Congenital Factor V Deficiency

Mendelian MONDO:0009210 Pathograph 34 Show in embeddings browser Rare bleeding disorder Inherited blood coagulation disorder

An autosomal recessive bleeding disorder caused by biallelic variants in F5, the gene encoding coagulation factor V (proaccelerin or labile factor). It is among the rarest of the inherited bleeding disorders, at roughly one per million. Factor V is the non-enzymatic cofactor of the prothrombinase complex: once activated to factor Va it assembles with the protease factor Xa on an anionic phospholipid surface and accelerates the conversion of prothrombin to thrombin by several orders of magnitude. A defect in factor V therefore sits in the common pathway, downstream of both the tissue-factor (extrinsic) and contact-activated (intrinsic) arms, so both the prothrombin time and the activated partial thromboplastin time are prolonged while the thrombin time stays normal. That screening picture, followed by a low factor V activity assay, is what establishes the diagnosis. The disorder's most distinctive feature is how poorly residual factor V activity predicts bleeding. Patients with undetectable plasma factor V often bleed far less than expected, and the leading explanation is that about a fifth of the body's factor V is stored in platelet alpha-granules rather than in plasma. This platelet-derived pool, released locally at a wound, together with the physiologically low tissue factor pathway inhibitor levels seen in factor-V-deficient plasma, supports enough thrombin generation to rescue many patients from fatal haemorrhage. The clinical phenotype is usually mucocutaneous bleeding - epistaxis, gingival bleeding, easy bruising, menorrhagia and postoperative bleeding - but a minority, especially neonates with the lowest levels, suffer life-threatening intracranial haemorrhage. Two deficiency types are described by analogy with other factor deficiencies - type I (cross-reactive-material-negative, antigen and activity reduced together) and type II (cross-reactive-material-positive, a dysfunctional molecule present at near-normal antigen). They converge on the same prothrombinase cofactor defect and are not curated here as separate diseases. Three things are deliberately hedged. First, there is no licensed factor-V-specific concentrate; treatment still rests on fresh frozen plasma, with platelet transfusion, antifibrinolytics and recombinant activated factor VII as adjuncts, and liver transplantation as a definitive cure in the most severe cases. Second, the genotype-phenotype correlation is weak and no node claims otherwise. Third, acquired factor V deficiency (autoantibody-mediated) and combined factor V and factor VIII deficiency (LMAN1/MCFD2, a trafficking defect) are different entities and are recorded only as differential diagnoses.

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1
Inheritance
9
Pathophys.
16
Phenotypes
2
Gaps
34
Pathograph
1
Genes
5
Medical Actions
2
Differentials
4
Models
1
References
1
Deep Research
👪

Inheritance

1
Autosomal recessive HP:0000007
Symptomatic disease requires two defective F5 alleles, homozygous or compound heterozygous. Heterozygous carriers have approximately half-normal factor V levels and are usually asymptomatic.
Autosomal recessive
Show evidence (2 references)
PMID:19598066 SUPPORT REVIEW SYNTHESIS Other
"Patients with FV deficiency and clinically significant manifestations (mainly involving mucosal tracts) show very low or unmeasurable plasma FV levels and are usually homozygous or compound heterozygous for mutations located in the FV gene ( F5)."
States the biallelic requirement for symptomatic disease. Graded OTHER with quote_role REVIEW_SYNTHESIS because the source is a narrative review.
PMID:19598066 SUPPORT REVIEW SYNTHESIS Other
"Heterozygous carriers have approximately half-normal levels of FV and are usually asymptomatic."
States the asymptomatic carrier state recorded in this block's description.
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Discussions and Knowledge Gaps

2
Why does plasma factor V activity predict bleeding severity so poorly, and can platelet factor V or thrombin generation do better?
KNOWLEDGE GAP OPEN fv_activity_severity_discordance
Attached to
pathophysiology#Systemic Bleeding Tendency pathophysiology#Preserved Platelet-Dependent Thrombin Generation
Patients with undetectable plasma factor V range from mild bleeders to neonates with fatal intracranial haemorrhage, and plasma FV:C does not sort them. The leading candidate explanations - residual platelet factor V and low TFPI sustaining thrombin generation - are supported by case-level work, and thrombin generation in platelet-rich plasma may track bleeding better than a one-stage plasma assay, but no prospective study has established a platelet or thrombin-generation measure as a clinical predictor. This bears directly on which laboratory value should set a prophylaxis threshold.
Show evidence (1 reference)
PMID:19438479 SUPPORT REVIEW SYNTHESIS Other
"While the reasons for this variable phenotypic expression are largely unknown, several observations from different laboratories indicate platelets as crucial players in FV deficiency."
States that the reasons for the variable phenotype are largely unknown and points to platelets as the leading candidate, which is the gap here.
Can a factor-V-specific replacement therapy be developed and licensed?
KNOWLEDGE GAP OPEN fv_no_licensed_concentrate
Attached to
treatments#
Factor V deficiency is the rare bleeding disorder still without a licensed factor-specific concentrate, unlike factor X and factor XIII deficiencies. Two candidates have reached preclinical or in-vitro stage - a plasma-derived factor V concentrate that corrects clotting times and thrombin generation in patient plasma, and an engineered activated factor V (superFVa) - but neither has completed human trials, so plasma and platelet transfusion remain the only options.
Show evidence (2 references)
PMID:41167601 SUPPORT REVIEW SYNTHESIS Other
"Congenital factor V (FV) deficiency, affecting approximately 1 in 1 million individuals worldwide, remains among the rare bleeding disorders (RBDs) without a licensed factor-specific replacement therapy."
States the unmet therapeutic need this gap is about.
PMID:29578313 SUPPORT In Vitro
"The novel plasma-derived FV concentrate was effective to correct "in vitro" severe FV deficiency in patients."
A candidate concentrate shown to work in vitro, the preclinical state of the art this gap tracks.
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Pathophysiology

9
Biallelic F5 Loss-of-Function Variants
Homozygous or compound heterozygous variants in F5 on chromosome 1q24. Missense substitutions predominate; the reported spectrum also includes nonsense, frameshift, splice-site and large-deletion alleles, with more than two thirds of the published severe-deficiency alleles being null mutations that reduce factor V expression.
hepatocyte, the principal site of factor V synthesis CL:0000182 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves hepatocyte, the principal site of factor V 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 V The variant protein is either not made, not secreted, or secreted in a form that cannot act as a prothrombinase cofactor.
Show evidence (2 references)
PMID:19598066 SUPPORT REVIEW SYNTHESIS Other
"A total of 56 mutations have been published to date as being responsible for severe or moderately severe FV deficiency; more than two thirds of these are null mutations (mainly decreasing FV expression), with the remaining being missense mutations (usually impairing FV secretion)."
Describes the mutational spectrum and the predominance of null alleles that reduce factor V expression.
PMID:9576178 SUPPORT Human Clinical
"Sequence analysis of the 5'- and 3'-untranslated, coding and adjacent regions of the factor V gene revealed the presence of a 4 bp deletion in exon 13."
A worked homozygous null allele, the first reported F5 mutation causing a type I quantitative deficiency.
Reduced Functional Plasma Factor V
The functional deficit measured in plasma as factor V coagulant activity (FV:C). In type I disease the immunoreactive antigen falls with it; in type II a dysfunctional molecule is still present at near-normal antigen. Residual activity grades the deficiency into mild, moderate and severe strata but predicts bleeding only weakly.
factor V cofactor available for prothrombinase assembly GO:0008047 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves decreased factor V cofactor available for prothrombinase assembly, annotated with enzyme activator activity (GO:0008047). GO:0008047 is a molecular function from the Gene Ontology.
Animal models
F5 Thr1898Met knock-in mouse Mouse recapitulates A missense knock-in reproduces the reduced circulating factor V activity and the prolonged clotting times of mild human disease in a viable animal.
Downstream
Impaired Prothrombinase Cofactor Function Less circulating functional factor V means less factor Va available to serve as the prothrombinase cofactor.
Show evidence (2 references)
PMID:9576178 SUPPORT Human Clinical
"We have studied a young girl with very mild bleeding symptoms and undetectable levels of plasma factor V antigen and activity (<0.3% and <1.6% of normal, respectively)."
Documents concordantly reduced factor V activity and antigen (a type I pattern) in a genetically confirmed patient.
PMID:24787990 SUPPORT In Vitro
"The His147Arg mutation was associated with normal antigen levels, both in cell lysates and conditioned media, whereas FV activity was significantly reduced to 63.5 ± 17.0%."
A type II pattern - preserved antigen against reduced activity - shown by expression study, the structural counterpart of the type I case above.
Impaired Prothrombinase Cofactor Function
The non-redundant step. Activated factor V (factor Va) is the non-enzymatic cofactor of the prothrombinase complex, assembling with factor Xa on an anionic phospholipid surface and accelerating prothrombin cleavage far beyond what factor Xa achieves alone. Because both the extrinsic and intrinsic arms of the cascade converge on this common-pathway step, neither can compensate for the defect.
activated platelet supplying the anionic phospholipid surface CL:0000233 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves activated platelet supplying 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 ↓ DECREASED 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.
Downstream
Reduced Thrombin Generation Less functional prothrombinase converts less prothrombin to thrombin.
Show evidence (1 reference)
PMID:35593819 SUPPORT REVIEW SYNTHESIS Other
"Either thrombin or factor Xa converts factor V to the plasma cofactor of the prothrombinase complex. This complex, composed of calcium, phospholipids, factor Va, and factor Xa, is essential for converting prothrombin to thrombin."
States the composition of prothrombinase and the cofactor role of factor Va that this node depends on.
Reduced Thrombin Generation
The functional common denominator of the disease. Thrombin is needed 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 ↓ DECREASED 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.
Downstream
Impaired Fibrin Clot Formation Insufficient thrombin to convert fibrinogen to fibrin at the rate a haemostatic plug requires.
Show evidence (1 reference)
PMID:18695002 SUPPORT Human Clinical
"Thrombin generation in FV-deficient plasma was only measurable at high tissue factor concentrations"
Documents the reduced thrombin generation of factor-V-deficient plasma that this node asserts.
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 why both the prothrombin time and the activated partial thromboplastin time are prolonged while the thrombin time, which tests the fibrinogen-to-fibrin step directly, remains normal.
blood coagulation, fibrin clot formation GO:0072378 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased blood coagulation, fibrin clot formation (GO:0072378). GO:0072378 is a biological process from the Gene Ontology.
Animal models
fv mutant zebrafish Zebrafish partially recapitulates Loss of fv delays clot occlusion after vascular injury, reproducing the impaired clot formation of the human disease in a screenable vertebrate.
Downstream
Systemic Bleeding Tendency A slowly formed or unstable clot fails to secure haemostasis, producing spontaneous and provoked bleeding.
Prolonged prothrombin time
Prolonged partial thromboplastin time
Show evidence (1 reference)
PMID:35593819 SUPPORT REVIEW SYNTHESIS Other
"Initial laboratory evaluation shows prolonged prothrombin time and activated partial thromboplastin time (aPTT) with a normal thrombin time."
States the simultaneous prolongation of both screening tests with a normal thrombin time that a common-pathway defect predicts.
Systemic Bleeding Tendency
The clinical endpoint. Bleeding is predominantly mucocutaneous but can be intracranial in the most severely affected. Severity broadly tracks residual factor V activity, but the correlation is imperfect and this entry does not overstate it.
Animal models
F5 knockout mouse Mouse partially recapitulates Complete absence of factor V produces fatal spontaneous bleeding, reproducing the organism-level bleeding tendency.
F5 transgene-rescued mouse Mouse rescues Minimal liver-directed factor V expression rescues the otherwise fatal bleeding of the null mouse, modelling the viability threshold rather than the symptomatic human phenotype.
Downstream
Epistaxis
Gingival bleeding
Bruising susceptibility
Subcutaneous hemorrhage
Menorrhagia
Prolonged bleeding after surgery
Prolonged bleeding after dental extraction
Joint hemorrhage
Intramuscular hematoma
Gastrointestinal hemorrhage
Abnormal umbilical stump bleeding
Intracranial hemorrhage The most feared complication, concentrated in neonates and infants with the lowest factor V levels.
Post-partum hemorrhage
Show evidence (2 references)
PMID:42074284 SUPPORT Human Clinical
"Clinically, congenital FV deficiency most commonly presents with epistaxis, easy bruising, hematomas, and menorrhagia. Severe manifestations, such as gastrointestinal bleeding, hematuria, hemarthrosis, or central nervous system hemorrhage, are relatively uncommon"
Enumerates the common and the severe bleeding manifestations wired to this node.
PMID:9886321 SUPPORT INDIRECT Human Clinical
"The severity of bleeding symptoms was only partially related to the degree of factor V deficiency in plasma."
Records the limit on the severity claim. Marked INDIRECT because it constrains how strongly residual activity predicts bleeding rather than asserting the bleeding tendency itself.
Residual Platelet Factor V
About a fifth to a quarter of the body's factor V is stored in platelet alpha-granules, acquired by megakaryocyte endocytosis of plasma factor V rather than synthesised in the platelet. In patients with undetectable plasma factor V, a measurable platelet-derived factor V/Va pool can persist and be released locally at a wound, where it is the predominant cofactor for thrombin generation at the platelet surface. This pool, not any residual plasma factor V, is the leading explanation for the mild phenotype of many severely deficient patients.
platelet storing factor V in alpha-granules CL:0000233 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves platelet storing factor V in alpha-granules, annotated with platelet (CL:0000233). CL:0000233 is a cell type from the Cell Ontology. megakaryocyte endocytosing plasma factor V CL:0000556 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves megakaryocyte endocytosing plasma factor V, annotated with megakaryocyte (CL:0000556). CL:0000556 is a cell type from the Cell Ontology.
platelet alpha granule, the factor V store GO:0031091 Gene Ontology (GO) Relation: this pathophysiological event involves this cellular component This pathophysiological event involves platelet alpha granule, the factor V store, annotated with platelet alpha granule (GO:0031091). GO:0031091 is a cellular component from the Gene Ontology.
Downstream
Preserved Platelet-Dependent Thrombin Generation Locally released platelet factor V/Va supports thrombin generation at the platelet surface despite absent plasma factor V.
Show evidence (2 references)
PMID:25896652 SUPPORT Human Clinical
"release of the patient's platelet-derived FV/Va (7% of normal) following platelet activation resulted in robust thrombin generation, similar to that in an individual with normal plasma- and platelet-derived FV concentrations"
Shows that platelet-derived factor V/Va alone supports near-normal thrombin generation in an individual with no detectable plasma factor V.
PMID:19861681 SUPPORT Human Clinical
"patients with undetectable plasma FV may contain functional FV in their platelets. In combination with low TFPI level, residual platelet FV allows sufficient thrombin generation to rescue these patients from fatal bleeding."
States the protective role of residual platelet factor V, together with low TFPI, in patients with undetectable plasma factor V.
Low Plasma Tissue Factor Pathway Inhibitor
Factor-V-deficient plasma carries physiologically low levels of tissue factor pathway inhibitor, possibly because factor V affects TFPI stability or clearance in vivo. The reduced TFPI lowers the factor V threshold needed for minimal thrombin generation and so works alongside residual platelet factor V to protect deficient patients from severe bleeding.
TFPI hgnc:11760 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves TFPI (hgnc:11760). hgnc:11760 is a gene from the HUGO Gene Nomenclature Committee.
tissue factor pathway inhibitor serine protease inhibitor activity GO:0004867 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves decreased tissue factor pathway inhibitor serine protease inhibitor activity, annotated with serine-type endopeptidase inhibitor activity (GO:0004867). GO:0004867 is a molecular function from the Gene Ontology.
Downstream
Preserved Platelet-Dependent Thrombin Generation Lower TFPI lifts the inhibitory brake on the initiating tissue-factor complex, reducing the factor V requirement for thrombin generation.
Show evidence (2 references)
PMID:18695002 SUPPORT Human Clinical
"Plasma TFPI antigen and activity levels were indeed lower (P < .001) in FV-deficient patients (n = 11; 4.0 +/- 1.0 ng/mL free TFPI) than in controls (n = 20; 11.5 +/- 4.8 ng/mL)"
Quantifies the reduced TFPI in factor-V-deficient patients.
PMID:18695002 SUPPORT Human Clinical
"Low TFPI levels decreased the FV requirement for minimal thrombin generation in FV-deficient plasma to less than 1% and might therefore protect FV-deficient patients from severe bleeding."
States how low TFPI lowers the factor V threshold for thrombin generation, which is the protective edge asserted here.
Preserved Platelet-Dependent Thrombin Generation
The convergence of residual platelet factor V and low TFPI: enough thrombin is generated at the activated platelet surface to secure a minimally haemostatic clot even when plasma factor V is undetectable. This is the mechanistic reason bleeding severity is discordant with plasma FV:C, and it is why a patient can be protected whose plasma assay reads zero.
activated platelet surface where thrombin is generated CL:0000233 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves activated platelet surface where thrombin is generated, annotated with platelet (CL:0000233). CL:0000233 is a cell type from the Cell Ontology.
platelet-surface thrombin generation GO:0007596 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves platelet-surface thrombin generation, annotated with blood coagulation (GO:0007596). GO:0007596 is a biological process from the Gene Ontology.
Show evidence (2 references)
PMID:25896652 SUPPORT Human Clinical
"resulted in robust thrombin generation, similar to that in an individual with normal plasma- and platelet-derived FV concentrations"
Direct support: in an individual with no detectable plasma factor V, platelet-derived factor V/Va sustains near-normal thrombin generation.
PMID:21320286 SUPPORT INDIRECT Human Clinical
"suggest that thrombin generation in PRP may predict bleeding tendency in patients with undetectable plasma FV"
The mirror-image case: a severely affected patient whose platelet-rich plasma generates no thrombin. Marked INDIRECT because it supports the node through the negative/predictive direction rather than demonstrating preserved generation 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 V 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

