Congenital Prothrombin Deficiency

Genetic MONDO:0013361 Pathograph 33 Show in embeddings browser Bleeding Disorder Coagulation Disorder Rare Bleeding Disorder

Congenital prothrombin (factor II) deficiency is the rarest of the inherited coagulation factor deficiencies, caused by biallelic pathogenic variants in F2. Prothrombin sits at the convergence point of the coagulation cascade: the prothrombinase complex - factor Xa with factor Va as cofactor, assembled on an anionic phospholipid surface in the presence of calcium - cleaves the zymogen to thrombin, and thrombin is the effector that converts fibrinogen to fibrin, activates platelets through protease-activated receptors, feeds back on factors V, VIII and XI, activates factor XIII to cross-link the fibrin mesh, and, complexed with thrombomodulin, switches on the protein C anticoagulant arm. Because a single defect removes all of those outputs at once, the bleeding is out of proportion to what a single-pathway lesion would predict. Two biochemical forms are distinguished by the relationship between antigen and activity: type I (hypoprothrombinaemia) reduces both roughly in parallel, while type II (dysprothrombinaemia) leaves a normal or near-normal amount of a dysfunctional protein, so activity falls disproportionately. That antigen-versus-activity discrepancy is the diagnostic signature. Prothrombin is vitamin K-dependent, and gamma-carboxylation of its Gla domain is what allows it to dock on the procoagulant membrane surface, which is why the acquired vitamin K-related deficiencies phenocopy the congenital disorder. Complete absence of prothrombin has never been observed in a living human and appears to be incompatible with life; every described patient retains some residual activity.

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Inheritance

Autosomal recessive inheritance HP:0000007

Homozygotes and compound heterozygotes for F2 pathogenic variants are symptomatic; single heterozygotes usually remain asymptomatic and are detected only incidentally or after a haemostatic challenge.

Autosomal recessive inheritance

Show evidence (2 references)

PMID:23190616 SUPPORT Human Clinical

"Inherited factor II deficiency is an extremely rare autosomal recessive disorder affecting both genders: clinical bleeding can vary widely in homozygous individuals, and heterozygotes often remain clinically asymptomatic."

A four-patient series states the recessive inheritance pattern and the asymptomatic heterozygote state directly.

PMID:40747195 SUPPORT Human Clinical

"Homozygous and compound heterozygous forms are symptomatic, while heterozygotes are usually asymptomatic but may bleed during surgery, childbirth, or dental extractions"

Supports the biallelic requirement and the challenge-dependent expression seen in carriers.

◆

Subtypes

Type I (Hypoprothrombinaemia)

True quantitative deficiency: prothrombin coagulant activity and prothrombin antigen are reduced concordantly, because less normal protein is made, secreted, or retained in the circulation. Severe cases (activity below about 5% of normal) can bleed without trauma.

Show evidence (2 references)

PMID:19598065 SUPPORT Human Clinical

"hypoprothrombinemia (type I deficiency), characterized by concomitantly low levels of activity and antigen"

Defines type I as the form in which activity and antigen fall together, which is the discriminator this subtype is keyed on.

PMID:40747195 SUPPORT Human Clinical

"Type I (hypoprothrombinemia), a quantitative deficiency with severely reduced prothrombin activity and antigen (<5% of normal), causing severe bleeding symptoms even without trauma."

Gives the quantitative character of type I and the activity range at which spontaneous bleeding is described.

Type II (Dysprothrombinaemia)

Qualitative defect: a normal or near-normal amount of a dysfunctional prothrombin is synthesized and secreted, so the antigen concentration is preserved while coagulant activity is disproportionately low. The resulting activity-to-antigen discrepancy is what distinguishes this subtype at the bench.

Show evidence (2 references)

PMID:23852823 SUPPORT Human Clinical

"dysprothrombinemia (type II deficiency), characterized by the normal or near-normal synthesis of a dysfunctional protein"

Defines type II as normal or near-normal synthesis of a dysfunctional protein, the defining feature of this subtype.

