Thrombophilia

Complex MONDO:0002305 Pathograph 17 Show in embeddings browser Blood Coagulation Disease

An inherited or acquired shift of hemostasis toward thrombosis, most often manifesting as venous thromboembolism (deep vein thrombosis and pulmonary embolism). This entry models the root concept plus the five classic hereditary subtypes: factor V Leiden (activated protein C resistance), prothrombin G20210A, and deficiencies of antithrombin, protein C, and protein S. Each subtype reflects either a gain of procoagulant function (factor V Leiden, prothrombin G20210A) or a loss of natural anticoagulant function (antithrombin, protein C, protein S deficiency), and all five converge on the same downstream coagulation-activation and thrombus-formation pathway. Acquired, antiphospholipid-antibody-mediated thrombophilia is a mechanistically distinct, autoimmune disease already modeled in Antiphospholipid_Syndrome.yaml and is cross-referenced rather than duplicated here. Penetrance is incomplete and strongly modified by transient exposures (surgery, immobility, pregnancy, estrogen, cancer, inflammation), so a hereditary thrombophilia genotype is a risk factor for, not a guarantee of, clinical thrombosis.

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9
Pathophys.
11
Phenotypes
17
Pathograph
5
Genes
4
Medical Actions
5
Subtypes
1
Models
2
References
1
Deep Research
◆

Subtypes

5
Factor V Leiden Thrombophilia (Activated Protein C Resistance) MONDO:0008560
F5 hgnc:3542 HUGO Gene Nomenclature Committee (hgnc) Relation: this subtype is caused by variation in this gene This subtype is caused by variation in F5 (hgnc:3542). hgnc:3542 is a gene from the HUGO Gene Nomenclature Committee. Autosomal dominant inheritance
The most common hereditary thrombophilia, caused by an F5 c.1601G>A (p.Arg534Gln; legacy p.Arg506Gln/1691G>A) missense variant that removes one of the proteolytic cleavage sites activated protein C (APC) uses to inactivate factor Va, rendering factor Va resistant to APC and prolonging procoagulant activity.
Show evidence (2 references)
PMID:20301542 SUPPORT Human Clinical
"The diagnosis of factor V Leiden thrombophilia is established in a proband by identification of a heterozygous or homozygous c.1601G>A (p.Arg534Gln) variant in F5 on molecular genetic testing."
GeneReviews establishes the causal F5 variant and diagnostic criterion for this subtype.
PMID:20301542 SUPPORT Human Clinical
"Factor V Leiden thrombophilia is inherited in an autosomal dominant manner."
GeneReviews states the inheritance pattern for this subtype.
Prothrombin G20210A Thrombophilia MONDO:0008559
F2 hgnc:3535 HUGO Gene Nomenclature Committee (hgnc) Relation: this subtype is caused by variation in this gene This subtype is caused by variation in F2 (hgnc:3535). hgnc:3535 is a gene from the HUGO Gene Nomenclature Committee. Autosomal dominant inheritance
The second most common hereditary thrombophilia, caused by an F2 c.*97G>A (legacy g.20210G>A) variant in the prothrombin 3' untranslated region that increases prothrombin mRNA processing efficiency and raises circulating prothrombin concentration, expanding the substrate available for thrombin generation.
Show evidence (2 references)
PMID:20301327 SUPPORT Human Clinical
"The diagnosis of prothrombin thrombophilia is established in a proband by identification of a heterozygous or homozygous 20210G>A variant (also known as c.*97G>A) in F2, the gene encoding prothrombin."
GeneReviews establishes the causal F2 variant and diagnostic criterion for this subtype.
PMID:40429442 SUPPORT Human Clinical
"The second most common cause of hereditary thrombophilia is the FII G20210A mutation occurring in the FII gene where guanine is replaced by adenine at position 20210 in the FII gene, resulting in an increased synthesis of FII"
Describes the variant and its consequence of increased prothrombin (FII) synthesis.
Antithrombin III Deficiency MONDO:0013144
SERPINC1 hgnc:775 HUGO Gene Nomenclature Committee (hgnc) Relation: this subtype is caused by variation in this gene This subtype is caused by variation in SERPINC1 (hgnc:775). hgnc:775 is a gene from the HUGO Gene Nomenclature Committee. Autosomal dominant inheritance
The most thrombogenic classic hereditary thrombophilia, caused by SERPINC1 variants that reduce the level (type I, quantitative) or function (type II, qualitative) of antithrombin, the principal serpin inhibitor of thrombin and factor Xa.
Show evidence (2 references)
PMID:41706600 SUPPORT Human Clinical
"Hereditary AT deficiency (hATD) is a rare autosomal dominant disorder caused by mutations in the gene encoding AT (SERPINC1), resulting in decreased AT levels or activity."
Establishes the causal gene, inheritance pattern, and quantitative/qualitative nature of this subtype.
PMID:41706600 SUPPORT Human Clinical
"As the most thrombogenic inherited thrombophilia, hATD confers a lifetime venous thromboembolism (VTE) risk of up to 85%, with similar annual VTE incidence in both pediatric and adult patients."
Documents the exceptionally high lifetime VTE risk that distinguishes this subtype from the other four.
Protein C Deficiency MONDO:0019145
PROC hgnc:9451 HUGO Gene Nomenclature Committee (hgnc) Relation: this subtype is caused by variation in this gene This subtype is caused by variation in PROC (hgnc:9451). hgnc:9451 is a gene from the HUGO Gene Nomenclature Committee. Autosomal dominant inheritance Autosomal recessive inheritance
A hereditary thrombophilia caused by PROC variants that reduce the level or function of protein C, a vitamin K-dependent zymogen that, once activated on the endothelial surface, inactivates factors Va and VIIIa. Severe (typically homozygous or compound heterozygous) deficiency can present as neonatal purpura fulminans.
Show evidence (2 references)
PMID:30702334 SUPPORT Human Clinical
"Protein C (PC) deficiency is a heritable or acquired risk factor for thrombophilia, with presentations varying from asymptomatic to venous thromboembolism to neonatal purpura fulminans, a life-threatening disorder."
Establishes the clinical spectrum of this subtype from asymptomatic carriage to neonatal purpura fulminans.
PMID:30702334 SUPPORT Human Clinical
"Hereditary PC deficiency is caused by mutation in the PC (PROC) gene located on chromosome 2q14.3."
Establishes the causal gene for this subtype.
Protein S Deficiency MONDO:0019144
PROS1 hgnc:9456 HUGO Gene Nomenclature Committee (hgnc) Relation: this subtype is caused by variation in this gene This subtype is caused by variation in PROS1 (hgnc:9456). hgnc:9456 is a gene from the HUGO Gene Nomenclature Committee. Autosomal dominant inheritance Autosomal recessive inheritance
A hereditary thrombophilia caused by PROS1 variants that reduce the level or function of protein S, a vitamin K-dependent glycoprotein that is a non-enzymatic cofactor for activated protein C (and, independently, for tissue factor pathway inhibitor). Severe deficiency can present as neonatal purpura fulminans.
Show evidence (2 references)
PMID:42429079 SUPPORT Human Clinical
"Protein S (PROS1) is a vitamin K-dependent plasma glycoprotein that was originally described as a non-enzymatic cofactor of activated protein C in the regulation of blood coagulation."
Establishes the causal gene and the classic anticoagulant-cofactor mechanism for this subtype.
PMID:40429442 SUPPORT Human Clinical
"Congenital PS deficiency follows an autosomal dominant inheritance pattern."
States the inheritance pattern for this subtype.
⚙

Pathophysiology

9
Factor V Leiden-Mediated Activated Protein C Resistance
The F5 p.Arg534Gln (Leiden) variant abolishes an APC cleavage site on factor Va, so factor Va escapes proteolytic inactivation by activated protein C and remains procoagulant for longer than normal, sustaining prothrombinase activity and thrombin generation.
blood coagulation GO:0007596 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased blood coagulation (GO:0007596). GO:0007596 is a biological process from the Gene Ontology. ↑ INCREASED negative regulation of blood coagulation GO:0030195 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased negative regulation of blood coagulation (GO:0030195). GO:0030195 is a biological process from the Gene Ontology. ↓ DECREASED
Downstream
Coagulation Cascade Activation and Thrombin-Driven Fibrin Formation Persistently active factor Va sustains prothrombinase complex activity, amplifying thrombin generation and downstream fibrin formation.
Show evidence (2 references)
PMID:40429442 SUPPORT Human Clinical
"The Arg506Gln mutation impairs the normal inactivation of FVa by APC, leading to an increased thrombin generation and a hypercoagulable state."
Directly describes the molecular mechanism by which the Leiden variant increases thrombin generation.
PMID:26492443 SUPPORT Human Clinical
"Factor V Leiden (FVLeiden ) is a common hereditary thrombophilia that causes activated protein C (APC) resistance."
Confirms the APC-resistance mechanism and establishes this as a common hereditary thrombophilia.
Prothrombin G20210A-Associated Increased Prothrombin Synthesis
The F2 c.*97G>A 3' UTR variant increases prothrombin mRNA processing efficiency, raising steady-state plasma prothrombin concentration and expanding the substrate pool available for thrombin generation.
blood coagulation GO:0007596 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased blood coagulation (GO:0007596). GO:0007596 is a biological process from the Gene Ontology. ↑ INCREASED
Downstream
Coagulation Cascade Activation and Thrombin-Driven Fibrin Formation Elevated circulating prothrombin increases the substrate available to the prothrombinase complex, amplifying thrombin generation.
Show evidence (1 reference)
PMID:40429442 SUPPORT Human Clinical
"The second most common cause of hereditary thrombophilia is the FII G20210A mutation occurring in the FII gene where guanine is replaced by adenine at position 20210 in the FII gene, resulting in an increased synthesis of FII"
Directly describes the molecular consequence of the variant on prothrombin (FII) synthesis.
Antithrombin Deficiency
Reduced antithrombin level (type I) or function (type II) impairs serpin-mediated inhibition of thrombin, factor Xa, and other activated serine protease coagulation factors, removing a principal brake on the coagulation cascade.
negative regulation of blood coagulation GO:0030195 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased negative regulation of blood coagulation (GO:0030195). GO:0030195 is a biological process from the Gene Ontology. ↓ DECREASED
Downstream
Coagulation Cascade Activation and Thrombin-Driven Fibrin Formation Loss of antithrombin-mediated inhibition of thrombin and factor Xa permits unchecked amplification of the coagulation cascade.
Show evidence (2 references)
PMID:41706600 SUPPORT Human Clinical
"Antithrombin (AT), a glycoprotein, plays a key role in anticoagulation by inhibiting coagulation proteases."
Establishes antithrombin's normal anticoagulant role, the loss of which defines this node.
PMID:40429442 SUPPORT Human Clinical
"Antithrombin is a physiological natural anticoagulant. It belongs to the family of serine protease inhibitors (serpin), and it targets procoagulant serine proteases, such as activated FII, FIX, FX, and FXI, reducing clot formation."
Describes the serpin mechanism and the range of coagulation proteases antithrombin normally inhibits.
Protein C Deficiency
Reduced level or function of protein C impairs generation of activated protein C (APC) on the thrombomodulin/endothelial protein C receptor complex, so APC-mediated proteolytic inactivation of factors Va and VIIIa is diminished and their procoagulant activity persists.
hepatocyte CL:0000182 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves hepatocyte (CL:0000182). CL:0000182 is a cell type from the Cell Ontology.
negative regulation of blood coagulation GO:0030195 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased negative regulation of blood coagulation (GO:0030195). GO:0030195 is a biological process from the Gene Ontology. ↓ DECREASED
Downstream
Coagulation Cascade Activation and Thrombin-Driven Fibrin Formation Diminished APC-mediated inactivation of factors Va and VIIIa allows sustained prothrombinase and intrinsic tenase activity, amplifying thrombin generation.
Warfarin-Induced Transient Anticoagulant Depletion Because protein C has a short plasma half-life, a deficient baseline makes the transient post-warfarin-initiation fall in protein C activity proportionally more severe.
Show evidence (3 references)
PMID:40429442 SUPPORT Human Clinical
"It is synthesized in hepatocytes and circulates as a heterodimeric complex composed of heavy and light chains."
Establishes hepatocyte synthesis of protein C, supporting the cell-type binding on this node.
PMID:40429442 SUPPORT Human Clinical
"APC exerts its anticoagulant function by interacting with PS as a cofactor, inactivating key coagulation factors. Specifically, APC cleaves FVa at Arg534, Arg334, and Arg707, effectively downregulating thrombin generation."
Describes the normal APC-mediated inactivation of factor Va that is diminished when protein C is deficient.
PMID:40429442 SUPPORT Human Clinical
"A deficiency in PC leads to a hypercoagulable state, increasing the risk of VTE, including DVT and PE."
Directly links protein C deficiency to a hypercoagulable state and venous thromboembolism.
Protein S Deficiency
Reduced level or free/functional activity of protein S diminishes its cofactor support for APC-mediated inactivation of factors Va and VIIIa (and, independently, for tissue factor pathway inhibitor), so procoagulant factor activity persists longer than normal.
negative regulation of blood coagulation GO:0030195 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased negative regulation of blood coagulation (GO:0030195). GO:0030195 is a biological process from the Gene Ontology. ↓ DECREASED
Animal models
Platelet-specific Pros1 knockout mouse (Pros1lox/loxPf4-Cre+) Mouse partially recapitulates Loss of platelet-derived protein S increases venous thrombus propensity by impairing its cofactor role for activated protein C and tissue factor pathway inhibitor, limiting factor X activation and thrombin generation within the growing thrombus at low shear rates. It does not increase arterial thrombosis propensity, unlike the systemic human deficiency, which is not restricted to a low-shear vascular bed.
Downstream
Coagulation Cascade Activation and Thrombin-Driven Fibrin Formation Diminished APC-cofactor activity allows sustained factor Va/VIIIa activity and amplified thrombin generation, particularly under the low-shear conditions of venous flow.
Warfarin-Induced Transient Anticoagulant Depletion Because protein S has a short plasma half-life relative to the procoagulant vitamin K-dependent factors, a deficient baseline makes the transient post-warfarin-initiation fall in protein S activity proportionally more severe.
Show evidence (3 references)
PMID:41180656 SUPPORT Human Clinical
"Protein C and protein S are vitamin K-dependent glycoproteins that function as critical anticoagulants by regulating the coagulation cascade."
Establishes protein S as a vitamin K-dependent anticoagulant regulator of the coagulation cascade.
PMID:41180656 SUPPORT Human Clinical
"Protein S enhances the anticoagulant effect of protein C by serving as its cofactor; thus, deficiency in either protein leads to impaired inactivation of factors Va and VIIIa, fostering a prothrombotic state"
Directly describes the cofactor mechanism and its loss in protein S deficiency.
DOI:10.1182/blood.2019003630 SUPPORT Model Organism
"At a low shear rate, PSplt functions as a cofactor for both activated protein C and tissue factor pathway inhibitor, thereby limiting factor X activation and thrombin generation within the growing thrombus"
Mouse model evidence for the dual APC/TFPI cofactor mechanism of protein S in limiting venous thrombin generation.
Coagulation Cascade Activation and Thrombin-Driven Fibrin Formation
The shared downstream convergence point for all five hereditary thrombophilia subtypes: whichever specific gain of procoagulant or loss of anticoagulant function is present, the net effect is unchecked thrombin generation and thrombin-driven crosslinking of fibrinogen into an insoluble fibrin network.
platelet CL:0000233 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves platelet (CL:0000233). CL:0000233 is a cell type from the Cell Ontology.
blood coagulation GO:0007596 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased blood coagulation (GO:0007596). GO:0007596 is a biological process from the Gene Ontology. ↑ INCREASED fibrin clot formation GO:0072378 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased fibrin clot formation, annotated with blood coagulation, fibrin clot formation (GO:0072378). GO:0072378 is a biological process from the Gene Ontology. ↑ INCREASED
Downstream
Pathological Venous Thrombus Formation Thrombin-driven fibrin formation, together with platelet participation, builds the crosslinked fibrin-platelet scaffold of a pathological intravascular venous thrombus.
Show evidence (3 references)
PMID:39167180 SUPPORT Human Clinical
"The highest risk was associated with homozygous FVL (OR 5.58, 95% CI 4.61-6.74), homozygous FII (OR 5.16, 95% CI 3.12-8.52), and compound heterozygosity (OR 4.64, 95% CI 2.25-9.58)."
Quantifies the elevated VTE risk conferred by the highest-risk genotypes among the classic thrombophilias.
PMID:39167180 SUPPORT Human Clinical
"PC (OR 3.23, 95% CI 2.05-5.08), PS (OR 3.01, 95% CI 2.26-4.02), and AT deficiency (OR 4.01, 95% CI 2.50-6.44) demonstrated an intermediate VTE risk."
Quantifies the elevated VTE risk conferred by the three natural-anticoagulant-deficiency subtypes.
DOI:10.1161/JAHA.121.023018 SUPPORT Human Clinical
"The 5 classic thrombophilias are associated with a dose‐graded risk of VTE in middle‐aged and older adults."
A population cohort study confirms that thrombotic risk scales with the number of classic thrombophilia variants carried, consistent with convergence on one shared downstream effector.
Pathological Venous Thrombus Formation
Crosslinked fibrin and aggregated platelets assemble into a pathological intravascular thrombus, most often in the deep veins of the legs or pelvis. Hereditary thrombophilia is classically associated with venous, not arterial, thrombosis.
vein UBERON:0001638 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in vein (UBERON:0001638). UBERON:0001638 is an anatomical location from the Uberon multi-species anatomy ontology.
Downstream
Venous Thrombus Embolization to Pulmonary Arteries
Show evidence (2 references)
PMID:20301542 SUPPORT Human Clinical
"Factor V Leiden thrombophilia is characterized by venous thromboembolism (VTE) manifesting most commonly in adults as deep vein thrombosis (DVT) in the legs or pulmonary embolism."
Establishes deep vein thrombosis of the legs as the characteristic site of thrombus formation.
PMID:40429442 SUPPORT Human Clinical
"Hereditary thrombophilias are classically associated with venous thromboembolism (VTE), while their role in arterial thrombosis remains uncertain and highly debated."
Establishes that the venous, not arterial, circulation is the classically affected compartment.
Venous Thrombus Embolization to Pulmonary Arteries
A deep vein thrombus can dislodge and travel to the pulmonary arteries, producing pulmonary embolism, the other principal clinical manifestation of hereditary thrombophilia alongside deep vein thrombosis.
pulmonary artery UBERON:0002012 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in pulmonary artery (UBERON:0002012). UBERON:0002012 is an anatomical location from the Uberon multi-species anatomy ontology.
Show evidence (1 reference)
PMID:20301327 SUPPORT Human Clinical
"Prothrombin thrombophilia is characterized by venous thromboembolism (VTE) manifest most commonly in adults as deep-vein thrombosis (DVT) in the legs or pulmonary embolism."
Establishes pulmonary embolism as a characteristic clinical manifestation alongside DVT.
Warfarin-Induced Transient Anticoagulant Depletion
Because protein C and protein S have short plasma half-lives (protein C approximately 8 hours) relative to the procoagulant vitamin K-dependent clotting factors (24-72 hours), initiating vitamin K antagonist therapy (warfarin) without heparin bridging causes their activity to fall faster than that of the procoagulant factors, producing a paradoxical transient hypercoagulable state. This is proportionally more severe when baseline protein C or protein S activity is already reduced by hereditary deficiency, and can precipitate microvascular thrombosis and skin necrosis.
Downstream
Warfarin-Induced Skin Necrosis
Show evidence (2 references)
PMID:41180656 SUPPORT Human Clinical
"The initiation of warfarin therapy leads to a rapid decline in protein C and protein S levels due to their relatively short half-lives (protein C ~8 h), in contrast to other vitamin K-dependent clotting factors such as factors II, IX, and X (24–72 h)"
Directly describes the differential half-life mechanism that produces the transient hypercoagulable state.
PMID:41180656 SUPPORT Human Clinical
"This creates a transient hypercoagulable state, especially in individuals with underlying deficiencies, predisposing them to microvascular thrombosis and subsequent skin necrosis"
Links the transient hypercoagulable state to microvascular thrombosis and skin necrosis, particularly in individuals with underlying protein C/S deficiency.
⬡