16
Blood 15
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 (1 reference)
PMID:9886321 SUPPORT Human Clinical
"The most frequent symptoms included epistaxis and excessive bleeding after surgery."
Names epistaxis among the most frequent symptoms in a 35-patient cohort.
Gingival bleeding FREQUENT HP:0000225 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Gingival bleeding (HP:0000225). HP:0000225 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:40421928 SUPPORT Human Clinical
"The most common symptoms included gingival (n = 15, 38.5%) and cutaneous bleeding (n = 13, 33.3%) in 39 patients."
Reports gingival bleeding as the most common symptom (38.5%), which places it in the FREQUENT band.
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 (1 reference)
PMID:42074284 SUPPORT Human Clinical
"Clinically, congenital FV deficiency most commonly presents with epistaxis, easy bruising, hematomas, and menorrhagia."
Lists easy bruising among the most common presentations.
Subcutaneous hemorrhage FREQUENT HP:0001933 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Cutaneous hemorrhage, annotated with Subcutaneous hemorrhage (HP:0001933). HP:0001933 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:40421928 SUPPORT Human Clinical
"The most common symptoms included gingival (n = 15, 38.5%) and cutaneous bleeding (n = 13, 33.3%) in 39 patients."
Reports cutaneous bleeding in 33.3% of patients, in the FREQUENT band.
Menorrhagia FREQUENT HP:0000132 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Menorrhagia (HP:0000132). HP:0000132 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:40421928 SUPPORT Human Clinical
"Menorrhagia (n = 7) was observed in 38.9% of 18 female patients of reproductive age."
Quantifies menorrhagia among reproductive-age women (38.9%), in the FREQUENT band.
Prolonged bleeding after surgery HP:0004846 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Prolonged bleeding after surgery (HP:0004846). HP:0004846 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:9886321 SUPPORT Human Clinical
"The most frequent symptoms included epistaxis and excessive bleeding after surgery."
Names excessive bleeding after surgery among the most frequent symptoms.
Prolonged bleeding after dental extraction HP:0006298 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Prolonged bleeding after dental extraction (HP:0006298). HP:0006298 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:42074284 SUPPORT Human Clinical
"In childhood, ecchymosis, epistaxis, bleeding after tooth extraction, menorrhagia"
A cohort patient with bleeding after tooth extraction.
Joint hemorrhage HP:0005261 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hemarthrosis, annotated with Joint hemorrhage (HP:0005261). HP:0005261 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:9886321 SUPPORT Human Clinical
"Haemarthroses and muscle haematomas were less common, even in severely deficient patients."
Reports haemarthrosis as a less common manifestation even in severe disease.
Gastrointestinal hemorrhage HP:0002239 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Gastrointestinal hemorrhage (HP:0002239). HP:0002239 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:42074284 SUPPORT Human Clinical
"Severe manifestations, such as gastrointestinal bleeding, hematuria, hemarthrosis, or central nervous system hemorrhage, are relatively uncommon"
Lists gastrointestinal bleeding among the uncommon severe manifestations.
Abnormal umbilical stump bleeding HP:0011884 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Umbilical cord bleeding, annotated with Abnormal umbilical stump bleeding (HP:0011884). HP:0011884 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:36125894 SUPPORT Human Clinical
"Umbilical bleeding, anterior fontanelle tensed"
A reported factor V deficiency case presenting with umbilical bleeding in the neonatal period.
Intracranial hemorrhage HP:0002170 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Intracranial hemorrhage (HP:0002170). HP:0002170 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:36125894 SUPPORT Human Clinical
"Among the previous spontaneous intracranial hemorrhages in the congenital FV deficiency cases, most spontaneous intracranial hemorrhages occurred in infancy (13 of 20). All of the patients had FV activity less than 5% of normal."
Documents the concentration of intracranial haemorrhage in infancy and in patients with the lowest factor V activity.
Post-partum hemorrhage HP:0011891 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Postpartum hemorrhage, annotated with Post-partum hemorrhage (HP:0011891). HP:0011891 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:15660985 SUPPORT Human Clinical
"patients with severe deficiency bleed considerably at the time of delivery. However, bleeding can be controlled properly by administration of fresh frozen plasma with excellent foetal outcome."
Reports considerable delivery-associated bleeding in severely deficient women, controllable with plasma.
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:36125894 SUPPORT Human Clinical
"The coagulation tests revealed a significantly prolonged prothrombin time (PT) of 51 s and an activated partial thromboplastin time (APTT) of 73.7"
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:36125894 SUPPORT Human Clinical
"The coagulation tests revealed a significantly prolonged prothrombin time (PT) of 51 s and an activated partial thromboplastin time (APTT) of 73.7"
Documents the simultaneously prolonged activated partial thromboplastin time in the same case.
Reduced coagulation factor V activity HP:0003225 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Reduced factor V activity, annotated with Reduced coagulation factor V activity (HP:0003225). HP:0003225 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:40421928 SUPPORT Human Clinical
"The study cohort comprised 45 patients with confirmed FV:C reductions (undetectable to 48%), including six mild (FV:C >10%), 31 moderate (FV:C 1%-10%), and eight severe (FV:C <1%) patients."
Documents reduced factor V coagulant activity, with the severity strata, across a national cohort.
Musculoskeletal 1
Intramuscular hematoma HP:0012233 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Muscle hematoma, annotated with Intramuscular hematoma (HP:0012233). HP:0012233 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:9886321 SUPPORT Human Clinical
"Haemarthroses and muscle haematomas were less common, even in severely deficient patients."
Reports muscle haematoma as a less common manifestation.
🧬

Genetic Associations

1
F5
Gene: F5 hgnc:3542 gene page HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is F5 (hgnc:3542). hgnc:3542 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE variant_origin: GERMLINE
Show evidence (2 references)
PMID:19486170 SUPPORT Human Clinical
"A total of 42 genetic alterations (of which 33 were uniquely different mutations), comprising 19 missense mutations, eight nonsense mutations, four small deletions and two splice site mutations, were identified by this study."
Documents the mutational spectrum of F5 in a genotyped cohort.
PMID:42074284 SUPPORT Human Clinical
"Overall, 3 of 15 causal variants (20%)—including two large deletions and a non-canonical splice-altering variant—would not have been reliably detected using routine exon-focused sequencing alone."
Supports the note that routine sequencing misses a fraction of F5 alleles, which is why MLPA is needed.
💊

Medical Actions

5
Fresh frozen plasma
Action: Fresh Frozen Plasma TransfusionNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Fresh Frozen Plasma Transfusion (NCIT:C116475). NCIT:C116475 is a clinical intervention from the NCI Thesaurus. NCIT:C116475
Agent: fresh frozen plasma Relation: this treatment uses this therapeutic agent This treatment uses fresh frozen plasma.
Platform: Protein replacement
The mainstay of treatment, because no factor-V-specific concentrate is licensed. Plasma supplies intact factor V; dosing targets a haemostatic factor V level (commonly above 20 IU/dL), and because the plasma half-life of factor V is short, repeated infusions are needed. Virus-inactivated (solvent-detergent) plasma is preferred.
Mechanism Target:
RESTORES Reduced Functional Plasma Factor V — Donor plasma supplies functional factor V, restoring the prothrombinase cofactor at the node immediately downstream of the genetic lesion.
Show evidence (2 references)
PMID:39191405 SUPPORT REVIEW SYNTHESIS Other
"The mainstay of treatment includes fresh-frozen plasma, preferentially virus-inactivated."
States fresh frozen plasma as the mainstay and the preference for virus-inactivated product.
PMID:39022653 SUPPORT REVIEW SYNTHESIS Other
"Because of the relatively short plasma half-life of FV (16-36 hours), daily infusions are required to keep FV at hemostatic levels (ie, above 20 IU/dL)"
States the haemostatic target level and why repeated infusions are needed.
Platelet transfusion
Action: Platelet TransfusionNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Platelet Transfusion (NCIT:C15366). NCIT:C15366 is a clinical intervention from the NCI Thesaurus. NCIT:C15366
Platform: Other
Used when plasma alone is ineffective, exploiting the platelet factor V pool that localises to the site of bleeding. Platelet concentrates have been combined with plasma for refractory bleeding.
Mechanism Target:
RESTORES Residual Platelet Factor V — Transfused platelets deliver factor V/Va that localises at the injury site, supplementing the patient's platelet-derived pool.
Show evidence (1 reference)
PMID:39022653 SUPPORT REVIEW SYNTHESIS Other
"a combination of platelet concentrates and SD-FFP has been used when SD-FFP alone was ineffective"
States the rationale for platelet transfusion and its use when plasma alone fails.
Antifibrinolytic therapy
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: 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, used for mucosal and minor bleeding and as cover for minor procedures. It does not correct the coagulation defect; it protects the clot that does form from premature lysis, so it is adjunctive.
Mechanism Target:
MODULATES Impaired Fibrin Clot Formation — Inhibiting plasminogen activation prolongs survival of the weak clot that forms, acting on clot persistence rather than on thrombin generation.
Show evidence (1 reference)
PMID:19141156 SUPPORT REVIEW SYNTHESIS Other
"Antifibrinolytics can also provide benefit, especially for mucosal bleeding."
States the indication for antifibrinolytics in factor V deficiency.
Recombinant activated factor VII
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: recombinant activated factor VII (eptacog alfa) NCIT:C81125 NCI Thesaurus (NCIT) Relation: this treatment uses this therapeutic agent This treatment uses recombinant activated factor VII (eptacog alfa), annotated with Eptacog Alfa (NCIT:C81125). NCIT:C81125 is a therapeutic agent from the NCI Thesaurus.
Platform: Other
A bypassing agent used off-label for severe bleeding, for patients with factor V inhibitors, or where plasma causes allergy or volume overload. It increases thrombin generation at the injury site rather than replacing factor V.
Mechanism Target:
BYPASSES Reduced Thrombin Generation — Pharmacological activated factor VII drives thrombin generation at the site of injury, bypassing the factor V cofactor deficit rather than correcting it.
Show evidence (2 references)
PMID:39022653 SUPPORT REVIEW SYNTHESIS Other
"Off-label recombinant FVIIa (rFVIIa) was successfully used in cases with FV inhibitors (not infrequent) or allergy to FFP or to avoid volume overload"
States the indications for recombinant activated factor VII in factor V deficiency.
PMID:40788998 SUPPORT Human Clinical
"Bleeding control was achieved with recombinant factor VIIa."
A worked case of bleeding controlled with recombinant activated factor VII in a patient who had developed a factor V inhibitor.
Liver transplantation
Action: Liver TransplantationNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Liver Transplantation (NCIT:C15271). NCIT:C15271 is a clinical intervention from the NCI Thesaurus. NCIT:C15271
Platform: Surgery
Definitive cure for the most severe cases, since factor V is synthesised in the liver. Reserved for patients with life-threatening bleeding unmanageable by plasma; it corrects factor V levels and abolishes the need for infusions.
Mechanism Target:
RESTORES Reduced Functional Plasma Factor V — A donor liver synthesises normal factor V, permanently restoring the circulating pool.
Show evidence (1 reference)
PMID:29250911 SUPPORT Human Clinical
"He received an orthotopic liver transplant at age 5 months, resulting in correction of his FV levels. He has not required any plasma infusions post-transplantation and has had no further bleeding episodes."
A worked case in which liver transplantation corrected factor V levels and cured the bleeding phenotype.
🔬

