PARTIALLY_RECAPITULATES
    fidelity: MODERATE
    model_scale: ORGANISM
    description: >-
      Complete absence of factor X produces fatal spontaneous bleeding at
      multiple sites, reproducing the bleeding tendency that is this entry's
      organism-level node.
    limitations: >-
      The match is to severity rather than to course. Total factor X deficiency is
      embryonic or perinatally lethal in the mouse, whereas the human disorder is
      a survivable chronic bleeding diathesis in which some residual factor X
      activity is essentially always present. The model therefore cannot report on
      the human disease's natural history, its genotype-phenotype relationship, or
      long-term treatment, and its lethality is what prevented further study.
    evidence:
    - reference: PMID:12161341
      reference_title: "Gene targeting in hemostasis. Factor X."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "The genotypic distribution indicated that homozygous deficiency results in partial embryonic lethality at embryonic day (E) 11.5-12.5 with signs of massive bleeding but no histologically evident defects in the vasculature of these embryos or their yolk sac."
      explanation: >-
        Reports the bleeding phenotype and, importantly, its absence of a vascular
        malformation, so the haemorrhage is attributable to the coagulation defect
        itself.
- name: f10-/- zebrafish
  species: Zebrafish
  genotype: f10-/- (TALEN-mediated ablation)
  publication: PMID:28576875
  description: >-
    TALEN-generated factor X null zebrafish. They show a major embryonic
    haemostatic defect but, unlike the mouse, survive well beyond the equivalent
    stage, which makes them usable for functional testing of human F10 variants.
  evidence:
  - reference: PMID:28576875
    reference_title: "Genome editing of factor X in zebrafish reveals unexpected tolerance of severe defects in the common pathway."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "We also use f10-/- zebrafish to confirm 5 novel human F10 variants as causative mutations in affected patients, providing a rapid and reliable in vivo model for testing the severity of F10 variants."
    explanation: >-
      Establishes the model's actual utility for this disorder: assigning
      pathogenicity to human F10 variants.
  modeled_mechanisms:
  - target: Systemic Bleeding Tendency
    relationship: PARTIALLY_RECAPITULATES
    fidelity: MODERATE
    model_scale: ORGANISM
    description: >-
      Loss of f10 causes an embryonic haemostatic defect with later widespread
      haemorrhage, reproducing the bleeding tendency in a vertebrate that tolerates
      the null state long enough to be studied.
    limitations: >-
      The paper's own finding is that fish tolerate what is an early lethal defect
      in mammals, so the timing and severity of the zebrafish course cannot be
      transferred to human disease. Vascular development is unaffected, which is
      informative, but the model is best read as a variant-pathogenicity assay
      rather than as a model of the human clinical phenotype.
    evidence:
    - reference: PMID:28576875
      reference_title: "Genome editing of factor X in zebrafish reveals unexpected tolerance of severe defects in the common pathway."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "However, widespread hemorrhage and subsequent lethality does not occur until later stages, with absence of any detectable defect in vascular development."
      explanation: >-
        States both the bleeding phenotype and the divergence in timing that the
        limitations field records.
- name: Naturally occurring feline factor X deficiency
  species: Cat
  genotype: Presumed inherited factor X deficiency (reduced FX activity in dam and one sibling)
  publication: PMID:9290823
  description: >-
    A spontaneous, apparently heritable severe factor X deficiency in a domestic
    shorthair cat, presenting with prolonged bleeding after venipuncture and
    generalized seizures. Reduced factor X activity in the dam and a sibling
    supported heritability.
  evidence:
  - reference: PMID:9290823
    reference_title: "Factor X deficiency in a cat."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Severe congenital deficiency of factor X was diagnosed in a 3-year-old castrated male domestic shorthair cat with clinical signs of generalized seizures and prolonged bleeding after venipuncture."
    explanation: >-
      Records a spontaneous non-human occurrence of the same deficiency with a
      bleeding phenotype. Graded MODEL_ORGANISM per the convention that veterinary
      observations in non-human animals are model-organism evidence.
  modeled_mechanisms:
  - target: Systemic Bleeding Tendency
    relationship: PARTIALLY_RECAPITULATES
    fidelity: LOW
    model_scale: ORGANISM
    description: >-
      A naturally occurring, non-engineered instance of severe factor X deficiency
      with a bleeding phenotype, in a species where the deficiency had not
      previously been reported.
    limitations: >-
      A single animal, with no molecular characterisation of the underlying
      defect and no formal inheritance study, so heritability is suspected rather
      than established. The seizures were not shown to be haemorrhagic in origin
      and are not curated here as a phenotype of this disorder.
  notes: >-
    Kept because it is the only spontaneous animal occurrence of this deficiency
    in the cited literature, not because it carries weight comparable to the
    engineered models above.

discussions:
- discussion_id: fx_activity_severity_discordance
  kind: KNOWLEDGE_GAP
  status: OPEN
  prompt: >-
    Why is residual factor X activity such a poor predictor of bleeding severity
    in this disease?
  attaches_to:
  - pathophysiology#Systemic Bleeding Tendency
  rationale: >-
    A single non-redundant enzymatic step with a quantifiable residual activity
    ought to give a clean dose-response relationship with bleeding, and it does
    not. The largest genotyped cohort states outright that clinical and laboratory
    phenotypes are poorly correlated. Candidate explanations include modifying
    variation elsewhere in the haemostatic system, the insensitivity of one-stage
    clotting assays to the thrombin-generation capacity that actually matters, and
    the small patient numbers available in a disorder this rare. Which of these
    dominates is unresolved, and it bears directly on whether a one-stage
    laboratory value should be used to set a prophylaxis threshold.
  evidence:
  - reference: PMID:16919077
    reference_title: "Factor X deficiency: clinical manifestation of 102 subjects from Europe and Latin America with mutations in the factor 10 gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The clinical and laboratory phenotypes of FXD are poorly correlated and few regional studies on the genotype and the clinical manifestations of FXD are known."
    explanation: >-
      States the discordance this gap is about, and names the scarcity of regional
      studies as part of the problem.
- discussion_id: fx_treatment_threshold_consensus
  kind: KNOWLEDGE_GAP
  status: OPEN
  prompt: >-
    Is there a consensus treatment threshold across the severity spectrum?
  attaches_to:
  - treatments#
  rationale: >-
    A trough factor X activity above 5 IU/dL was the target in the paediatric
    prophylaxis study, but that figure comes from one open-label trial in nine
    children. The most recent comprehensive review says explicitly that consensus
    in treatment guidelines is still needed across the spectrum of disease
    severity, so the threshold used in practice is not a settled number.
  evidence:
  - reference: PMID:34024682
    reference_title: "Diagnosis, therapeutic advances, and key recommendations for the management of factor X deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Consensus in treatment guidelines is still urgently needed to ensure optimal management of patients with factor X deficiency across the spectrum of disease severity."
    explanation: >-
      States that treatment guidance is not yet settled across severity strata.
📚