Pathograph

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

Phenotypes

11
Blood 2
Deep Venous Thrombosis HP:0002625 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Deep venous thrombosis (HP:0002625). HP:0002625 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:20301542 SUPPORT Human Clinical
"Factor V Leiden thrombophilia is characterized by venous thromboembolism (VTE) manifesting most commonly in adults as deep vein thrombosis (DVT) in the legs or pulmonary embolism."
GeneReviews identifies DVT of the legs as the most common manifestation.
Neonatal Purpura Fulminans HP:0000979 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Purpura (HP:0000979). HP:0000979 is a phenotype from the Human Phenotype Ontology.
HPO has no dedicated "purpura fulminans" term; HP:0000979 Purpura is used here as the closest available term (a deliberate choice, not an oversight).
Show evidence (2 references)
PMID:30702334 SUPPORT Human Clinical
"Protein C (PC) deficiency is a heritable or acquired risk factor for thrombophilia, with presentations varying from asymptomatic to venous thromboembolism to neonatal purpura fulminans, a life-threatening disorder."
Establishes neonatal purpura fulminans as a severe presentation of protein C deficiency.
PMID:24144709 SUPPORT Human Clinical
"We report a case of a 6-year-old girl with severe protein S deficiency due to a homozygous mutation and recurrent episodes of skin necrosis. She developed purpura fulminans at birth"
Directly reports neonatal purpura fulminans in a patient with homozygous (severe) protein S deficiency, correctly scoped to the protein S subtype.
Cardiovascular 1
Pulmonary Embolism HP:0002204 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Pulmonary embolism (HP:0002204). HP:0002204 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:20301327 SUPPORT Human Clinical
"Prothrombin thrombophilia is characterized by venous thromboembolism (VTE) manifest most commonly in adults as deep-vein thrombosis (DVT) in the legs or pulmonary embolism."
GeneReviews identifies pulmonary embolism as a characteristic manifestation.
Other 8
Recurrent Venous Thromboembolism Recurrent thromboembolism HP:0004831 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Recurrent thromboembolism (HP:0004831). HP:0004831 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:39167180 SUPPORT Human Clinical
"Nevertheless, the risk of recurrent VTE was not negligible for any thrombophilia."
Directly establishes recurrent VTE as a real, quantified event across all five classic thrombophilias, not merely a management consideration.
Cerebral Venous Sinus Thrombosis HP:0033724 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Cerebral venous sinus thrombosis (HP:0033724). HP:0033724 is a phenotype from the Human Phenotype Ontology.
Show evidence (4 references)
PMID:39406200 SUPPORT Human Clinical
"This mutation is known to confer an increased risk for CVT in the Western population, with a prevalence of around 10–25%"
Directly reports factor V Leiden as conferring increased risk specifically for cerebral venous (sinus) thrombosis, the phenotype's defining feature.
PMID:39406200 SUPPORT Human Clinical
"AT deficiency is an autosomal dominant disorder and is one of the rare conditions that cause CVT."
Directly states that antithrombin deficiency causes cerebral venous (sinus) thrombosis.
DOI:10.1177/10760296241256360 SUPPORT Human Clinical
"Current guidelines recommend the standard-of-care anticoagulation (vitamin K antagonists or low-molecular-weight heparin) in patients with cerebral venous thrombosis (CVT)."
Confirms cerebral venous thrombosis is managed within the same anticoagulation framework as other venous thromboembolism; it does not itself establish hereditary thrombophilia as a cause, so support is partial and supplementary to the two etiology references above.
+ 1 more reference
Resistance to Activated Protein C HP:0012175 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Resistance to activated protein C (HP:0012175). HP:0012175 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:26492443 SUPPORT Human Clinical
"Factor V Leiden (FVLeiden ) is a common hereditary thrombophilia that causes activated protein C (APC) resistance."
Directly establishes APC resistance as the defining laboratory phenotype of this subtype.
Reduced Antithrombin Activity Reduced antithrombin III activity HP:0001976 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Reduced antithrombin III activity (HP:0001976). HP:0001976 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:41706600 SUPPORT Human Clinical
"Diagnosis is typically based on persistently low functional AT activity levels (<70% of age-appropriate normal values) and can be confirmed by genetic testing."
Establishes reduced antithrombin activity as the diagnostic laboratory phenotype.
Reduced Protein C Activity HP:0005543 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Reduced protein C activity (HP:0005543). HP:0005543 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:40429442 SUPPORT Human Clinical
"The PC activity assay is the recommended screening test and can be either clot-based or chromogenic, depending on the assay design."
Establishes reduced protein C activity as the primary diagnostic laboratory phenotype.
Reduced Protein S Activity HP:0004855 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Reduced protein S activity (HP:0004855). HP:0004855 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:40429442 SUPPORT Human Clinical
"PS functional activity assays measure the biological activity of PS by assessing its ability to function as a cofactor for APC in the inactivation of FVa and FVIIIa."
Establishes reduced protein S activity as the diagnostic laboratory phenotype.
Recurrent Pregnancy Loss
HP:0200067 (Recurrent spontaneous abortion) exists in HPO but is not bindable here: its full ancestor closure (`Recurrent spontaneous abortion -> Pregnancy history -> Past medical history -> All`, verified with `runoak -i sqlite:obo:hp ancestors HP:0200067`) does not pass through HP:0000118 (Phenotypic abnormality), the root the PhenotypeTerm dynamic enum requires, and there is no MONDO disease term for recurrent pregnancy loss either. This is a deliberate needs-term/NTR gap, not an oversight.
Show evidence (1 reference)
PMID:38674167 SUPPORT Human Clinical
"With an odds ratios of 2.44 for FVL, 2.08 for PT, and a notably high 3.45 for protein S deficiency, their findings underscore the substantial impact of these genetic factors on RPL."
Quantifies the association between the three thrombophilia subtypes and recurrent pregnancy loss; support is partial because the association is heterogeneous across the broader literature and causality is not established.
Warfarin-Induced Skin Necrosis HP:0001038 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Warfarin-induced skin necrosis (HP:0001038). HP:0001038 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:41180656 SUPPORT Human Clinical
"The review highlights that WSN predominantly affects middle-aged women and is often associated with protein C or S deficiency, initiation of high-dose warfarin without appropriate heparin bridging, and other thrombophilic disorders."
Directly links this phenotype to underlying protein C or protein S deficiency and unbridged warfarin initiation.
🧬

Genetic Associations

5
F5 (The c.1601G>A (p.Arg534Gln) variant is causal for factor V Leiden thrombophilia and is the most common hereditary thrombophilia in individuals of European ancestry.)
Gene: F5 hgnc:3542 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
Autosomal dominant inheritance
Show evidence (2 references)
PMID:40429442 SUPPORT Human Clinical
"This variant accounts for over 90% of inherited APCR cases and remains the most common genetic risk factor for thrombophilia in individuals of European descent, with a population prevalence from 1% to 5% on average, which is even higher among patients with VTE (10–20%)."
Establishes F5 Leiden as the dominant cause of hereditary APC resistance and quantifies its population and VTE-cohort prevalence.
PMID:40429442 SUPPORT Human Clinical
"Heterozygosity for FV Leiden increases the lifetime risk of thrombosis by approximately 7-fold, while homozygosity, though rare, confers a roughly 20-fold increase in risk"
Quantifies the zygosity-dependent thrombotic risk conferred by the F5 Leiden variant.
F2 (The c.*97G>A (legacy g.20210G>A) 3' UTR variant is causal for prothrombin thrombophilia, the second most common hereditary thrombophilia in individuals of European ancestry.)
Gene: F2 hgnc:3535 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is F2 (hgnc:3535). hgnc:3535 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE
Autosomal dominant inheritance
Show evidence (2 references)
PMID:40429442 SUPPORT Human Clinical
"The FII G20210A mutation is mostly found in individuals of European descent, with an estimated prevalence of 1% to 3% in the general population."
Quantifies the population prevalence of the F2 G20210A variant.
PMID:40429442 SUPPORT Human Clinical
"Among individuals with VTE, the prevalence of Factor II G20210A is significantly higher (6% to 10%), compared to the general population."
Quantifies the enrichment of the F2 G20210A variant among VTE patients relative to the general population.
SERPINC1 (Loss-of-function or reduced-activity SERPINC1 variants cause hereditary antithrombin deficiency, the most thrombogenic of the classic hereditary thrombophilias.)
Gene: SERPINC1 hgnc:775 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is SERPINC1 (hgnc:775). hgnc:775 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE
Autosomal dominant inheritance
Show evidence (1 reference)
PMID:41706600 SUPPORT Human Clinical
"The reported prevalence of hATD among European and North American cohorts ranges from 1 in 500 to 1 in 5000 individuals."
Quantifies the population prevalence of hereditary antithrombin deficiency.
PROC (Loss-of-function PROC variants cause hereditary protein C deficiency; severe (typically biallelic) deficiency can present as neonatal purpura fulminans.)
Gene: PROC hgnc:9451 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is PROC (hgnc:9451). hgnc:9451 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE
Autosomal dominant inheritance
Show evidence (1 reference)
PMID:40429442 SUPPORT Human Clinical
"It has been estimated that in patients with suspected hereditary VTE, the prevalence of PC deficiency is 5–10%. Among the general Caucasian population, the prevalence of PC deficiency is estimated to be 0.2–0.4%"
Quantifies protein C deficiency prevalence in the general population and among VTE patients.
PROS1 (Loss-of-function PROS1 variants cause hereditary protein S deficiency; severe (typically biallelic) deficiency can present as neonatal purpura fulminans.)
Gene: PROS1 hgnc:9456 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is PROS1 (hgnc:9456). hgnc:9456 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE
Autosomal dominant inheritance
Show evidence (1 reference)
PMID:40429442 SUPPORT Human Clinical
"The estimated incidence of mild congenital PS deficiency is approximately 1 in 500 individuals, while severe PS deficiency is exceedingly rare, with an unknown prevalence due to diagnostic challenges"
Quantifies the population prevalence of congenital protein S deficiency.
💊

Medical Actions

4
Acute Anticoagulation via Heparin-Potentiated Antithrombin
Action: anticoagulation therapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is anticoagulation therapy (NCIT:C63341). NCIT:C63341 is a clinical intervention from the NCI Thesaurus. Ontology label: Anticoagulation Therapy NCIT:C63341
Agent: low molecular weight heparin NCIT:C2578 NCI Thesaurus (NCIT) Relation: this treatment uses this therapeutic agent This treatment uses low molecular weight heparin (NCIT:C2578). NCIT:C2578 is a therapeutic agent from the NCI Thesaurus.
Therapeutic unfractionated or low-molecular-weight heparin potentiates antithrombin-mediated inhibition of thrombin and factor Xa. Because heparin's mechanism depends on antithrombin, its anticoagulant effect can be attenuated in antithrombin deficiency; antithrombin concentrate replacement (below) addresses this specifically. Agent, dose, and duration are individualized to the clinical circumstances.
Mechanism Target:
INHIBITS Coagulation Cascade Activation and Thrombin-Driven Fibrin Formation — Heparin-enhanced antithrombin activity inhibits thrombin and factor Xa, suppressing the coagulation reactions that generate and stabilize fibrin.
Show evidence (1 reference)
PMID:20301542 SUPPORT Human Clinical
"The first acute venous thrombosis is treated according to current guidelines."
GeneReviews establishes standard-guideline anticoagulation as first-line management of acute VTE in this disease.
Long-Term Oral Anticoagulation with Heparin-Bridged Initiation
Action: anticoagulation therapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is anticoagulation therapy (NCIT:C63341). NCIT:C63341 is a clinical intervention from the NCI Thesaurus. Ontology label: Anticoagulation Therapy NCIT:C63341
Agent: warfarin CHEBI:10033 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses warfarin (CHEBI:10033). CHEBI:10033 is a therapeutic agent from Chemical Entities of Biological Interest. rivaroxaban CHEBI:68579 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses rivaroxaban (CHEBI:68579). CHEBI:68579 is a therapeutic agent from Chemical Entities of Biological Interest.
Long-term oral anticoagulation (vitamin K antagonists such as warfarin, or direct oral anticoagulants) reduces the risk of recurrent venous thromboembolism; duration is individualized to the risk of recurrence versus bleeding. When warfarin is used, initiation should be bridged with heparin and avoid high loading doses, because unbridged warfarin initiation can precipitate warfarin-induced skin necrosis, particularly in protein C or protein S deficiency (see Warfarin-Induced Transient Anticoagulant Depletion). Direct oral anticoagulants avoid this mechanism and are an emerging alternative in this setting.
Mechanism Target:
INHIBITS Coagulation Cascade Activation and Thrombin-Driven Fibrin Formation — Vitamin K antagonism or direct factor Xa/thrombin inhibition suppresses ongoing coagulation-cascade activation, reducing the risk of recurrent thrombus formation.
BYPASSES Warfarin-Induced Transient Anticoagulant Depletion — Heparin bridging during warfarin initiation, or use of a direct oral anticoagulant instead of warfarin, avoids the transient protein C/S depletion window that can precipitate skin necrosis.
Show evidence (2 references)
PMID:20301542 SUPPORT Human Clinical
"The duration of oral anticoagulation therapy should be based on an assessment of the risks for VTE recurrence and anticoagulant-related bleeding."
GeneReviews frames long-term anticoagulation duration around the recurrence-versus-bleeding risk tradeoff.
PMID:41180656 SUPPORT Human Clinical
"Direct oral anticoagulants (DOACs) like rivaroxaban and apixaban are emerging alternatives due to favorable pharmacokinetics"
Identifies DOACs as an emerging alternative that avoids the warfarin-specific transient hypercoagulable window.
Antithrombin Concentrate Replacement 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: antithrombin III (human) NCIT:C136824 NCI Thesaurus (NCIT) Relation: this treatment uses this therapeutic agent This treatment uses antithrombin III (human), annotated with Therapeutic Human Antithrombin-III (NCIT:C136824). NCIT:C136824 is a therapeutic agent from the NCI Thesaurus.
Human antithrombin III concentrate directly restores antithrombin activity in hereditary antithrombin deficiency, used during high-risk periods (surgery, pregnancy, peripartum) or for treatment/prevention of thromboembolism when heparin-potentiated endogenous antithrombin is insufficient because the endogenous pool itself is deficient.
Mechanism Target:
RESTORES Antithrombin Deficiency — Exogenous antithrombin concentrate directly restores plasma antithrombin activity, re-establishing serpin-mediated inhibition of thrombin and factor Xa.
Show evidence (1 reference)
PMID:41706600 SUPPORT Human Clinical
"In August 2025, the U.S. Food and Drug Administration (FDA) approved an expanded indication for antithrombin III concentrate (human) to include pediatric patients with hATD, representing the first product specifically approved for this population."
Documents the FDA-approved indication for antithrombin concentrate replacement therapy in hereditary antithrombin deficiency.
Protein C Concentrate Replacement 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: protein C concentrate NCIT:C87607 NCI Thesaurus (NCIT) Relation: this treatment uses this therapeutic agent This treatment uses protein C concentrate (NCIT:C87607). NCIT:C87607 is a therapeutic agent from the NCI Thesaurus.
Plasma-derived protein C concentrate directly restores protein C activity in severe congenital protein C deficiency, the exact parallel of antithrombin concentrate replacement above. It is used as long-term prophylaxis and for acute treatment of purpura fulminans and disseminated intravascular coagulation, and as a bridge during initiation of vitamin K antagonist therapy to avoid the transient hypercoagulable state (see Warfarin-Induced Transient Anticoagulant Depletion).
Mechanism Target:
RESTORES Protein C Deficiency — Exogenous protein C concentrate directly restores plasma protein C activity, re-establishing APC-mediated inactivation of factors Va and VIIIa.
Show evidence (1 reference)
PMID:39286606 SUPPORT Human Clinical
"Protein C concentrate (Ceprotin; Baxalta US Inc, a Takeda company; Takeda Manufacturing Austria AG) is prepared from human plasma using a multistep purification process, including monoclonal antibody immune affinity chromatography, to yield a highly purified protein C concentrate, which is..."
Documents the FDA/EMA-recognized indication for protein C concentrate replacement therapy in severe congenital protein C deficiency, the exact parallel of the antithrombin concentrate indication above.
🌍

Environmental Factors

2
Estrogen-Containing Oral Contraceptive Use
exposure to oral contraceptive ECTO:9002149 Environmental Conditions, Treatments and Exposures Ontology (ECTO) Relation: this environmental factor is this exposure This environmental factor is exposure to oral contraceptive (ECTO:9002149). ECTO:9002149 is an exposure from the Environmental Conditions, Treatments and Exposures Ontology.
Estrogen-containing hormonal contraception supplies a "second hit" that can precipitate venous thromboembolism in carriers of an otherwise silent hereditary thrombophilia genotype.
Show evidence (1 reference)
PMID:20301327 SUPPORT Human Clinical
"Women heterozygous for 20210G>A with a history of VTE and women homozygous for 20210G>A with or without prior VTE should avoid estrogen-containing contraception and hormone replacement therapy (HRT)."
GeneReviews management guidance for prothrombin thrombophilia parallels the factor V Leiden guidance.
Mechanism Target:
EXACERBATES Pathological Venous Thrombus Formation — Estrogen exposure amplifies the venous thrombosis risk of an underlying hereditary thrombophilia genotype.
Show evidence (1 reference)
PMID:20301542 SUPPORT Human Clinical
"Women with a history of VTE who are heterozygous for the factor V Leiden variant and women homozygous for the factor V Leiden variant with or without prior VTE should avoid estrogen-containing contraception and HRT."
GeneReviews management guidance directly reflects the exacerbating effect of estrogen exposure in factor V Leiden carriers.
Hormone Replacement Therapy Exposure
exposure to hormone replacement therapy ECTO:2000005 Environmental Conditions, Treatments and Exposures Ontology (ECTO) Relation: this environmental factor is this exposure This environmental factor is exposure to hormone replacement therapy (ECTO:2000005). ECTO:2000005 is an exposure from the Environmental Conditions, Treatments and Exposures Ontology.
Exogenous hormone replacement therapy, like oral contraception, supplies a transient prothrombotic exposure that can precipitate venous thromboembolism in carriers of a hereditary thrombophilia genotype.
Show evidence (1 reference)
PMID:20301542 SUPPORT Human Clinical
"Women with a history of VTE who are heterozygous for the factor V Leiden variant and women homozygous for the factor V Leiden variant with or without prior VTE should avoid estrogen-containing contraception and HRT."
GeneReviews management guidance identifies HRT as a risk-amplifying exposure alongside estrogen-containing contraception.
Mechanism Target:
EXACERBATES Pathological Venous Thrombus Formation — Hormone replacement therapy amplifies the venous thrombosis risk of an underlying hereditary thrombophilia genotype.
Show evidence (1 reference)
PMID:20301542 SUPPORT Human Clinical
"Women electing use of short-term HRT for severe menopausal symptoms should avoid oral formulations."
GeneReviews management guidance reflects the exacerbating effect of HRT exposure in factor V Leiden carriers.
🔬

Diagnosis

5
Factor V Leiden: Activated Protein C Resistance Assay with Confirmatory F5 Genotyping
A two-step laboratory workup: an activated protein C (APC) resistance functional clotting assay is used as the initial screen, and a positive result is confirmed by targeted F5 c.1601G>A (p.Arg534Gln) genetic testing.
coagulation study NCIT:C62662 NCI Thesaurus (NCIT)
Results: Reduced anticoagulant response to added activated protein C (a low APC ratio) on the functional screen, confirmed by identification of a heterozygous or homozygous F5 c.1601G>A variant on genetic testing.
Show evidence (2 references)
PMID:40429442 SUPPORT Human Clinical
"The diagnosis of FV Leiden typically involves a two-step process: the initial detection of APC resistance through a functional clotting assay, followed by confirmatory genetic testing for the 1691G > A substitution."
Directly describes the two-step functional-assay-then-genotyping diagnostic workup for this subtype.
PMID:20301542 SUPPORT Human Clinical
"The diagnosis of factor V Leiden thrombophilia is established in a proband by identification of a heterozygous or homozygous c.1601G>A (p.Arg534Gln) variant in F5 on molecular genetic testing."
GeneReviews confirms genetic testing for the F5 variant as the diagnostic criterion.
Prothrombin G20210A: F2 Genotyping
The diagnosis is established directly by targeted genetic testing for the F2 c.*97G>A (legacy 20210G>A) variant; unlike factor V Leiden, there is no widely used functional screening assay upstream of genotyping.
genetic testing NCIT:C15709 NCI Thesaurus (NCIT)
Results: Identification of a heterozygous or homozygous F2 c.*97G>A variant.
Show evidence (1 reference)
PMID:20301327 SUPPORT Human Clinical
"The diagnosis of prothrombin thrombophilia is established in a proband by identification of a heterozygous or homozygous 20210G>A variant (also known as c.*97G>A) in F2, the gene encoding prothrombin."
GeneReviews states the diagnostic criterion for this subtype.
Antithrombin Deficiency: Activity Assay with Reflex Antigen Testing
Laboratory testing recommends starting with a functional antithrombin activity assay; if activity is reduced, follow-up antigen testing and calculation of the activity-to-antigen ratio distinguishes type I (quantitative) from type II (qualitative) deficiency. Direct oral anticoagulants can falsely elevate or normalize results depending on the assay type, and testing physiologic anticoagulant levels is recommended only after three months of anticoagulation for an acute thrombotic event to avoid consumption-related false positives. The ISTH SSC's 2020 laboratory-testing recommendations (DOI:10.1111/jth.14648) are the international reference standard for this workup; that communication has no retrievable abstract or full text in the reference cache, so it is cited here for provenance rather than quoted.
coagulation study NCIT:C62662 NCI Thesaurus (NCIT)
Results: Reduced antithrombin activity, with a follow-up antigen assay and activity-to-antigen ratio distinguishing type I from type II deficiency.
Show evidence (2 references)
PMID:40429442 SUPPORT Human Clinical
"Laboratory testing guidelines for diagnosing antithrombin deficiency recommend starting with an activity assay. If activity levels are reduced, follow-up testing should include an antigen assay and the calculation of the activity-to-antigen ratio"
Directly describes the activity-first, reflex-antigen diagnostic algorithm for this subtype.
PMID:40429442 SUPPORT Human Clinical
"Testing physiologic anticoagulant levels is recommended after three months of anticoagulation for acute thrombosis."
Establishes the timing rule for testing natural-anticoagulant levels relative to an acute thrombotic event, applicable to the antithrombin, protein C, and protein S activity assays.
Protein C Deficiency: Activity Assay
Protein C activity (clot-based or chromogenic) is the recommended screening test; a chromogenic assay offers higher specificity but cannot detect the rare type IIb deficiency, which a clot-based assay can identify at the cost of lower specificity.
coagulation study NCIT:C62662 NCI Thesaurus (NCIT)
Results: Reduced protein C activity.
Show evidence (1 reference)
PMID:40429442 SUPPORT Human Clinical
"The PC activity assay is the recommended screening test and can be either clot-based or chromogenic, depending on the assay design."
Directly identifies the recommended screening assay for this subtype.
Protein S Deficiency: Free Antigen and Functional Activity Assay
Protein S functional activity is assessed by its ability to act as an APC cofactor in inactivating factors Va and VIIIa; free and total protein S antigen are measured separately by immunoassay. Reference ranges are sex-, age-, and pregnancy-dependent (women have lower total and free protein S than men; total protein S rises with age), so results must be interpreted against appropriately stratified ranges and repeated outside pregnancy, hormonal therapy, or acute-phase states.
coagulation study NCIT:C62662 NCI Thesaurus (NCIT)
Results: Reduced free and/or total protein S antigen, or reduced protein S functional activity with normal antigen (type II/III).
Show evidence (2 references)
PMID:40429442 SUPPORT Human Clinical
"PS functional activity assays measure the biological activity of PS by assessing its ability to function as a cofactor for APC in the inactivation of FVa and FVIIIa."
Directly describes the functional-cofactor basis of the protein S activity assay.
PMID:40429442 SUPPORT Human Clinical
"Notably, women generally have lower total and free protein S levels than men. Total PS levels increase with age, particularly in women, due to hormonal variations, whereas free PS levels remain stable over time."
Establishes the sex- and age-dependence of protein S reference ranges relevant to result interpretation.
📊