Biochemical Markers

1
Factor V coagulant activity (FV:C) (DECREASED)
Pathograph Readouts
Readout Of Reduced Functional Plasma Factor V
FV:C measures the functional consequence of the genetic lesion at the level of circulating protein activity, and defines the conventional severity strata.
Reference Ranges
(patients with congenital factor V deficiency)
Severe deficiency (< 1.0 % of normal FV:C) Moderate deficiency (1.0–10.0 % of normal FV:C) Mild deficiency (≥ 10.0 % of normal FV:C)
The severity bands are the plasma FV:C strata, stated as a percentage of normal. Mild is above 10%, moderate 1-10%, severe below 1%. They grade the deficiency; they predict bleeding only weakly (see the knowledge gap on activity-severity discordance).
Show evidence (1 reference)
PMID:35593819 SUPPORT REVIEW SYNTHESIS Other
"Mild factor V deficiency is identified by plasma activity greater than 10% of normal. Moderate deficiency shows activity from 1% to 10%, and severe deficiency presents with activity less than 1%."
Source for the three severity bands encoded here.
Show evidence (1 reference)
PMID:40421928 SUPPORT Human Clinical
"The study cohort comprised 45 patients with confirmed FV:C reductions (undetectable to 48%), including six mild (FV:C >10%), 31 moderate (FV:C 1%-10%), and eight severe (FV:C <1%) patients."
Applies the FV:C severity strata to a national cohort, confirming the assay is the quantity that grades the disease.
🔬

Diagnosis

3
Coagulation screen
The screening picture that prompts factor-specific assays: prolonged prothrombin time and prolonged activated partial thromboplastin time with a normal thrombin time, because the defect is in the common pathway and spares the fibrinogen-to-fibrin step.
coagulation screening blood test NCIT:C217390 NCI Thesaurus (NCIT)
Show evidence (1 reference)
PMID:35593819 SUPPORT REVIEW SYNTHESIS Other
"Initial laboratory evaluation shows prolonged prothrombin time and activated partial thromboplastin time (aPTT) with a normal thrombin time. A low plasma factor V level confirms the diagnosis."
States the screening abnormalities and that a low factor V level confirms the diagnosis.
Plasma mixing study
Distinguishes an inherited factor deficiency from an acquired inhibitor: correction of the prolonged PT and aPTT on mixing with normal plasma indicates a deficiency, while persistent prolongation indicates an inhibitor.
plasma mixing coagulation test NCIT:C217390 NCI Thesaurus (NCIT)
Show evidence (1 reference)
PMID:35593819 SUPPORT REVIEW SYNTHESIS Other
"Improvement of these parameters after mixing suggests an inherited form, with normal plasma replacing the missing factor. Persistent prothrombin time and aPTT prolongation after mixing indicates an acquired form, as an inhibitor in the patient's plasma prevents normalization."
States the interpretation of the mixing study that distinguishes inherited from acquired factor V deficiency.
F5 sequencing
Confirms the diagnosis, establishes the inheritance pattern for counselling, and identifies the causative variants. Multiplex ligation-dependent probe amplification is needed alongside sequencing because routine exon-focused sequencing misses large deletions and some splice variants.
F5 genetic testing NCIT:C15709 NCI Thesaurus (NCIT)
Show evidence (1 reference)
PMID:42074284 SUPPORT Human Clinical
"Multiplex ligation-dependent probe amplification (MLPA) was used to detect large deletions and duplications."
Documents the assays used to achieve a complete molecular diagnosis.
📊

Prevalence

1
Worldwide
Point Prevalence 0.1 per 100,000 1–9 per 1,000,000
Reported as approximately 1 in 1,000,000 in the homozygous (severe) form, which normalises to 0.1 per 100,000.
Show evidence (2 references)
PMID:19598066 SUPPORT REVIEW SYNTHESIS Other
"Congenital factor V (FV) deficiency is a bleeding disorder associated with mild to severe hemorrhagic symptoms and a prevalence in the general population of 1 in 1,000,000 in the homozygous form."
States the worldwide frequency normalised in this record.
PMID:39191405 SUPPORT REVIEW SYNTHESIS Other
"Congenital FV deficiency is a rare bleeding disorder with an incidence of 1 per million live births, considering the most severe homozygous form."
An independent review statement of the same order-of-magnitude frequency.
🔀

Differential Diagnoses

2

Conditions with similar clinical presentations that must be differentiated from Congenital Factor V Deficiency:

Acquired factor V deficiency Not Yet Curated MONDO:0035737
Overlapping Features An autoantibody-mediated factor V deficiency, clinically and by coagulation screen resembling the congenital form but of later onset and distinguished by a plasma mixing study that fails to correct. It is a different entity, often following exposure to bovine thrombin, surgery, malignancy or antibiotics.
Show evidence (1 reference)
PMID:35593819 SUPPORT REVIEW SYNTHESIS Other
"Persistent prothrombin time and aPTT prolongation after mixing indicates an acquired form, as an inhibitor in the patient's plasma prevents normalization."
States the mixing-study finding that distinguishes acquired from congenital factor V deficiency.
Combined factor V and factor VIII deficiency Not Yet Curated MONDO:0018175
Overlapping Features A separate autosomal recessive disorder caused by LMAN1 or MCFD2 defects in the ER-to-Golgi cargo receptor that transports both factor V and factor VIII. Both factors are mildly to moderately reduced together, which the isolated factor assay distinguishes from isolated factor V deficiency.
Show evidence (1 reference)
PMID:19141156 SUPPORT REVIEW SYNTHESIS Other
"FV deficiency can be caused by mutations in the FV gene or in genes encoding components of a putative cargo receptor that transports FV (and factor VIII) from the endoplasmic reticulum to the Golgi."
Names the cargo-receptor mechanism that produces combined FV and FVIII deficiency, the entity this differential separates out.
🐁

Animal Models

4
F5 knockout mouse
The Cui et al. (1996) factor V knockout. About half of homozygous embryos die at embryonic day 9-10, possibly from a yolk-sac vascular abnormality; the rest reach term but die of massive haemorrhage within two hours of birth. The model established the absolute requirement for factor V in prothrombinase activity and revealed a developmental role for the coagulation system.
Species
Mouse
Genotype
Fv-/- (targeted deletion of coagulation factor V)
Publication
PMID:8900278
Pathograph links
Systemic Bleeding Tendency partially recapitulates fidelity: moderate observes: organism Complete absence of factor V produces fatal spontaneous bleeding, reproducing the organism-level bleeding tendency.
Limitations: Total factor V deficiency is embryonic or perinatally lethal in the mouse, whereas human disease is a survivable chronic diathesis in which some residual factor V (plasma or platelet) is essentially always present. The model cannot report the human natural history, genotype-phenotype relation, or long-term treatment, and its lethality is why human complete deficiency is so rare.
Show evidence (1 reference)
PMID:8900278 SUPPORT Model Organism
"approximately half of homozygous embryos deficient in factor V (Fv-/-), which have been generated by gene targeting, die at embryonic day (E) 9-10, possibly as a result of an abnormality in the yolk-sac vasculature."
Reports the embryonic lethality that is the model's key divergence from the survivable human disease.
Show evidence (1 reference)
PMID:8900278 SUPPORT Model Organism
"The remaining Fv-/- mice progress normally to term, but die from massive haemorrhage within 2 hours of birth."
Reports the fatal perinatal bleeding phenotype of complete factor V loss.
F5 transgene-rescued mouse
A factor V minigene expressed at under 0.1% of normal in the liver rescues Fv-/- mice through the perinatal period to adulthood without spontaneous haemorrhage, demonstrating that minimal factor V expression suffices for survival - a plausible explanation for why nearly all human patients retain some residual factor V.
Species
Mouse
Genotype
Tg(Malb-Fv);Fv-/- (liver-directed low-level factor V minigene on a null background)
Publication
PMID:10669158
Pathograph links
Systemic Bleeding Tendency rescues fidelity: moderate observes: organism Minimal liver-directed factor V expression rescues the otherwise fatal bleeding of the null mouse, modelling the viability threshold rather than the symptomatic human phenotype.
Limitations: The transgene is expressed from a heterologous promoter at a fixed low level, not from the native locus, so it tests a viability threshold rather than reproducing any particular human genotype or its bleeding pattern.
Show evidence (1 reference)
PMID:10669158 SUPPORT Model Organism
"We conclude that FV present at <0.1% is sufficient to support postnatal survival."
States the viability threshold this rescue model establishes.
Show evidence (1 reference)
PMID:10669158 SUPPORT Model Organism
"Rescued Tg+,Fv-/- mice have undetectable FV (<0.1%) in both plasma and platelet compartments, but survive the perinatal period and mature to adulthood without spontaneous hemorrhage."
Shows that below-detection factor V rescues survival, the model's central finding.
F5 Thr1898Met knock-in mouse
A 2025 CRISPR knock-in carrying a missense variant chosen in silico to give a mild phenotype. Homozygotes are viable with no spontaneous bleeding, reduced factor V activity (around 24.5%) and prolonged PT and aPTT - the first viable pathological mouse model of the disease, usable for testing new therapies.
Species
Mouse
Genotype
F5 Thr1898Met missense knock-in (CRISPR/Cas9 homology-directed repair, homozygous)
Publication
PMID:40455764
Pathograph links
Reduced Functional Plasma Factor V recapitulates fidelity: moderate observes: molecular A missense knock-in reproduces the reduced circulating factor V activity and the prolonged clotting times of mild human disease in a viable animal.
Limitations: The model carries one engineered missense allele chosen for mildness, so it represents the mild end of the spectrum and does not reproduce severe or null-allele disease or its intracranial-haemorrhage risk.
Readouts
Plasma factor V activity
Direction: DECREASED
Interpretation: Reduced factor V activity in homozygous knock-in mice.
Show evidence (1 reference)
PMID:40455764 SUPPORT Model Organism
"FV levels in homozygous animals were 24.5% ± 5.1"
Quantifies the reduced factor V activity in the knock-in mouse.
Show evidence (1 reference)
PMID:40455764 SUPPORT Model Organism
"A viable FV-deficient mouse model was generated by introducing a missense mutation in FV. The model exhibits a mild phenotype of the disease, akin to that observed in humans."
The authors' statement that the knock-in is a viable model with a mild human-like phenotype.
fv mutant zebrafish
An ENU-derived factor V nonsense zebrafish line. Homozygous larvae show prolonged time to occlusion after venous laser injury and poor survival beyond 12 days post-fertilisation; the line phenocopies human parahaemophilia and is a tool for drug screening.
Species
Zebrafish
Genotype
fv homozygous nonsense mutant (ENU-induced, premature stop in exon 2)
Publication
PMID:38874909
Pathograph links
Impaired Fibrin Clot Formation partially recapitulates fidelity: low observes: organism Loss of fv delays clot occlusion after vascular injury, reproducing the impaired clot formation of the human disease in a screenable vertebrate.
Limitations: Zebrafish tolerate factor V loss longer than mammals, and the paper reports an apparently dominant pattern in the fish, so the inheritance and timing do not transfer to the human disease; the model is best read as a variant/drug-screening tool rather than a faithful clinical model.
Show evidence (1 reference)
PMID:38874909 SUPPORT Model Organism
"fv homozygous larvae had poor survival beyond 12 dpf."
Documents the larval lethality that bounds the model's fidelity.
Show evidence (1 reference)
PMID:38874909 SUPPORT Model Organism
"Homozygous and heterozygous 5 days post fertilization (dpf) larvae for fviii and fv deficient mutants exhibited prolonged time to occlusion after venous laser injury compared to wild-type controls."
Reports the haemostatic defect in the factor V mutant zebrafish.
{ }

Source YAML

click to show 
name: Congenital Factor V Deficiency
creation_date: "2026-10-12T04:05:10Z"
category: Mendelian
synonyms:
- Owren disease
- Parahemophilia
- Proaccelerin deficiency
- hereditary factor V deficiency
- labile factor deficiency
description: >-
  An autosomal recessive bleeding disorder caused by biallelic variants in F5,
  the gene encoding coagulation factor V (proaccelerin or labile factor). It is
  among the rarest of the inherited bleeding disorders, at roughly one per
  million.