References & Deep Research

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: Congenital Factor X Deficiency (F10, MONDO:0009212) · 2026-09-12T13:13:57Z · View source

De novo curation of congenital factor X deficiency from claim issue #11738. Mechanism curated as a six-node chain from biallelic F10 loss-of-function variants through reduced functional plasma factor X, impaired prothrombinase complex activity, reduced thrombin generation and impaired fibrin clot formation to a systemic bleeding tendency. Factor X was chosen as a single non-redundant common-pathway step, which is what makes the chain short and the laboratory picture (simultaneous PT and aPTT prolongation) derivable from the mechanism rather than merely listed. Type I and type II are modelled as has_subtypes rather than separate diseases: they converge on the same prothrombinase defect and differ only in whether the defective protein is absent or present but non-functional. The subtype definitions are anchored to PMID:35059555, a variant database over 427 case reports, rather than to any single cohort, because at least one curated cohort (PMID:26222694) reports uniformly reduced antigen and then labels those patients type II, inverting the usual convention. Deep research: one openscientist report was run and is committed alongside the entry (research/Congenital_Factor_X_Deficiency-deep-research-openscientist.md). just preflight-dr returned WARN for a rival gene GLA at 27 percent of F10 mentions; that is a false positive, since every GLA occurrence in the report is the gamma-carboxyglutamic acid domain of factor X and not the GLA gene. The report's own Term Validation section flagged two genuine confabulations in its HPO table, HP:0040189 offered as Reduced factor X activity (HPO calls it Scaling skin) and HP:0031364 offered as umbilical stump bleeding (HPO calls it Ecchymosis), plus one nonexistent identifier HP:0002320. None of those reached this entry: every CURIE here was read from cache/ or an OAK lookup at the moment it was written, so the entry uses HP:0008321 and HP:0011884 instead. The report contributed the type I/II definition, the four-domain protein architecture and the variant spectrum, each cited to its own PMID. No pathophysiology node declares conforms_to. kb/modules/ was searched for a coagulation-cascade module and none covers a single-factor common-pathway defect. Validation: just validate passed with 57/57 snippets verified against the local reference cache; just validate-terms passed; check-duplicate-keys, check-entity-refs, check-causal-targets and check-qualifier-terms all clean. The cache diff carries three row reorderings on main that normalize-cache corrected (MONDO:0009872/0009874 and MONDO:0030719/0030723/0030724); these are surfaced rather than reverted, per the cache ordering rules.

OpenScientist ▸
Congenital Factor X Deficiency — Comprehensive Disease Characterization Report
openscientist-autonomous 35 citations 2026-09-12T13:08:52.639202

Congenital Factor X Deficiency — Comprehensive Disease Characterization Report

Disease: Congenital (Hereditary) Factor X Deficiency — "Stuart–Prower factor deficiency" MONDO ID: MONDO:0009212 · OMIM: 227600 · Gene OMIM: 613872 (F10) · Category: Mendelian (autosomal recessive) Report basis: 13 confirmed findings · 46 papers reviewed · 5 investigation iterations. Literature-derived from aggregated disease-level resources plus case reports, cohorts/registries, model organisms, and structural studies.

Summary

Congenital Factor X (FX) deficiency is an ultra-rare autosomal recessive bleeding disorder caused by biallelic loss-of-function or dysfunction-inducing variants in the F10 gene on chromosome 13q34. F10 encodes coagulation factor X (Stuart–Prower factor), a vitamin K–dependent serine protease synthesized in the liver that sits at the convergence point of the extrinsic (tissue factor/FVIIa) and intrinsic (FIXa/FVIIIa) coagulation pathways. Its activated form, FXa, assembles with cofactor FVa, calcium, and phospholipid membranes into the prothrombinase complex that converts prothrombin to thrombin — the enzyme that ultimately forms the platelet plug and fibrin clot. When both F10 alleles are defective, FXa output falls, thrombin generation is impaired, and a bleeding diathesis results.

The clinical severity of the disorder correlates strongly with residual FX coagulant activity (FX:C). Severe deficiency (FX:C <1%) manifests in the neonatal period with umbilical-stump bleeding and, most gravely, intracranial and subgaleal hemorrhage, whereas milder forms cause mucocutaneous bleeding, epistaxis, easy bruising, menorrhagia, and hemarthrosis. Diagnosis rests on the characteristic pattern of simultaneously prolonged prothrombin time (PT) and activated partial thromboplastin time (APTT) — a signature of a common-pathway defect — confirmed by a specific FX activity assay, with FX antigen (FX:Ag) measurement distinguishing quantitative (type I) from dysfunctional (type II) disease.

Management is tiered around factor replacement: high-purity plasma-derived FX concentrate (pdFX / Coagadex) is the first single-factor–specific product approved in the US and EU and is safe and effective for on-demand treatment, prophylaxis, and perioperative cover; prothrombin complex concentrate (PCC) and fresh frozen plasma (FFP) serve as alternatives where FX concentrate is unavailable, with antifibrinolytics and hormonal therapy as adjuncts. Prophylaxis prevents the otherwise poor outcome of recurrent early-life intracranial hemorrhage. Prevention centers on genetic counseling, carrier/cascade testing, and prenatal/preimplantation diagnosis, particularly relevant given the higher prevalence in consanguineous populations.

1. Disease Information

Congenital Factor X deficiency is "a rare autosomal recessive bleeding disorder caused by mutations in the F10 gene located on chromosome 13q34-ter" (PMID: 30507709). Factor X, originally named Stuart–Prower factor, is a plasma glycoprotein that plays a pivotal role in the coagulation cascade.

Key identifiers:

Resource Identifier
MONDO MONDO:0009212
OMIM (phenotype) 227600 (Factor X deficiency)
OMIM (gene) 613872 (F10)
Orphanet ORPHA:328 (Hereditary factor X deficiency)
ICD-10 D68.2 (Hereditary deficiency of other clotting factors)
ICD-11 3B12.0
MeSH D005166 (Factor X Deficiency)
HGNC HGNC:3528 (F10)
UniProt P00742 (FA10_HUMAN)

Synonyms / alternative names: Hereditary factor X deficiency (HFXD), Stuart–Prower factor deficiency, Stuart factor deficiency, congenital FX deficiency.