Prevalence

5
European-ancestry general population
Carrier Frequency 3000.0 per 100,000 (1000.0–5000.0) >1 in 1,000 Factor V Leiden Thrombophilia
Reported as 1%-5% in the general European-ancestry population and 10%-20% among patients with venous thromboembolism.
Show evidence (1 reference)
PMID:40429442 SUPPORT
"This variant accounts for over 90% of inherited APCR cases and remains the most common genetic risk factor for thrombophilia in individuals of European descent, with a population prevalence from 1% to 5% on average, which is even higher among patients with VTE (10–20%)."
Source for the general-population and VTE-cohort prevalence estimates.
European-ancestry general population
Carrier Frequency 2000.0 per 100,000 (1000.0–3000.0) >1 in 1,000 Prothrombin G20210A Thrombophilia
Reported as 1%-3% in the general European-ancestry population and 6%-10% among patients with venous thromboembolism.
Show evidence (1 reference)
PMID:40429442 SUPPORT
"The FII G20210A mutation is mostly found in individuals of European descent, with an estimated prevalence of 1% to 3% in the general population."
Source for the general-population prevalence estimate.
European and North American cohorts
Carrier Frequency 100.0 per 100,000 (20.0–200.0) >1 in 1,000 Antithrombin III Deficiency
Reported as 1 in 500 to 1 in 5000 individuals; banded ABOVE_1_IN_1000 for consistency with the other four subtypes' banding convention, using the higher-prevalence (1 in 500) end of the reported range as the class-defining estimate. The low end of the range (1 in 5000) would itself fall in a rarer band.
Show evidence (1 reference)
PMID:41706600 SUPPORT
"The reported prevalence of hATD among European and North American cohorts ranges from 1 in 500 to 1 in 5000 individuals."
Source for the population prevalence estimate.
General Caucasian population
Carrier Frequency 300.0 per 100,000 (200.0–400.0) >1 in 1,000 Protein C Deficiency
Reported as 0.2%-0.4% in the general Caucasian population and 5%-10% among patients with suspected hereditary VTE.
Show evidence (1 reference)
PMID:40429442 SUPPORT
"It has been estimated that in patients with suspected hereditary VTE, the prevalence of PC deficiency is 5–10%. Among the general Caucasian population, the prevalence of PC deficiency is estimated to be 0.2–0.4%"
Source for the general-population and VTE-cohort prevalence estimates.
General population (mild congenital deficiency)
Carrier Frequency 200.0 per 100,000 >1 in 1,000 Protein S Deficiency
Reported as approximately 1 in 500 individuals for mild congenital deficiency; severe deficiency is exceedingly rare with unknown prevalence.
Show evidence (1 reference)
PMID:40429442 SUPPORT
"The estimated incidence of mild congenital PS deficiency is approximately 1 in 500 individuals, while severe PS deficiency is exceedingly rare, with an unknown prevalence due to diagnostic challenges"
Source for the general-population prevalence estimate.
🐁

Animal Models

1
Platelet-specific Pros1 knockout mouse (Pros1lox/loxPf4-Cre+)
A conditional knockout that eliminates protein S expression specifically in platelets (and their megakaryocyte precursors) while sparing the systemic, largely hepatocyte-derived plasma protein S pool.
Species
Mouse
Genotype
Pros1lox/loxPf4-Cre+ (platelet lineage-restricted Pros1 deletion via Platelet factor 4-Cre)
Publication
DOI:10.1182/blood.2019003630
Pathograph links
Protein S Deficiency partially recapitulates fidelity: moderate Loss of platelet-derived protein S increases venous thrombus propensity by impairing its cofactor role for activated protein C and tissue factor pathway inhibitor, limiting factor X activation and thrombin generation within the growing thrombus at low shear rates. It does not increase arterial thrombosis propensity, unlike the systemic human deficiency, which is not restricted to a low-shear vascular bed.
Limitations: This model isolates only the platelet-derived pool of protein S via a platelet-lineage-restricted knockout; it does not reproduce the systemic (predominantly hepatocyte-synthesized) protein S deficiency that defines the human hereditary disorder, so its venous-versus-arterial selectivity may not generalize to human patients with global protein S deficiency.
Readouts
Venous (vena cava) thrombus propensity
Direction: INCREASED
Interpretation: Platelet protein S loss increases thrombus formation at low shear (vena cava) but not at high shear (carotid artery), consistent with a cofactor role for APC/TFPI-mediated factor X control specifically within the growing venous thrombus.
Show evidence (1 reference)
DOI:10.1182/blood.2019003630 SUPPORT Model Organism
"inactivation of PSplt expression using the Platelet factor 4 (Pf4)-Cre transgene (Pros1lox/loxPf4-Cre+) in mice promotes thrombus propensity in the vena cava, where shear rates are low, but not in the carotid artery, where shear rates are high"
Directly reports the venous-specific thrombus-propensity phenotype of the platelet Pros1 knockout mouse.
Show evidence (1 reference)
DOI:10.1182/blood.2019003630 SUPPORT Model Organism
"At a low shear rate, PSplt functions as a cofactor for both activated protein C and tissue factor pathway inhibitor, thereby limiting factor X activation and thrombin generation within the growing thrombus"
Establishes the mechanistic role of platelet-derived protein S as an APC/TFPI cofactor limiting thrombin generation, informative for the protein S deficiency node even though it isolates only the platelet-derived pool.
{ }

Source YAML

click to show 
name: Thrombophilia
creation_date: "2026-08-26T00:00:00Z"
category: Complex
synonyms:
- hypercoagulability
- hypercoagulable state
- prothrombotic state
- excessive blood clotting
parents:
- Blood Coagulation Disease
description: >-
  An inherited or acquired shift of hemostasis toward thrombosis, most often
  manifesting as venous thromboembolism (deep vein thrombosis and pulmonary
  embolism). This entry models the root concept plus the five classic
  hereditary subtypes: factor V Leiden (activated protein C resistance),
  prothrombin G20210A, and deficiencies of antithrombin, protein C, and
  protein S. Each subtype reflects either a gain of procoagulant function
  (factor V Leiden, prothrombin G20210A) or a loss of natural anticoagulant
  function (antithrombin, protein C, protein S deficiency), and all five
  converge on the same downstream coagulation-activation and thrombus-formation
  pathway. Acquired, antiphospholipid-antibody-mediated thrombophilia is a
  mechanistically distinct, autoimmune disease already modeled in
  Antiphospholipid_Syndrome.yaml and is cross-referenced rather than
  duplicated here. Penetrance is incomplete and strongly modified by
  transient exposures (surgery, immobility, pregnancy, estrogen, cancer,
  inflammation), so a hereditary thrombophilia genotype is a risk factor for,
  not a guarantee of, clinical thrombosis.
notes: >-
  Current expert guidance (ASH 2023, BSH 2022) favors selective, action-oriented
  thrombophilia testing rather than broad panel screening: testing is
  discouraged after clearly provoked VTE or before starting combined oral
  contraceptives, and is reserved for situations where the result would
  change management (e.g., anticoagulation duration after a major transient
  or hormonal risk factor, or selected cerebral/splanchnic thrombosis).
  MTHFR polymorphisms (C677T, A1298C) are not included among the classic
  thrombophilias modeled here because they are not associated with a
  clinically meaningful increase in VTE risk and are explicitly discouraged
  as thrombophilia markers by current guidelines (PMID:40429442).
disease_term:
  preferred_term: thrombophilia
  term:
    id: MONDO:0002305
    label: thrombophilia

has_subtypes:
- name: Factor V Leiden Thrombophilia
  display_name: Factor V Leiden Thrombophilia (Activated Protein C Resistance)
  subtype_term:
    preferred_term: factor V Leiden thrombophilia
    term:
      id: MONDO:0008560
      label: thrombophilia due to activated protein C resistance
  description: >-
    The most common hereditary thrombophilia, caused by an F5 c.1601G>A
    (p.Arg534Gln; legacy p.Arg506Gln/1691G>A) missense variant that removes
    one of the proteolytic cleavage sites activated protein C (APC) uses to
    inactivate factor Va, rendering factor Va resistant to APC and prolonging
    procoagulant activity.
  genes:
  - preferred_term: F5
    term:
      id: hgnc:3542
      label: F5
  inheritance:
  - name: Autosomal dominant inheritance
    inheritance_term:
      preferred_term: Autosomal dominant inheritance
      term:
        id: HP:0000006
        label: Autosomal dominant inheritance
    penetrance: INCOMPLETE
  evidence:
  - reference: PMID:20301542
    reference_title: Factor V Leiden Thrombophilia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The diagnosis of factor V Leiden thrombophilia is established in a proband by identification of a heterozygous or homozygous c.1601G>A (p.Arg534Gln) variant in F5 on molecular genetic testing."
    explanation: GeneReviews establishes the causal F5 variant and diagnostic criterion for this subtype.
  - reference: PMID:20301542
    reference_title: Factor V Leiden Thrombophilia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Factor V Leiden thrombophilia is inherited in an autosomal dominant manner."
    explanation: GeneReviews states the inheritance pattern for this subtype.
- name: Prothrombin G20210A Thrombophilia
  display_name: Prothrombin G20210A Thrombophilia
  subtype_term:
    preferred_term: prothrombin G20210A thrombophilia
    term:
      id: MONDO:0008559
      label: thrombophilia due to thrombin defect
  description: >-
    The second most common hereditary thrombophilia, caused by an F2
    c.*97G>A (legacy g.20210G>A) variant in the prothrombin 3' untranslated
    region that increases prothrombin mRNA processing efficiency and raises
    circulating prothrombin concentration, expanding the substrate available
    for thrombin generation.
  genes:
  - preferred_term: F2
    term:
      id: hgnc:3535
      label: F2
  inheritance:
  - name: Autosomal dominant inheritance
    inheritance_term:
      preferred_term: Autosomal dominant inheritance
      term:
        id: HP:0000006
        label: Autosomal dominant inheritance
    penetrance: INCOMPLETE
  evidence:
  - reference: PMID:20301327
    reference_title: Prothrombin Thrombophilia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The diagnosis of prothrombin thrombophilia is established in a proband by identification of a heterozygous or homozygous 20210G>A variant (also known as c.*97G>A) in F2, the gene encoding prothrombin."
    explanation: GeneReviews establishes the causal F2 variant and diagnostic criterion for this subtype.
  - reference: PMID:40429442
    reference_title: "From Circulating Biomarkers to Polymorphic Variants: A Narrative Review of Challenges in Thrombophilia Evaluation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The second most common cause of hereditary thrombophilia is the FII G20210A mutation occurring in the FII gene where guanine is replaced by adenine at position 20210 in the FII gene, resulting in an increased synthesis of FII"
    explanation: Describes the variant and its consequence of increased prothrombin (FII) synthesis.
- name: Antithrombin III Deficiency
  display_name: Antithrombin III Deficiency
  subtype_term:
    preferred_term: antithrombin III deficiency
    term:
      id: MONDO:0013144
      label: hereditary antithrombin deficiency
  description: >-
    The most thrombogenic classic hereditary thrombophilia, caused by
    SERPINC1 variants that reduce the level (type I, quantitative) or
    function (type II, qualitative) of antithrombin, the principal serpin
    inhibitor of thrombin and factor Xa.
  genes:
  - preferred_term: SERPINC1
    term:
      id: hgnc:775
      label: SERPINC1
  inheritance:
  - name: Autosomal dominant inheritance
    inheritance_term:
      preferred_term: Autosomal dominant inheritance
      term:
        id: HP:0000006
        label: Autosomal dominant inheritance
    penetrance: INCOMPLETE
  evidence:
  - reference: PMID:41706600
    reference_title: "Hereditary Antithrombin Deficiency in Pediatric Patients: Pathophysiology, Clinical Features, Diagnosis, and Antithrombin Replacement Therapy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Hereditary AT deficiency (hATD) is a rare autosomal dominant disorder caused by mutations in the gene encoding AT (SERPINC1), resulting in decreased AT levels or activity."
    explanation: Establishes the causal gene, inheritance pattern, and quantitative/qualitative nature of this subtype.
  - reference: PMID:41706600
    reference_title: "Hereditary Antithrombin Deficiency in Pediatric Patients: Pathophysiology, Clinical Features, Diagnosis, and Antithrombin Replacement Therapy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "As the most thrombogenic inherited thrombophilia, hATD confers a lifetime venous thromboembolism (VTE) risk of up to 85%, with similar annual VTE incidence in both pediatric and adult patients."
    explanation: Documents the exceptionally high lifetime VTE risk that distinguishes this subtype from the other four.
- name: Protein C Deficiency
  display_name: Protein C Deficiency
  subtype_term:
    preferred_term: protein C deficiency
    term:
      id: MONDO:0019145
      label: hereditary thrombophilia due to congenital protein C deficiency
  description: >-
    A hereditary thrombophilia caused by PROC variants that reduce the level
    or function of protein C, a vitamin K-dependent zymogen that, once
    activated on the endothelial surface, inactivates factors Va and VIIIa.
    Severe (typically homozygous or compound heterozygous) deficiency can
    present as neonatal purpura fulminans.
  genes:
  - preferred_term: PROC
    term:
      id: hgnc:9451
      label: PROC
  inheritance:
  - name: Autosomal dominant inheritance
    inheritance_term:
      preferred_term: Autosomal dominant inheritance
      term:
        id: HP:0000006
        label: Autosomal dominant inheritance
    penetrance: INCOMPLETE
    description: >-
      Heterozygous PROC variants cause the common, incompletely penetrant
      mild/moderate deficiency.
  - name: Autosomal recessive inheritance
    inheritance_term:
      preferred_term: Autosomal recessive inheritance
      term:
        id: HP:0000007
        label: Autosomal recessive inheritance
    description: >-
      Homozygous or compound heterozygous PROC variants cause severe
      congenital protein C deficiency, presenting as neonatal purpura
      fulminans.
    evidence:
    - reference: PMID:39286606
      reference_title: "Comprehensive literature review of protein C concentrate use in patients with severe congenital protein C deficiency."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Severe congenital protein C deficiency (SCPCD) is a rare autosomal recessive disorder caused by either homozygous or compound heterozygous mutations in the PROC gene located on chromosome 2(q13-14)"
      explanation: Directly states the autosomal recessive inheritance and biallelic genotype of the severe form of protein C deficiency.
  evidence:
  - reference: PMID:30702334
    reference_title: Protein C Deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Protein C (PC) deficiency is a heritable or acquired risk factor for thrombophilia, with presentations varying from asymptomatic to venous thromboembolism to neonatal purpura fulminans, a life-threatening disorder."
    explanation: Establishes the clinical spectrum of this subtype from asymptomatic carriage to neonatal purpura fulminans.
  - reference: PMID:30702334
    reference_title: Protein C Deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Hereditary PC deficiency is caused by mutation in the PC (PROC) gene located on chromosome 2q14.3."
    explanation: Establishes the causal gene for this subtype.
- name: Protein S Deficiency
  display_name: Protein S Deficiency
  subtype_term:
    preferred_term: protein S deficiency
    term:
      id: MONDO:0019144
      label: hereditary thrombophilia due to congenital protein S deficiency
  description: >-
    A hereditary thrombophilia caused by PROS1 variants that reduce the
    level or function of protein S, a vitamin K-dependent glycoprotein that
    is a non-enzymatic cofactor for activated protein C (and, independently,
    for tissue factor pathway inhibitor). Severe deficiency can present as
    neonatal purpura fulminans.
  genes:
  - preferred_term: PROS1
    term:
      id: hgnc:9456
      label: PROS1
  inheritance:
  - name: Autosomal dominant inheritance
    inheritance_term:
      preferred_term: Autosomal dominant inheritance
      term:
        id: HP:0000006
        label: Autosomal dominant inheritance
    penetrance: INCOMPLETE
    description: >-
      Heterozygous PROS1 variants cause the common, incompletely penetrant
      mild deficiency.
  - name: Autosomal recessive inheritance
    inheritance_term:
      preferred_term: Autosomal recessive inheritance
      term:
        id: HP:0000007
        label: Autosomal recessive inheritance
    description: >-
      Homozygous or compound heterozygous (biallelic) PROS1 variants cause
      a distinct, more severe, life-threatening deficiency, which can
      present as neonatal purpura fulminans.
    evidence:
    - reference: PMID:40429442
      reference_title: "From Circulating Biomarkers to Polymorphic Variants: A Narrative Review of Challenges in Thrombophilia Evaluation."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Heterozygous mutation typically exhibit a mild PS deficiency, whereas homozygous or compound heterozygous mutations result in severe PS deficiency, which can lead to life-threatening thrombotic complications."
      explanation: Directly documents the biallelic (homozygous or compound heterozygous) genotype behind the severe, life-threatening form of protein S deficiency, distinct from the heterozygous mild form.
  evidence:
  - reference: PMID:42429079
    reference_title: "Protein S: a vitamin K-dependent factor bridging haemostasis, tissue homeostasis and cancer."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Protein S (PROS1) is a vitamin K-dependent plasma glycoprotein that was originally described as a non-enzymatic cofactor of activated protein C in the regulation of blood coagulation."
    explanation: Establishes the causal gene and the classic anticoagulant-cofactor mechanism for this subtype.
  - reference: PMID:40429442
    reference_title: "From Circulating Biomarkers to Polymorphic Variants: A Narrative Review of Challenges in Thrombophilia Evaluation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Congenital PS deficiency follows an autosomal dominant inheritance pattern."
    explanation: States the inheritance pattern for this subtype.