  Factor V is the non-enzymatic cofactor of the prothrombinase complex: once
  activated to factor Va it assembles with the protease factor Xa on an anionic
  phospholipid surface and accelerates the conversion of prothrombin to thrombin
  by several orders of magnitude. A defect in factor V therefore sits in the
  common pathway, downstream of both the tissue-factor (extrinsic) and
  contact-activated (intrinsic) arms, so both the prothrombin time and the
  activated partial thromboplastin time are prolonged while the thrombin time
  stays normal. That screening picture, followed by a low factor V activity
  assay, is what establishes the diagnosis.

  The disorder's most distinctive feature is how poorly residual factor V
  activity predicts bleeding. Patients with undetectable plasma factor V often
  bleed far less than expected, and the leading explanation is that about a fifth
  of the body's factor V is stored in platelet alpha-granules rather than in
  plasma. This platelet-derived pool, released locally at a wound, together with
  the physiologically low tissue factor pathway inhibitor levels seen in
  factor-V-deficient plasma, supports enough thrombin generation to rescue many
  patients from fatal haemorrhage. The clinical phenotype is usually
  mucocutaneous bleeding - epistaxis, gingival bleeding, easy bruising,
  menorrhagia and postoperative bleeding - but a minority, especially neonates
  with the lowest levels, suffer life-threatening intracranial haemorrhage.

  Two deficiency types are described by analogy with other factor deficiencies -
  type I (cross-reactive-material-negative, antigen and activity reduced
  together) and type II (cross-reactive-material-positive, a dysfunctional
  molecule present at near-normal antigen). They converge on the same
  prothrombinase cofactor defect and are not curated here as separate diseases.