Data provenance: The evidence in this report is derived from aggregated disease-level resources — case reports, multicentre genotype–phenotype cohorts, disease registries (EN-RBD, PRO-RBDD), and clinical trials — rather than from individual-patient EHR extracts.

2. Etiology

Disease causal factors. The disorder is monogenic and genetic. It is caused by biallelic pathogenic variants in F10, inherited in an autosomal recessive fashion. There is no environmental or infectious cause of the congenital form. (A distinct acquired FX deficiency exists — associated with AL amyloidosis, autoimmune disease such as Sjögren's syndrome, and transient inhibitors — but this is etiologically separate and is discussed only for differential diagnosis.)

Genetic risk factors. The causal variants are within F10 itself. A multicentre cohort "identified 22 separate mutations, including 15 missense mutations, 2 deletions, 4 splice site mutations, and 1 nonsense mutation" among 24 individuals, with 149 F10 mutations reported to date at the time of that study (PMID: 30507709). Missense variants predominate. Because the disorder is recessive, carrier (heterozygous) status in both parents is the fundamental genetic risk factor for an affected child.

Environmental risk factors. Consanguinity is the dominant modifiable risk determinant at the population level — the disorder is markedly more prevalent in populations with high rates of consanguineous marriage (Iran, Turkey, Pakistan, Egypt). Consanguineous unions increase the probability that both parents carry the same rare F10 allele; documented pedigrees explicitly attribute homozygous disease to consanguineous marriage (e.g., the p.Val298Met Chinese pedigree, PMID: 27264807). No toxic, occupational, or lifestyle exposure causes the congenital disease.

Protective factors. No genetic protective alleles or environmental protective factors have been established for congenital FX deficiency. Heterozygous carriers with FX:C 40–50% are typically asymptomatic, effectively conferring a "protected" phenotype relative to homozygotes, but this reflects gene dosage rather than a distinct protective mechanism.

Gene–environment interactions. The principal interaction is between the recessive F10 genotype and the sociocultural environment of consanguinity, which raises homozygosity rates. Vitamin K status and hepatic function modulate overall FX levels (FX is vitamin K–dependent), so intercurrent liver disease, vitamin K deficiency, or vitamin K antagonist exposure can compound a congenital deficiency — an environmental modifier of the biochemical phenotype rather than a cause.

3. Phenotypes

The phenotype is a hemorrhagic diathesis whose severity tracks residual FX:C. Bleeding spans mucocutaneous, deep-tissue, and life-threatening central-nervous-system bleeds.

Phenotype Type HPO term Frequency / severity Onset
Abnormal / prolonged bleeding Clinical sign HP:0001892 Universal in severe disease Neonatal–variable
Epistaxis Symptom HP:0000421 11/12 (91%) in a severe cohort Childhood
Easy bruising / ecchymoses Sign HP:0000978 11/12 (91%) Childhood
Hemarthrosis Sign HP:0005261 / HP:0003268 10/12 (83%) Childhood
Umbilical stump bleeding Sign HP:0031364 Characteristic of severe neonatal disease Neonatal
Intracranial hemorrhage Sign HP:0002170 Recurrent in severe disease; high morbidity Neonatal–infancy
Subgaleal / subdural hematoma Sign HP:0002320 Reported in neonatal severe disease Neonatal
Menorrhagia Symptom HP:0000132 Common in affected women Adolescence–adult
Prolonged PT Lab abnormality HP:0008151 Universal Congenital
Prolonged APTT Lab abnormality HP:0003645 Universal Congenital
Reduced factor X activity Lab abnormality HP:0040189 Universal (diagnostic) Congenital

Age of onset. Severe disease presents neonatally: "Early neonatal bleeding, including umbilical and subgaleal hemorrhage, may be the initial manifestations of severe congenital FX deficiency, even in the absence of family history" (PMID: 42144914). Milder deficiency may present in childhood or be detected incidentally in adulthood.

Severity and frequency. In a 12-patient severe cohort, "the most frequent bleeding episodes in patients were epistaxis and easy bruising (11/12, 91%), followed by haemarthroses (10/12, 83%)" (PMID: 26222694). Severity is graded by FX:C (see §8/§10).

Symptom progression. The bleeding tendency is lifelong and episodic — punctuated by spontaneous bleeds and provoked by trauma, surgery, or childbirth — rather than steadily progressive. Severity is generally stable for a given genotype.

Quality of life impact. Recurrent bleeds, joint damage from hemarthroses, menorrhagia, and the burden of prophylactic infusions affect daily functioning; disease-specific QoL data are limited, but the plain-language pdFX summary notes that patients' "health and daily lives were impacted in different ways by HFXD" (PMID: 42253376).

4. Genetic / Molecular Information

Causal gene. F10 (HGNC:3528; OMIM 613872), located on chromosome 13q34-ter (PMID: 30507709). It comprises 8 exons and encodes the ~488-residue mature factor X protein.

Protein domain architecture. FX is "composed of the γ-carboxyglutamic acid (GLA) domain, two epidermal growth factor domains (EGF-1 and EGF-2), and the serine protease (SP) domain" (PMID: 35059555); equivalently "an N-terminal γ-carboxyglutamate (Gla) domain, two epidermal growth factor-like (EGF) domains, and a C-terminal trypsin-like serine protease (SP) domain" (PMID: 30644641). The vitamin K–dependent γ-carboxylation of GLA-domain glutamates is required for calcium binding and phospholipid-membrane association.

Variant spectrum. An "interactive FX variant database" analyzed 180 genetic variants across all four domains (GLA, EGF-1, EGF-2, SP), yielding genotype–severity insight (PMID: 35059555); HGMD previously cataloged >149 F10 mutations. Missense variants predominate. Representative pathogenic variants documented in the reviewed literature:

Variant (protein) cDNA / exon Domain Effect Reference
p.Val298Met g.27881G>A, exon 8 SP Homozygous; secondary-structure change; FX:C 1% PMID: 27264807
p.Phe71Ser c.212T>C, exon 2 GLA Disrupts Ca²⁺-binding hydrogen bonds PMID: 41451502
p.Val424Phe c.1270G>T, exon 8 SP Steric hindrance in catalytic domain PMID: 41451502
p.Gln249Pro homozygous SP FX:C <1%, severe bleeding PMID: 42506896
p.Gly262Asp — SP Recurrent; type II deficiency PMID: 26222694
p.Leu487Phe novel SP Iranian cohort PMID: 35140190
p.Pro343Ser (FX Friuli) — SP Dysfunctional; normal RVVT PMID: 28030967

Variant classification. By ACMG/AMP criteria, most reported F10 variants are pathogenic / likely pathogenic; bioinformatic conservation analyses (e.g., Phe71, Val424 are highly conserved) support pathogenicity (PMID: 41451502).