pathophysiology:
- name: Factor V Leiden-Mediated Activated Protein C Resistance
  subtypes:
  - Factor V Leiden Thrombophilia
  role: trigger
  biological_scale: MOLECULAR
  description: >-
    The F5 p.Arg534Gln (Leiden) variant abolishes an APC cleavage site on
    factor Va, so factor Va escapes proteolytic inactivation by activated
    protein C and remains procoagulant for longer than normal, sustaining
    prothrombinase activity and thrombin generation.
  biological_processes:
  - preferred_term: blood coagulation
    term:
      id: GO:0007596
      label: blood coagulation
    modifier: INCREASED
  - preferred_term: negative regulation of blood coagulation
    term:
      id: GO:0030195
      label: negative regulation of blood coagulation
    modifier: DECREASED
  evidence:
  - reference: PMID:40429442
    reference_title: "From Circulating Biomarkers to Polymorphic Variants: A Narrative Review of Challenges in Thrombophilia Evaluation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The Arg506Gln mutation impairs the normal inactivation of FVa by APC, leading to an increased thrombin generation and a hypercoagulable state."
    explanation: Directly describes the molecular mechanism by which the Leiden variant increases thrombin generation.
  - reference: PMID:26492443
    reference_title: Factor V Leiden.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Factor V Leiden (FVLeiden ) is a common hereditary thrombophilia that causes activated protein C (APC) resistance."
    explanation: Confirms the APC-resistance mechanism and establishes this as a common hereditary thrombophilia.
  downstream:
  - target: Coagulation Cascade Activation and Thrombin-Driven Fibrin Formation
    causal_link_type: DIRECT
    description: >-
      Persistently active factor Va sustains prothrombinase complex activity,
      amplifying thrombin generation and downstream fibrin formation.
- name: Prothrombin G20210A-Associated Increased Prothrombin Synthesis
  subtypes:
  - Prothrombin G20210A Thrombophilia
  role: trigger
  biological_scale: MOLECULAR
  description: >-
    The F2 c.*97G>A 3' UTR variant increases prothrombin mRNA processing
    efficiency, raising steady-state plasma prothrombin concentration and
    expanding the substrate pool available for thrombin generation.
  biological_processes:
  - preferred_term: blood coagulation
    term:
      id: GO:0007596
      label: blood coagulation
    modifier: INCREASED
  evidence:
  - reference: PMID:40429442
    reference_title: "From Circulating Biomarkers to Polymorphic Variants: A Narrative Review of Challenges in Thrombophilia Evaluation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The second most common cause of hereditary thrombophilia is the FII G20210A mutation occurring in the FII gene where guanine is replaced by adenine at position 20210 in the FII gene, resulting in an increased synthesis of FII"
    explanation: Directly describes the molecular consequence of the variant on prothrombin (FII) synthesis.
  downstream:
  - target: Coagulation Cascade Activation and Thrombin-Driven Fibrin Formation
    causal_link_type: DIRECT
    description: >-
      Elevated circulating prothrombin increases the substrate available to
      the prothrombinase complex, amplifying thrombin generation.
- name: Antithrombin Deficiency
  subtypes:
  - Antithrombin III Deficiency
  role: trigger
  biological_scale: MOLECULAR
  description: >-
    Reduced antithrombin level (type I) or function (type II) impairs
    serpin-mediated inhibition of thrombin, factor Xa, and other activated
    serine protease coagulation factors, removing a principal brake on the
    coagulation cascade.
  biological_processes:
  - preferred_term: negative regulation of blood coagulation
    term:
      id: GO:0030195
      label: negative regulation of blood coagulation
    modifier: DECREASED
  evidence:
  - reference: PMID:41706600
    reference_title: "Hereditary Antithrombin Deficiency in Pediatric Patients: Pathophysiology, Clinical Features, Diagnosis, and Antithrombin Replacement Therapy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Antithrombin (AT), a glycoprotein, plays a key role in anticoagulation by inhibiting coagulation proteases."
    explanation: Establishes antithrombin's normal anticoagulant role, the loss of which defines this node.
  - reference: PMID:40429442
    reference_title: "From Circulating Biomarkers to Polymorphic Variants: A Narrative Review of Challenges in Thrombophilia Evaluation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Antithrombin is a physiological natural anticoagulant. It belongs to the family of serine protease inhibitors (serpin), and it targets procoagulant serine proteases, such as activated FII, FIX, FX, and FXI, reducing clot formation."
    explanation: Describes the serpin mechanism and the range of coagulation proteases antithrombin normally inhibits.
  downstream:
  - target: Coagulation Cascade Activation and Thrombin-Driven Fibrin Formation
    causal_link_type: DIRECT
    description: >-
      Loss of antithrombin-mediated inhibition of thrombin and factor Xa
      permits unchecked amplification of the coagulation cascade.
- name: Protein C Deficiency
  subtypes:
  - Protein C Deficiency
  role: trigger
  biological_scale: MOLECULAR
  cell_types:
  - preferred_term: hepatocyte
    term:
      id: CL:0000182
      label: hepatocyte
  description: >-
    Reduced level or function of protein C impairs generation of activated
    protein C (APC) on the thrombomodulin/endothelial protein C receptor
    complex, so APC-mediated proteolytic inactivation of factors Va and
    VIIIa is diminished and their procoagulant activity persists.
  biological_processes:
  - preferred_term: negative regulation of blood coagulation
    term:
      id: GO:0030195
      label: negative regulation of blood coagulation
    modifier: DECREASED
  evidence:
  - reference: PMID:40429442
    reference_title: "From Circulating Biomarkers to Polymorphic Variants: A Narrative Review of Challenges in Thrombophilia Evaluation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "It is synthesized in hepatocytes and circulates as a heterodimeric complex composed of heavy and light chains."
    explanation: Establishes hepatocyte synthesis of protein C, supporting the cell-type binding on this node.
  - reference: PMID:40429442
    reference_title: "From Circulating Biomarkers to Polymorphic Variants: A Narrative Review of Challenges in Thrombophilia Evaluation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "APC exerts its anticoagulant function by interacting with PS as a cofactor, inactivating key coagulation factors. Specifically, APC cleaves FVa at Arg534, Arg334, and Arg707, effectively downregulating thrombin generation."
    explanation: Describes the normal APC-mediated inactivation of factor Va that is diminished when protein C is deficient.
  - reference: PMID:40429442
    reference_title: "From Circulating Biomarkers to Polymorphic Variants: A Narrative Review of Challenges in Thrombophilia Evaluation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A deficiency in PC leads to a hypercoagulable state, increasing the risk of VTE, including DVT and PE."
    explanation: Directly links protein C deficiency to a hypercoagulable state and venous thromboembolism.
  downstream:
  - target: Coagulation Cascade Activation and Thrombin-Driven Fibrin Formation
    causal_link_type: DIRECT
    description: >-
      Diminished APC-mediated inactivation of factors Va and VIIIa allows
      sustained prothrombinase and intrinsic tenase activity, amplifying
      thrombin generation.
  - target: Warfarin-Induced Transient Anticoagulant Depletion
    causal_link_type: DIRECT
    description: >-
      Because protein C has a short plasma half-life, a deficient baseline
      makes the transient post-warfarin-initiation fall in protein C
      activity proportionally more severe.
    evidence:
    - reference: PMID:41180656
      reference_title: "Warfarin-induced skin necrosis: a narrative review of clinical features, risk factors, and treatment strategies."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Protein C deficiency, most commonly implicated in WSN, is typically inherited in an autosomal dominant pattern."
      explanation: Identifies protein C deficiency as the most common predisposing condition for warfarin-induced skin necrosis.
- name: Protein S Deficiency
  subtypes:
  - Protein S Deficiency
  role: trigger
  biological_scale: MOLECULAR
  description: >-
    Reduced level or free/functional activity of protein S diminishes its
    cofactor support for APC-mediated inactivation of factors Va and VIIIa
    (and, independently, for tissue factor pathway inhibitor), so procoagulant
    factor activity persists longer than normal.
  biological_processes:
  - preferred_term: negative regulation of blood coagulation
    term:
      id: GO:0030195
      label: negative regulation of blood coagulation
    modifier: DECREASED
  evidence:
  - reference: PMID:41180656
    reference_title: "Warfarin-induced skin necrosis: a narrative review of clinical features, risk factors, and treatment strategies."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Protein C and protein S are vitamin K-dependent glycoproteins that function as critical anticoagulants by regulating the coagulation cascade."
    explanation: Establishes protein S as a vitamin K-dependent anticoagulant regulator of the coagulation cascade.
  - reference: PMID:41180656
    reference_title: "Warfarin-induced skin necrosis: a narrative review of clinical features, risk factors, and treatment strategies."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Protein S enhances the anticoagulant effect of protein C by serving as its cofactor; thus, deficiency in either protein leads to impaired inactivation of factors Va and VIIIa, fostering a prothrombotic state"
    explanation: Directly describes the cofactor mechanism and its loss in protein S deficiency.
  - reference: DOI:10.1182/blood.2019003630
    reference_title: Platelet protein S limits venous but not arterial thrombosis propensity by controlling coagulation in the thrombus
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "At a low shear rate, PSplt functions as a cofactor for both activated protein C and tissue factor pathway inhibitor, thereby limiting factor X activation and thrombin generation within the growing thrombus"
    explanation: Mouse model evidence for the dual APC/TFPI cofactor mechanism of protein S in limiting venous thrombin generation.
  downstream:
  - target: Coagulation Cascade Activation and Thrombin-Driven Fibrin Formation
    causal_link_type: DIRECT
    description: >-
      Diminished APC-cofactor activity allows sustained factor Va/VIIIa
      activity and amplified thrombin generation, particularly under the
      low-shear conditions of venous flow.
  - target: Warfarin-Induced Transient Anticoagulant Depletion
    causal_link_type: DIRECT
    description: >-
      Because protein S has a short plasma half-life relative to the
      procoagulant vitamin K-dependent factors, a deficient baseline makes
      the transient post-warfarin-initiation fall in protein S activity
      proportionally more severe.
- name: Coagulation Cascade Activation and Thrombin-Driven Fibrin Formation
  role: central_effector
  biological_scale: CELLULAR
  conforms_to: "thrombogenesis#Coagulation Cascade Activation and Thrombin-Driven Fibrin Formation"
  description: >-
    The shared downstream convergence point for all five hereditary
    thrombophilia subtypes: whichever specific gain of procoagulant or loss
    of anticoagulant function is present, the net effect is unchecked
    thrombin generation and thrombin-driven crosslinking of fibrinogen into
    an insoluble fibrin network.
  cell_types:
  - preferred_term: platelet
    term:
      id: CL:0000233
      label: platelet
  biological_processes:
  - preferred_term: blood coagulation
    term:
      id: GO:0007596
      label: blood coagulation
    modifier: INCREASED
  - preferred_term: fibrin clot formation
    term:
      id: GO:0072378
      label: blood coagulation, fibrin clot formation
    modifier: INCREASED
  evidence:
  - reference: PMID:39167180
    reference_title: "Venous thromboembolism risk in adults with hereditary thrombophilia: a systematic review and meta-analysis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The highest risk was associated with homozygous FVL (OR 5.58, 95% CI 4.61-6.74), homozygous FII (OR 5.16, 95% CI 3.12-8.52), and compound heterozygosity (OR 4.64, 95% CI 2.25-9.58)."
    explanation: Quantifies the elevated VTE risk conferred by the highest-risk genotypes among the classic thrombophilias.
  - reference: PMID:39167180
    reference_title: "Venous thromboembolism risk in adults with hereditary thrombophilia: a systematic review and meta-analysis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "PC (OR 3.23, 95% CI 2.05-5.08), PS (OR 3.01, 95% CI 2.26-4.02), and AT deficiency (OR 4.01, 95% CI 2.50-6.44) demonstrated an intermediate VTE risk."
    explanation: Quantifies the elevated VTE risk conferred by the three natural-anticoagulant-deficiency subtypes.
  - reference: DOI:10.1161/JAHA.121.023018
    reference_title: "Classic Thrombophilias and Thrombotic Risk Among Middle‐Aged and Older Adults: A Population‐Based Cohort Study"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The 5 classic thrombophilias are associated with a dose‐graded risk of VTE in middle‐aged and older adults."
    explanation: A population cohort study confirms that thrombotic risk scales with the number of classic thrombophilia variants carried, consistent with convergence on one shared downstream effector.
  downstream:
  - target: Pathological Venous Thrombus Formation
    causal_link_type: DIRECT
    description: >-
      Thrombin-driven fibrin formation, together with platelet participation,
      builds the crosslinked fibrin-platelet scaffold of a pathological
      intravascular venous thrombus.
- name: Pathological Venous Thrombus Formation
  role: effector
  biological_scale: TISSUE
  conforms_to: "thrombogenesis#Pathological Fibrin-Platelet Thrombus Formation"
  description: >-
    Crosslinked fibrin and aggregated platelets assemble into a pathological
    intravascular thrombus, most often in the deep veins of the legs or
    pelvis. Hereditary thrombophilia is classically associated with venous,
    not arterial, thrombosis.
  locations:
  - preferred_term: vein
    term:
      id: UBERON:0001638
      label: vein
  evidence:
  - reference: PMID:20301542
    reference_title: Factor V Leiden Thrombophilia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Factor V Leiden thrombophilia is characterized by venous thromboembolism (VTE) manifesting most commonly in adults as deep vein thrombosis (DVT) in the legs or pulmonary embolism."
    explanation: Establishes deep vein thrombosis of the legs as the characteristic site of thrombus formation.
  - reference: PMID:40429442
    reference_title: "From Circulating Biomarkers to Polymorphic Variants: A Narrative Review of Challenges in Thrombophilia Evaluation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Hereditary thrombophilias are classically associated with venous thromboembolism (VTE), while their role in arterial thrombosis remains uncertain and highly debated."
    explanation: Establishes that the venous, not arterial, circulation is the classically affected compartment.
  downstream:
  - target: Venous Thrombus Embolization to Pulmonary Arteries
    causal_link_type: DIRECT
- name: Venous Thrombus Embolization to Pulmonary Arteries
  role: consequence
  biological_scale: ORGANISM
  conforms_to: "thrombogenesis#Venous Thrombus Embolization to Pulmonary Arteries"
  description: >-
    A deep vein thrombus can dislodge and travel to the pulmonary arteries,
    producing pulmonary embolism, the other principal clinical manifestation
    of hereditary thrombophilia alongside deep vein thrombosis.
  locations:
  - preferred_term: pulmonary artery
    term:
      id: UBERON:0002012
      label: pulmonary artery
  evidence:
  - reference: PMID:20301327
    reference_title: Prothrombin Thrombophilia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Prothrombin thrombophilia is characterized by venous thromboembolism (VTE) manifest most commonly in adults as deep-vein thrombosis (DVT) in the legs or pulmonary embolism."
    explanation: Establishes pulmonary embolism as a characteristic clinical manifestation alongside DVT.
- name: Warfarin-Induced Transient Anticoagulant Depletion
  subtypes:
  - Protein C Deficiency
  - Protein S Deficiency
  role: trigger
  biological_scale: ORGANISM
  description: >-
    Because protein C and protein S have short plasma half-lives (protein C
    approximately 8 hours) relative to the procoagulant vitamin K-dependent
    clotting factors (24-72 hours), initiating vitamin K antagonist therapy
    (warfarin) without heparin bridging causes their activity to fall faster
    than that of the procoagulant factors, producing a paradoxical transient
    hypercoagulable state. This is proportionally more severe when baseline
    protein C or protein S activity is already reduced by hereditary
    deficiency, and can precipitate microvascular thrombosis and skin
    necrosis.
  evidence:
  - reference: PMID:41180656
    reference_title: "Warfarin-induced skin necrosis: a narrative review of clinical features, risk factors, and treatment strategies."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The initiation of warfarin therapy leads to a rapid decline in protein C and protein S levels due to their relatively short half-lives (protein C ~8 h), in contrast to other vitamin K-dependent clotting factors such as factors II, IX, and X (24–72 h)"
    explanation: Directly describes the differential half-life mechanism that produces the transient hypercoagulable state.
  - reference: PMID:41180656
    reference_title: "Warfarin-induced skin necrosis: a narrative review of clinical features, risk factors, and treatment strategies."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This creates a transient hypercoagulable state, especially in individuals with underlying deficiencies, predisposing them to microvascular thrombosis and subsequent skin necrosis"
    explanation: Links the transient hypercoagulable state to microvascular thrombosis and skin necrosis, particularly in individuals with underlying protein C/S deficiency.
  downstream:
  - target: Warfarin-Induced Skin Necrosis
    causal_link_type: DIRECT

phenotypes:
- name: Deep Venous Thrombosis
  category: Physical
  phenotype_term:
    preferred_term: Deep venous thrombosis
    term:
      id: HP:0002625
      label: Deep venous thrombosis
  description: >-
    Thrombus formation in the deep veins, most often of the legs; the most
    common clinical manifestation of hereditary thrombophilia.
  evidence:
  - reference: PMID:20301542
    reference_title: Factor V Leiden Thrombophilia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Factor V Leiden thrombophilia is characterized by venous thromboembolism (VTE) manifesting most commonly in adults as deep vein thrombosis (DVT) in the legs or pulmonary embolism."
    explanation: GeneReviews identifies DVT of the legs as the most common manifestation.
- name: Pulmonary Embolism
  category: Physical
  phenotype_term:
    preferred_term: Pulmonary embolism
    term:
      id: HP:0002204
      label: Pulmonary embolism
  description: >-
    Embolization of a venous thrombus (usually originating as a DVT) to the
    pulmonary arteries.
  evidence:
  - reference: PMID:20301327
    reference_title: Prothrombin Thrombophilia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Prothrombin thrombophilia is characterized by venous thromboembolism (VTE) manifest most commonly in adults as deep-vein thrombosis (DVT) in the legs or pulmonary embolism."
    explanation: GeneReviews identifies pulmonary embolism as a characteristic manifestation.
- name: Recurrent Venous Thromboembolism
  category: Physical
  phenotype_term:
    preferred_term: Recurrent thromboembolism
    term:
      id: HP:0004831
      label: Recurrent thromboembolism
  description: >-
    Recurrence of venous thromboembolism, more common with higher-risk
    genotypes (homozygosity, compound heterozygosity, or combined
    thrombophilias) and used clinically to inform anticoagulation duration.
  evidence:
  - reference: PMID:39167180
    reference_title: "Venous thromboembolism risk in adults with hereditary thrombophilia: a systematic review and meta-analysis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Nevertheless, the risk of recurrent VTE was not negligible for any thrombophilia."
    explanation: Directly establishes recurrent VTE as a real, quantified event across all five classic thrombophilias, not merely a management consideration.
- name: Cerebral Venous Sinus Thrombosis
  category: Physical
  phenotype_term:
    preferred_term: Cerebral venous sinus thrombosis
    term:
      id: HP:0033724
      label: Cerebral venous sinus thrombosis
  description: >-
    Thrombosis of the cerebral venous sinuses, a less common but recognized
    unusual-site manifestation of hereditary thrombophilia, more frequent in
    younger adults and in women with hormonal or pregnancy-related risk.
  evidence:
  - reference: PMID:39406200
    reference_title: "Cerebral Venous Sinus Thrombosis: Current Updates in the Asian Context."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This mutation is known to confer an increased risk for CVT in the Western population, with a prevalence of around 10–25%"
    explanation: Directly reports factor V Leiden as conferring increased risk specifically for cerebral venous (sinus) thrombosis, the phenotype's defining feature.
  - reference: PMID:39406200
    reference_title: "Cerebral Venous Sinus Thrombosis: Current Updates in the Asian Context."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "AT deficiency is an autosomal dominant disorder and is one of the rare conditions that cause CVT."
    explanation: Directly states that antithrombin deficiency causes cerebral venous (sinus) thrombosis.
  - reference: DOI:10.1177/10760296241256360
    reference_title: "Efficacy and Safety of Direct Oral Anticoagulants in Cerebral Venous Thrombosis: Meta-Analysis of Randomized Clinical Trials"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Current guidelines recommend the standard-of-care anticoagulation (vitamin K antagonists or low-molecular-weight heparin) in patients with cerebral venous thrombosis (CVT)."
    explanation: Confirms cerebral venous thrombosis is managed within the same anticoagulation framework as other venous thromboembolism; it does not itself establish hereditary thrombophilia as a cause, so support is partial and supplementary to the two etiology references above.
  - reference: DOI:10.1182/bloodadvances.2020002781
    reference_title: "Incidence of VTE in asymptomatic children with deficiencies of antithrombin, protein C, and protein S: a prospective cohort study"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Although antithrombin, protein C, and protein S defects are well-recognized inherited risk factors for venous thromboembolism (VTE) in adults, whether they predispose children to these vascular disorders as well is undefined."
    explanation: Supports natural-anticoagulant deficiencies as recognized VTE risk factors; the cohort's own events were dominated by usual-site VTE, so support for the unusual cerebral-sinus site specifically is partial.
- name: Resistance to Activated Protein C
  category: Laboratory
  subtype: Factor V Leiden Thrombophilia
  phenotype_term:
    preferred_term: Resistance to activated protein C
    term:
      id: HP:0012175
      label: Resistance to activated protein C
  description: >-
    The laboratory hallmark of factor V Leiden thrombophilia, detected as a
    reduced anticoagulant response to added activated protein C in a
    clotting assay.
  evidence:
  - reference: PMID:26492443
    reference_title: Factor V Leiden.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Factor V Leiden (FVLeiden ) is a common hereditary thrombophilia that causes activated protein C (APC) resistance."
    explanation: Directly establishes APC resistance as the defining laboratory phenotype of this subtype.
- name: Reduced Antithrombin Activity
  category: Laboratory
  subtype: Antithrombin III Deficiency
  phenotype_term:
    preferred_term: Reduced antithrombin III activity
    term:
      id: HP:0001976
      label: Reduced antithrombin III activity
  description: >-
    The laboratory hallmark of antithrombin deficiency; diagnosis is
    typically based on persistently low functional antithrombin activity.
  evidence:
  - reference: PMID:41706600
    reference_title: "Hereditary Antithrombin Deficiency in Pediatric Patients: Pathophysiology, Clinical Features, Diagnosis, and Antithrombin Replacement Therapy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Diagnosis is typically based on persistently low functional AT activity levels (<70% of age-appropriate normal values) and can be confirmed by genetic testing."
    explanation: Establishes reduced antithrombin activity as the diagnostic laboratory phenotype.
- name: Reduced Protein C Activity
  category: Laboratory
  subtype: Protein C Deficiency
  phenotype_term:
    preferred_term: Reduced protein C activity
    term:
      id: HP:0005543
      label: Reduced protein C activity
  description: The laboratory hallmark of protein C deficiency.
  evidence:
  - reference: PMID:40429442
    reference_title: "From Circulating Biomarkers to Polymorphic Variants: A Narrative Review of Challenges in Thrombophilia Evaluation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The PC activity assay is the recommended screening test and can be either clot-based or chromogenic, depending on the assay design."
    explanation: Establishes reduced protein C activity as the primary diagnostic laboratory phenotype.
- name: Reduced Protein S Activity
  category: Laboratory
  subtype: Protein S Deficiency
  phenotype_term:
    preferred_term: Reduced protein S activity
    term:
      id: HP:0004855
      label: Reduced protein S activity
  description: The laboratory hallmark of protein S deficiency.
  evidence:
  - reference: PMID:40429442
    reference_title: "From Circulating Biomarkers to Polymorphic Variants: A Narrative Review of Challenges in Thrombophilia Evaluation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "PS functional activity assays measure the biological activity of PS by assessing its ability to function as a cofactor for APC in the inactivation of FVa and FVIIIa."
    explanation: Establishes reduced protein S activity as the diagnostic laboratory phenotype.
- name: Recurrent Pregnancy Loss
  category: Physical
  phenotype_term:
    preferred_term: Recurrent pregnancy loss
  notes: >-
    HP:0200067 (Recurrent spontaneous abortion) exists in HPO but is not
    bindable here: its full ancestor closure (`Recurrent spontaneous
    abortion -> Pregnancy history -> Past medical history -> All`, verified
    with `runoak -i sqlite:obo:hp ancestors HP:0200067`) does not pass
    through HP:0000118 (Phenotypic abnormality), the root the PhenotypeTerm
    dynamic enum requires, and there is no MONDO disease term for recurrent
    pregnancy loss either. This is a deliberate needs-term/NTR gap, not an
    oversight.
  description: >-
    An association between hereditary thrombophilia (particularly factor V
    Leiden, prothrombin G20210A, and protein S deficiency) and recurrent
    pregnancy loss has been reported, though the association is
    heterogeneous across studies and confounded by selection bias, and
    routine thrombophilia testing after pregnancy loss is not uniformly
    recommended.
  evidence:
  - reference: PMID:38674167
    reference_title: Risk Factors of Thrombophilia-Related Mutations for Early and Late Pregnancy Loss.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "With an odds ratios of 2.44 for FVL, 2.08 for PT, and a notably high 3.45 for protein S deficiency, their findings underscore the substantial impact of these genetic factors on RPL."
    explanation: Quantifies the association between the three thrombophilia subtypes and recurrent pregnancy loss; support is partial because the association is heterogeneous across the broader literature and causality is not established.
- name: Warfarin-Induced Skin Necrosis
  category: Physical
  subtypes:
  - Protein C Deficiency
  - Protein S Deficiency
  phenotype_term:
    preferred_term: Warfarin-induced skin necrosis
    term:
      id: HP:0001038
      label: Warfarin-induced skin necrosis
  description: >-
    Painful, hemorrhagic skin lesions progressing to full-thickness necrosis,
    typically emerging within days of starting warfarin without heparin
    bridging; most strongly associated with underlying protein C or protein
    S deficiency.
  evidence:
  - reference: PMID:41180656
    reference_title: "Warfarin-induced skin necrosis: a narrative review of clinical features, risk factors, and treatment strategies."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The review highlights that WSN predominantly affects middle-aged women and is often associated with protein C or S deficiency, initiation of high-dose warfarin without appropriate heparin bridging, and other thrombophilic disorders."
    explanation: Directly links this phenotype to underlying protein C or protein S deficiency and unbridged warfarin initiation.
- name: Neonatal Purpura Fulminans
  category: Physical
  subtypes:
  - Protein C Deficiency
  - Protein S Deficiency
  phenotype_term:
    preferred_term: Purpura
    term:
      id: HP:0000979
      label: Purpura
  description: >-
    A life-threatening presentation of severe (typically homozygous or
    compound heterozygous) protein C or protein S deficiency, with
    disseminated dermal microvascular thrombosis and necrosis presenting
    in the neonatal period.
  notes: >-
    HPO has no dedicated "purpura fulminans" term; HP:0000979 Purpura is
    used here as the closest available term (a deliberate choice, not an
    oversight).
  evidence:
  - reference: PMID:30702334
    reference_title: Protein C Deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Protein C (PC) deficiency is a heritable or acquired risk factor for thrombophilia, with presentations varying from asymptomatic to venous thromboembolism to neonatal purpura fulminans, a life-threatening disorder."
    explanation: Establishes neonatal purpura fulminans as a severe presentation of protein C deficiency.
  - reference: PMID:24144709
    reference_title: Anticoagulant treatment with rivaroxaban in severe protein S deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We report a case of a 6-year-old girl with severe protein S deficiency due to a homozygous mutation and recurrent episodes of skin necrosis. She developed purpura fulminans at birth"
    explanation: Directly reports neonatal purpura fulminans in a patient with homozygous (severe) protein S deficiency, correctly scoped to the protein S subtype.