  Three things are deliberately hedged. First, there is no licensed
  factor-V-specific concentrate; treatment still rests on fresh frozen plasma,
  with platelet transfusion, antifibrinolytics and recombinant activated factor
  VII as adjuncts, and liver transplantation as a definitive cure in the most
  severe cases. Second, the genotype-phenotype correlation is weak and no node
  claims otherwise. Third, acquired factor V deficiency (autoantibody-mediated)
  and combined factor V and factor VIII deficiency (LMAN1/MCFD2, a trafficking
  defect) are different entities and are recorded only as differential diagnoses.
disease_term:
  preferred_term: congenital factor V deficiency
  term:
    id: MONDO:0009210
    label: congenital factor V deficiency
parents:
- Rare bleeding disorder
- Inherited blood coagulation disorder
inheritance:
- name: Autosomal recessive
  inheritance_term:
    preferred_term: Autosomal recessive
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  description: >-
    Symptomatic disease requires two defective F5 alleles, homozygous or compound
    heterozygous. Heterozygous carriers have approximately half-normal factor V
    levels and are usually asymptomatic.
  evidence:
  - reference: PMID:19598066
    reference_title: "Factor V deficiency."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: "Patients with FV deficiency and clinically significant manifestations (mainly involving mucosal tracts) show very low or unmeasurable plasma FV levels and are usually homozygous or compound heterozygous for mutations located in the FV gene ( F5)."
    explanation: >-
      States the biallelic requirement for symptomatic disease. Graded OTHER with
      quote_role REVIEW_SYNTHESIS because the source is a narrative review.
  - reference: PMID:19598066
    reference_title: "Factor V deficiency."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: "Heterozygous carriers have approximately half-normal levels of FV and are usually asymptomatic."
    explanation: >-
      States the asymptomatic carrier state recorded in this block's description.
pathophysiology:
- name: Biallelic F5 Loss-of-Function Variants
  biological_scale: MOLECULAR
  description: >-
    Homozygous or compound heterozygous variants in F5 on chromosome 1q24.
    Missense substitutions predominate; the reported spectrum also includes
    nonsense, frameshift, splice-site and large-deletion alleles, with more than
    two thirds of the published severe-deficiency alleles being null mutations
    that reduce factor V expression.
  genetic_context:
    variant_origin: GERMLINE
    functional_impact_category: LOSS_OF_FUNCTION
  cell_types:
  - preferred_term: hepatocyte, the principal site of factor V synthesis
    term:
      id: CL:0000182
      label: hepatocyte
  downstream:
  - target: Reduced Functional Plasma Factor V
    description: >-
      The variant protein is either not made, not secreted, or secreted in a form
      that cannot act as a prothrombinase cofactor.
  evidence:
  - reference: PMID:19598066
    reference_title: "Factor V deficiency."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: "A total of 56 mutations have been published to date as being responsible for severe or moderately severe FV deficiency; more than two thirds of these are null mutations (mainly decreasing FV expression), with the remaining being missense mutations (usually impairing FV secretion)."
    explanation: >-
      Describes the mutational spectrum and the predominance of null alleles that
      reduce factor V expression.
  - reference: PMID:9576178
    reference_title: "Severe coagulation factor V deficiency caused by a 4 bp deletion in the factor V gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Sequence analysis of the 5'- and 3'-untranslated, coding and adjacent regions of the factor V gene revealed the presence of a 4 bp deletion in exon 13."
    explanation: >-
      A worked homozygous null allele, the first reported F5 mutation causing a
      type I quantitative deficiency.
- name: Reduced Functional Plasma Factor V
  biological_scale: MOLECULAR
  description: >-
    The functional deficit measured in plasma as factor V coagulant activity
    (FV:C). In type I disease the immunoreactive antigen falls with it; in type II
    a dysfunctional molecule is still present at near-normal antigen. Residual
    activity grades the deficiency into mild, moderate and severe strata but
    predicts bleeding only weakly.
  molecular_functions:
  - preferred_term: factor V cofactor available for prothrombinase assembly
    modifier: DECREASED
    term:
      id: GO:0008047
      label: enzyme activator activity
  downstream:
  - target: Impaired Prothrombinase Cofactor Function
    description: >-
      Less circulating functional factor V means less factor Va available to
      serve as the prothrombinase cofactor.
  evidence:
  - reference: PMID:9576178
    reference_title: "Severe coagulation factor V deficiency caused by a 4 bp deletion in the factor V gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We have studied a young girl with very mild bleeding symptoms and undetectable levels of plasma factor V antigen and activity (<0.3% and <1.6% of normal, respectively)."
    explanation: >-
      Documents concordantly reduced factor V activity and antigen (a type I
      pattern) in a genetically confirmed patient.
  - reference: PMID:24787990
    reference_title: "Functional characterization of a novel missense mutation, His147Arg, in A1 domain of FV protein causing type II deficiency."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "The His147Arg mutation was associated with normal antigen levels, both in cell lysates and conditioned media, whereas FV activity was significantly reduced to 63.5 ± 17.0%."
    explanation: >-
      A type II pattern - preserved antigen against reduced activity - shown by
      expression study, the structural counterpart of the type I case above.
- name: Impaired Prothrombinase Cofactor Function
  biological_scale: MOLECULAR
  description: >-
    The non-redundant step. Activated factor V (factor Va) is the non-enzymatic
    cofactor of the prothrombinase complex, assembling with factor Xa on an
    anionic phospholipid surface and accelerating prothrombin cleavage far beyond
    what factor Xa achieves alone. Because both the extrinsic and intrinsic arms
    of the cascade converge on this common-pathway step, neither 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 supplying the anionic phospholipid surface
    term:
      id: CL:0000233
      label: platelet
  downstream:
  - target: Reduced Thrombin Generation
    description: >-
      Less functional prothrombinase converts less prothrombin to thrombin.
  evidence:
  - reference: PMID:35593819
    reference_title: "Factor V Deficiency."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: "Either thrombin or factor Xa converts factor V to the plasma cofactor of the prothrombinase complex. This complex, composed of calcium, phospholipids, factor Va, and factor Xa, is essential for converting prothrombin to thrombin."
    explanation: >-
      States the composition of prothrombinase and the cofactor role of factor Va
      that this node depends on.
- name: Reduced Thrombin Generation
  biological_scale: MOLECULAR
  description: >-
    The functional common denominator of the disease. Thrombin is needed 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.
  evidence:
  - reference: PMID:18695002
    reference_title: "Low plasma levels of tissue factor pathway inhibitor in patients with congenital factor V deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Thrombin generation in FV-deficient plasma was only measurable at high tissue factor concentrations"
    explanation: >-
      Documents the reduced thrombin generation of factor-V-deficient plasma that
      this node asserts.
- 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 why both the
    prothrombin time and the activated partial thromboplastin time are prolonged
    while the thrombin time, which tests the fibrinogen-to-fibrin step directly,
    remains normal.
  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: >-
      A slowly formed or unstable clot fails to secure haemostasis, producing
      spontaneous and provoked bleeding.
  - target: Prolonged prothrombin time
  - target: Prolonged partial thromboplastin time
  evidence:
  - reference: PMID:35593819
    reference_title: "Factor V Deficiency."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: "Initial laboratory evaluation shows prolonged prothrombin time and activated partial thromboplastin time (aPTT) with a normal thrombin time."
    explanation: >-
      States the simultaneous prolongation of both screening tests with a normal
      thrombin time that a common-pathway defect predicts.
- name: Systemic Bleeding Tendency
  biological_scale: ORGANISM
  description: >-
    The clinical endpoint. Bleeding is predominantly mucocutaneous but can be
    intracranial in the most severely affected. Severity broadly tracks residual
    factor V activity, but the correlation is imperfect and this entry does not
    overstate it.
  downstream:
  - target: Epistaxis
  - target: Gingival bleeding
  - target: Bruising susceptibility
  - target: Subcutaneous hemorrhage
  - target: Menorrhagia
  - target: Prolonged bleeding after surgery
  - target: Prolonged bleeding after dental extraction
  - target: Joint hemorrhage
  - target: Intramuscular hematoma
  - target: Gastrointestinal hemorrhage
  - target: Abnormal umbilical stump bleeding
  - target: Intracranial hemorrhage
    description: >-
      The most feared complication, concentrated in neonates and infants with
      the lowest factor V levels.
  - target: Post-partum hemorrhage
  evidence:
  - reference: PMID:42074284
    reference_title: "Genetic and Clinical Characteristics of Russian Patients with Congenital Factor V Deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Clinically, congenital FV deficiency most commonly presents with epistaxis, easy bruising, hematomas, and menorrhagia. Severe manifestations, such as gastrointestinal bleeding, hematuria, hemarthrosis, or central nervous system hemorrhage, are relatively uncommon"
    explanation: >-
      Enumerates the common and the severe bleeding manifestations wired to this
      node.
  - reference: PMID:9886321
    reference_title: "Symptoms of inherited factor V deficiency in 35 Iranian patients."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "The severity of bleeding symptoms was only partially related to the degree of factor V deficiency in plasma."
    explanation: >-
      Records the limit on the severity claim. Marked INDIRECT because it
      constrains how strongly residual activity predicts bleeding rather than
      asserting the bleeding tendency itself.
- name: Residual Platelet Factor V
  biological_scale: CELLULAR
  description: >-
    About a fifth to a quarter of the body's factor V is stored in platelet
    alpha-granules, acquired by megakaryocyte endocytosis of plasma factor V
    rather than synthesised in the platelet. In patients with undetectable plasma
    factor V, a measurable platelet-derived factor V/Va pool can persist and be
    released locally at a wound, where it is the predominant cofactor for
    thrombin generation at the platelet surface. This pool, not any residual
    plasma factor V, is the leading explanation for the mild phenotype of many
    severely deficient patients.
  cell_types:
  - preferred_term: platelet storing factor V in alpha-granules
    term:
      id: CL:0000233
      label: platelet
  - preferred_term: megakaryocyte endocytosing plasma factor V
    term:
      id: CL:0000556
      label: megakaryocyte
  cellular_components:
  - preferred_term: platelet alpha granule, the factor V store
    term:
      id: GO:0031091
      label: platelet alpha granule
  downstream:
  - target: Preserved Platelet-Dependent Thrombin Generation
    description: >-
      Locally released platelet factor V/Va supports thrombin generation at the
      platelet surface despite absent plasma factor V.
  evidence:
  - reference: PMID:25896652
    reference_title: "Platelets and platelet-derived factor Va confer hemostatic competence in complete factor V deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "release of the patient's platelet-derived FV/Va (7% of normal) following platelet activation resulted in robust thrombin generation, similar to that in an individual with normal plasma- and platelet-derived FV concentrations"
    explanation: >-
      Shows that platelet-derived factor V/Va alone supports near-normal thrombin
      generation in an individual with no detectable plasma factor V.
  - reference: PMID:19861681
    reference_title: "Residual platelet factor V ensures thrombin generation in patients with severe congenital factor V deficiency and mild bleeding symptoms."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "patients with undetectable plasma FV may contain functional FV in their platelets. In combination with low TFPI level, residual platelet FV allows sufficient thrombin generation to rescue these patients from fatal bleeding."
    explanation: >-
      States the protective role of residual platelet factor V, together with low
      TFPI, in patients with undetectable plasma factor V.
- name: Low Plasma Tissue Factor Pathway Inhibitor
  biological_scale: MOLECULAR
  description: >-
    Factor-V-deficient plasma carries physiologically low levels of tissue factor
    pathway inhibitor, possibly because factor V affects TFPI stability or
    clearance in vivo. The reduced TFPI lowers the factor V threshold needed for
    minimal thrombin generation and so works alongside residual platelet factor V
    to protect deficient patients from severe bleeding.
  genes:
  - preferred_term: TFPI
    term:
      id: hgnc:11760
      label: TFPI
  molecular_functions:
  - preferred_term: tissue factor pathway inhibitor serine protease inhibitor activity
    modifier: DECREASED
    term:
      id: GO:0004867
      label: serine-type endopeptidase inhibitor activity
  downstream:
  - target: Preserved Platelet-Dependent Thrombin Generation
    description: >-
      Lower TFPI lifts the inhibitory brake on the initiating tissue-factor
      complex, reducing the factor V requirement for thrombin generation.
  evidence:
  - reference: PMID:18695002
    reference_title: "Low plasma levels of tissue factor pathway inhibitor in patients with congenital factor V deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Plasma TFPI antigen and activity levels were indeed lower (P < .001) in FV-deficient patients (n = 11; 4.0 +/- 1.0 ng/mL free TFPI) than in controls (n = 20; 11.5 +/- 4.8 ng/mL)"
    explanation: >-
      Quantifies the reduced TFPI in factor-V-deficient patients.
  - reference: PMID:18695002
    reference_title: "Low plasma levels of tissue factor pathway inhibitor in patients with congenital factor V deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Low TFPI levels decreased the FV requirement for minimal thrombin generation in FV-deficient plasma to less than 1% and might therefore protect FV-deficient patients from severe bleeding."
    explanation: >-
      States how low TFPI lowers the factor V threshold for thrombin generation,
      which is the protective edge asserted here.
- name: Preserved Platelet-Dependent Thrombin Generation
  biological_scale: CELLULAR
  description: >-
    The convergence of residual platelet factor V and low TFPI: enough thrombin
    is generated at the activated platelet surface to secure a minimally
    haemostatic clot even when plasma factor V is undetectable. This is the
    mechanistic reason bleeding severity is discordant with plasma FV:C, and it
    is why a patient can be protected whose plasma assay reads zero.
  cell_types:
  - preferred_term: activated platelet surface where thrombin is generated
    term:
      id: CL:0000233
      label: platelet
  biological_processes:
  - preferred_term: platelet-surface thrombin generation
    term:
      id: GO:0007596
      label: blood coagulation
  evidence:
  - reference: PMID:25896652
    reference_title: "Platelets and platelet-derived factor Va confer hemostatic competence in complete factor V deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "resulted in robust thrombin generation, similar to that in an individual with normal plasma- and platelet-derived FV concentrations"
    explanation: >-
      Direct support: in an individual with no detectable plasma factor V,
      platelet-derived factor V/Va sustains near-normal thrombin generation.
  - reference: PMID:21320286
    reference_title: "Homozygous F5 deep-intronic splicing mutation resulting in severe factor V deficiency and undetectable thrombin generation in platelet-rich plasma."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "suggest that thrombin generation in PRP may predict bleeding tendency in patients with undetectable plasma FV"
    explanation: >-
      The mirror-image case: a severely affected patient whose platelet-rich
      plasma generates no thrombin. Marked INDIRECT because it supports the node
      through the negative/predictive direction rather than demonstrating
      preserved generation itself.
phenotypes:
- category: Hematologic
  name: Epistaxis
  description: >-
    Nosebleeds, among the most frequent presenting symptoms across cohorts.
  phenotype_term:
    preferred_term: Epistaxis
    term:
      id: HP:0000421
      label: Epistaxis
  evidence:
  - reference: PMID:9886321
    reference_title: "Symptoms of inherited factor V deficiency in 35 Iranian patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The most frequent symptoms included epistaxis and excessive bleeding after surgery."
    explanation: >-
      Names epistaxis among the most frequent symptoms in a 35-patient cohort.
- category: Hematologic
  name: Gingival bleeding
  frequency: FREQUENT
  description: >-
    Gum bleeding, the most common symptom in the Chinese national cohort (38.5%).
  phenotype_term:
    preferred_term: Gingival bleeding
    term:
      id: HP:0000225
      label: Gingival bleeding
  evidence:
  - reference: PMID:40421928
    reference_title: "Nationwide Study on Factor V Deficiency in China: Clinical Characteristics, Genotype, and Treatment Approaches."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The most common symptoms included gingival (n = 15, 38.5%) and cutaneous bleeding (n = 13, 33.3%) in 39 patients."
    explanation: >-
      Reports gingival bleeding as the most common symptom (38.5%), which places
      it in the FREQUENT band.
- category: Hematologic
  name: Bruising susceptibility
  description: >-
    Easy bruising, a common spontaneous manifestation.
  phenotype_term:
    preferred_term: Easy bruising
    term:
      id: HP:0000978
      label: Bruising susceptibility
  evidence:
  - reference: PMID:42074284
    reference_title: "Genetic and Clinical Characteristics of Russian Patients with Congenital Factor V Deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Clinically, congenital FV deficiency most commonly presents with epistaxis, easy bruising, hematomas, and menorrhagia."
    explanation: >-
      Lists easy bruising among the most common presentations.
- category: Hematologic
  name: Subcutaneous hemorrhage
  frequency: FREQUENT
  description: >-
    Cutaneous bleeding (ecchymoses), reported in a third of the Chinese cohort.
  phenotype_term:
    preferred_term: Cutaneous hemorrhage
    term:
      id: HP:0001933
      label: Subcutaneous hemorrhage
  evidence:
  - reference: PMID:40421928