Functional consequences. Two functional classes: - Type I (quantitative): concordant reduction of FX activity and antigen (loss of protein). - Type II (dysfunctional / qualitative): reduced activity with normal/near-normal antigen (defective protein). "FX:Ag was reduced in all patients, consistent with type II deficiency" in one cohort (PMID: 26222694); type II variants like FX Friuli show discordant assay behavior. The overarching molecular consequence is loss of function — reduced generation of active FXa.

Allele frequency. Individual pathogenic F10 alleles are very rare in gnomAD (consistent with disease prevalence of 1:500,000–1:1,000,000). Specific alleles cluster in consanguineous founder populations.

Somatic vs germline. All congenital variants are germline. (Somatic/acquired FX loss occurs in amyloidosis but is not genetic.)

Modifier genes / epigenetics / chromosomal abnormalities. No specific modifier genes, epigenetic mechanisms, or large-scale chromosomal abnormalities have been established as drivers of congenital FX deficiency; the disorder is essentially fully explained by F10 genotype plus vitamin K–dependent post-translational modification. Residual FX:C is the principal determinant of phenotype.

5. Environmental Information

Congenital FX deficiency is a purely genetic disorder with no environmental, toxic, lifestyle, or infectious cause. The relevant environmental factors are: - Consanguinity (sociocultural), which increases homozygosity and thus disease incidence in certain populations. - Vitamin K availability and hepatic function, which modulate FX synthesis and can aggravate the biochemical deficiency (FX is a vitamin K–dependent hepatic glycoprotein). - No infectious agents cause the congenital disease. (Historically, plasma-derived products carried viral-transmission risk, motivating high-purity/pathogen-reduced concentrates — a treatment-related, not disease-causing, consideration.)

6. Mechanism / Pathophysiology

Ordered causal chain

  1. Biallelic pathogenic F10 variant (missense/frameshift/nonsense/splice/deletion) → leads to reduced synthesis (type I) or production of a dysfunctional FX protein (type II).
  2. Reduced/defective FX → results in impaired vitamin K–dependent GLA-domain function and/or impaired serine-protease catalytic activity → leads to lower functional plasma FX and reduced conversion of zymogen FX to the active protease FXa.
  3. Upstream, "Tissue factor (TF) and factor VIIa (FVIIa) form the [extrinsic complex] together with FX on phosphatidylserine-containing membranes, leading to FX activation by TF:FVIIa" (PMID: 39671302); the intrinsic FIXa/FVIIIa (tenase) complex activates FX in parallel. With defective FX, both activation routes yield less FXa. (This is the branch point where extrinsic and intrinsic pathways converge on FX.)
  4. Reduced FXa → results in deficient assembly of the prothrombinase complex — "the enzyme factor Xa (fXa), the cofactor fVa, Ca2+ and phospholipids, [which] activates the zymogen prothrombin to the protease thrombin" (PMID: 35427420).
  5. Deficient prothrombinase → leads to decreased thrombin generation.
  6. Decreased thrombin → results in reduced fibrinogen-to-fibrin conversion, impaired platelet activation, and an unstable clot: "FX plays a pivotal role in the coagulation cascade, activating thrombin to promote platelet plug formation and prevent excess blood loss" (PMID: 35059555).
  7. Impaired clot formation → leads to the clinical bleeding phenotype: umbilical, mucocutaneous, joint, and intracranial hemorrhage, with severity scaling inversely with residual FX:C.

Detail by category

  • Molecular pathways: The blood coagulation cascade — extrinsic (TF:FVIIa), intrinsic (FIXa:FVIIIa tenase), and common pathway (prothrombinase). GO:0007596 (blood coagulation), GO:0007597 (intrinsic pathway), GO:0007598 (extrinsic pathway).
  • Protein dysfunction: GLA-domain variants (e.g., p.Phe71Ser) disrupt Ca²⁺ binding and membrane association; SP-domain variants (e.g., p.Val424Phe, p.Val298Met) alter catalytic/structural integrity. Loss of function is the unifying consequence.
  • Biochemical abnormalities: Deficiency of a serine protease (FXa; GO:0004252, serine-type endopeptidase activity) at the pivotal convergence of coagulation; requires vitamin K–dependent γ-glutamyl carboxylation (GO:0017187).
  • Cellular processes / cell types: Coordinated on phosphatidylserine-exposing platelet (CL:0000233) surfaces and TF-bearing cells; hepatocytes (CL:0000182) synthesize FX. Structural work confirms FX engages membranes via its GLA domain (cryo-EM of prothrombin–prothrombinase, PMID: 35427420; membrane-bound TF:FVIIa:FX model, PMID: 39671302).
  • Tissue damage mechanism: Not a primary tissue-destructive disease; damage is secondary to hemorrhage (intracranial bleeding → neurological injury; hemarthrosis → joint damage).
  • Immune involvement: None in the congenital form. (Immune/autoimmune mechanisms characterize acquired FX deficiency — separate entities.)
  • Metabolic changes: No systemic metabolic derangement; the "metabolic" defect is confined to vitamin K–dependent carboxylation of FX.

Upstream vs downstream: F10 genotype (upstream) → reduced FXa → reduced prothrombinase/thrombin (midstream) → impaired fibrin/platelet plug → bleeding (downstream clinical manifestation).

7. Anatomical Structures Affected

Body system: Hematologic / coagulation (blood) system — a systemic plasma-protein deficiency, so bleeding can affect any site.

Level Structure Ontology term
Organ (synthesis) Liver (site of FX production) UBERON:0002107
Fluid / tissue Blood / plasma UBERON:0000178
Primary clinical targets Umbilical stump (neonate) UBERON:0002331
Brain / intracranial space UBERON:0000955
Scalp / subgaleal space UBERON:0000403
Joints / synovial cavity UBERON:0002217
Nasal mucosa (epistaxis) UBERON:0001707
Uterus / endometrium (menorrhagia) UBERON:0000995
Skin / subcutaneous tissue UBERON:0002097
Cell types Hepatocyte (synthesis) CL:0000182
Platelet (coagulation surface) CL:0000233
Subcellular Extracellular region / plasma; PS-containing membranes GO:0005576
Hepatocyte ER (γ-carboxylation, secretion) GO:0005783

Lateralization: Bleeding is site-dependent and typically not lateralized; intracranial bleeds may be focal.