genetic:
- name: F5
  gene_term:
    preferred_term: F5
    term:
      id: hgnc:3542
      label: F5
  subtype: Factor V Leiden Thrombophilia
  relationship_type: CAUSATIVE
  association: >-
    The c.1601G>A (p.Arg534Gln) variant is causal for factor V Leiden
    thrombophilia and is the most common hereditary thrombophilia in
    individuals of European ancestry.
  inheritance:
  - name: Autosomal dominant inheritance
    inheritance_term:
      preferred_term: Autosomal dominant inheritance
      term:
        id: HP:0000006
        label: Autosomal dominant inheritance
    penetrance: INCOMPLETE
  evidence:
  - reference: PMID:40429442
    reference_title: "From Circulating Biomarkers to Polymorphic Variants: A Narrative Review of Challenges in Thrombophilia Evaluation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This variant accounts for over 90% of inherited APCR cases and remains the most common genetic risk factor for thrombophilia in individuals of European descent, with a population prevalence from 1% to 5% on average, which is even higher among patients with VTE (10–20%)."
    explanation: Establishes F5 Leiden as the dominant cause of hereditary APC resistance and quantifies its population and VTE-cohort prevalence.
  - reference: PMID:40429442
    reference_title: "From Circulating Biomarkers to Polymorphic Variants: A Narrative Review of Challenges in Thrombophilia Evaluation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Heterozygosity for FV Leiden increases the lifetime risk of thrombosis by approximately 7-fold, while homozygosity, though rare, confers a roughly 20-fold increase in risk"
    explanation: Quantifies the zygosity-dependent thrombotic risk conferred by the F5 Leiden variant.
- name: F2
  gene_term:
    preferred_term: F2
    term:
      id: hgnc:3535
      label: F2
  subtype: Prothrombin G20210A Thrombophilia
  relationship_type: CAUSATIVE
  association: >-
    The c.*97G>A (legacy g.20210G>A) 3' UTR variant is causal for
    prothrombin thrombophilia, the second most common hereditary
    thrombophilia in individuals of European ancestry.
  inheritance:
  - name: Autosomal dominant inheritance
    inheritance_term:
      preferred_term: Autosomal dominant inheritance
      term:
        id: HP:0000006
        label: Autosomal dominant inheritance
    penetrance: INCOMPLETE
  evidence:
  - reference: PMID:40429442
    reference_title: "From Circulating Biomarkers to Polymorphic Variants: A Narrative Review of Challenges in Thrombophilia Evaluation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The FII G20210A mutation is mostly found in individuals of European descent, with an estimated prevalence of 1% to 3% in the general population."
    explanation: Quantifies the population prevalence of the F2 G20210A variant.
  - reference: PMID:40429442
    reference_title: "From Circulating Biomarkers to Polymorphic Variants: A Narrative Review of Challenges in Thrombophilia Evaluation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Among individuals with VTE, the prevalence of Factor II G20210A is significantly higher (6% to 10%), compared to the general population."
    explanation: Quantifies the enrichment of the F2 G20210A variant among VTE patients relative to the general population.
- name: SERPINC1
  gene_term:
    preferred_term: SERPINC1
    term:
      id: hgnc:775
      label: SERPINC1
  subtype: Antithrombin III Deficiency
  relationship_type: CAUSATIVE
  association: >-
    Loss-of-function or reduced-activity SERPINC1 variants cause hereditary
    antithrombin deficiency, the most thrombogenic of the classic hereditary
    thrombophilias.
  inheritance:
  - name: Autosomal dominant inheritance
    inheritance_term:
      preferred_term: Autosomal dominant inheritance
      term:
        id: HP:0000006
        label: Autosomal dominant inheritance
    penetrance: INCOMPLETE
  evidence:
  - reference: PMID:41706600
    reference_title: "Hereditary Antithrombin Deficiency in Pediatric Patients: Pathophysiology, Clinical Features, Diagnosis, and Antithrombin Replacement Therapy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The reported prevalence of hATD among European and North American cohorts ranges from 1 in 500 to 1 in 5000 individuals."
    explanation: Quantifies the population prevalence of hereditary antithrombin deficiency.
- name: PROC
  gene_term:
    preferred_term: PROC
    term:
      id: hgnc:9451
      label: PROC
  subtype: Protein C Deficiency
  relationship_type: CAUSATIVE
  association: >-
    Loss-of-function PROC variants cause hereditary protein C deficiency;
    severe (typically biallelic) deficiency can present as neonatal
    purpura fulminans.
  inheritance:
  - name: Autosomal dominant inheritance
    inheritance_term:
      preferred_term: Autosomal dominant inheritance
      term:
        id: HP:0000006
        label: Autosomal dominant inheritance
    penetrance: INCOMPLETE
  evidence:
  - reference: PMID:40429442
    reference_title: "From Circulating Biomarkers to Polymorphic Variants: A Narrative Review of Challenges in Thrombophilia Evaluation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "It has been estimated that in patients with suspected hereditary VTE, the prevalence of PC deficiency is 5–10%. Among the general Caucasian population, the prevalence of PC deficiency is estimated to be 0.2–0.4%"
    explanation: Quantifies protein C deficiency prevalence in the general population and among VTE patients.
- name: PROS1
  gene_term:
    preferred_term: PROS1
    term:
      id: hgnc:9456
      label: PROS1
  subtype: Protein S Deficiency
  relationship_type: CAUSATIVE
  association: >-
    Loss-of-function PROS1 variants cause hereditary protein S deficiency;
    severe (typically biallelic) deficiency can present as neonatal
    purpura fulminans.
  inheritance:
  - name: Autosomal dominant inheritance
    inheritance_term:
      preferred_term: Autosomal dominant inheritance
      term:
        id: HP:0000006
        label: Autosomal dominant inheritance
    penetrance: INCOMPLETE
  evidence:
  - reference: PMID:40429442
    reference_title: "From Circulating Biomarkers to Polymorphic Variants: A Narrative Review of Challenges in Thrombophilia Evaluation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The estimated incidence of mild congenital PS deficiency is approximately 1 in 500 individuals, while severe PS deficiency is exceedingly rare, with an unknown prevalence due to diagnostic challenges"
    explanation: Quantifies the population prevalence of congenital protein S deficiency.

diagnosis:
- name: "Factor V Leiden: Activated Protein C Resistance Assay with Confirmatory F5 Genotyping"
  description: >-
    A two-step laboratory workup: an activated protein C (APC) resistance
    functional clotting assay is used as the initial screen, and a positive
    result is confirmed by targeted F5 c.1601G>A (p.Arg534Gln) genetic
    testing.
  diagnosis_term:
    preferred_term: coagulation study
    term:
      id: NCIT:C62662
      label: Coagulation Study
  results: >-
    Reduced anticoagulant response to added activated protein C (a low APC
    ratio) on the functional screen, confirmed by identification of a
    heterozygous or homozygous F5 c.1601G>A variant on genetic testing.
  evidence:
  - reference: PMID:40429442
    reference_title: "From Circulating Biomarkers to Polymorphic Variants: A Narrative Review of Challenges in Thrombophilia Evaluation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The diagnosis of FV Leiden typically involves a two-step process: the initial detection of APC resistance through a functional clotting assay, followed by confirmatory genetic testing for the 1691G > A substitution."
    explanation: Directly describes the two-step functional-assay-then-genotyping diagnostic workup for this subtype.
  - reference: PMID:20301542
    reference_title: Factor V Leiden Thrombophilia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The diagnosis of factor V Leiden thrombophilia is established in a proband by identification of a heterozygous or homozygous c.1601G>A (p.Arg534Gln) variant in F5 on molecular genetic testing."
    explanation: GeneReviews confirms genetic testing for the F5 variant as the diagnostic criterion.
- name: "Prothrombin G20210A: F2 Genotyping"
  description: >-
    The diagnosis is established directly by targeted genetic testing for
    the F2 c.*97G>A (legacy 20210G>A) variant; unlike factor V Leiden, there
    is no widely used functional screening assay upstream of genotyping.
  diagnosis_term:
    preferred_term: genetic testing
    term:
      id: NCIT:C15709
      label: Genetic Testing
  results: >-
    Identification of a heterozygous or homozygous F2 c.*97G>A variant.
  evidence:
  - reference: PMID:20301327
    reference_title: Prothrombin Thrombophilia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The diagnosis of prothrombin thrombophilia is established in a proband by identification of a heterozygous or homozygous 20210G>A variant (also known as c.*97G>A) in F2, the gene encoding prothrombin."
    explanation: GeneReviews states the diagnostic criterion for this subtype.
- name: "Antithrombin Deficiency: Activity Assay with Reflex Antigen Testing"
  description: >-
    Laboratory testing recommends starting with a functional antithrombin
    activity assay; if activity is reduced, follow-up antigen testing and
    calculation of the activity-to-antigen ratio distinguishes type I
    (quantitative) from type II (qualitative) deficiency. Direct oral
    anticoagulants can falsely elevate or normalize results depending on the
    assay type, and testing physiologic anticoagulant levels is recommended
    only after three months of anticoagulation for an acute thrombotic
    event to avoid consumption-related false positives. The ISTH SSC's 2020
    laboratory-testing recommendations (DOI:10.1111/jth.14648) are the
    international reference standard for this workup; that communication
    has no retrievable abstract or full text in the reference cache, so it
    is cited here for provenance rather than quoted.
  diagnosis_term:
    preferred_term: coagulation study
    term:
      id: NCIT:C62662
      label: Coagulation Study
  results: >-
    Reduced antithrombin activity, with a follow-up antigen assay and
    activity-to-antigen ratio distinguishing type I from type II deficiency.
  evidence:
  - reference: PMID:40429442
    reference_title: "From Circulating Biomarkers to Polymorphic Variants: A Narrative Review of Challenges in Thrombophilia Evaluation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Laboratory testing guidelines for diagnosing antithrombin deficiency recommend starting with an activity assay. If activity levels are reduced, follow-up testing should include an antigen assay and the calculation of the activity-to-antigen ratio"
    explanation: Directly describes the activity-first, reflex-antigen diagnostic algorithm for this subtype.
  - reference: PMID:40429442
    reference_title: "From Circulating Biomarkers to Polymorphic Variants: A Narrative Review of Challenges in Thrombophilia Evaluation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Testing physiologic anticoagulant levels is recommended after three months of anticoagulation for acute thrombosis."
    explanation: Establishes the timing rule for testing natural-anticoagulant levels relative to an acute thrombotic event, applicable to the antithrombin, protein C, and protein S activity assays.
- name: "Protein C Deficiency: Activity Assay"
  description: >-
    Protein C activity (clot-based or chromogenic) is the recommended
    screening test; a chromogenic assay offers higher specificity but
    cannot detect the rare type IIb deficiency, which a clot-based assay
    can identify at the cost of lower specificity.
  diagnosis_term:
    preferred_term: coagulation study
    term:
      id: NCIT:C62662
      label: Coagulation Study
  results: Reduced protein C activity.
  evidence:
  - reference: PMID:40429442
    reference_title: "From Circulating Biomarkers to Polymorphic Variants: A Narrative Review of Challenges in Thrombophilia Evaluation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The PC activity assay is the recommended screening test and can be either clot-based or chromogenic, depending on the assay design."
    explanation: Directly identifies the recommended screening assay for this subtype.
- name: "Protein S Deficiency: Free Antigen and Functional Activity Assay"
  description: >-
    Protein S functional activity is assessed by its ability to act as an
    APC cofactor in inactivating factors Va and VIIIa; free and total
    protein S antigen are measured separately by immunoassay. Reference
    ranges are sex-, age-, and pregnancy-dependent (women have lower total
    and free protein S than men; total protein S rises with age), so
    results must be interpreted against appropriately stratified ranges and
    repeated outside pregnancy, hormonal therapy, or acute-phase states.
  diagnosis_term:
    preferred_term: coagulation study
    term:
      id: NCIT:C62662
      label: Coagulation Study
  results: Reduced free and/or total protein S antigen, or reduced protein S functional activity with normal antigen (type II/III).
  evidence:
  - reference: PMID:40429442
    reference_title: "From Circulating Biomarkers to Polymorphic Variants: A Narrative Review of Challenges in Thrombophilia Evaluation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "PS functional activity assays measure the biological activity of PS by assessing its ability to function as a cofactor for APC in the inactivation of FVa and FVIIIa."
    explanation: Directly describes the functional-cofactor basis of the protein S activity assay.
  - reference: PMID:40429442
    reference_title: "From Circulating Biomarkers to Polymorphic Variants: A Narrative Review of Challenges in Thrombophilia Evaluation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Notably, women generally have lower total and free protein S levels than men. Total PS levels increase with age, particularly in women, due to hormonal variations, whereas free PS levels remain stable over time."
    explanation: Establishes the sex- and age-dependence of protein S reference ranges relevant to result interpretation.

environmental:
- name: Estrogen-Containing Oral Contraceptive Use
  exposure_term:
    preferred_term: exposure to oral contraceptive
    term:
      id: ECTO:9002149
      label: exposure to oral contraceptive
  description: >-
    Estrogen-containing hormonal contraception supplies a "second hit" that
    can precipitate venous thromboembolism in carriers of an otherwise
    silent hereditary thrombophilia genotype.
  influences_mechanisms:
  - target: Pathological Venous Thrombus Formation
    environmental_effect: EXACERBATES
    causal_link_type: DIRECT
    description: >-
      Estrogen exposure amplifies the venous thrombosis risk of an
      underlying hereditary thrombophilia genotype.
    evidence:
    - reference: PMID:20301542
      reference_title: Factor V Leiden Thrombophilia.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Women with a history of VTE who are heterozygous for the factor V Leiden variant and women homozygous for the factor V Leiden variant with or without prior VTE should avoid estrogen-containing contraception and HRT."
      explanation: GeneReviews management guidance directly reflects the exacerbating effect of estrogen exposure in factor V Leiden carriers.
  evidence:
  - reference: PMID:20301327
    reference_title: Prothrombin Thrombophilia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Women heterozygous for 20210G>A with a history of VTE and women homozygous for 20210G>A with or without prior VTE should avoid estrogen-containing contraception and hormone replacement therapy (HRT)."
    explanation: GeneReviews management guidance for prothrombin thrombophilia parallels the factor V Leiden guidance.
- name: Hormone Replacement Therapy Exposure
  exposure_term:
    preferred_term: exposure to hormone replacement therapy
    term:
      id: ECTO:2000005
      label: exposure to hormone replacement therapy
  description: >-
    Exogenous hormone replacement therapy, like oral contraception, supplies
    a transient prothrombotic exposure that can precipitate venous
    thromboembolism in carriers of a hereditary thrombophilia genotype.
  influences_mechanisms:
  - target: Pathological Venous Thrombus Formation
    environmental_effect: EXACERBATES
    causal_link_type: DIRECT
    description: >-
      Hormone replacement therapy amplifies the venous thrombosis risk of
      an underlying hereditary thrombophilia genotype.
    evidence:
    - reference: PMID:20301542
      reference_title: Factor V Leiden Thrombophilia.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Women electing use of short-term HRT for severe menopausal symptoms should avoid oral formulations."
      explanation: GeneReviews management guidance reflects the exacerbating effect of HRT exposure in factor V Leiden carriers.
  evidence:
  - reference: PMID:20301542
    reference_title: Factor V Leiden Thrombophilia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Women with a history of VTE who are heterozygous for the factor V Leiden variant and women homozygous for the factor V Leiden variant with or without prior VTE should avoid estrogen-containing contraception and HRT."
    explanation: GeneReviews management guidance identifies HRT as a risk-amplifying exposure alongside estrogen-containing contraception.

animal_models:
- name: Platelet-specific Pros1 knockout mouse (Pros1lox/loxPf4-Cre+)
  species: Mouse
  genotype: Pros1lox/loxPf4-Cre+ (platelet lineage-restricted Pros1 deletion via Platelet factor 4-Cre)
  publication: DOI:10.1182/blood.2019003630
  description: >-
    A conditional knockout that eliminates protein S expression specifically
    in platelets (and their megakaryocyte precursors) while sparing the
    systemic, largely hepatocyte-derived plasma protein S pool.
  modeled_mechanisms:
  - target: Protein S Deficiency
    relationship: PARTIALLY_RECAPITULATES
    fidelity: MODERATE
    description: >-
      Loss of platelet-derived protein S increases venous thrombus
      propensity by impairing its cofactor role for activated protein C and
      tissue factor pathway inhibitor, limiting factor X activation and
      thrombin generation within the growing thrombus at low shear rates.
      It does not increase arterial thrombosis propensity, unlike the
      systemic human deficiency, which is not restricted to a low-shear
      vascular bed.
    limitations: >-
      This model isolates only the platelet-derived pool of protein S via a
      platelet-lineage-restricted knockout; it does not reproduce the
      systemic (predominantly hepatocyte-synthesized) protein S deficiency
      that defines the human hereditary disorder, so its venous-versus-arterial
      selectivity may not generalize to human patients with global protein S
      deficiency.
    readouts:
    - name: Venous (vena cava) thrombus propensity
      target: Protein S Deficiency
      direction: INCREASED
      interpretation: >-
        Platelet protein S loss increases thrombus formation at low shear
        (vena cava) but not at high shear (carotid artery), consistent with
        a cofactor role for APC/TFPI-mediated factor X control specifically
        within the growing venous thrombus.
      evidence:
      - reference: DOI:10.1182/blood.2019003630
        reference_title: "Platelet protein S limits venous but not arterial thrombosis propensity by controlling coagulation in the thrombus"
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "inactivation of PSplt expression using the Platelet factor 4 (Pf4)-Cre transgene (Pros1lox/loxPf4-Cre+) in mice promotes thrombus propensity in the vena cava, where shear rates are low, but not in the carotid artery, where shear rates are high"
        explanation: Directly reports the venous-specific thrombus-propensity phenotype of the platelet Pros1 knockout mouse.
  evidence:
  - reference: DOI:10.1182/blood.2019003630
    reference_title: "Platelet protein S limits venous but not arterial thrombosis propensity by controlling coagulation in the thrombus"
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "At a low shear rate, PSplt functions as a cofactor for both activated protein C and tissue factor pathway inhibitor, thereby limiting factor X activation and thrombin generation within the growing thrombus"
    explanation: >-
      Establishes the mechanistic role of platelet-derived protein S as an
      APC/TFPI cofactor limiting thrombin generation, informative for the
      protein S deficiency node even though it isolates only the
      platelet-derived pool.

treatments:
- name: Acute Anticoagulation via Heparin-Potentiated Antithrombin
  description: >-
    Therapeutic unfractionated or low-molecular-weight heparin potentiates
    antithrombin-mediated inhibition of thrombin and factor Xa. Because
    heparin's mechanism depends on antithrombin, its anticoagulant effect
    can be attenuated in antithrombin deficiency; antithrombin concentrate
    replacement (below) addresses this specifically. Agent, dose, and
    duration are individualized to the clinical circumstances.
  treatment_term:
    preferred_term: anticoagulation therapy
    term:
      id: NCIT:C63341
      label: Anticoagulation Therapy
    therapeutic_agent:
    - preferred_term: low molecular weight heparin
      term:
        id: NCIT:C2578
        label: Low Molecular Weight Heparin
  target_mechanisms:
  - target: Coagulation Cascade Activation and Thrombin-Driven Fibrin Formation
    treatment_effect: INHIBITS
    description: >-
      Heparin-enhanced antithrombin activity inhibits thrombin and factor
      Xa, suppressing the coagulation reactions that generate and stabilize
      fibrin.
  evidence:
  - reference: PMID:20301542
    reference_title: Factor V Leiden Thrombophilia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The first acute venous thrombosis is treated according to current guidelines."
    explanation: GeneReviews establishes standard-guideline anticoagulation as first-line management of acute VTE in this disease.
- name: Long-Term Oral Anticoagulation with Heparin-Bridged Initiation
  description: >-
    Long-term oral anticoagulation (vitamin K antagonists such as warfarin,
    or direct oral anticoagulants) reduces the risk of recurrent venous
    thromboembolism; duration is individualized to the risk of recurrence
    versus bleeding. When warfarin is used, initiation should be bridged
    with heparin and avoid high loading doses, because unbridged warfarin
    initiation can precipitate warfarin-induced skin necrosis, particularly
    in protein C or protein S deficiency (see Warfarin-Induced Transient
    Anticoagulant Depletion). Direct oral anticoagulants avoid this
    mechanism and are an emerging alternative in this setting.
  treatment_term:
    preferred_term: anticoagulation therapy
    term:
      id: NCIT:C63341
      label: Anticoagulation Therapy
    therapeutic_agent:
    - preferred_term: warfarin
      term:
        id: CHEBI:10033
        label: warfarin
    - preferred_term: rivaroxaban
      term:
        id: CHEBI:68579
        label: rivaroxaban
  target_mechanisms:
  - target: Coagulation Cascade Activation and Thrombin-Driven Fibrin Formation
    treatment_effect: INHIBITS
    description: >-
      Vitamin K antagonism or direct factor Xa/thrombin inhibition
      suppresses ongoing coagulation-cascade activation, reducing the risk
      of recurrent thrombus formation.
  - target: Warfarin-Induced Transient Anticoagulant Depletion
    treatment_effect: BYPASSES
    description: >-
      Heparin bridging during warfarin initiation, or use of a direct oral
      anticoagulant instead of warfarin, avoids the transient protein C/S
      depletion window that can precipitate skin necrosis.
  evidence:
  - reference: PMID:20301542
    reference_title: Factor V Leiden Thrombophilia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The duration of oral anticoagulation therapy should be based on an assessment of the risks for VTE recurrence and anticoagulant-related bleeding."
    explanation: GeneReviews frames long-term anticoagulation duration around the recurrence-versus-bleeding risk tradeoff.
  - reference: PMID:41180656
    reference_title: "Warfarin-induced skin necrosis: a narrative review of clinical features, risk factors, and treatment strategies."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Direct oral anticoagulants (DOACs) like rivaroxaban and apixaban are emerging alternatives due to favorable pharmacokinetics"
    explanation: Identifies DOACs as an emerging alternative that avoids the warfarin-specific transient hypercoagulable window.
- name: Antithrombin Concentrate Replacement Therapy
  description: >-
    Human antithrombin III concentrate directly restores antithrombin
    activity in hereditary antithrombin deficiency, used during high-risk
    periods (surgery, pregnancy, peripartum) or for treatment/prevention of
    thromboembolism when heparin-potentiated endogenous antithrombin is
    insufficient because the endogenous pool itself is deficient.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: antithrombin III (human)
      term:
        id: NCIT:C136824
        label: Therapeutic Human Antithrombin-III
  therapeutic_modality: PROTEIN_REPLACEMENT
  target_mechanisms:
  - target: Antithrombin Deficiency
    treatment_effect: RESTORES
    description: >-
      Exogenous antithrombin concentrate directly restores plasma
      antithrombin activity, re-establishing serpin-mediated inhibition of
      thrombin and factor Xa.
  evidence:
  - reference: PMID:41706600
    reference_title: "Hereditary Antithrombin Deficiency in Pediatric Patients: Pathophysiology, Clinical Features, Diagnosis, and Antithrombin Replacement Therapy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In August 2025, the U.S. Food and Drug Administration (FDA) approved an expanded indication for antithrombin III concentrate (human) to include pediatric patients with hATD, representing the first product specifically approved for this population."
    explanation: Documents the FDA-approved indication for antithrombin concentrate replacement therapy in hereditary antithrombin deficiency.
- name: Protein C Concentrate Replacement Therapy
  description: >-
    Plasma-derived protein C concentrate directly restores protein C
    activity in severe congenital protein C deficiency, the exact
    parallel of antithrombin concentrate replacement above. It is used as
    long-term prophylaxis and for acute treatment of purpura fulminans and
    disseminated intravascular coagulation, and as a bridge during
    initiation of vitamin K antagonist therapy to avoid the transient
    hypercoagulable state (see Warfarin-Induced Transient Anticoagulant
    Depletion).
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: protein C concentrate
      term:
        id: NCIT:C87607
        label: Protein C Concentrate
  therapeutic_modality: PROTEIN_REPLACEMENT
  target_mechanisms:
  - target: Protein C Deficiency
    treatment_effect: RESTORES
    description: >-
      Exogenous protein C concentrate directly restores plasma protein C
      activity, re-establishing APC-mediated inactivation of factors Va
      and VIIIa.
  evidence:
  - reference: PMID:39286606
    reference_title: "Comprehensive literature review of protein C concentrate use in patients with severe congenital protein C deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Protein C concentrate (Ceprotin; Baxalta US Inc, a Takeda company; Takeda Manufacturing Austria AG) is prepared from human plasma using a multistep purification process, including monoclonal antibody immune affinity chromatography, to yield a highly purified protein C concentrate, which is indicated for the prophylaxis and treatment of patients with SCPCD"
    explanation: Documents the FDA/EMA-recognized indication for protein C concentrate replacement therapy in severe congenital protein C deficiency, the exact parallel of the antithrombin concentrate indication above.