    reference_title: "Nationwide Study on Factor V Deficiency in China: Clinical Characteristics, Genotype, and Treatment Approaches."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The most common symptoms included gingival (n = 15, 38.5%) and cutaneous bleeding (n = 13, 33.3%) in 39 patients."
    explanation: >-
      Reports cutaneous bleeding in 33.3% of patients, in the FREQUENT band.
- category: Hematologic
  name: Menorrhagia
  frequency: FREQUENT
  description: >-
    Heavy menstrual bleeding, a common and sometimes dominant manifestation in
    affected women; present in 38.9% of reproductive-age women in the Chinese
    cohort.
  phenotype_term:
    preferred_term: Menorrhagia
    term:
      id: HP:0000132
      label: Menorrhagia
  evidence:
  - reference: PMID:40421928
    reference_title: "Nationwide Study on Factor V Deficiency in China: Clinical Characteristics, Genotype, and Treatment Approaches."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Menorrhagia (n = 7) was observed in 38.9% of 18 female patients of reproductive age."
    explanation: >-
      Quantifies menorrhagia among reproductive-age women (38.9%), in the
      FREQUENT band.
- category: Hematologic
  name: Prolonged bleeding after surgery
  description: >-
    Excessive postoperative bleeding, among the most frequent symptoms.
  phenotype_term:
    preferred_term: Prolonged bleeding after surgery
    term:
      id: HP:0004846
      label: Prolonged bleeding after surgery
  evidence:
  - reference: PMID:9886321
    reference_title: "Symptoms of inherited factor V deficiency in 35 Iranian patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The most frequent symptoms included epistaxis and excessive bleeding after surgery."
    explanation: >-
      Names excessive bleeding after surgery among the most frequent symptoms.
- category: Hematologic
  name: Prolonged bleeding after dental extraction
  description: >-
    Excessive bleeding after dental extraction, a common provoked manifestation.
  phenotype_term:
    preferred_term: Prolonged bleeding after dental extraction
    term:
      id: HP:0006298
      label: Prolonged bleeding after dental extraction
  evidence:
  - reference: PMID:42074284
    reference_title: "Genetic and Clinical Characteristics of Russian Patients with Congenital Factor V Deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In childhood, ecchymosis, epistaxis, bleeding after tooth extraction, menorrhagia"
    explanation: >-
      A cohort patient with bleeding after tooth extraction.
- category: Hematologic
  name: Joint hemorrhage
  description: >-
    Haemarthrosis, less common than mucosal bleeding and usually confined to
    more severely affected patients.
  phenotype_term:
    preferred_term: Hemarthrosis
    term:
      id: HP:0005261
      label: Joint hemorrhage
  evidence:
  - reference: PMID:9886321
    reference_title: "Symptoms of inherited factor V deficiency in 35 Iranian patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Haemarthroses and muscle haematomas were less common, even in severely deficient patients."
    explanation: >-
      Reports haemarthrosis as a less common manifestation even in severe disease.
- category: Hematologic
  name: Intramuscular hematoma
  description: >-
    Muscle haematoma, less common than mucosal bleeding.
  phenotype_term:
    preferred_term: Muscle hematoma
    term:
      id: HP:0012233
      label: Intramuscular hematoma
  evidence:
  - reference: PMID:9886321
    reference_title: "Symptoms of inherited factor V deficiency in 35 Iranian patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Haemarthroses and muscle haematomas were less common, even in severely deficient patients."
    explanation: >-
      Reports muscle haematoma as a less common manifestation.
- category: Hematologic
  name: Gastrointestinal hemorrhage
  description: >-
    Gastrointestinal bleeding, a rare but serious manifestation.
  phenotype_term:
    preferred_term: Gastrointestinal hemorrhage
    term:
      id: HP:0002239
      label: Gastrointestinal hemorrhage
  evidence:
  - reference: PMID:42074284
    reference_title: "Genetic and Clinical Characteristics of Russian Patients with Congenital Factor V Deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Severe manifestations, such as gastrointestinal bleeding, hematuria, hemarthrosis, or central nervous system hemorrhage, are relatively uncommon"
    explanation: >-
      Lists gastrointestinal bleeding among the uncommon severe manifestations.
- category: Hematologic
  name: Abnormal umbilical stump bleeding
  description: >-
    Umbilical cord bleeding, a neonatal presenting sign of severe deficiency.
  phenotype_term:
    preferred_term: Umbilical cord bleeding
    term:
      id: HP:0011884
      label: Abnormal umbilical stump bleeding
  evidence:
  - reference: PMID:36125894
    reference_title: "Congenital coagulation factor V deficiency with intracranial hemorrhage."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Umbilical bleeding, anterior fontanelle tensed"
    explanation: >-
      A reported factor V deficiency case presenting with umbilical bleeding in
      the neonatal period.
- category: Neurologic
  name: Intracranial hemorrhage
  description: >-
    The most feared complication, concentrated in neonates and infants with the
    lowest factor V levels and sometimes the presenting event.
  phenotype_term:
    preferred_term: Intracranial hemorrhage
    term:
      id: HP:0002170
      label: Intracranial hemorrhage
  evidence:
  - reference: PMID:36125894
    reference_title: "Congenital coagulation factor V deficiency with intracranial hemorrhage."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Among the previous spontaneous intracranial hemorrhages in the congenital FV deficiency cases, most spontaneous intracranial hemorrhages occurred in infancy (13 of 20). All of the patients had FV activity less than 5% of normal."
    explanation: >-
      Documents the concentration of intracranial haemorrhage in infancy and in
      patients with the lowest factor V activity.
- category: Reproductive
  name: Post-partum hemorrhage
  description: >-
    Excessive bleeding at delivery in severely deficient women, controllable with
    plasma replacement.
  phenotype_term:
    preferred_term: Postpartum hemorrhage
    term:
      id: HP:0011891
      label: Post-partum hemorrhage
  evidence:
  - reference: PMID:15660985
    reference_title: "Pregnancy and oral contraceptives in factor V deficiency: a study of 22 patients (five homozygotes and 17 heterozygotes) and review of the literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "patients with severe deficiency bleed considerably at the time of delivery. However, bleeding can be controlled properly by administration of fresh frozen plasma with excellent foetal outcome."
    explanation: >-
      Reports considerable delivery-associated bleeding in severely deficient
      women, controllable with plasma.
- category: Laboratory
  name: Prolonged prothrombin time
  description: >-
    Prolonged PT, reflecting the common-pathway defect.
  phenotype_term:
    preferred_term: Prolonged prothrombin time
    term:
      id: HP:0008151
      label: Prolonged prothrombin time
  evidence:
  - reference: PMID:36125894
    reference_title: "Congenital coagulation factor V deficiency with intracranial hemorrhage."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The coagulation tests revealed a significantly prolonged prothrombin time (PT) of 51 s and an activated partial thromboplastin time (APTT) of 73.7"
    explanation: >-
      Documents a markedly prolonged prothrombin time in a confirmed case.
- category: Laboratory
  name: Prolonged partial thromboplastin time
  description: >-
    Prolonged aPTT, prolonged simultaneously with the PT because the defect is in
    the common pathway.
  phenotype_term:
    preferred_term: Prolonged activated partial thromboplastin time
    term:
      id: HP:0003645
      label: Prolonged partial thromboplastin time
  evidence:
  - reference: PMID:36125894
    reference_title: "Congenital coagulation factor V deficiency with intracranial hemorrhage."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The coagulation tests revealed a significantly prolonged prothrombin time (PT) of 51 s and an activated partial thromboplastin time (APTT) of 73.7"
    explanation: >-
      Documents the simultaneously prolonged activated partial thromboplastin
      time in the same case.
- category: Laboratory
  name: Reduced coagulation factor V activity
  description: >-
    Reduced plasma factor V coagulant activity, the specific assay that confirms
    the diagnosis.
  phenotype_term:
    preferred_term: Reduced factor V activity
    term:
      id: HP:0003225
      label: Reduced coagulation factor V activity
  evidence:
  - reference: PMID:40421928
    reference_title: "Nationwide Study on Factor V Deficiency in China: Clinical Characteristics, Genotype, and Treatment Approaches."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The study cohort comprised 45 patients with confirmed FV:C reductions (undetectable to 48%), including six mild (FV:C >10%), 31 moderate (FV:C 1%-10%), and eight severe (FV:C <1%) patients."
    explanation: >-
      Documents reduced factor V coagulant activity, with the severity strata,
      across a national cohort.
genetic:
- name: F5
  gene_term:
    preferred_term: F5
    term:
      id: hgnc:3542
      label: F5
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  gene_disease_validity:
  - validity_classification: DEFINITIVE
    classified_by: CLINGEN
    external_id: CGGV:assertion_beaa3af3-7d91-4d53-b081-de0e660c16c6-2020-03-25T160000.000Z
    evidence:
    - reference: CGGV:assertion_beaa3af3-7d91-4d53-b081-de0e660c16c6-2020-03-25T160000.000Z
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "| F5 | HGNC:3542 | congenital factor V deficiency | MONDO:0009210 | AR | Definitive | SOP6 | Hemostasis/Thrombosis Gene Curation Expert Panel | 2020-03-25T16:00:00.000Z |"
      explanation: >-
        ClinGen's Hemostasis/Thrombosis GCEP classifies the F5-congenital factor V
        deficiency relationship (autosomal recessive) as Definitive.
  notes: >-
    F5 is on chromosome 1q24 and spans 25 exons. The disorder is genetically
    heterogeneous, with missense variants predominating and the remainder null
    (nonsense, frameshift, splice-site, large deletions distributed across the
    gene); no single founder variant dominates, and routine exon-focused
    sequencing misses an appreciable fraction of alleles (large deletions,
    non-canonical splice variants), so multiplex ligation-dependent probe
    amplification is needed alongside sequencing. Per-gene case fractions are not
    curated because F5 is the sole causative locus.
  evidence:
  - reference: PMID:19486170
    reference_title: "Factor 5 mutation profile in German patients with homozygous and heterozygous factor V deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A total of 42 genetic alterations (of which 33 were uniquely different mutations), comprising 19 missense mutations, eight nonsense mutations, four small deletions and two splice site mutations, were identified by this study."
    explanation: >-
      Documents the mutational spectrum of F5 in a genotyped cohort.
  - reference: PMID:42074284
    reference_title: "Genetic and Clinical Characteristics of Russian Patients with Congenital Factor V Deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Overall, 3 of 15 causal variants (20%)—including two large deletions and a non-canonical splice-altering variant—would not have been reliably detected using routine exon-focused sequencing alone."
    explanation: >-
      Supports the note that routine sequencing misses a fraction of F5 alleles,
      which is why MLPA is needed.
biochemical:
- name: Factor V coagulant activity (FV:C)
  biomarker_term:
    preferred_term: factor V coagulant activity
    term:
      id: NCIT:C98726
      label: Factor V Measurement
  presence: DECREASED
  readouts:
  - target: Reduced Functional Plasma Factor V
    relationship: READOUT_OF
    description: >-
      FV:C measures the functional consequence of the genetic lesion at the level
      of circulating protein activity, and defines the conventional severity
      strata.
  reference_ranges:
  - unit: "% of normal FV:C"
    population: patients with congenital factor V deficiency
    interpretation_bands:
    - name: Severe deficiency
      upper_bound: 1.0
      unit: "% of normal FV:C"
      abnormal_flag: CRITICAL_LOW
      severity: SEVERE
    - name: Moderate deficiency
      lower_bound: 1.0
      upper_bound: 10.0
      unit: "% of normal FV:C"
      abnormal_flag: LOW
      severity: MODERATE
    - name: Mild deficiency
      lower_bound: 10.0
      unit: "% of normal FV:C"
      abnormal_flag: LOW
      severity: MILD
    notes: >-
      The severity bands are the plasma FV:C strata, stated as a percentage of
      normal. Mild is above 10%, moderate 1-10%, severe below 1%. They grade the
      deficiency; they predict bleeding only weakly (see the knowledge gap on
      activity-severity discordance).
    evidence:
    - reference: PMID:35593819
      reference_title: "Factor V Deficiency."
      supports: SUPPORT
      evidence_source: OTHER
      quote_role: REVIEW_SYNTHESIS
      snippet: "Mild factor V deficiency is identified by plasma activity greater than 10% of normal. Moderate deficiency shows activity from 1% to 10%, and severe deficiency presents with activity less than 1%."
      explanation: >-
        Source for the three severity bands encoded here.
  evidence:
  - reference: PMID:40421928
    reference_title: "Nationwide Study on Factor V Deficiency in China: Clinical Characteristics, Genotype, and Treatment Approaches."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The study cohort comprised 45 patients with confirmed FV:C reductions (undetectable to 48%), including six mild (FV:C >10%), 31 moderate (FV:C 1%-10%), and eight severe (FV:C <1%) patients."
    explanation: >-
      Applies the FV:C severity strata to a national cohort, confirming the assay
      is the quantity that grades the disease.
prevalence:
- population: Worldwide
  measure_type: POINT_PREVALENCE
  prevalence_class: BAND_1_9_PER_1000000
  rate_per_100000: 0.1
  rate_denominator: POPULATION
  notes: >-
    Reported as approximately 1 in 1,000,000 in the homozygous (severe) form,
    which normalises to 0.1 per 100,000.
  evidence:
  - reference: PMID:19598066
    reference_title: "Factor V deficiency."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: "Congenital factor V (FV) deficiency is a bleeding disorder associated with mild to severe hemorrhagic symptoms and a prevalence in the general population of 1 in 1,000,000 in the homozygous form."
    explanation: >-
      States the worldwide frequency normalised in this record.
  - reference: PMID:39191405
    reference_title: "Clinical, Laboratory, and Molecular Aspects of Factor V Deficiency."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: "Congenital FV deficiency is a rare bleeding disorder with an incidence of 1 per million live births, considering the most severe homozygous form."
    explanation: >-
      An independent review statement of the same order-of-magnitude frequency.
diagnosis:
- name: Coagulation screen
  description: >-
    The screening picture that prompts factor-specific assays: prolonged
    prothrombin time and prolonged activated partial thromboplastin time with a
    normal thrombin time, because the defect is in the common pathway and spares
    the fibrinogen-to-fibrin step.
  diagnosis_term:
    preferred_term: coagulation screening blood test
    term:
      id: NCIT:C217390
      label: Diagnostic Blood Testing
  evidence:
  - reference: PMID:35593819
    reference_title: "Factor V Deficiency."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: "Initial laboratory evaluation shows prolonged prothrombin time and activated partial thromboplastin time (aPTT) with a normal thrombin time. A low plasma factor V level confirms the diagnosis."
    explanation: >-
      States the screening abnormalities and that a low factor V level confirms
      the diagnosis.
- name: Plasma mixing study
  description: >-
    Distinguishes an inherited factor deficiency from an acquired inhibitor:
    correction of the prolonged PT and aPTT on mixing with normal plasma
    indicates a deficiency, while persistent prolongation indicates an inhibitor.
  diagnosis_term:
    preferred_term: plasma mixing coagulation test
    term:
      id: NCIT:C217390
      label: Diagnostic Blood Testing
  evidence:
  - reference: PMID:35593819
    reference_title: "Factor V Deficiency."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: "Improvement of these parameters after mixing suggests an inherited form, with normal plasma replacing the missing factor. Persistent prothrombin time and aPTT prolongation after mixing indicates an acquired form, as an inhibitor in the patient's plasma prevents normalization."
    explanation: >-
      States the interpretation of the mixing study that distinguishes inherited
      from acquired factor V deficiency.
- name: F5 sequencing
  description: >-
    Confirms the diagnosis, establishes the inheritance pattern for counselling,
    and identifies the causative variants. Multiplex ligation-dependent probe
    amplification is needed alongside sequencing because routine exon-focused
    sequencing misses large deletions and some splice variants.
  diagnosis_term:
    preferred_term: F5 genetic testing
    term:
      id: NCIT:C15709
      label: Genetic Testing
  evidence:
  - reference: PMID:42074284
    reference_title: "Genetic and Clinical Characteristics of Russian Patients with Congenital Factor V Deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Multiplex ligation-dependent probe amplification (MLPA) was used to detect large deletions and duplications."
    explanation: >-
      Documents the assays used to achieve a complete molecular diagnosis.
differential_diagnoses:
- name: Acquired factor V deficiency
  description: >-
    An autoantibody-mediated factor V deficiency, clinically and by coagulation
    screen resembling the congenital form but of later onset and distinguished by
    a plasma mixing study that fails to correct. It is a different entity, often
    following exposure to bovine thrombin, surgery, malignancy or antibiotics.
  disease_term:
    preferred_term: acquired factor V deficiency
    term:
      id: MONDO:0035737
      label: acquired factor V deficiency
  evidence:
  - reference: PMID:35593819
    reference_title: "Factor V Deficiency."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: "Persistent prothrombin time and aPTT prolongation after mixing indicates an acquired form, as an inhibitor in the patient's plasma prevents normalization."
    explanation: >-
      States the mixing-study finding that distinguishes acquired from congenital
      factor V deficiency.
- name: Combined factor V and factor VIII deficiency
  description: >-
    A separate autosomal recessive disorder caused by LMAN1 or MCFD2 defects in
    the ER-to-Golgi cargo receptor that transports both factor V and factor VIII.
    Both factors are mildly to moderately reduced together, which the isolated
    factor assay distinguishes from isolated factor V deficiency.
  disease_term:
    preferred_term: combined deficiency of factor V and factor VIII
    term:
      id: MONDO:0018175
      label: combined deficiency of factor V and factor VIII
  evidence:
  - reference: PMID:19141156