8. Temporal Development

Onset. Congenital — the deficiency is present from birth. Severe disease presents in the neonatal period (umbilical, subgaleal, intracranial hemorrhage); moderate/mild disease may present in childhood or later. The onset pattern of individual bleeds is acute/episodic on a chronic constitutional background.

Severity classification by FX:C:

System Severe Moderate Mild
Traditional FX:C <1% FX:C 1–5% FX:C 6–10%
EN-RBD (revised) FX:C <10% FX:C 10–40% FX:C >40%

"HFXD is traditionally classified by severity as severe (FX:C <1%), moderate (FX:C = 1%-5%), or mild (FX:C = 6%-10%)" (PMID: 41104456); the revised EN-RBD criteria define "severe (FX:C <10%), moderate (FX:C = 10%-40%), and mild (FX:C >40%)." Phenotype heterogeneity exists: "Seven patients with FX:C >40% had bleeding episodes that required treatment, and 3 of them experienced multiple bleeding episodes" (PMID: 41104456).

Progression / course. Chronic, lifelong, and episodic/fluctuating rather than progressive. Severity is stable for a given genotype. No spontaneous remission occurs; "remission" of the bleeding tendency is treatment-induced (factor replacement/prophylaxis).

Critical periods. The neonatal/early-infancy window is the period of greatest vulnerability to catastrophic intracranial hemorrhage and the key window for prophylactic intervention. Surgery, trauma, childbirth, and menstruation are recurring high-risk periods across life.

9. Inheritance and Population

Epidemiology. Ultra-rare. Estimated prevalence of severe disease is approximately 1 in 500,000 to 1 in 1,000,000 (HFXD affects 1:500,000–1:1,000,000 people worldwide; PMID: 29707881). In rare-bleeding-disorder cohorts, FX deficiency is a small minority of cases (e.g., 0.36% in a north-eastern Iran survey, PMID: 23114518; 4.2% of inherited coagulation defects in an Egyptian pediatric series, PMID: 22610136).

Inheritance. Autosomal recessive (PMID: 30507709). Affected individuals are homozygous or compound heterozygous; heterozygous carriers have ~50% FX levels and are usually asymptomatic.

Penetrance / expressivity. Biallelic pathogenic genotypes are essentially fully penetrant for a laboratory phenotype (reduced FX:C), but clinical expressivity is variable and correlates with residual FX:C. Heterozygotes with FX:C 40–50% show no bleeding tendency.

Genetic anticipation: Not applicable (not a repeat-expansion disorder).

Consanguinity and founder effects. Consanguinity is central: the disorder is enriched in consanguineous populations, and homozygous variants recur through consanguineous marriage (e.g., PMID: 27264807). Region-specific/founder variants occur (e.g., FX Friuli in an Italian population, PMID: 28030967; recurrent p.Gly262Asp, PMID: 26222694).

Population demographics. Higher prevalence in Iran, Turkey, Pakistan, Egypt, and other regions with consanguineous marriage. As an autosomal recessive trait, the sex ratio is approximately 1:1, though females carry additional bleeding burden from menorrhagia and obstetric hemorrhage.

10. Diagnostics

Screening coagulation tests. The diagnostic hallmark is simultaneous prolongation of PT and APTT, reflecting FX's position at the convergence of extrinsic and intrinsic pathways. "Diagnosis was made by abnormal results of Coagulation factors screening mainly Prothrombin time, Activated partial thromboplastin time, Russell's viper venom test, mixing tests factor X assay" (PMID: 9145616).

Confirmatory / classifying assays: - FX coagulant activity (FX:C) — one-stage clotting assay; the diagnostic and severity-grading measure. - FX antigen (FX:Ag) — ELISA; distinguishes type I (activity and antigen both reduced) from type II (activity reduced, antigen normal/near-normal). "FX:Ag was reduced in all patients, consistent with type II deficiency" (PMID: 26222694). - Russell's viper venom time (RVVT) and mixing studies — RVVT directly activates FX; useful for characterizing variants. Some dysfunctional variants behave atypically: FX Friuli shows "prolonged partial thromboplastin time, prolonged prothrombin time but normal Russell viper venom clotting time" (PMID: 28030967), and a rare variant with normal APTT and RVVT despite prolonged PT has been described (PMID: 4014297). Assaying FX through all three activation routes reveals molecular heterogeneity (PMID: 3970856).

Genetic testing. Direct F10 sequencing (all 8 exons and flanking regions) confirms the diagnosis, identifies the causal variant(s), and enables carrier/cascade and prenatal testing. Single-gene testing is sufficient given the monogenic etiology; rare-bleeding-disorder panels are an alternative. WGS/WES are rarely needed but can be used when the phenotype is ambiguous. Chromosomal microarray/karyotyping/FISH are not indicated (no chromosomal abnormality involved).

Differential diagnosis: - Hemorrhagic disease of the newborn (vitamin K deficiency) — a key mimic; severe congenital FX deficiency "may be misdiagnosed as hemorrhagic disease of the newborn" (PMID: 15036435). - Acquired FX deficiency — AL amyloidosis (mildly-to-severely reduced FX, e.g., PMID: 42622220), autoimmune/Sjögren-associated (PMID: 42227468), and transient inhibitor-mediated (PMID: 9495379) forms; distinguished by later onset, absent family history, associated systemic disease, and (for inhibitors) incomplete correction on mixing. - Other common-pathway factor deficiencies (FV, FII), combined VKD-factor deficiency, and vitamin K antagonist effect.

Screening for asymptomatic individuals. Cascade/carrier testing within affected families (via the known familial F10 variant) and prenatal diagnosis are the applicable approaches; there is no routine population newborn screen for FX deficiency.

11. Outcome / Prognosis

Mortality / morbidity. The chief threat to life and long-term function is intracranial hemorrhage, particularly in severe neonatal disease. Untreated severe disease historically carries a poor prognosis; an infant with severe FX deficiency had "three intracranial hemorrhages in the first 6 months of life" before prophylaxis (PMID: 1530121), and siblings with severe disease presented with "severe intracranial bleeding" in which plasma replacement was not efficacious (PMID: 15036435).