prevalence:
- subtype: Factor V Leiden Thrombophilia
  population: European-ancestry general population
  measure_type: CARRIER_FREQUENCY
  prevalence_class: ABOVE_1_IN_1000
  rate_per_100000: 3000.0
  rate_low: 1000.0
  rate_high: 5000.0
  notes: >-
    Reported as 1%-5% in the general European-ancestry population and
    10%-20% among patients with venous thromboembolism.
  evidence:
  - reference: PMID:40429442
    reference_title: "From Circulating Biomarkers to Polymorphic Variants: A Narrative Review of Challenges in Thrombophilia Evaluation."
    supports: SUPPORT
    snippet: "This variant accounts for over 90% of inherited APCR cases and remains the most common genetic risk factor for thrombophilia in individuals of European descent, with a population prevalence from 1% to 5% on average, which is even higher among patients with VTE (10–20%)."
    explanation: Source for the general-population and VTE-cohort prevalence estimates.
- subtype: Prothrombin G20210A Thrombophilia
  population: European-ancestry general population
  measure_type: CARRIER_FREQUENCY
  prevalence_class: ABOVE_1_IN_1000
  rate_per_100000: 2000.0
  rate_low: 1000.0
  rate_high: 3000.0
  notes: >-
    Reported as 1%-3% in the general European-ancestry population and
    6%-10% among patients with venous thromboembolism.
  evidence:
  - reference: PMID:40429442
    reference_title: "From Circulating Biomarkers to Polymorphic Variants: A Narrative Review of Challenges in Thrombophilia Evaluation."
    supports: SUPPORT
    snippet: "The FII G20210A mutation is mostly found in individuals of European descent, with an estimated prevalence of 1% to 3% in the general population."
    explanation: Source for the general-population prevalence estimate.
- subtype: Antithrombin III Deficiency
  population: European and North American cohorts
  measure_type: CARRIER_FREQUENCY
  prevalence_class: ABOVE_1_IN_1000
  rate_per_100000: 100.0
  rate_low: 20.0
  rate_high: 200.0
  notes: >-
    Reported as 1 in 500 to 1 in 5000 individuals; banded ABOVE_1_IN_1000
    for consistency with the other four subtypes' banding convention, using
    the higher-prevalence (1 in 500) end of the reported range as the
    class-defining estimate. The low end of the range (1 in 5000) would
    itself fall in a rarer band.
  evidence:
  - reference: PMID:41706600
    reference_title: "Hereditary Antithrombin Deficiency in Pediatric Patients: Pathophysiology, Clinical Features, Diagnosis, and Antithrombin Replacement Therapy."
    supports: SUPPORT
    snippet: "The reported prevalence of hATD among European and North American cohorts ranges from 1 in 500 to 1 in 5000 individuals."
    explanation: Source for the population prevalence estimate.
- subtype: Protein C Deficiency
  population: General Caucasian population
  measure_type: CARRIER_FREQUENCY
  prevalence_class: ABOVE_1_IN_1000
  rate_per_100000: 300.0
  rate_low: 200.0
  rate_high: 400.0
  notes: >-
    Reported as 0.2%-0.4% in the general Caucasian population and 5%-10%
    among patients with suspected hereditary VTE.
  evidence:
  - reference: PMID:40429442
    reference_title: "From Circulating Biomarkers to Polymorphic Variants: A Narrative Review of Challenges in Thrombophilia Evaluation."
    supports: SUPPORT
    snippet: "It has been estimated that in patients with suspected hereditary VTE, the prevalence of PC deficiency is 5–10%. Among the general Caucasian population, the prevalence of PC deficiency is estimated to be 0.2–0.4%"
    explanation: Source for the general-population and VTE-cohort prevalence estimates.
- subtype: Protein S Deficiency
  population: General population (mild congenital deficiency)
  measure_type: CARRIER_FREQUENCY
  prevalence_class: ABOVE_1_IN_1000
  rate_per_100000: 200.0
  notes: >-
    Reported as approximately 1 in 500 individuals for mild congenital
    deficiency; severe deficiency is exceedingly rare with unknown
    prevalence.
  evidence:
  - reference: PMID:40429442
    reference_title: "From Circulating Biomarkers to Polymorphic Variants: A Narrative Review of Challenges in Thrombophilia Evaluation."
    supports: SUPPORT
    snippet: "The estimated incidence of mild congenital PS deficiency is approximately 1 in 500 individuals, while severe PS deficiency is exceedingly rare, with an unknown prevalence due to diagnostic challenges"
    explanation: Source for the general-population prevalence estimate.

references:
- reference: PMID:20301542
  title: Factor V Leiden Thrombophilia.
  tags:
  - GeneReviews
- reference: PMID:20301327
  title: Prothrombin Thrombophilia.
  tags:
  - GeneReviews
📚

References & Deep Research

References

2
PMID:20301542
Factor V Leiden Thrombophilia.
No top-level findings curated for this source.
PMID:20301327
Prothrombin Thrombophilia.
No top-level findings curated for this source.

Deep Research

1
Falcon ▸
Disease Characteristics Research Template
Edison Scientific Literature 15 citations 2026-08-26T16:42:34.581106

Question: You are an expert researcher providing comprehensive, well-cited information.

Provide detailed information focusing on: 1. Key concepts and definitions with current understanding 2. Recent developments and latest research (prioritize 2023-2024 sources) 3. Current applications and real-world implementations 4. Expert opinions and analysis from authoritative sources 5. Relevant statistics and data from recent studies

Format as a comprehensive research report with proper citations. Include URLs and publication dates where available. Always prioritize recent, authoritative sources and provide specific citations for all major claims.

Disease Characteristics Research Template

Target Disease

  • Disease Name: Thrombophilia
  • MONDO ID: (if available)
  • Category: Complex

Research Objectives

Please provide a comprehensive research report on Thrombophilia covering all of the disease characteristics listed below. This report will be used to populate a disease knowledge base entry. Be thorough and cite primary literature (PMID preferred) for all claims.

For each section, suggested databases/resources are listed. These are the first places you should search for information on each topic.

1. Disease Information

Search first: OMIM, Orphanet, ICD-10/ICD-11, MeSH, PubMed

  • What is the disease? Provide a concise overview.
  • What are the key identifiers? (OMIM, Orphanet, ICD-10/ICD-11, MeSH, Mondo)
  • What are the common synonyms and alternative names?
  • Is the information derived from individual patients (e.g., EHR) or aggregated disease-level resources?

2. Etiology

  • Disease Causal Factors: What are the primary causes? (genetic, environmental, infectious, mechanistic)
  • Risk Factors:

    Search first: PubMed, Cochrane Library, UpToDate, clinical guidelines, ClinVar, ClinGen, GWAS Catalog, PheGenI, CTD, CDC, WHO, epidemiological databases

  • Genetic risk factors (causal variants, susceptibility loci, modifier genes)
  • Environmental risk factors (toxins, lifestyle, occupational exposures, age, sex, family history)
  • Protective Factors:

    Search first: PubMed, Cochrane Library, clinical trial databases, GWAS Catalog, gnomAD, WHO, CDC, nutrition databases

  • Genetic protective factors (protective variants, modifier alleles)
  • Environmental protective factors (diet, lifestyle, exposures that reduce risk)
  • Gene-Environment Interactions: How do genetic and environmental factors interact to influence disease?

    Search first: CTD, PubMed, PheGenI, GxE databases

3. Phenotypes

Search first: HPO (Human Phenotype Ontology), OMIM, Orphanet, PubMed, clinicaltrials.gov, MedDRA, SNOMED CT, DECIPHER, LOINC

For each phenotype, provide: - Phenotype type: symptoms, clinical signs, physical manifestations, behavioral changes, or laboratory abnormalities

For symptoms/signs: HPO, OMIM, Orphanet, PubMed For behavioral changes: HPO, DSM, RDoC (Research Domain Criteria), PubMed For laboratory abnormalities: LOINC, SNOMED CT, LabTests Online, PubMed - Phenotype characteristics: Search first: OMIM, Orphanet, HPO, PubMed - Age of symptom onset (neonatal, childhood, adult-onset, late-onset) - Symptom severity (mild, moderate, severe, variable) - Symptom progression (stable, progressive, episodic, fluctuating) - Frequency among affected individuals (percentage or qualitative) - Quality of life impact: Effects on daily functioning and well-being (per-phenotype when possible) Search first: EQ-5D database, SF-36, WHO QOL databases, PubMed - Suggest HPO (Human Phenotype Ontology) terms for each phenotype

4. Genetic/Molecular Information

  • Causal Genes: Gene mutations or chromosomal abnormalities responsible for disease (gene symbols, OMIM IDs)

    Search first: OMIM, ClinVar, HGMD, Ensembl, NCBI Gene

  • Pathogenic Variants:
  • Affected genes (gene symbols, HGNC IDs) > Search first: OMIM, NCBI Gene, Ensembl, HGNC, UniProt, GeneCards
  • Variant classification (pathogenic, likely pathogenic, VUS per ACMG/AMP guidelines) > Search first: ClinVar, ClinGen, ACMG/AMP guidelines, VarSome
  • Variant type/class (missense, frameshift, nonsense, splice-site, structural)
  • Allele frequency in population databases > Search first: gnomAD, 1000 Genomes, ExAC, TOPMed, dbSNP
  • Somatic vs germline origin > Search first: COSMIC (somatic), ClinVar, ICGC, TCGA
  • Functional consequences (loss of function, gain of function, dominant negative)
  • Modifier Genes: Genes that modify disease severity or expression
  • Epigenetic Information: DNA methylation, histone modifications, chromatin changes affecting disease

    Search first: ENCODE, Roadmap Epigenomics, MethBase, DiseaseMeth

  • Chromosomal Abnormalities: Large-scale genetic changes (aneuploidy, translocations, inversions)

    Search first: DECIPHER, ClinVar, ECARUCA, UCSC Genome Browser

5. Environmental Information

  • Environmental Factors: Non-genetic contributing factors (toxins, radiation, pollution, occupational exposure)

    Search first: CTD (Comparative Toxicogenomics Database), TOXNET, PubMed, EPA databases

  • Lifestyle Factors: Behavioral factors (smoking, diet, exercise, alcohol consumption)

    Search first: CDC databases, WHO, PubMed, NHANES

  • Infectious Agents: If applicable, pathogens causing or triggering disease (bacteria, viruses, fungi, parasites)

    Search first: NCBI Taxonomy, ViPR, BV-BRC, MicrobeDB, GIDEON

6. Mechanism / Pathophysiology

  • Molecular Pathways: Specific signaling cascades or biochemical pathways involved (Wnt, MAPK, mTOR, PI3K-AKT, etc.)

    Search first: KEGG, Reactome, WikiPathways, PathBank, BioCyc

  • Cellular Processes: Cell-level mechanisms (apoptosis, autophagy, cell cycle dysregulation, inflammation, etc.)

    Search first: Gene Ontology (GO), Reactome, KEGG, PubMed

  • Protein Dysfunction: How protein structure or function is altered (misfolding, aggregation, loss of function, gain of function)

    Search first: UniProt, PDB (Protein Data Bank), InterPro, Pfam, AlphaFold

  • Metabolic Changes: Alterations in metabolic processes (energy metabolism, lipid metabolism, amino acid metabolism)

    Search first: KEGG, BioCyc, HMDB (Human Metabolome Database), BRENDA

  • Immune System Involvement: Role of immune response (autoimmunity, immunodeficiency, chronic inflammation)

    Search first: ImmPort, Immunome Database, IEDB, Gene Ontology

  • Tissue Damage Mechanisms: How tissues/ are injured (oxidative stress, ischemia, fibrosis, necrosis)

    Search first: PubMed, Gene Ontology, Reactome

  • Biochemical Abnormalities: Specific molecular defects (enzyme deficiencies, receptor dysfunction, ion channel defects)

    Search first: BRENDA, UniProt, KEGG, OMIM, PubMed

  • Epigenetic Changes: DNA methylation, histone modifications affecting gene expression in disease

    Search first: ENCODE, Roadmap Epigenomics, MethBase, DiseaseMeth

  • Molecular Profiling (if available):
  • Transcriptomics/gene expression changes > Search first: GEO (Gene Expression Omnibus), ArrayExpress, GTEx, Human Cell Atlas, SRA
  • Proteomics findings > Search first: PRIDE, ProteomeXchange, Human Protein Atlas, STRING, BioGRID
  • Metabolomics signatures > Search first: MetaboLights, Metabolomics Workbench, HMDB, METLIN
  • Lipidomics alterations > Search first: LIPID MAPS, SwissLipids, LipidHome, Metabolomics Workbench
  • Genomic structural features > Search first: UCSC Genome Browser, Ensembl, NCBI, dbVar, DGV
  • Advanced Technologies (if applicable):
  • Single-cell analysis findings (cell-type specific mechanisms, cellular heterogeneity) > Search first: Human Cell Atlas, Single Cell Portal, GEO, CELLxGENE
  • Spatial transcriptomics findings > Search first: GEO, Spatial Research, Vizgen, 10x Genomics data
  • Multi-omics integration results > Search first: TCGA, ICGC, cBioPortal, LinkedOmics, PubMed
  • Functional genomics screens (CRISPR, RNAi) > Search first: DepMap, GenomeRNAi, PubMed, BioGRID ORCS

For each mechanism, describe: - The causal chain from initial trigger to clinical manifestation - Which mechanisms are upstream vs downstream - What cell types and biological processes are involved - Suggest GO terms for biological processes and CL terms for cell types

7. Anatomical Structures Affected

  • Organ Level:
  • Primary organs directly affected
  • Secondary organ involvement (complications, secondary effects)
  • Body systems involved (cardiovascular, nervous, digestive, respiratory, endocrine, etc.)

    Search first: Uberon, FMA (Foundational Model of Anatomy), OMIM, HPO, ICD-11, MeSH, SNOMED CT

  • Tissue and Cell Level:
  • Specific tissue types affected (epithelial, connective, muscle, nervous)
  • Specific cell populations targeted (with Cell Ontology terms)

    Search first: Uberon, Human Protein Atlas, Cell Ontology, Human Cell Atlas, CellMarker, PanglaoDB

  • Subcellular Level:
  • Cellular compartments involved (mitochondria, nucleus, ER, lysosomes) (with GO Cellular Component terms)

    Search first: Gene Ontology (Cellular Component), UniProt, Human Protein Atlas

  • Localization:
  • Specific anatomical sites (with UBERON terms) > Search first: FMA, Uberon, NeuroNames (for brain), SNOMED CT
  • Lateralization (unilateral, bilateral, asymmetric) > Search first: HPO, clinical literature, imaging databases

8. Temporal Development

  • Onset:
  • Typical age of onset (congenital, pediatric, adult, geriatric)
  • Onset pattern (acute, subacute, chronic, insidious)

    Search first: OMIM, Orphanet, HPO, PubMed

  • Progression:
  • Disease stages (early, intermediate, advanced, end-stage) > Search first: Cancer Staging Manual (AJCC), WHO classifications, PubMed
  • Progression rate (rapid, slow, variable)
  • Disease course pattern (episodic, relapsing-remitting, progressive, stable)
  • Disease duration (self-limited, chronic lifelong)

    Search first: Disease registries, longitudinal cohort databases, natural history studies, PubMed, Orphanet, OMIM

  • Patterns:
  • Remission patterns (spontaneous, treatment-induced) > Search first: Clinical trial databases, disease registries, PubMed
  • Critical periods (time windows of vulnerability or opportunity for intervention) > Search first: PubMed, developmental biology databases, clinical guidelines

9. Inheritance and Population

  • Epidemiology:
  • Prevalence (cases per 100,000 at given time)
  • Incidence (new cases per 100,000 per year)

    Search first: Orphanet, CDC, WHO, GBD (Global Burden of Disease), national registries, SEER, disease registries

  • For Genetic Etiology:
  • Inheritance pattern (AD, AR, X-linked, mitochondrial, multifactorial, polygenic) > Search first: OMIM, Orphanet, ClinVar, GTR (Genetic Testing Registry)
  • Penetrance (complete, incomplete, age-dependent) > Search first: ClinVar, OMIM, PubMed, ClinGen
  • Expressivity (variable, consistent) > Search first: OMIM, ClinVar, PubMed
  • Genetic anticipation (increasing severity in successive generations) > Search first: OMIM, PubMed (especially for repeat expansion disorders)
  • Germline mosaicism > Search first: ClinVar, OMIM, genetic counseling literature, PubMed
  • Founder effects (population-specific mutations) > Search first: gnomAD, population genetics databases, PubMed
  • Consanguinity role > Search first: OMIM, population studies, genetic counseling resources
  • Carrier frequency > Search first: gnomAD, carrier screening databases, GeneReviews, GTR
  • Population Demographics:
  • Affected populations (ethnic or demographic groups with higher prevalence) > Search first: gnomAD, 1000 Genomes, PAGE Study, PubMed, population registries
  • Geographic distribution (endemic areas, regional variation) > Search first: WHO, CDC, GBD, Orphanet, geographic epidemiology databases
  • Geographic distribution of specific variants
  • Sex ratio (male:female) > Search first: Disease registries, OMIM, PubMed, epidemiological databases
  • Age distribution of affected individuals > Search first: CDC, disease registries, SEER, Orphanet

10. Diagnostics

  • Clinical Tests:
  • Laboratory tests (blood, urine, tissue chemistry, specific enzyme assays) > Search first: LOINC, LabTests Online, PubMed
  • Biomarkers (proteins, metabolites, genetic markers, circulating biomarkers) > Search first: FDA Biomarker List, BEST (Biomarkers, EndpointS, and other Tools), PubMed
  • Imaging studies (X-ray, CT, MRI, PET, ultrasound) > Search first: RadLex, DICOM, Radiopaedia, imaging databases
  • Functional tests (pulmonary function, cardiac stress tests) > Search first: LOINC, clinical guidelines, PubMed
  • Electrophysiology (EEG, EMG, ECG, nerve conduction studies) > Search first: LOINC, clinical neurophysiology databases, PubMed
  • Biopsy findings (histopathology, immunohistochemistry) > Search first: SNOMED CT, College of American Pathologists resources, PubMed
  • Pathology findings (microscopic examination) > Search first: SNOMED CT, Digital Pathology databases, PubMed
  • Genetic Testing:

    Search first: GTR (Genetic Testing Registry), GeneReviews, ClinGen

  • Overview of recommended genetic testing approach
  • Whole genome sequencing (WGS) utility > Search first: GTR, ClinVar, GEL (Genomics England), gnomAD
  • Whole exome sequencing (WES) utility > Search first: GTR, ClinVar, OMIM, GeneMatcher
  • Gene panels (which panels, which genes) > Search first: GTR, ClinVar, laboratory-specific databases
  • Single gene testing > Search first: GTR, ClinVar, OMIM, GeneReviews
  • Chromosomal microarray (CMA) > Search first: DECIPHER, ClinVar, dbVar, ECARUCA
  • Karyotyping > Search first: Chromosome Abnormality Database, ClinVar, cytogenetics resources
  • FISH > Search first: ClinVar, cytogenetics databases, PubMed
  • Mitochondrial DNA testing > Search first: MITOMAP, MSeqDR, ClinVar, GTR
  • Repeat expansion testing > Search first: GTR, ClinVar, repeat expansion databases, PubMed
  • Omics-Based Diagnostics (if applicable):
  • RNA sequencing / transcriptomics > Search first: GEO, ArrayExpress, GTEx, RNA-seq databases
  • Proteomics > Search first: PRIDE, ProteomeXchange, FDA Biomarker database
  • Metabolomics > Search first: MetaboLights, Metabolomics Workbench, HMDB
  • Epigenomics > Search first: GEO, ENCODE, Roadmap Epigenomics, MethBase
  • Liquid biopsy > Search first: COSMIC, ClinVar, liquid biopsy databases, PubMed
  • Clinical Criteria:
  • Standardized diagnostic criteria (DSM, ICD, society guidelines) > Search first: DSM-5, ICD-11, clinical society guidelines, UpToDate
  • Differential diagnosis (other conditions to rule out, with distinguishing features) > Search first: DynaMed, UpToDate, clinical decision support systems
  • Screening:
  • Screening methods for asymptomatic individuals (newborn screening, carrier screening, cascade screening) > Search first: ACMG recommendations, CDC newborn screening, GTR

11. Outcome/Prognosis

  • Survival and Mortality:
  • Survival rate (5-year, 10-year, overall) > Search first: SEER, cancer registries, disease-specific registries, PubMed
  • Life expectancy (with and without treatment if applicable) > Search first: Orphanet, disease registries, actuarial databases, PubMed
  • Mortality rate > Search first: CDC, WHO, GBD, national mortality databases
  • Disease-specific mortality (deaths directly attributable to disease) > Search first: Disease registries, CDC Wonder, GBD, PubMed
  • Morbidity and Function:
  • Morbidity (disease-related disability and health impacts) > Search first: GBD, WHO, disability databases, PubMed
  • Disability outcomes (long-term functional impairments) > Search first: ICF (International Classification of Functioning), disability registries
  • Quality of life measures (EQ-5D, SF-36, PROMIS, disease-specific tools) > Search first: EQ-5D database, SF-36, PROMIS, PubMed
  • Disease Course:
  • Complications (secondary problems: infections, organ failure, etc.) > Search first: ICD codes, disease registries, clinical databases, PubMed
  • Recovery potential (likelihood and extent of recovery, with vs without treatment) > Search first: Natural history studies, rehabilitation databases, PubMed
  • Prediction:
  • Prognostic factors (age, disease severity, biomarkers, treatment response) > Search first: Prognostic models databases, clinical calculators, PubMed
  • Prognostic biomarkers (molecular markers predicting disease course) > Search first: FDA Biomarker database, PubMed, cancer prognostic databases

12. Treatment

  • Pharmacotherapy:
  • Pharmacological treatments (drug names, drug classes, mechanisms of action) > Search first: DrugBank, RxNorm, ATC classification, DailyMed, FDA databases
  • Pharmacogenomics (how genetic variants affect drug metabolism, efficacy, toxicity) > Search first: PharmGKB, CPIC (Clinical Pharmacogenetics), FDA Table of PGx Biomarkers
  • Advanced Therapeutics:
  • Gene therapy (viral vectors, CRISPR, gene replacement, gene editing) > Search first: ClinicalTrials.gov, FDA gene therapy database, ASGCT resources
  • Cell therapy (stem cell transplant, CAR-T, cellular therapeutics) > Search first: ClinicalTrials.gov, FDA cell therapy database, FACT standards
  • RNA-based therapies (ASOs, siRNA, mRNA therapies) > Search first: ClinicalTrials.gov, FDA approvals, PubMed
  • Targeted therapies (treatments directed at specific molecular targets) > Search first: My Cancer Genome, OncoKB, ClinicalTrials.gov, FDA approvals
  • Immunotherapies (checkpoint inhibitors, monoclonal antibodies) > Search first: Cancer Immunotherapy Database, FDA approvals, ClinicalTrials.gov
  • Surgical and Interventional:
  • Surgical interventions (types of surgery, timing, outcomes) > Search first: CPT codes, surgical registries, clinical guidelines, PubMed
  • Supportive and Rehabilitative:
  • Supportive care (symptom management, pain control, nutrition) > Search first: Clinical guidelines, Cochrane Library, PubMed
  • Rehabilitation (physical therapy, occupational therapy, speech therapy) > Search first: Rehabilitation medicine databases, clinical guidelines, PubMed
  • Experimental:
  • Experimental treatments in clinical trials (with NCT identifiers if available) > Search first: ClinicalTrials.gov, EU Clinical Trials Register, WHO ICTRP
  • Treatment Outcomes:
  • Treatment response rates > Search first: Clinical trial databases, FDA reviews, systematic reviews, PubMed
  • Side effects and adverse events > Search first: FDA Adverse Event Reporting System (FAERS), MedWatch, PubMed
  • Treatment Strategy:
  • Treatment algorithms (clinical pathways, decision trees) > Search first: Clinical practice guidelines, NCCN Guidelines, UpToDate
  • Combination therapies > Search first: ClinicalTrials.gov, treatment guidelines, PubMed
  • Personalized medicine approaches (genotype-guided treatment) > Search first: My Cancer Genome, CIViC, PharmGKB, precision medicine databases

For each treatment, suggest NCIT (NCI Thesaurus) clinical-intervention terms where applicable.