    reference_title: "Factor V deficiency: a concise review."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: "FV deficiency can be caused by mutations in the FV gene or in genes encoding components of a putative cargo receptor that transports FV (and factor VIII) from the endoplasmic reticulum to the Golgi."
    explanation: >-
      Names the cargo-receptor mechanism that produces combined FV and FVIII
      deficiency, the entity this differential separates out.
treatments:
- name: Fresh frozen plasma
  description: >-
    The mainstay of treatment, because no factor-V-specific concentrate is
    licensed. Plasma supplies intact factor V; dosing targets a haemostatic
    factor V level (commonly above 20 IU/dL), and because the plasma half-life of
    factor V is short, repeated infusions are needed. Virus-inactivated
    (solvent-detergent) plasma is preferred.
  therapeutic_modality: PROTEIN_REPLACEMENT
  treatment_term:
    preferred_term: Fresh Frozen Plasma Transfusion
    term:
      id: NCIT:C116475
      label: Fresh Frozen Plasma Transfusion
    therapeutic_agent:
    - preferred_term: fresh frozen plasma
  notes: >-
    The therapeutic agent is left unbound: NCIT:C89783 Fresh Frozen Plasma is a
    biospecimen term, not a pharmacologic substance, so it is not a valid
    ChemicalEntityTerm; the transfusion action carries the binding.
  target_mechanisms:
  - target: Reduced Functional Plasma Factor V
    treatment_effect: RESTORES
    description: >-
      Donor plasma supplies functional factor V, restoring the prothrombinase
      cofactor at the node immediately downstream of the genetic lesion.
  evidence:
  - reference: PMID:39191405
    reference_title: "Clinical, Laboratory, and Molecular Aspects of Factor V Deficiency."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: "The mainstay of treatment includes fresh-frozen plasma, preferentially virus-inactivated."
    explanation: >-
      States fresh frozen plasma as the mainstay and the preference for
      virus-inactivated product.
  - reference: PMID:39022653
    reference_title: "Rare inherited coagulation disorders: no longer orphan and neglected."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: "Because of the relatively short plasma half-life of FV (16-36 hours), daily infusions are required to keep FV at hemostatic levels (ie, above 20 IU/dL)"
    explanation: >-
      States the haemostatic target level and why repeated infusions are needed.
- name: Platelet transfusion
  description: >-
    Used when plasma alone is ineffective, exploiting the platelet factor V pool
    that localises to the site of bleeding. Platelet concentrates have been
    combined with plasma for refractory bleeding.
  therapeutic_modality: OTHER
  treatment_term:
    preferred_term: Platelet Transfusion
    term:
      id: NCIT:C15366
      label: Platelet Transfusion
  target_mechanisms:
  - target: Residual Platelet Factor V
    treatment_effect: RESTORES
    description: >-
      Transfused platelets deliver factor V/Va that localises at the injury site,
      supplementing the patient's platelet-derived pool.
  evidence:
  - reference: PMID:39022653
    reference_title: "Rare inherited coagulation disorders: no longer orphan and neglected."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: "a combination of platelet concentrates and SD-FFP has been used when SD-FFP alone was ineffective"
    explanation: >-
      States the rationale for platelet transfusion and its use when plasma alone
      fails.
- name: Antifibrinolytic therapy
  description: >-
    Tranexamic acid, used for mucosal and minor bleeding and as cover for minor
    procedures. It does not correct the coagulation defect; it protects the clot
    that does form from premature lysis, so it is adjunctive.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    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
    treatment_effect: MODULATES
    description: >-
      Inhibiting plasminogen activation prolongs survival of the weak clot that
      forms, acting on clot persistence rather than on thrombin generation.
  evidence:
  - reference: PMID:19141156
    reference_title: "Factor V deficiency: a concise review."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: "Antifibrinolytics can also provide benefit, especially for mucosal bleeding."
    explanation: >-
      States the indication for antifibrinolytics in factor V deficiency.
- name: Recombinant activated factor VII
  description: >-
    A bypassing agent used off-label for severe bleeding, for patients with
    factor V inhibitors, or where plasma causes allergy or volume overload. It
    increases thrombin generation at the injury site rather than replacing
    factor V.
  therapeutic_modality: OTHER
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: recombinant activated factor VII (eptacog alfa)
      term:
        id: NCIT:C81125
        label: Eptacog Alfa
  target_mechanisms:
  - target: Reduced Thrombin Generation
    treatment_effect: BYPASSES
    description: >-
      Pharmacological activated factor VII drives thrombin generation at the site
      of injury, bypassing the factor V cofactor deficit rather than correcting it.
  evidence:
  - reference: PMID:39022653
    reference_title: "Rare inherited coagulation disorders: no longer orphan and neglected."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: "Off-label recombinant FVIIa (rFVIIa) was successfully used in cases with FV inhibitors (not infrequent) or allergy to FFP or to avoid volume overload"
    explanation: >-
      States the indications for recombinant activated factor VII in factor V
      deficiency.
  - reference: PMID:40788998
    reference_title: "Inhibitor Development in Severe Congenital Factor V Deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Bleeding control was achieved with recombinant factor VIIa."
    explanation: >-
      A worked case of bleeding controlled with recombinant activated factor VII
      in a patient who had developed a factor V inhibitor.
- name: Liver transplantation
  description: >-
    Definitive cure for the most severe cases, since factor V is synthesised in
    the liver. Reserved for patients with life-threatening bleeding unmanageable
    by plasma; it corrects factor V levels and abolishes the need for infusions.
  therapeutic_modality: SURGERY
  treatment_term:
    preferred_term: Liver Transplantation
    term:
      id: NCIT:C15271
      label: Liver Transplantation
  target_mechanisms:
  - target: Reduced Functional Plasma Factor V
    treatment_effect: RESTORES
    description: >-
      A donor liver synthesises normal factor V, permanently restoring the
      circulating pool.
  evidence:
  - reference: PMID:29250911
    reference_title: "Management of intracranial hemorrhage in severe factor V deficiency and definitive treatment with liver transplantation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "He received an orthotopic liver transplant at age 5 months, resulting in correction of his FV levels. He has not required any plasma infusions post-transplantation and has had no further bleeding episodes."
    explanation: >-
      A worked case in which liver transplantation corrected factor V levels and
      cured the bleeding phenotype.
animal_models:
- name: F5 knockout mouse
  species: Mouse
  genotype: Fv-/- (targeted deletion of coagulation factor V)
  publication: PMID:8900278
  description: >-
    The Cui et al. (1996) factor V knockout. About half of homozygous embryos die
    at embryonic day 9-10, possibly from a yolk-sac vascular abnormality; the rest
    reach term but die of massive haemorrhage within two hours of birth. The model
    established the absolute requirement for factor V in prothrombinase activity
    and revealed a developmental role for the coagulation system.
  evidence:
  - reference: PMID:8900278
    reference_title: "Fatal haemorrhage and incomplete block to embryogenesis in mice lacking coagulation factor V."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "The remaining Fv-/- mice progress normally to term, but die from massive haemorrhage within 2 hours of birth."
    explanation: >-
      Reports the fatal perinatal bleeding phenotype of complete factor V loss.
  modeled_mechanisms:
  - target: Systemic Bleeding Tendency
    relationship: PARTIALLY_RECAPITULATES
    fidelity: MODERATE
    model_scale: ORGANISM
    description: >-
      Complete absence of factor V produces fatal spontaneous bleeding,
      reproducing the organism-level bleeding tendency.
    limitations: >-
      Total factor V deficiency is embryonic or perinatally lethal in the mouse,
      whereas human disease is a survivable chronic diathesis in which some
      residual factor V (plasma or platelet) is essentially always present. The
      model cannot report the human natural history, genotype-phenotype relation,
      or long-term treatment, and its lethality is why human complete deficiency
      is so rare.
    evidence:
    - reference: PMID:8900278
      reference_title: "Fatal haemorrhage and incomplete block to embryogenesis in mice lacking coagulation factor V."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "approximately half of homozygous embryos deficient in factor V (Fv-/-), which have been generated by gene targeting, die at embryonic day (E) 9-10, possibly as a result of an abnormality in the yolk-sac vasculature."
      explanation: >-
        Reports the embryonic lethality that is the model's key divergence from
        the survivable human disease.
- name: F5 transgene-rescued mouse
  species: Mouse
  genotype: Tg(Malb-Fv);Fv-/- (liver-directed low-level factor V minigene on a null background)
  publication: PMID:10669158
  description: >-
    A factor V minigene expressed at under 0.1% of normal in the liver rescues
    Fv-/- mice through the perinatal period to adulthood without spontaneous
    haemorrhage, demonstrating that minimal factor V expression suffices for
    survival - a plausible explanation for why nearly all human patients retain
    some residual factor V.
  evidence:
  - reference: PMID:10669158
    reference_title: "Rescue of fatal neonatal hemorrhage in factor V deficient mice by low level transgene expression."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Rescued Tg+,Fv-/- mice have undetectable FV (<0.1%) in both plasma and platelet compartments, but survive the perinatal period and mature to adulthood without spontaneous hemorrhage."
    explanation: >-
      Shows that below-detection factor V rescues survival, the model's central
      finding.
  modeled_mechanisms:
  - target: Systemic Bleeding Tendency
    relationship: RESCUES
    fidelity: MODERATE
    model_scale: ORGANISM
    description: >-
      Minimal liver-directed factor V expression rescues the otherwise fatal
      bleeding of the null mouse, modelling the viability threshold rather than
      the symptomatic human phenotype.
    limitations: >-
      The transgene is expressed from a heterologous promoter at a fixed low
      level, not from the native locus, so it tests a viability threshold rather
      than reproducing any particular human genotype or its bleeding pattern.
    evidence:
    - reference: PMID:10669158
      reference_title: "Rescue of fatal neonatal hemorrhage in factor V deficient mice by low level transgene expression."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "We conclude that FV present at <0.1% is sufficient to support postnatal survival."
      explanation: >-
        States the viability threshold this rescue model establishes.
- name: F5 Thr1898Met knock-in mouse
  species: Mouse
  genotype: F5 Thr1898Met missense knock-in (CRISPR/Cas9 homology-directed repair, homozygous)
  publication: PMID:40455764
  description: >-
    A 2025 CRISPR knock-in carrying a missense variant chosen in silico to give a
    mild phenotype. Homozygotes are viable with no spontaneous bleeding, reduced
    factor V activity (around 24.5%) and prolonged PT and aPTT - the first viable
    pathological mouse model of the disease, usable for testing new therapies.
  evidence:
  - reference: PMID:40455764
    reference_title: "Development of a novel and viable knock-in factor V deficiency murine model: Utility for an ultra-rare disease."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "A viable FV-deficient mouse model was generated by introducing a missense mutation in FV. The model exhibits a mild phenotype of the disease, akin to that observed in humans."
    explanation: >-
      The authors' statement that the knock-in is a viable model with a mild
      human-like phenotype.
  modeled_mechanisms:
  - target: Reduced Functional Plasma Factor V
    relationship: RECAPITULATES
    fidelity: MODERATE
    model_scale: MOLECULAR
    description: >-
      A missense knock-in reproduces the reduced circulating factor V activity and
      the prolonged clotting times of mild human disease in a viable animal.
    limitations: >-
      The model carries one engineered missense allele chosen for mildness, so it
      represents the mild end of the spectrum and does not reproduce severe or
      null-allele disease or its intracranial-haemorrhage risk.
    readouts:
    - name: Plasma factor V activity
      target: Reduced Functional Plasma Factor V
      direction: DECREASED
      interpretation: Reduced factor V activity in homozygous knock-in mice.
      evidence:
      - reference: PMID:40455764
        reference_title: "Development of a novel and viable knock-in factor V deficiency murine model: Utility for an ultra-rare disease."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "FV levels in homozygous animals were 24.5% ± 5.1"
        explanation: >-
          Quantifies the reduced factor V activity in the knock-in mouse.
- name: fv mutant zebrafish
  species: Zebrafish
  genotype: fv homozygous nonsense mutant (ENU-induced, premature stop in exon 2)
  publication: PMID:38874909
  description: >-
    An ENU-derived factor V nonsense zebrafish line. Homozygous larvae show
    prolonged time to occlusion after venous laser injury and poor survival
    beyond 12 days post-fertilisation; the line phenocopies human parahaemophilia
    and is a tool for drug screening.
  evidence:
  - reference: PMID:38874909
    reference_title: "Characterization of zebrafish coagulation cofactors Fviii and Fv mutants and modeling hemophilia A and factor V deficiency."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Homozygous and heterozygous 5 days post fertilization (dpf) larvae for fviii and fv deficient mutants exhibited prolonged time to occlusion after venous laser injury compared to wild-type controls."
    explanation: >-
      Reports the haemostatic defect in the factor V mutant zebrafish.
  modeled_mechanisms:
  - target: Impaired Fibrin Clot Formation
    relationship: PARTIALLY_RECAPITULATES
    fidelity: LOW
    model_scale: ORGANISM
    description: >-
      Loss of fv delays clot occlusion after vascular injury, reproducing the
      impaired clot formation of the human disease in a screenable vertebrate.
    limitations: >-
      Zebrafish tolerate factor V loss longer than mammals, and the paper reports
      an apparently dominant pattern in the fish, so the inheritance and timing do
      not transfer to the human disease; the model is best read as a
      variant/drug-screening tool rather than a faithful clinical model.
    evidence:
    - reference: PMID:38874909
      reference_title: "Characterization of zebrafish coagulation cofactors Fviii and Fv mutants and modeling hemophilia A and factor V deficiency."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "fv homozygous larvae had poor survival beyond 12 dpf."
      explanation: >-
        Documents the larval lethality that bounds the model's fidelity.
discussions:
- discussion_id: fv_activity_severity_discordance
  kind: KNOWLEDGE_GAP
  status: OPEN
  prompt: >-
    Why does plasma factor V activity predict bleeding severity so poorly, and
    can platelet factor V or thrombin generation do better?
  attaches_to:
  - pathophysiology#Systemic Bleeding Tendency
  - pathophysiology#Preserved Platelet-Dependent Thrombin Generation
  rationale: >-
    Patients with undetectable plasma factor V range from mild bleeders to
    neonates with fatal intracranial haemorrhage, and plasma FV:C does not sort
    them. The leading candidate explanations - residual platelet factor V and low
    TFPI sustaining thrombin generation - are supported by case-level work, and
    thrombin generation in platelet-rich plasma may track bleeding better than a
    one-stage plasma assay, but no prospective study has established a platelet or
    thrombin-generation measure as a clinical predictor. This bears directly on
    which laboratory value should set a prophylaxis threshold.
  evidence:
  - reference: PMID:19438479
    reference_title: "Advances in understanding the bleeding diathesis in factor V deficiency."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: "While the reasons for this variable phenotypic expression are largely unknown, several observations from different laboratories indicate platelets as crucial players in FV deficiency."
    explanation: >-
      States that the reasons for the variable phenotype are largely unknown and
      points to platelets as the leading candidate, which is the gap here.
- discussion_id: fv_no_licensed_concentrate
  kind: KNOWLEDGE_GAP
  status: OPEN
  prompt: >-
    Can a factor-V-specific replacement therapy be developed and licensed?
  attaches_to:
  - treatments#
  rationale: >-
    Factor V deficiency is the rare bleeding disorder still without a licensed
    factor-specific concentrate, unlike factor X and factor XIII deficiencies.
    Two candidates have reached preclinical or in-vitro stage - a plasma-derived
    factor V concentrate that corrects clotting times and thrombin generation in
    patient plasma, and an engineered activated factor V (superFVa) - but neither
    has completed human trials, so plasma and platelet transfusion remain the only
    options.
  evidence:
  - reference: PMID:41167601
    reference_title: "From Fresh Frozen Plasma to First-in-Human: Bringing Coagulation Factor V Deficiency into Therapeutic Trials."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: "Congenital factor V (FV) deficiency, affecting approximately 1 in 1 million individuals worldwide, remains among the rare bleeding disorders (RBDs) without a licensed factor-specific replacement therapy."
    explanation: >-
      States the unmet therapeutic need this gap is about.
  - reference: PMID:29578313
    reference_title: "\"In vitro\" correction of the severe factor V deficiency-related coagulopathy by a novel plasma-derived factor V concentrate."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "The novel plasma-derived FV concentrate was effective to correct \"in vitro\" severe FV deficiency in patients."
    explanation: >-
      A candidate concentrate shown to work in vitro, the preclinical state of
      the art this gap tracks.
references:
- reference: PMID:35593819
  title: "Factor V Deficiency."
  tags:
  - StatPearls
notes: >-
  Scope: this entry covers congenital (inherited) factor V deficiency only.
  Acquired factor V deficiency and combined factor V and factor VIII deficiency
  are different entities and appear only as differential diagnoses. Type I
  (CRM-negative) and type II (CRM-positive) are not curated as separate diseases
  because they converge on the same prothrombinase cofactor defect; the two
  patterns are illustrated instead on the Reduced Functional Plasma Factor V node
  (a type I null allele and a type II missense variant). The deep-research report
  under research/ was used only as a lead list; every claim here was verified
  against primary PubMed sources fetched into references_cache/.
📚