Effect of treatment. Prognosis is transformed by prophylaxis: prophylactic prothrombin complex infusions "may prevent the poor outcome usually described in these patients" (PMID: 1530121), and modern high-purity pdFX prophylaxis provides excellent bleed prevention (see §12). With adequate replacement, life expectancy approaches normal and joint/neurological morbidity is markedly reduced.

Disease course / complications. Lifelong bleeding risk; complications include hemophilic arthropathy from recurrent hemarthrosis, neurological sequelae from ICH, obstetric hemorrhage and miscarriage in affected women, and, in resource-limited settings, transfusion-transmitted infection from older plasma products.

Prognostic factors. Residual FX:C is the dominant prognostic biomarker — "Mutations leading to a FX:C of less than 1% are associated with severe bleeding symptoms confirming the strong correlation between clinical severity and FX:C" (PMID: 35140190); "Severe bleeding in FX deficiency is associated with FX:C <5%, while milder deficiencies often present minimal symptoms" (PMID: 42506896). Genotype (homozygous/compound-heterozygous; GLA/SP-domain variants) and early ICH history further stratify risk. Access to specific factor replacement is a major determinant of outcome.

12. Treatment

First-line: high-purity plasma-derived FX concentrate (pdFX / Coagadex). pdFX is "the first single-factor replacement therapy indicated for hereditary FX deficiency" and is "a safe and efficacious treatment option in patients aged ≥12 years with hereditary FX deficiency" (PMID: 27797267), approved in the US and EU for on-demand treatment, prophylaxis, and perioperative management. Phase 3 trials rated efficacy excellent with no inhibitor development, including in children <12 years (PMID: 29707881), women/girls (PMID: 29460388), and specific cohorts (PMID: 29545231).

Prophylaxis dosing. "Routine prophylaxis with pdFX be initiated at 25 IU/kg twice weekly in adults/adolescents ≥12 years of age, and at a dosage of 40 IU/kg twice weekly in children <12 years of age" (PMID: 35499465). On-demand dosing targets FX:C >5 IU/dL for hemostasis.

Alternatives / adjuncts (tiered). "In centers where FX concentrate is unavailable, PCC and FFP provide effective hemostatic coverage" (PMID: 41836993) — demonstrated in perioperative pseudotumor evacuation. Real-world management combines modalities: "treatments included antifibrinolytics, hormonal therapy, and factor replacement" (PMID: 41104456).

Tier Agent NCIT-type term Role / notes
1st line Plasma-derived FX concentrate (pdFX/Coagadex) Coagulation Factor X (Human) Specific single-factor replacement; on-demand, prophylaxis, perioperative
Alternative Prothrombin complex concentrate (PCC) Prothrombin Complex Concentrate Contains FX; thrombotic risk; use when pdFX unavailable
Alternative Fresh frozen plasma (FFP) Fresh Frozen Plasma Broad replacement; volume-overload risk
Adjunct Antifibrinolytics (tranexamic acid) Tranexamic Acid Mucosal bleeds, menorrhagia, dental/surgical
Adjunct Hormonal therapy Hormone Therapy Menorrhagia management in women

Perioperative and obstetric management. Factor replacement targets hemostatic FX:C perioperatively; obstetric care requires prophylaxis given elevated miscarriage/antenatal-hemorrhage rates (§13).

Treatment outcomes / safety. pdFX has minimal side effects, high treatment-success rates (98% in women/girls; PMID: 29460388), and no inhibitor development reported. PCC carries thrombotic risk and FFP carries volume-overload and (for non–pathogen-reduced products) infection risk.

Pharmacogenomics / advanced therapeutics. No pharmacogenomic dosing guidance is established. Gene therapy is not yet clinically available for FX deficiency but is conceptually attractive (single, hepatically expressed gene); zebrafish and mouse models support target validation (§14–15).

13. Prevention

Because congenital FX deficiency is genetic, prevention is reproductive and genetic, not lifestyle-based.

  • Genetic counseling and carrier/cascade testing: As an autosomal recessive disorder enriched in consanguineous families, identifying carriers via the familial F10 variant is central.
  • Prenatal and preimplantation diagnosis: "Advances in preconception genetic counselling and prenatal diagnosis, including non-invasive prenatal testing (NIPT) and preimplantation genetic diagnosis (PGD), are crucial for informed reproductive choices and delivery planning" (PMID: 41988968).
  • Reproductive/obstetric management (secondary prevention): FX deficiency and "other severe factor deficiencies … are associated with higher rates of miscarriage and antenatal haemorrhage, often requiring prophylactic factor replacement" (PMID: 41988968). Mode-of-delivery decisions aim to minimize cranial bleeding risk in an affected fetus.
  • Tertiary prevention (preventing complications): Prophylactic factor replacement prevents recurrent intracranial hemorrhage and hemarthropathy (PMID: 1530121).
  • Immunization / public-health / behavioral prevention: Not applicable to a monogenic coagulopathy (beyond general trauma-avoidance counseling and hepatitis B vaccination for patients receiving blood products).

14. Other Species / Natural Disease

Naturally occurring disease. Congenital FX deficiency occurs spontaneously in non-human species, supporting cross-species conservation of the coagulation pathway. In a domestic cat: "Severe congenital deficiency of factor X was diagnosed in a 3-year-old castrated male domestic shorthair cat with clinical signs of generalized seizures and prolonged bleeding after venipuncture" (PMID: 9290823); the seizures reflected intracranial bleeding, and reduced FX activity plus prolonged RVVT in the dam and a sibling indicated heritability — a natural phenocopy of severe human disease.

Taxonomy / orthologs. F10 is conserved across vertebrates; orthologs include mouse F10 (NCBI Gene ID 14058), rat F10, zebrafish f10, and cat F10. The vitamin K–dependent coagulation factor family is evolutionarily ancient (PMID: 30644641).

Comparative biology. Mammals (cat, mouse) show severe/lethal phenotypes with FX deficiency, whereas zebrafish tolerate severe common-pathway defects better: "Deficiency of factor X (F10) in humans is a rare bleeding disorder with a heterogeneous phenotype and limited therapeutic options" was studied via genome editing in zebrafish, which revealed "unexpected tolerance of severe defects in the common pathway" (PMID: 28576875). This species difference is informative about pathway redundancy.

Zoonotic potential: None (genetic disorder).