13. Prevention

  • Prevention Levels:
  • Primary prevention (preventing disease occurrence: vaccination, risk factor modification) > Search first: CDC, WHO, USPSTF recommendations, Cochrane Library
  • Secondary prevention (early detection and treatment: screening programs, early intervention) > Search first: USPSTF, CDC screening guidelines, WHO
  • Tertiary prevention (preventing complications in those with disease) > Search first: Clinical guidelines, disease management protocols, PubMed
  • Immunization: Vaccine strategies (if applicable)

    Search first: CDC vaccine schedules, WHO immunization, FDA vaccine database

  • Screening and Early Detection:
  • Screening programs (population-based: newborn screening, cancer screening) > Search first: CDC screening programs, USPSTF, cancer screening databases
  • Genetic screening (carrier screening, preimplantation genetic diagnosis, prenatal testing) > Search first: ACMG recommendations, ACOG guidelines, GTR
  • Risk stratification (identifying high-risk individuals for targeted prevention) > Search first: Risk prediction models, clinical calculators, PubMed
  • Behavioral Interventions: Lifestyle modifications to reduce risk

    Search first: CDC, WHO, behavioral intervention databases, Cochrane Library

  • Counseling: Genetic counseling (risk assessment, family planning guidance)

    Search first: NSGC resources, ACMG guidelines, GeneReviews

  • Public Health:
  • Public health interventions (sanitation, vector control, health education) > Search first: CDC, WHO, public health databases, PubMed
  • Environmental interventions (reducing environmental risk factors) > Search first: EPA databases, WHO environmental health, PubMed
  • Prophylaxis: Preventive medications or procedures

    Search first: Clinical guidelines, FDA approvals, PubMed

14. Other Species / Natural Disease

  • Taxonomy: Species affected (with NCBI Taxon identifiers)

    Search first: NCBI Taxonomy

  • Breed: Specific breeds affected (with VBO identifiers if applicable)

    Search first: VBO (Vertebrate Breed Ontology)

  • Gene: Orthologous genes in other species (with NCBI Gene IDs)

    Search first: NCBI Gene

  • Natural Disease:
  • Naturally occurring disease in other species (companion animals, wildlife) > Search first: OMIA (Online Mendelian Inheritance in Animals), VetCompass, PubMed
  • Veterinary relevance and importance in animal health > Search first: OMIA, veterinary databases, PubMed
  • Comparative Biology:
  • Comparative pathology (similarities and differences across species) > Search first: OMIA, comparative pathology databases, PubMed
  • Evolutionary conservation of disease mechanisms > Search first: HomoloGene, OrthoMCL, Alliance of Genome Resources
  • Transmission (if applicable):
  • Zoonotic potential > Search first: CDC zoonotic diseases, WHO zoonoses, GIDEON
  • Cross-species susceptibility > Search first: NCBI Taxonomy, veterinary databases, PubMed

15. Model Organisms

  • Model Types:
  • Model organism type (mammalian, invertebrate, cellular, in vitro) > Search first: Alliance of Genome Resources, model organism databases
  • Specific model systems (mouse, rat, zebrafish, Drosophila, C. elegans, yeast, cell lines, organoids, iPSCs) > Search first: MGI, RGD, ZFIN, FlyBase, WormBase, SGD, ATCC, Cellosaurus
  • Induced models (drug treatment, surgical intervention, environmental manipulation) > Search first: MGI, model organism databases, PubMed
  • Genetic Models:
  • Types available (knockout, knock-in, transgenic, conditional, humanized) > Search first: MGI, IMPC, KOMP, EuMMCR, IMSR
  • Model Characteristics:
  • Phenotype recapitulation (how well model reproduces human disease features) > Search first: Model organism databases, comparative studies, PubMed
  • Model limitations (aspects of human disease not captured) > Search first: Model organism databases, PubMed, review articles
  • Applications:
  • Research applications (what aspects of disease can be studied) > Search first: Model organism databases, PubMed
  • Resources:
  • Model databases > Search first: MGI, RGD, ZFIN, FlyBase, WormBase, IMSR, EMMA, MMRRC

Citation Requirements

  • Cite primary literature (PMID preferred) for all mechanistic and clinical claims
  • Prioritize recent reviews and landmark papers
  • Include direct quotes from abstracts where possible to support key statements
  • Distinguish evidence source types: human clinical, model organism, in vitro, computational

Output Format

Structure your response as a comprehensive narrative organized by the sections above. For each section, provide: - Factual content with specific details (numbers, percentages, gene names, variant nomenclature) - Ontology term suggestions (HPO, GO, CL, UBERON, CHEBI, NCIT, MONDO) where applicable - Evidence citations with PMIDs - Direct quotes from abstracts to support key claims - Clear indication when information is not available or not applicable for this disease

This report will be used to populate a disease knowledge base entry with: - Pathophysiology descriptions with causal chains - Gene/protein annotations (HGNC, GO terms) - Phenotype associations (HP terms) with frequencies - Cell type involvement (CL terms) - Anatomical locations (UBERON terms) - Chemical entities (CHEBI terms) - Treatment annotations (NCIT terms) - Evidence items with PMIDs and exact abstract quotes - Epidemiology, prognosis, diagnostic, and prevention information - Animal model descriptions with phenotype recapitulation details

Thrombophilia: comprehensive disease-characteristics report

Scope and evidence note. Thrombophilia is a heterogeneous predisposition, not one anatomically localized disease. The clinically meaningful outcome is usually venous thromboembolism (VTE), while arterial thrombosis is much less consistently related to inherited thrombophilia. Evidence below is labeled as human clinical/cohort, guideline, model-organism, or exploratory. URLs are DOI links unless otherwise stated.

Executive summary

Thrombophilia denotes an inherited or acquired shift of hemostasis toward thrombosis. The five classic inherited forms are factor V Leiden, prothrombin G20210A, and deficiencies of antithrombin, protein C, or protein S. Antiphospholipid syndrome (APS) is the principal acquired thrombophilia. Open Targets links the umbrella entity to MONDO:0002305, inherited thrombophilia to MONDO:0100240, and the strongest established targets to F5, F2, SERPINC1, PROC, and PROS1. These associations are supported by clinical and genetic evidence rather than by a single causal gene for the umbrella disorder (OpenTargets Search: thrombophilia).

The central causal chain is: inherited/acquired defect plus a transient exposure—surgery, immobility, cancer, pregnancy, estrogen, inflammation, or infection—causes inadequate control of factor Xa/thrombin, excessive fibrin formation, venous obstruction, embolization, ischemia, and chronic post-thrombotic injury. Penetrance is incomplete and strongly exposure-dependent.

The dominant contemporary expert view is selective, action-oriented testing, not broad panels. ASH 2023 generally recommends against testing after unprovoked VTE if standard management is indefinite anticoagulation, but conditionally supports testing in selected hormone-associated or major transient-risk VTE and selected cerebral/splanchnic thrombosis when the result would determine whether anticoagulation is stopped. BSH similarly discourages routine testing after clearly provoked VTE and routine screening of asymptomatic relatives; APS testing is more actionable because triple positivity affects both duration and choice of anticoagulant (miceli2025fromcirculatingbiomarkers pages 8-9, miceli2025fromcirculatingbiomarkers pages 6-8, miceli2025fromcirculatingbiomarkers pages 5-6).

1. Disease information

Definition and classification

Thrombophilia—also called a hypercoagulable state, prothrombotic state, or, for genetic forms, hereditary/inherited thrombophilia—is an increased tendency to form clinically inappropriate thrombi. It may be:

  • Inherited: factor V Leiden/APC resistance; F2 G20210A; antithrombin, protein C, or protein S deficiency; much rarer defects affecting thrombomodulin, heparin cofactor II, fibrinogen, or other regulators.
  • Acquired: APS; cancer; myeloproliferative neoplasms; paroxysmal nocturnal hemoglobinuria; pregnancy/postpartum state; estrogen exposure; surgery, trauma, immobilization; inflammatory/infectious disease; nephrotic syndrome; and heparin-induced thrombocytopenia. These acquired illnesses are etiologies or provoking conditions, not interchangeable diagnoses.
  • Complex/multifactorial: most clinical events reflect gene–gene and gene–environment interaction rather than a genotype acting alone.

Identifiers

  • MONDO: thrombophilia MONDO:0002305; inherited thrombophilia MONDO:0100240; AD protein-S-deficiency thrombophilia MONDO:0012868; X-linked thrombophilia due to factor IX defect MONDO:0010432; congenital HRG-deficiency thrombophilia MONDO:0013143 (OpenTargets Search: thrombophilia).
  • MeSH: Thrombophilia; Venous Thromboembolism is a separate outcome concept.
  • ICD-10-CM: D68.5 Primary thrombophilia and D68.6 Other thrombophilia are commonly used; APS and individual thrombotic events also have distinct codes. ICD-11 should be mapped to the relevant thrombophilic disorder and separately to the thrombotic manifestation rather than treating the umbrella term as a single lesion.
  • OMIM/Orphanet: use subtype records rather than one umbrella record—e.g., factor V Leiden, prothrombin thrombophilia, antithrombin deficiency, protein C deficiency, and protein S deficiency.

The report is synthesized from aggregated resources, cohorts, guidelines, and primary studies. It is not individual-patient/EHR evidence unless a cited cohort explicitly used medical records.

2. Etiology and risk/protective factors

Genetic causal factors

The classic mechanisms are gain of coagulation function (F5, F2) or loss of endogenous anticoagulant function (SERPINC1, PROC, PROS1). In a population cohort of 29,387 middle-aged/older adults, pathogenic PROC/PROS1/SERPINC1 variants occurred in 908 participants (3.1%) and conferred HR 1.6 for incident VTE; heterozygous factor V Leiden and F2 G20210A conferred HR 1.8 and 1.6. One classic variant gave HR 1.7, whereas two or more gave HR 3.9, demonstrating a dose-graded genetic effect. The study abstract states: “The 5 classic thrombophilias are associated with a dose-graded risk of VTE” (human population cohort; Manderstedt et al., 2022, DOI: https://doi.org/10.1161/JAHA.121.023018).

Factor V Leiden prevalence is approximately 1–5% in European-ancestry populations and 10–20% among VTE patients; heterozygotes have about sevenfold and homozygotes about 20-fold higher lifetime thrombosis risk in summarized evidence. F2 G20210A occurs in roughly 1–3% of the general population and 6–10% of VTE patients, with a two- to threefold risk increase in heterozygotes (miceli2025fromcirculatingbiomarkers pages 14-15). These frequencies vary markedly by ancestry and should not be extrapolated universally.

Rare candidate genes include THBD, SERPIND1, HRG, ADAMTS13, F8, F9, F11, fibrinolysis genes, and regulators of VWF. However, evidence is weaker than for the classic five. Approximately one-third of familial/recurrent thrombosis remains molecularly unexplained, and known variants explain only part of estimated VTE heritability—about 30% in general-population analyses and 50% in twins (d’andrea2021raredefectslooking pages 2-3, d’andrea2021raredefectslooking pages 7-9).

Acquired and environmental factors

Major risk factors are advancing age, previous VTE, active cancer, surgery/trauma, hospitalization, immobilization or paralysis, central venous catheters, pregnancy/puerperium, estrogen-containing contraception or hormone therapy, obesity, smoking, long travel, nephrotic syndrome, inflammatory bowel disease, severe infection/COVID-19, and autoimmune disease. Acquired inflammation activates endothelium, monocytes, neutrophils and platelets, increases tissue factor and NET formation, and suppresses anticoagulant/fibrinolytic pathways.

Gene–environment interaction

Factor V Leiden or an anticoagulant deficiency may remain silent until estrogen exposure, pregnancy, surgery, immobility, or cancer supplies the second “hit.” APC resistance itself can also be acquired through pregnancy, postpartum physiology, exogenous hormones, high factor VIII, or protein S deficiency (miceli2025fromcirculatingbiomarkers pages 6-8). This interaction explains incomplete penetrance and why exposure avoidance/prophylaxis is often more useful than lifelong treatment of an asymptomatic genotype.

Protective factors

No protective allele is sufficiently validated for clinical use. Some variants affecting coagulation factors may reduce thrombosis but increase bleeding, precluding simple classification as beneficial. Practical protective factors are mobility, weight management, smoking cessation, hydration/movement during prolonged travel, avoiding estrogen in high-risk carriers, and appropriate perioperative/pregnancy thromboprophylaxis. These reduce exposure-mediated risk but do not erase inherited susceptibility.

3. Phenotypes

Thrombophilia is often asymptomatic until thrombosis. Frequency and onset depend on subtype, zygosity, age, and exposures.

  • Deep-vein thrombosis: unilateral limb pain, swelling, warmth and erythema; usually acute/episodic, most often adult-onset. Suggested HPO: HP:0002625 Deep venous thrombosis, HP:0009763 Limb pain, HP:0000988 Skin edema.
  • Pulmonary embolism: acute dyspnea, pleuritic pain, tachycardia, hypoxemia, syncope or shock; severity ranges from incidental to fatal. HPO: HP:0002204 Pulmonary embolism, HP:0002094 Dyspnea, HP:0001649 Tachycardia, HP:0012418 Hypoxemia.
  • Cerebral venous thrombosis: headache, papilledema, focal deficits, seizures, altered consciousness; often affects younger adults and women with hormonal/pregnancy risk. HPO: HP:0002140 Cerebral venous thrombosis, HP:0002315 Headache, HP:0001250 Seizure.
  • Splanchnic thrombosis: abdominal pain, portal hypertension, bowel ischemia, splenomegaly or incidental thrombosis. HPO: HP:0002626 Venous thrombosis, HP:0002027 Abdominal pain, HP:0001409 Portal hypertension.
  • Recurrent VTE/unusual-site thrombosis: suggests stronger or combined thrombophilia but is not diagnostic. HPO: HP:0004420 Recurrent thrombophlebitis where applicable.
  • Severe biallelic PROC/PROS1 deficiency: neonatal purpura fulminans with dermal microvascular thrombosis, necrosis and disseminated thrombosis. HPO: HP:0001019 Erythema, HP:0000961 Cyanosis, HP:0002639 Abnormality of coagulation; add a specific purpura-fulminans term where supported by the current HPO release.
  • Pregnancy morbidity: most strongly established for APS. Associations between inherited thrombophilia and recurrent loss are heterogeneous. A 2024 synthesis reported OR 2.44 for factor V Leiden, 2.08 for F2 G20210A, and 3.45 for protein S deficiency across cited pregnancy-loss evidence, but selection bias and treatment uncertainty remain substantial (borsi2024riskfactorsof pages 12-13).
  • Laboratory phenotype: APC resistance; reduced antithrombin/protein C/free protein S activity or antigen; persistent lupus anticoagulant/anticardiolipin/anti-β2GPI in APS; elevated thrombin-generation potential. D-dimer identifies fibrin turnover in suspected acute VTE but does not diagnose inherited thrombophilia.

Quality-of-life impairment derives from the event: pain, breathlessness, anticoagulant burden, bleeding anxiety, post-thrombotic syndrome, chronic thromboembolic pulmonary hypertension, work loss, and fear of recurrence. A 2023 network meta-analysis explicitly states that post-thrombotic syndrome “has a major impact on the quality of life after deep venous thrombosis” (Shao et al., published 29 November 2023, DOI: https://doi.org/10.3390/jcm12237450).

4. Genetic and molecular information

Entity/subtype Molecular defect Inheritance/acquired status Typical phenotype/risk Recommended laboratory confirmation Ontology/gene identifiers
Factor V Leiden thrombophilia F5 c.1601G>A, p.Arg534Gln (legacy R506Q; historically 1691G>A); causes activated protein C resistance Autosomal dominant thrombophilia susceptibility; incomplete penetrance Common inherited thrombophilia; increased risk of first and recurrent venous thromboembolism, especially with estrogen exposure, pregnancy, surgery, or immobility (miceli2025fromcirculatingbiomarkers pages 14-15, miceli2025fromcirculatingbiomarkers pages 6-8) APC resistance assay as screen, followed by targeted F5 genotyping (miceli2025fromcirculatingbiomarkers pages 14-15) F5; thrombophilia MONDO:0002305; inherited thrombophilia MONDO:0100240 (OpenTargets Search: thrombophilia)
Prothrombin thrombophilia F2 c.*97G>A (legacy G20210A) in 3' UTR; associated with higher prothrombin levels Autosomal dominant thrombophilia susceptibility; incomplete penetrance Increased venous thromboembolism risk; risk may be amplified by coexisting provoking factors or additional thrombophilia variants (miceli2025fromcirculatingbiomarkers pages 14-15, miceli2025fromcirculatingbiomarkers pages 6-8) Targeted F2 genotyping for c.*97G>A F2; thrombophilia MONDO:0002305; inherited thrombophilia MONDO:0100240 (OpenTargets Search: thrombophilia)
Antithrombin deficiency Loss-of-function or reduced-activity variants in SERPINC1 causing quantitative or qualitative antithrombin deficiency Usually autosomal dominant inherited thrombophilia High-risk hereditary thrombophilia with strong VTE predisposition; events often occur at younger age and may recur (d’andrea2021raredefectslooking pages 2-3, miceli2025fromcirculatingbiomarkers pages 5-6) Initial antithrombin activity assay; if low, antigen assay and activity:antigen interpretation; consider molecular testing; test outside anticoagulant interference/acquired deficiency states (miceli2025fromcirculatingbiomarkers pages 6-8) SERPINC1; thrombophilia MONDO:0002305; inherited thrombophilia MONDO:0100240 (OpenTargets Search: thrombophilia)
Protein C deficiency Pathogenic variants in PROC with reduced protein C anticoagulant activity Usually autosomal dominant inherited thrombophilia; severe biallelic disease can present neonatally Increased VTE risk; severe deficiency may cause neonatal purpura fulminans (human and model evidence) (OpenTargets Search: thrombophilia) Protein C activity with confirmatory antigen/genetic testing as appropriate; avoid testing during acute thrombosis or anticoagulant interference when possible (miceli2025fromcirculatingbiomarkers pages 6-8) PROC; thrombophilia MONDO:0002305; inherited thrombophilia MONDO:0100240 (OpenTargets Search: thrombophilia)
Protein S deficiency Pathogenic variants in PROS1 causing reduced free/functional protein S Usually autosomal dominant inherited thrombophilia Increased VTE risk; severe deficiency can contribute to purpura fulminans; platelet and plasma protein S both modulate venous thrombosis biology (OpenTargets Search: thrombophilia) Free protein S antigen and/or functional assay with careful interpretation; confirm genetically when indicated; avoid confounding by pregnancy, estrogen use, and anticoagulants (miceli2025fromcirculatingbiomarkers pages 6-8) PROS1; thrombophilia due to protein S deficiency MONDO:0012868; inherited thrombophilia MONDO:0100240 (OpenTargets Search: thrombophilia)
Antiphospholipid syndrome (APS) Autoantibody-mediated thrombophilia: lupus anticoagulant, anticardiolipin, and anti-β2-glycoprotein I antibodies Acquired Venous and arterial thrombosis and pregnancy morbidity; triple-positive profile confers higher recurrence risk and often changes anticoagulant choice (miceli2025fromcirculatingbiomarkers pages 8-9, miceli2025fromcirculatingbiomarkers pages 5-6) Persistent antiphospholipid antibody positivity on repeat testing per APS criteria; include lupus anticoagulant, anticardiolipin, anti-β2GPI; interpret carefully with anticoagulants present (miceli2025fromcirculatingbiomarkers pages 8-9, miceli2025fromcirculatingbiomarkers pages 6-8) APS is an acquired thrombophilia; broader thrombophilia MONDO:0002305
Not recommended marker set Common MTHFR polymorphisms (e.g., C677T, A1298C) Genetic variants of low/uncertain thrombosis relevance Not recommended as routine thrombophilia markers because evidence does not support meaningful VTE risk stratification in most settings (miceli2025fromcirculatingbiomarkers pages 6-8) Do not include in standard thrombophilia panels unless a separate indication exists (miceli2025fromcirculatingbiomarkers pages 6-8) MTHFR; not a core recommended thrombophilia marker (miceli2025fromcirculatingbiomarkers pages 6-8)

Table: Compact reference table of the principal inherited and acquired thrombophilia entities, their molecular basis, clinical significance, and laboratory confirmation. It is useful for report standardization and for distinguishing core markers from tests such as MTHFR polymorphisms that are not routinely recommended.

Variant interpretation

  • F5 Leiden: germline missense, NM_000130.5:c.1601G>A, p.Arg534Gln; legacy p.Arg506Gln/1691G>A reflects older numbering. It produces resistance to APC-mediated factor Va inactivation—a gain of procoagulant persistence.
  • F2 G20210A: germline 3′-UTR variant c.*97G>A, increasing prothrombin expression.
  • SERPINC1, PROC, PROS1: heterogeneous germline missense, nonsense, splice, frameshift, deletion/duplication, and regulatory variants. Quantitative type-I deficiencies reduce antigen and activity; qualitative type-II deficiencies preferentially reduce activity.
  • Origin: classic inherited variants are germline. Somatic JAK2/CALR/MPL mutations indicate an acquired clonal myeloproliferative thrombophilia rather than inherited disease.
  • Classification: assign pathogenic/likely pathogenic/VUS using ACMG/AMP criteria plus phenotype, activity/antigen measurements, segregation, population frequency, and functional evidence. A VUS alone should not establish thrombophilia or dictate lifelong anticoagulation.

Allele frequency must be recorded from the current ancestry-specific gnomAD release for the exact transcript/build. Factor V Leiden and F2 G20210A are common low-penetrance susceptibility alleles; most severe natural-anticoagulant-deficiency variants are rare. Broad sequencing may detect VUS without improving management.