References & Deep Research

References

1
PMID:35593819
Factor V Deficiency.
No top-level findings curated for this source.

Deep Research

1

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

Evaluations and curation notes (2)

Record notes

Scope: this entry covers congenital (inherited) factor V deficiency only. Acquired factor V deficiency and combined factor V and factor VIII deficiency are different entities and appear only as differential diagnoses. Type I (CRM-negative) and type II (CRM-positive) are not curated as separate diseases because they converge on the same prothrombinase cofactor defect; the two patterns are illustrated instead on the Reduced Functional Plasma Factor V node (a type I null allele and a type II missense variant). The deep-research report under research/ was used only as a lead list; every claim here was verified against primary PubMed sources fetched into references_cache/.

Create: Congenital Factor V Deficiency · 2026-10-12T04:48:23Z · View source

De novo curation of congenital factor V deficiency (MONDO:0009210, F5). Pathophysiology chain from biallelic F5 loss-of-function through reduced plasma factor V, impaired prothrombinase cofactor function, reduced thrombin generation, impaired fibrin clot formation, to systemic bleeding; plus a compensation arm (residual platelet factor V + low TFPI -> preserved platelet-dependent thrombin generation) explaining the characteristic activity/severity discordance. 16 phenotypes (mucocutaneous bleeding, ICH, lab findings), F5 CAUSATIVE with ClinGen DEFINITIVE gene_disease_validity copied from CGGV record, FV:C biomarker with severity bands, prevalence ~1/million, diagnosis (coag screen/mixing study/F5 sequencing), differential diagnoses (acquired FV deficiency; combined FV+FVIII), treatments (FFP, platelet transfusion, antifibrinolytics, rFVIIa, liver transplant), four animal models (Cui 1996 knockout, transgene rescue, 2025 knock-in, zebrafish), two KNOWLEDGE_GAP discussions. The claude_code deep-research report under research/ was used as leads only; all primary sources were found and verified via PubMed and fetched into references_cache. Validation: validate-disorders passed (62/62 snippets, 0 issues), validate-terms passed, entity-refs/causal-targets/qualifier-terms/duplicate-keys/enum-values clean, 15/16 phenotypes causally connected, no GeneReviews chapter exists (StatPearls tagged), global compliance 82.4%.

Claude Code ▸
Congenital Factor V Deficiency (MONDO:0009210): research report
claude-haiku-5-5, claude-sonnet-5-5 13 citations 2026-10-12T04:06:22.612151

Congenital Factor V Deficiency (MONDO:0009210): research report

Verification status. I ran three web searches. They returned review-level sources but no abstract text I could quote, and none of the PMIDs were confirmed. Claims are tagged [sourced] where a search result supports them. Claims tagged [background] come from my own knowledge and have not been checked. The Term Validation and just preflight-dr steps in CLAUDE.md still apply, and so does the rule that every CURIE and PMID is read from a source before it is written. The ontology IDs below are leads, not bindings. I did not look up any of them. Please do not bind them, or quote snippets, without a lookup and just fetch-reference.

1. Disease information

  • Congenital factor V (FV) deficiency is a rare autosomal recessive bleeding disorder. It is caused by a deficiency of coagulation factor V (proaccelerin, labile factor). [sourced: NHF/HFA overview]
  • Synonyms: Owren's disease, parahemophilia, proaccelerin deficiency, labile factor deficiency. [sourced: same page]
  • Identifiers:
  • MONDO:0009210, given in the template.
  • HGNC:3542 appears in a GenCC submission linking F5 to MONDO:0009210. [sourced: GenCC]
  • The repo uses the lowercase form hgnc:3542.
  • OMIM 227400 [background, unverified].
  • Orphanet number: not found.
  • ICD-10 D68.2 (hereditary deficiency of other clotting factors) [background, unverified].
  • Do not confuse it with FV Leiden (thrombophilia), combined FV/FVIII deficiency (LMAN1/MCFD2), or acquired FV inhibitors. Combined FV/FVIII deficiency is a separate disease. [background]
  • The data are aggregated disease-level resources and case series, not EHR-derived.

2. Etiology

  • Causal factor: biallelic loss-of-function variants in F5. [sourced: Asselta & Peyvandi review, 2009] The review reports that 56 mutations had been published in severe or moderately severe FV deficiency. More than two thirds were null mutations, and the rest were mostly missense.
  • Heterozygous carriers have about half-normal FV and are usually asymptomatic. [sourced]
  • Risk factors:
  • Consanguinity raises the chance of homozygosity. [background]
  • No environmental risk factors are known.
  • Protective factors:
  • Platelet-derived FV can partly preserve hemostasis even when plasma FV is near zero. [sourced: Cornell VIVO record, "Platelets and platelet-derived factor Va confer hemostatic competence in complete factor V deficiency"]
  • Concurrent thrombophilic variants (e.g. FV Leiden in trans) can attenuate the bleeding phenotype. [background, unverified]
  • Gene–environment interactions: none established.

3. Phenotypes

Suggested HPO terms are leads and must be looked up before binding.

Phenotype Notes Suggested HPO
Mucosal bleeding (epistaxis, gum bleeding, menorrhagia) Most common feature. [sourced: 2019 overview] Epistaxis; Menorrhagia; Gingival bleeding
Easy bruising / ecchymoses Mild cases. [sourced] Bruising susceptibility
Postoperative or post-traumatic hemorrhage [sourced: NHF/HFA overview] Abnormal bleeding
Pulmonary and GI bleeding Severe cases. [sourced: NHF/HFA overview] Gastrointestinal hemorrhage
Intracranial hemorrhage Severe cases, including perinatal onset. A report links homozygous F5 splicing mutations to a high incidence of intracranial bleeding. [sourced: Haematologica] Intracranial hemorrhage
Hemarthrosis Uncommon. [background] Hemarthrosis
Prolonged PT and aPTT Laboratory finding. [background, unverified] Prolonged prothrombin time; Prolonged partial thromboplastin time
  • Onset runs from neonatal to adult. The mildest cases are diagnosed late.
  • Severity correlates imperfectly with plasma FV activity, and platelet FV helps account for the mismatch.
  • The course is lifelong. Bleeding is episodic.
  • Frequency percentages and quality-of-life data: not retrieved.

4. Genetic and molecular information

  • Gene: F5 (HGNC:3542), at 1q24.2 [background]. The protein is large, with A1-A2-B-A3-C1-C2 domains. [background]
  • Variant spectrum: null (nonsense, frameshift, splice) and missense variants spread across the gene. [sourced: 2019 overview]
  • Reported case series include an Indian cohort with three novel exon 13 deletions and an African American patient with two novel variants. [sourced via search summary; citations not verified]
  • Mechanism: loss of function. [sourced]
  • Modifier genes: not established in what I retrieved.
  • Epigenetic and chromosomal abnormalities: none known.
  • Allele frequencies (gnomAD) and ClinVar classifications: not retrieved.
  • Gene-disease validity: GenCC lists an F5–MONDO:0009210 submission. [sourced: GenCC] Run just check-gene-validity and copy the tier from ClinGen. Do not assign one.

5. Environmental information

None are known. There are no environmental, lifestyle, or infectious causes of the congenital form. Acquired FV deficiency (inhibitors, liver disease, DIC) is a separate entity.

6. Mechanism / pathophysiology

Causal chain: 1. Biallelic F5 loss-of-function variants lead to absent or reduced synthesis or secretion of FV. [sourced] 2. FV is made mainly in the liver (hepatocytes) and circulates as plasma FV. About 20% is stored in platelet α-granules. [sourced via search summary; hepatic synthesis is background] 3. Without FV there is no cofactor Va for factor Xa in the prothrombinase complex. Prothrombin conversion to thrombin on activated platelet surfaces is then impaired. [background] 4. Reduced thrombin generation leads to defective fibrin formation, and the PT and aPTT are prolonged. [background] 5. The result is mucosal and postoperative bleeding. The phenotype is variable because platelet FV/Va can partly compensate. [sourced: Cornell VIVO record] 6. Branch: in the most severe genotypes, with absent plasma and platelet FV, intracranial hemorrhage occurs, including perinatally. [sourced: Haematologica]

Suggested terms, to be verified by lookup: - GO: blood coagulation, thrombin generation, prothrombinase complex. - CL: hepatocyte, platelet, megakaryocyte. - GO CC: platelet alpha granule.

There are no single-cell, proteomic, or other omics findings in what I retrieved.

7. Anatomical structures affected

  • Systemic hemostasis, with the liver as the site of synthesis. Mucosae (nose, gut, uterus), brain, lung, and joints are the bleeding sites. [sourced / background]
  • Subcellular: platelet alpha granule. Laterality: not applicable.

8. Temporal development

  • Onset is congenital. The phenotype may present in the neonatal period, in childhood, or in adulthood.
  • The course is lifelong, non-progressive, and episodic. Intracranial hemorrhage is the main early-life risk. [sourced]
  • No remission patterns are described.

9. Inheritance and population

  • Autosomal recessive.
  • Prevalence: about 1 in 1,000,000 is the usual figure [background]. A 2025 knock-in mouse paper describes the disease as ultra-rare, "1–9 cases per million live births". [sourced: PMC12129228] Reconcile the two against Orphanet before choosing a prevalence_class. I found no Orphanet page.
  • Carrier frequency: not retrieved.
  • Consanguinity increases the disease frequency. [background]
  • Founder effects: I did not retrieve any; the Indian cohort exon 13 deletions are a lead. Sex ratio is expected to be equal, as expected for autosomal inheritance. [background]

10. Diagnostics

  • Prolonged PT and aPTT with a normal thrombin time. A mixing study corrects. [background]
  • FV activity assay, which is diagnostic. FV antigen can distinguish type I (quantitative) from type II (qualitative) deficiency. [background]
  • Heterozygotes have about 50% FV. [sourced]
  • Genetic testing: F5 sequencing, which is large and requires Sanger sequencing, a panel, or exome sequencing. [background]
  • Differential: combined FV/FVIII deficiency (LMAN1/MCFD2), acquired FV inhibitor, liver disease, vitamin K deficiency, DIC. [background]
  • Screening: none population-wide. Cascade testing of relatives is relevant.
  • GeneReviews chapter: not found in my search. Run just check-genereviews.

11. Outcome / prognosis

  • Bleeding severity is variable. Most patients have mucosal bleeding that is managed with treatment. Severe cases can involve life-threatening intracranial, pulmonary, or GI hemorrhage. [sourced]
  • Survival and life-expectancy data: not retrieved.
  • Prognostic factors: FV activity level and genotype, with platelet FV as a modifier. [sourced / background]

12. Treatment

  • There is no FV-specific concentrate. Fresh frozen plasma (FFP) is the mainstay. [sourced: Rare Coagulation Disorders; NHF/HFA overview]
  • Dosing: one review sets a target of FV above 20% for procedures and acute bleeding, with daily FFP infusions of 15–20 mL/kg typically enough. [sourced via search summary; verify at the source]
  • Platelet transfusion is added in severe or refractory bleeding. Platelet FV supports hemostasis after plasma infusion. [sourced: Cornell VIVO record]
  • Antifibrinolytics (aminocaproic acid or tranexamic acid) are used for mucosal bleeding. rFVIIa and prothrombin complex concentrate have been used in refractory cases. [sourced via search summary]
  • Experimental: a 2025 Thieme article, "From Fresh Frozen Plasma to First-in-human: Bringing Coagulation Factor V Deficiency into Therapeutic Trials", covers development of FV therapeutics, but I did not read it. [sourced: Thieme] I found no NCT identifiers.
  • NCIT leads to look up and not bind from memory: Pharmacotherapy (NCIT:C15986), Supportive Care (NCIT:C15747), and a plasma or blood transfusion term.
  • For the KB, use therapeutic_modality: PROTEIN_REPLACEMENT for FFP, only after a source check.

13. Prevention

  • No primary prevention.
  • Genetic counseling and cascade testing apply. Prenatal diagnosis is possible in families with a known variant. [background]
  • Prophylactic FFP before surgery or procedures is used as secondary and tertiary prevention. Peripartum and neonatal management planning is needed in severe cases. [background]
  • Avoid antiplatelet drugs. [background, unverified]

14. Other species

  • I did not search OMIA. Naturally occurring FV deficiency has been described in animals. I have not verified it and would not cite it without a source.

15. Model organisms

  • F5 knockout mice: about half die at E9–E10 with yolk-sac vascular and somite defects. The rest are born and die of massive hemorrhage within hours of birth. [sourced: PMC4260973 table T3; UMich listing] The primary paper is probably Cui et al. 1996. That attribution is a lead and not confirmed.
  • A 2025 knock-in model is viable and was developed for an ultra-rare disease. [sourced: PMC12129228]
  • A truncated mutant FV mouse affected hemostasis and embryonic development. [sourced: UCM record]
  • The null mouse is much more severe than most human cases, because human partial or platelet FV and residual variants soften the phenotype. This fits HUMAN_MODEL_MISMATCH or a PARTIALLY_RECAPITULATES link. [background]

Sources

Reference Validation

Checked with linkml-reference-validator 0.3.0.

Outcome Count
References checked 2
Resolved 2
Unresolved (possible confabulation) 0
Unverifiable 0
References weighed for topical relevance 2
On topic 1
Off topic 0

All extracted references resolved successfully.

Term Validation

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

Outcome Count
Terms checked 4
Resolved 3
Unresolved (possible confabulation) 0
Obsolete 0
Unverifiable 1

3 of 4 terms resolved to a current term; the rest could not be looked up either way.