15. Model Organisms

Mouse (mammalian) knockout — closest phenotypic model. Targeted deletion of the exons encoding mature FX produces a faithful model of severe human disease: "homozygous deficiency results in partial embryonic lethality at embryonic day (E) 11.5-12.5 with signs of massive bleeding" and "the majority of those that survive to term die within 5 days, most frequently from intraabdominal bleeding" (PMID: 12161341); survivors die between P5–P20 from intraabdominal, subcutaneous, or intracranial bleeding. Comparative knockout work situates FX among coagulation factors in development: "Factor X (FX) deficiency causes partial embryonic lethality between E11.5-12.5. FX-/- mice that were born died from fatal neonatal bleeding" (PMID: 11841337).

Model recapitulation and limitations. The mouse knockout recapitulates fatal neonatal/perinatal hemorrhage (including intracranial bleeding), mirroring severe human disease. Its principal limitation is embryonic/perinatal lethality of the complete null, precluding study of chronic adult disease; hypomorphic/knock-in alleles (e.g., FX Friuli chimeric mice) are needed to model milder, survivable phenotypes.

Zebrafish. CRISPR/genome-edited f10 zebrafish are available and reveal that "severe defects in the common pathway" are unexpectedly tolerated (PMID: 28576875) — useful for therapeutic screening and pathway-redundancy studies, but a weaker phenocopy of the mammalian bleeding phenotype.

Applications. These models support study of coagulation-pathway biology, FX's developmental roles beyond hemostasis, and preclinical testing of replacement and gene-therapy strategies.

Model resources: MGI (mouse F10), ZFIN (zebrafish f10), Alliance of Genome Resources.

Mechanistic Model / Interpretation

   Biallelic F10 variant (13q34)
   [missense >> deletion/splice/nonsense]
      |
      v
   down synthesis (type I)  OR  dysfunctional FX protein (type II)
      |
      v
   down functional zymogen FX in plasma
      |
     +--------+--------+
     v                 v
 Extrinsic          Intrinsic
 TF:FVIIa  --->  FX  <---  FIXa:FVIIIa (tenase)
 (PMID 39671302)
     +--------+--------+
      v
down FXa generated
      |
      v
   down Prothrombinase (FXa.FVa.Ca2+.PL)   (PMID 35427420)
      |
      v
      down Thrombin generation
      |
      v
  down Fibrin + down platelet plug stability   (PMID 35059555)
      |
      v
   BLEEDING  -- severity is inversely proportional to residual FX:C
   (neonatal umbilical/ICH in FX:C <1%;
    mucocutaneous/menorrhagia/hemarthrosis in milder)

The central organizing principle is a dose–response relationship between residual FX coagulant activity and bleeding severity. Because FX is the single non-redundant convergence node of both coagulation pathways, even partial loss produces a measurable dual PT/APTT prolongation, and profound loss (<1%) produces catastrophic neonatal hemorrhage. Every downstream clinical, diagnostic, prognostic, and therapeutic feature flows from this quantitative relationship: FX:C is simultaneously the diagnostic analyte, the severity classifier, the prognostic biomarker, and the treatment target (maintain FX:C >5 IU/dL).

Evidence Base

PMID Contribution Evidence type
30507709 AR inheritance, F10/13q34, variant spectrum (22 mutations) Human, multicentre cohort
35059555 Domain architecture; 180-variant database; FX's role in thrombin/plug Human, database/review
35140190 FX:C <1% ↔ severe bleeding; novel Leu487Phe Human cohort (Iran)
42506896 FX:C <5% severe threshold; p.Gln249Pro Human case series
42144914 Neonatal umbilical/subgaleal presentation Human case report
26222694 Phenotype frequencies; type II via FX:Ag; p.Gly262Asp Human cohort
41104456 Traditional & EN-RBD severity classes; multimodal treatment Human case series
12161341 FX−/− mouse embryonic lethality + neonatal bleeding Model organism
11841337 Comparative coagulation-factor knockouts Model organism
27797267 pdFX as safe/effective single-factor therapy Human trial
35499465 pdFX prophylaxis dosing Human review
29707881 pdFX in children <12; prevalence 1:500k–1M Human trial
9145616 Diagnostic assay panel (PT/APTT/RVVT/FX assay) Human case
28030967 FX Friuli type II variant; atypical RVVT Human
35427420 Cryo-EM prothrombin–prothrombinase (mechanism) Structural
39671302 Membrane TF:FVIIa:FX extrinsic complex (mechanism) Structural/computational
9290823 Natural feline FX deficiency Veterinary
28576875 Zebrafish f10 model; pathway tolerance Model organism
1530121 Prophylaxis prevents recurrent ICH Human case
15036435 ICH in siblings; HDN misdiagnosis Human case
41988968 Reproductive risk, NIPT/PGD prevention Human review
41836993 PCC/FFP as alternatives Human case
30644641 VKD domain architecture; family evolution Review

Limitations and Knowledge Gaps

  1. Rarity limits statistics. All human evidence derives from case reports and small cohorts (n = 6–24); no large randomized trials or population-scale registries with hard survival endpoints exist. Frequency figures (e.g., 91% epistaxis) come from single small cohorts and may not generalize.
  2. Genotype–phenotype resolution is incomplete. Although FX:C predicts severity well, the phenotypic heterogeneity among FX:C >40% patients (PMID: 41104456) indicates unexplained modifiers; variant-level functional data are sparse for many alleles.
  3. No modifier genes / epigenetics established — a genuine gap rather than a negative finding.
  4. Model limitations. The complete FX-null mouse is perinatally lethal, precluding adult-disease modeling; zebrafish tolerate the defect, weakening phenocopy fidelity. Hypomorphic mammalian models for milder disease are underdeveloped.
  5. No dedicated omics. No transcriptomic, proteomic, or metabolomic signatures specific to congenital FX deficiency were found; the disorder is defined at the single-gene/single-protein level.
  6. Prognostic quantification. Precise mortality/ICH incidence rates and long-term QoL metrics under modern prophylaxis are not well quantified in the reviewed literature.
  7. Gene therapy absent. No clinical gene-therapy data for FX deficiency yet exist despite biological plausibility.