Modifier effects include multiple thrombophilia variants, ABO/VWF/factor VIII levels, age, sex-specific hormone exposure, obesity, inflammatory disease, and cancer. Epigenetic signals and DNA methylation changes in endothelium/immune cells are biologically plausible but not validated diagnostic criteria. No recurrent chromosomal abnormality defines primary thrombophilia; karyotype/CMA/FISH are therefore not routine.

5. Environmental, lifestyle, and infectious information

Thrombosis follows Virchow’s triad: stasis, vascular/endothelial injury, and hypercoagulability. Environmental implementations include hospital VTE-risk assessment, mechanical and pharmacologic prophylaxis, catheter stewardship, early postoperative mobilization, and targeted pregnancy prophylaxis.

Smoking, obesity and inactivity increase risk; alcohol and specific diets are not accepted stand-alone thrombophilia causes. Occupational risk chiefly reflects prolonged immobility—e.g., long-haul travel or sedentary work—not a unique toxin. Severe infections, including SARS-CoV-2, can trigger endothelial injury, cytokine signaling, platelet activation and NET-mediated immunothrombosis. VITT is an acquired anti-PF4 antibody disorder following particular adenoviral-vector vaccines, not hereditary thrombophilia.

6. Mechanism/pathophysiology

Upstream-to-downstream causal chain

  1. Upstream trigger: F5/F2 susceptibility, loss of antithrombin/protein C/protein S, antiphospholipid antibodies, cancer/inflammation, estrogen, endothelial injury, or venous stasis.
  2. Regulatory failure: factor Xa/thrombin escape inhibition; factor Va/VIIIa persist; tissue-factor initiation and platelet phospholipid assembly amplify coagulation.
  3. Thrombin burst: fibrinogen becomes cross-linked fibrin; platelets activate; fibrinolysis is relatively inadequate.
  4. Thrombus propagation: low-flow venous environments permit erythrocyte/fibrin-rich clot growth, supported by endothelial cells, monocytes, neutrophils/NETs, and platelets.
  5. Clinical injury: venous obstruction causes edema/pain; embolization causes pulmonary vascular obstruction and right-heart strain; unusual-site thrombosis causes cerebral edema/hemorrhage or bowel/liver injury; chronic organization causes venous hypertension, PTS or chronic thromboembolic pulmonary hypertension.

Specific pathways and ontology suggestions

  • Protein C activation occurs on thrombin–thrombomodulin/EPCR-bearing endothelium; APC with protein S proteolyzes factors Va and VIIIa. Relevant GO: GO:0007596 blood coagulation, GO:0050818 regulation of coagulation, GO:0030195 negative regulation of blood coagulation, GO:0072378 blood coagulation, fibrin clot formation.
  • Antithrombin inhibits thrombin and factor Xa. Protein S supports APC and TFPI. A platelet-specific Pros1 knockout increased venous but not arterial thrombosis in mice by increasing factor X activation and thrombin within low-shear thrombi, showing cell- and flow-context specificity (model-organism evidence; Calzavarini et al., 2020, DOI: https://doi.org/10.1182/blood.2019003630).
  • Immunothrombosis involves neutrophils, cfDNA/NETs, platelets and endothelium. A family-based multi-omics study of 935 GAIT-2 participants estimated cfDNA heritability at 0.26 and identified rs1687391 near ORM1 at p=3.55×10⁻¹⁰; this remains exploratory, not a clinical biomarker (d’andrea2021raredefectslooking pages 7-9).
  • Suggested cell ontology: CL:0000115 endothelial cell, CL:0000233 platelet, CL:0000775 neutrophil, CL:0000576 monocyte, CL:0000232 erythrocyte, CL:0000182 hepatocyte.
  • Suggested subcellular/process terms: platelet alpha granule, secretory granule, plasma membrane, extracellular space, endoplasmic reticulum/Golgi for hepatic synthesis; NET formation and leukocyte activation where inflammatory thrombosis is documented.

No validated thrombophilia-specific single-cell, spatial-transcriptomic, proteomic, metabolomic, lipidomic, or epigenomic classifier is in routine care. Such platforms currently illuminate thromboinflammation rather than replace conventional testing.

7. Anatomical structures affected

The primary compartment is the vascular system, especially deep veins of the lower limbs and pelvis. Secondary sites include pulmonary arteries, cerebral venous sinuses, portal/mesenteric/splenic/hepatic veins, upper-extremity veins and catheter-associated veins. Severe deficiencies can affect dermal microvasculature.

Suggested anatomy terms include UBERON:0001638 vein, UBERON:0002018 blood vasculature, UBERON:0002048 lung, UBERON:0000955 brain, UBERON:0002107 liver, UBERON:0000948 heart, and site-specific vein terms from the current Uberon release. DVT is commonly unilateral; PE may be unilateral or bilateral; purpura fulminans is multifocal/symmetric.

8. Temporal development

Inherited predisposition is present from conception but typically manifests as an acute, episodic event in adulthood. Risk increases with age and cumulative exposures. Severe biallelic PROC/PROS1 defects present neonatally. Pediatric carriers can remain asymptomatic but become vulnerable during risk periods: in a prospective cohort, six VTEs occurred among 70 carriers over 287 observation-years—2.09% per patient-year—versus none among 64 noncarriers; 4/14 carriers exposed to a risk period developed VTE (human prospective cohort; Tormene et al., 2020, DOI: https://doi.org/10.1182/bloodadvances.2020002781).

There is no conventional staging system. A useful temporal model is: predisposition → provoking period → acute thrombosis → 3–6-month treatment phase → resolution, recurrence, or chronic sequelae. Genetic susceptibility is lifelong; the clot itself may resolve or organize. Critical intervention windows are prophylaxis before surgery/immobility and pregnancy/postpartum exposure, rapid anticoagulation after acute VTE, and reassessment before stopping therapy.

9. Inheritance and population

Most heterozygous F5, F2, SERPINC1, PROC and PROS1 thrombophilias behave as autosomal-dominant susceptibility traits with incomplete, age- and exposure-dependent penetrance and variable expressivity. Severe biallelic PROC/PROS1 disease is recessive and can cause neonatal purpura fulminans. Rare F9 gain-of-function thrombophilia is X-linked. Anticipation is not expected; germline mosaicism is not a prominent established feature.

Factor V Leiden has a founder distribution concentrated in European-derived populations and is uncommon in many East Asian and sub-Saharan African populations. F2 G20210A is also enriched in European/Mediterranean ancestry. Protein-deficiency variants are individually rare and geographically heterogeneous. Sex differences are dominated by pregnancy and estrogen exposure rather than simple Mendelian sex ratios.

“Prevalence of thrombophilia” cannot be represented by one valid global number because the umbrella includes common susceptibility alleles, rare high-risk deficiencies, and acquired conditions. Likewise, incidence applies more meaningfully to VTE—roughly 1–2 per 1,000 person-years in many adult populations, rising steeply with age—than to a lifelong genotype. Population ascertainment and ancestry must accompany every estimate.

10. Diagnostics

Distinguish acute-event diagnosis from thrombophilia testing

Suspected DVT/PE is evaluated with clinical pretest probability, D-dimer where appropriate, and objective imaging—compression ultrasonography for DVT and CT pulmonary angiography or V/Q scanning for PE. D-dimer is a fibrin-degradation marker and cannot define the underlying inherited state.

Core thrombophilia evaluation

  • F5 Leiden: APC-resistance assay followed by targeted genotyping; DNA testing is unaffected by anticoagulation.
  • F2 G20210A: targeted genotyping.
  • Antithrombin: activity first; if low, antigen and activity:antigen ratio, then genetics where actionable. Exclude liver dysfunction, proteinuria, DIC, acute thrombosis, surgery and heparin. The ISTH communication states: “Hereditary deficiency of antithrombin…causes a thrombophilia with a high risk for venous thromboembolism” (Van Cott et al., 2020, DOI: https://doi.org/10.1111/jth.14648).
  • Protein C: functional activity ± antigen; repeat when stable and off interfering vitamin-K antagonism.
  • Protein S: free protein-S antigen ± activity; interpret using sex/age/pregnancy-specific ranges and repeat outside pregnancy, estrogen exposure, acute illness and vitamin-K antagonism.
  • APS: lupus anticoagulant plus IgG/IgM anticardiolipin and anti-β2GPI; persistence must be demonstrated according to APS criteria. Anticoagulants can produce false lupus-anticoagulant results.

Do not measure natural anticoagulants during the acute phase if the result will be distorted; guidance summarized in the retrieved literature recommends testing after approximately three months of anticoagulation/clinical stabilization (miceli2025fromcirculatingbiomarkers pages 6-8). DOACs, heparins and warfarin interfere with multiple clot-based assays. DOAC-Stop/DOAC-Remove/filtration can reduce interference but may be incomplete and require local validation.

Who should be tested?

Testing should answer a management question. Higher-yield situations include young/recurrent VTE, strong first-degree family history, unusual sites, suspected severe natural-anticoagulant deficiency, neonatal purpura fulminans, or suspected APS—particularly if results change anticoagulant choice/duration, pregnancy prophylaxis, estrogen decisions, or family counseling.

ASH 2023 advises against routine testing after unprovoked VTE when the default is continuing anticoagulation; conditionally supports selected testing after hormonal or major transient provoking factors and in cerebral/splanchnic thrombosis if clinicians otherwise intend to stop anticoagulation. It recommends against universal testing before combined oral contraception but supports selective testing in families with known antithrombin, protein C or protein S deficiency (miceli2025fromcirculatingbiomarkers pages 8-9, miceli2025fromcirculatingbiomarkers pages 6-8). BSH 2022 discourages routine inherited testing after clearly provoked VTE, arterial thrombosis, unusual-site thrombosis without a management implication, and indiscriminate asymptomatic-relative screening (miceli2025fromcirculatingbiomarkers pages 5-6).

Not recommended routinely: MTHFR C677T/A1298C, PAI-1 polymorphisms, broad “thrombophilia panels,” WES/WGS, RNA-seq, CMA, karyotype, FISH, mitochondrial or repeat-expansion testing. WES/WGS may be considered in severe unexplained familial disease through specialist/research pathways but generates VUS and is not first-line.

Differentials include local compression, cancer-associated thrombosis, APS, HIT/VITT, myeloproliferative neoplasm, PNH, nephrotic/liver disease, DIC, severe infection, and medication-associated thrombosis.

11. Outcome and prognosis

Thrombophilia alone does not supply a meaningful five-year survival statistic. Prognosis is determined by thrombus location/severity, recurrence, cancer/cardiopulmonary comorbidity, bleeding risk, and treatment. Acute PE can be fatal; DVT may lead to PTS; recurrent emboli may lead to chronic thromboembolic pulmonary hypertension. Long-term anticoagulation reduces recurrence but increases bleeding.

Active cancer and an unprovoked first event are stronger recurrence predictors than most common inherited variants. Triple-positive APS is a high-recurrence acquired state and generally warrants long-term VKA rather than a DOAC (miceli2025fromcirculatingbiomarkers pages 8-9). Common thrombophilia has at most modest association with arterial disease; indiscriminate arterial-thrombosis testing is therefore low value.

QoL should be measured with VEINES-QOL/Sym for chronic venous disease/PTS, PEmb-QoL after PE, and generic EQ-5D/SF-36/PROMIS. Recovery after uncomplicated treated DVT/PE is often good, but persistent edema, pain, exercise limitation and recurrence anxiety can be substantial.

12. Treatment

Thrombophilia without thrombosis is generally not an indication for continuous anticoagulation. Treat the event and provoking context.

  • Acute VTE: therapeutic anticoagulation with a DOAC (apixaban, rivaroxaban, edoxaban or dabigatran), LMWH, unfractionated heparin, or warfarin according to renal/hepatic function, pregnancy, cancer, APS, interactions, bleeding risk and anatomy. Suggested NCIt terms: Anticoagulant Therapy, Direct Factor Xa Inhibitor, Low Molecular Weight Heparin, Vitamin K Antagonist.
  • Duration: usually at least three months; extend for unprovoked/recurrent VTE, persistent risk, APS, active cancer or high-risk thrombophilia when recurrence risk exceeds bleeding risk. Genotype alone rarely decides duration.
  • APS: warfarin/VKA is preferred for high-risk triple-positive APS; DOAC protection is inferior in this group (miceli2025fromcirculatingbiomarkers pages 8-9).
  • Pregnancy: LMWH is preferred because it does not cross the placenta; warfarin is teratogenic and DOACs are generally avoided. Prophylaxis depends on prior VTE, thrombophilia severity and family history—not genotype alone.
  • Severe protein C deficiency/purpura fulminans: protein C concentrate, anticoagulation and intensive supportive care; severe antithrombin deficiency may require antithrombin concentrate in selected high-risk situations.
  • Interventions: thrombolysis, thrombectomy, catheter-directed therapy, IVC filter or surgical embolectomy are reserved for selected life-/limb-threatening situations or contraindication/failure, not for thrombophilia itself.

For CVT, a 2024 meta-analysis of four RCTs/270 participants found similar recanalization with DOACs versus standard therapy (78.2% vs 83.2%) and no significant difference in major bleeding (1.2% vs 2.4%). The authors concluded: “DOACs and standard of care showed similar efficacy and safety profiles” (Chen et al., published 2024, DOI: https://doi.org/10.1177/10760296241256360). Applicability to triple-positive APS and pregnancy is limited.

No approved gene, cell, CRISPR, or RNA therapy treats common thrombophilia. Reducing antithrombin or protein S is being explored to rebalance bleeding disorders, but that strategy can itself create thrombosis and is not therapy for thrombophilia.

13. Prevention

  • Primary: avoid smoking and obesity; maintain mobility; manage cancer/inflammation; use perioperative/hospital VTE-risk assessment; avoid estrogen-containing contraception/HRT in high-risk carriers or women with prior estrogen-related VTE; provide LMWH prophylaxis during defined high-risk periods when indicated.
  • Secondary: recognize VTE promptly and ensure adequate anticoagulant dose/duration/adherence. Thrombophilia testing is secondary prevention only when it changes management.
  • Tertiary: manage PTS with activity, compression for symptom relief where appropriate, venous-ulcer care, rehabilitation and CTEPH referral; prevent recurrence while minimizing bleeding.
  • Screening: no population or newborn screening. Selective cascade testing is reasonable for a known severe SERPINC1/PROC/PROS1 familial defect when results will alter prophylaxis, pregnancy or estrogen decisions. APS is acquired, so relatives should not be screened merely because of family membership (miceli2025fromcirculatingbiomarkers pages 8-9).
  • Reproductive counseling: explain incomplete penetrance, 50% transmission risk for many heterozygous AD variants, and the distinction between carrying a susceptibility allele and having had VTE. Prenatal/PGT is technically possible for severe familial variants but rarely appropriate for common low-penetrance F5/F2 alleles.
  • Immunization: no vaccine prevents inherited thrombophilia. Routine vaccination benefits generally outweigh rare VITT risk; VITT requires its own diagnostic pathway.

14. Other species and natural disease

Naturally occurring thrombosis and inherited anticoagulant deficiencies occur in dogs, cats and horses, but veterinary evidence is fragmented and breed-specific. Candidate orthologs include canine/feline/equine F5, F2, SERPINC1, PROC and PROS1. Veterinary database confirmation through OMIA and current NCBI Taxonomy/Gene records is required before assigning a VBO breed term. Thrombophilia is not infectious or zoonotic; there is no cross-species transmission.

Comparative value lies in conserved coagulation biology, not identical epidemiology. Species differences in platelets, coagulation-factor levels, vessel size and experimental injury mean that animal thrombosis phenotypes do not directly estimate human penetrance.

15. Model organisms

  • Mouse (NCBI Taxon 10090): F5 Leiden knock-in, Serpinc1/Proc/Pros1 loss-of-function and conditional endothelial/platelet models. Complete protein C/S pathway disruption may cause embryonic/neonatal lethality or widespread thrombosis, whereas conditional models isolate cell-specific mechanisms. Endothelial thrombomodulin loss causes juvenile-onset thrombosis; platelet-specific Pros1 loss selectively augments low-shear venous thrombosis.
  • Zebrafish (Taxon 7955): transparent embryos and scalable genetics permit live thrombosis imaging and modifier screens. Complete protein C versus protein S loss can yield different phenotypes, illustrating that nominally linked anticoagulant pathways are not biologically interchangeable.
  • Rat/rabbit/pig: stasis, stenosis, endothelial injury and catheter models support pharmacology/device studies but model an induced thrombus more than lifelong inherited susceptibility.
  • In vitro: calibrated thrombin generation, endothelial–platelet flow systems, plasma reconstitution, hepatocyte models, and patient-derived iPSC endothelium/hepatocytes can test variant function.

Limitations include severe knockout lethality, supraphysiologic injury, interspecies hemostatic differences, and weak modeling of aging, cancer, pregnancy, obesity and polygenic background. Resources include MGI, IMPC, IMSR/MMRRC, ZFIN and the Alliance of Genome Resources.

Recent developments and active implementation

  1. Guideline shift (2023): ASH formalized decision-model-based selective testing. The major implication is that a positive result has little value if anticoagulation management will not change (miceli2025fromcirculatingbiomarkers pages 8-9, miceli2025fromcirculatingbiomarkers pages 6-8).
  2. CVT management (2024): German consensus guidance does not recommend general thrombophilia screening; it considers testing in young, spontaneous/recurrent CVT or positive family history when therapy would change. It increasingly accepts DOACs after the acute phase, while pregnancy prophylaxis remains LMWH-based.
  3. Laboratory implementation: adsorbent/filtration products can remove DOACs before clot-based assays, but incomplete removal and assay-specific validation remain concerns.
  4. Risk prediction: polygenic scores, thrombin generation, extracellular vesicles, NET/cfDNA markers and machine learning are research tools—not replacements for clinical risk assessment.
  5. Trials/registries: active examples include NCT04537416 FREYA (fertility, hypercoagulability and inflammation; observational; 1,000), NCT03206372 (VTE risk during hormonal exposure; observational; 2,640), NCT03910933 KIDCLOT (pediatric thrombosis/thrombophilia education; 248), and NCT06153394 (post-hepatectomy hypercoagulability; planned phase 3; 50). These study risk assessment/implementation rather than curative therapy.

Expert interpretation and evidence gaps

The most authoritative interpretation is that thrombophilia testing is a decision aid, not a diagnosis-generating fishing expedition. High-value results identify severe natural-anticoagulant deficiency or APS that changes pregnancy prophylaxis, estrogen counseling, family testing, anticoagulant duration, or—in APS—drug class. Low-value testing during acute thrombosis or anticoagulation creates false diagnoses, anxiety, insurance/employment concerns, unnecessary lifelong anticoagulation and avoidable bleeding.

Pregnancy-loss evidence needs particular caution. The 2024 Romanian cohort and earlier meta-analyses report associations, but selected referral populations, multiple-comparison testing, disputed markers such as MTHFR/PAI-1, and uncertain LMWH benefit prevent universal screening or genotype-directed treatment. ESHRE guidance conditionally recommends against LMWH for inherited-thrombophilia-associated recurrent loss because certainty is low (borsi2024riskfactorsof pages 12-13, borsi2024riskfactorsof pages 2-3).

The largest knowledge gaps are ancestry-diverse penetrance estimates, standardized functional interpretation of rare variants, prospective proof that testing improves outcomes, integration of polygenic/environmental risk, and validated omics markers. Until these are resolved, the appropriate knowledge-base representation is a hierarchy of molecular subtypes plus acquired causes and event phenotypes—not one monolithic disease with a single prevalence, prognosis, or treatment.

References

  1. (OpenTargets Search: thrombophilia): Open Targets Query (thrombophilia, 23 results). Buniello, A. et al. (2025). Open Targets Platform: facilitating therapeutic hypotheses building in drug discovery. Nucleic Acids Research.

  2. (miceli2025fromcirculatingbiomarkers pages 8-9): Giuseppe Miceli, Anna Maria Ciaccio, and Antonino Tuttolomondo. From circulating biomarkers to polymorphic variants: a narrative review of challenges in thrombophilia evaluation. May 2025. URL: https://doi.org/10.3390/jcm14103448, doi:10.3390/jcm14103448. This article has 17 citations.

  3. (miceli2025fromcirculatingbiomarkers pages 6-8): Giuseppe Miceli, Anna Maria Ciaccio, and Antonino Tuttolomondo. From circulating biomarkers to polymorphic variants: a narrative review of challenges in thrombophilia evaluation. May 2025. URL: https://doi.org/10.3390/jcm14103448, doi:10.3390/jcm14103448. This article has 17 citations.

  4. (miceli2025fromcirculatingbiomarkers pages 5-6): Giuseppe Miceli, Anna Maria Ciaccio, and Antonino Tuttolomondo. From circulating biomarkers to polymorphic variants: a narrative review of challenges in thrombophilia evaluation. May 2025. URL: https://doi.org/10.3390/jcm14103448, doi:10.3390/jcm14103448. This article has 17 citations.

  5. (miceli2025fromcirculatingbiomarkers pages 14-15): Giuseppe Miceli, Anna Maria Ciaccio, and Antonino Tuttolomondo. From circulating biomarkers to polymorphic variants: a narrative review of challenges in thrombophilia evaluation. May 2025. URL: https://doi.org/10.3390/jcm14103448, doi:10.3390/jcm14103448. This article has 17 citations.

  6. (d’andrea2021raredefectslooking pages 2-3): Giovanna D’Andrea and Maurizio Margaglione. Rare defects: looking at the dark face of the thrombosis. International Journal of Environmental Research and Public Health, 18(17):9146, Aug 2021. URL: https://doi.org/10.3390/ijerph18179146, doi:10.3390/ijerph18179146. This article has 5 citations.

  7. (d’andrea2021raredefectslooking pages 7-9): Giovanna D’Andrea and Maurizio Margaglione. Rare defects: looking at the dark face of the thrombosis. International Journal of Environmental Research and Public Health, 18(17):9146, Aug 2021. URL: https://doi.org/10.3390/ijerph18179146, doi:10.3390/ijerph18179146. This article has 5 citations.

  8. (borsi2024riskfactorsof pages 12-13): Ema Borsi, Ovidiu Potre, Ioana Ionita, Miruna Samfireag, Cristina Secosan, and Cristina Potre. Risk factors of thrombophilia-related mutations for early and late pregnancy loss. Medicina, 60:521, Mar 2024. URL: https://doi.org/10.3390/medicina60040521, doi:10.3390/medicina60040521. This article has 19 citations.

  9. (borsi2024riskfactorsof pages 2-3): Ema Borsi, Ovidiu Potre, Ioana Ionita, Miruna Samfireag, Cristina Secosan, and Cristina Potre. Risk factors of thrombophilia-related mutations for early and late pregnancy loss. Medicina, 60:521, Mar 2024. URL: https://doi.org/10.3390/medicina60040521, doi:10.3390/medicina60040521. This article has 19 citations.

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