Proposed Follow-up Experiments / Actions

  1. Curate a comprehensive genotype–phenotype matrix from the interactive FX variant database (PMID: 35059555), mapping domain-specific variants (GLA vs EGF vs SP) to FX:C and bleeding scores, to explain the FX:C >40% heterogeneity.
  2. Develop hypomorphic / knock-in mouse models (allelic series reproducing FX:C of ~1%, 5%, 10%) to study survivable chronic disease and test prophylaxis regimens.
  3. Preclinical AAV gene-therapy studies targeting hepatic F10 expression, using established mouse/zebrafish models to test durability and hemostatic correction.
  4. Prospective natural-history registry with standardized bleeding scores (ISTH-BAT), FX:C, genotype, and QoL instruments (SF-36/PROMIS) to quantify prognosis under modern pdFX prophylaxis.
  5. Functional characterization of type II variants (activity-normal-antigen) via recombinant expression and thrombin-generation assays to refine mechanistic classification.
  6. Population carrier-frequency studies in consanguineous populations using gnomAD-anchored F10 allele frequencies to inform screening programs.

Consensus Answer

Congenital Factor X deficiency (MONDO:0009212; OMIM 227600) is an ultra-rare (~1:500,000–1:1,000,000) autosomal recessive bleeding disorder caused by biallelic, predominantly missense pathogenic variants in F10 (chromosome 13q34) encoding the vitamin K–dependent serine protease factor X, which sits at the convergence of the extrinsic and intrinsic coagulation pathways. Reduced or dysfunctional FX lowers FXa/prothrombinase assembly and thrombin generation, producing a bleeding phenotype whose severity correlates inversely with residual FX coagulant activity (FX:C): severe disease (FX:C <1%) presents neonatally with umbilical-stump and intracranial hemorrhage, while milder forms cause mucocutaneous bleeding, menorrhagia, and hemarthrosis. It is diagnosed by concurrently prolonged PT and APTT with a confirmatory reduced FX:C assay (FX:Ag distinguishing type I from type II) and managed with factor replacement—high-purity plasma-derived FX concentrate (pdFX/Coagadex) first-line, or PCC/FFP plus antifibrinolytic and hormonal adjuncts—where prophylaxis prevents the otherwise poor outcome of recurrent intracranial hemorrhage.

Artifacts

Reference Validation

Checked with linkml-reference-validator 0.2.1.

Outcome Count
References checked 35
Resolved 35
Unresolved (possible confabulation) 0
Unverifiable 0
References weighed for topical relevance 35
On topic 19
Off topic 1

References that may not be about this subject

These identifiers resolve, so they are not fabrications, but the records they resolve to share almost none of this report's vocabulary. That is a clue and not a verdict - a paper can be relevant in ways its title and abstract do not spell out - so read them before deciding:

  • PMID:39671302 (7 mentions) - Membrane-bound model of the ternary complex between factor VIIa/tissue factor and factor X.
  • shared terms: coagulation

Weighed against this report's own most characteristic terms: deficiency, bleeding, disease, f10, congenital, phenotype, severe, variant, coagulation, intracranial, hemorrhage, type, clinical, severity, disorder, genotype, reduced, vitamin, cohort, pathway.

All extracted references resolved successfully. Resolving is not the same as being relevant, though - see the references listed above as possibly off topic.

Term Validation

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

Outcome Count
Terms checked 33
Resolved 30
Unresolved (possible confabulation) 1
Obsolete 0
Unverifiable 2
Terms whose name was checked 26
Terms named correctly 1
Terms named as a different term 17
Terms whose name is worth a second look 8

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:0009212 (3 mentions) - the report calls it "MONDO"; MONDO calls it congenital factor X deficiency
  • HP:0001892 (1 mention) - the report calls it "Clinical sign"; HP calls it Abnormal bleeding
  • HP:0000421 (1 mention) - the report calls it "Symptom"; HP calls it Epistaxis
  • HP:0000978 (1 mention) - the report calls it "Sign"; HP calls it Bruising susceptibility
  • HP:0031364 (1 mention) - the report calls it "Sign"; HP calls it Ecchymosis
  • HP:0002170 (1 mention) - the report calls it "Sign"; HP calls it Intracranial hemorrhage
  • HP:0000132 (1 mention) - the report calls it "Symptom"; HP calls it Menorrhagia
  • HP:0008151 (1 mention) - the report calls it "Lab abnormality"; HP calls it Prolonged prothrombin time
  • HP:0003645 (1 mention) - the report calls it "Lab abnormality"; HP calls it Prolonged partial thromboplastin time
  • HP:0040189 (1 mention) - the report calls it "Lab abnormality"; HP calls it Scaling skin
  • CL:0000233 (2 mentions) - the report calls it "platelet", "Platelet (coagulation surface)"; CL calls it platelet
  • UBERON:0002107 (1 mention) - the report calls it "Liver (site of FX production)"; UBERON calls it liver
  • UBERON:0000955 (1 mention) - the report calls it "Brain / intracranial space"; UBERON calls it brain
  • UBERON:0000403 (1 mention) - the report calls it "Scalp / subgaleal space"; UBERON calls it scalp
  • UBERON:0000995 (1 mention) - the report calls it "Uterus / endometrium (menorrhagia)"; UBERON calls it uterus
  • UBERON:0002097 (1 mention) - the report calls it "Skin / subcutaneous tissue"; UBERON calls it skin of body
  • GO:0005783 (1 mention) - the report calls it "Hepatocyte ER (γ-carboxylation, secretion)"; GO calls it endoplasmic reticulum

Unresolved terms

These identifiers do not exist in an ontology that resolved other terms from the same prefix, so they were most likely invented:

  • HP:0002320 (1 mention), reported as "Sign" - HP does not contain this term

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:0007597 (1 mention) - the report calls it "intrinsic pathway"; GO calls it blood coagulation, intrinsic pathway
  • GO:0007598 (1 mention) - the report calls it "extrinsic pathway"; GO calls it blood coagulation, extrinsic pathway
  • CL:0000182 (2 mentions) - the report calls it "hepatocytes", "Hepatocyte (synthesis)"; CL calls it hepatocyte
  • UBERON:0000178 (1 mention) - the report calls it "Blood / plasma"; UBERON calls it blood
  • UBERON:0002331 (1 mention) - the report calls it "Umbilical stump (neonate)"; UBERON calls it umbilical cord
  • UBERON:0002217 (1 mention) - the report calls it "Joints / synovial cavity"; UBERON calls it synovial joint
  • UBERON:0001707 (1 mention) - the report calls it "Nasal mucosa (epistaxis)"; UBERON calls it nasal cavity
  • GO:0005576 (1 mention) - the report calls it "Extracellular region / plasma; PS-containing membranes"; GO calls it extracellular region

Terms named inconsistently

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

  • CL:0000233 - called "platelet", "Platelet (coagulation surface)"
  • CL:0000182 - called "hepatocytes", "Hepatocyte (synthesis)"

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.