PMID:40747195 SUPPORT Human Clinical

"Type II (dysprothrombinemia) is a qualitative deficiency where prothrombin activity is decreased (around 10% of normal) but antigen levels remain normal or slightly reduced."

States the activity-versus-antigen dissociation that defines the qualitative subtype.

Discussions and Knowledge Gaps

How much of the variable bleeding severity in congenital prothrombin deficiency is explained by the simultaneous loss of the thrombin-thrombomodulin protein C anticoagulant arm?

KNOWLEDGE GAP OPEN anticoagulant_arm_offset

Attached to

pathophysiology#Reduced Thrombomodulin-Dependent Protein C Activation

Prothrombin deficiency removes an anticoagulant output at the same time as the procoagulant ones, so the net haemostatic deficit is not a simple subtraction. Nothing in the curated literature quantifies the offset in this disease, and its existence is one candidate explanation for why residual factor II activity predicts bleeding severity only loosely and why some dysprothrombin variants present with thrombosis instead. The node is therefore left without a downstream edge rather than being wired into the bleeding chain.

What is the human phenotype of complete prothrombin deficiency, and is the inference of lethality from animal models safe?

OPEN QUESTION OPEN no_human_null_phenotype

Attached to

pathophysiology#Deficient Thrombin Activity at the Site of Injury disease#Congenital Prothrombin Deficiency

No living patient with undetectable plasma prothrombin has ever been reported, and every described genotype leaves residual activity. The claim that complete absence is incompatible with life is therefore an inference from an absence of human observations plus two independent prothrombin-null mouse lines and a zebrafish model, not a human finding. This entry states it as a constraint on the disease model rather than as an observed human phenotype.

Show evidence (3 references)

PMID:23852823 SUPPORT Human Clinical

"No living patient with undetectable plasma prothrombin has been reported to date."

The human side of the claim is an absence of observations, which is what makes this an open question rather than a settled phenotype.

PMID:32132579 SUPPORT Model Organism

"Complete deficiency of the central clotting enzyme prothrombin has never been observed in humans and is incompatible with postnatal life in mice, thus limiting the ability to study its role in vivo."

States both halves of the inference and the reason it cannot be tested directly in humans.

PMID:39022653 SUPPORT Human Clinical

"No cases of aprothrombinemia have been reported, suggesting incompatibility with life"

An independent review draws the same inference, and its hedged wording ("suggesting") is the epistemic status this entry adopts.

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Pathophysiology

Biallelic F2 Pathogenic Variants

Homozygous or compound heterozygous pathogenic variants in F2, on chromosome 11, are the initiating lesion. Most are missense; nonsense, frameshift, splice-site and small in-frame deletions are also described. Variants distribute between the catalytic domain, the anion-binding exosite, the Na+-binding loop, the kringle domains, and the propeptide/Gla processing region, and the domain hit is what determines whether the result is a quantitative or a qualitative defect.

hepatocyte CL:0000182

serine-type endopeptidase activity of thrombin GO:0004252 ↓ DECREASED

Downstream

Reduced Hepatic Prothrombin Output Null, hypomorphic and secretion-impairing alleles reduce the amount of prothrombin reaching the circulation, producing the type I phenotype.

Circulating Dysfunctional Prothrombin Missense alleles in the catalytic, exosite, Na+-loop and kringle regions allow a normal quantity of protein to be secreted but leave it unable to be activated or to act normally once activated, producing the type II phenotype.

Defective Vitamin K-Dependent Gla-Domain Membrane Binding Variants at the propeptide cleavage site prevent the propeptide from being removed from the Gla domain, so the mature protein cannot present a normal calcium-dependent membrane-binding surface.

Show evidence (2 references)

PMID:25242243 SUPPORT Human Clinical

"Prothrombin deficiency is a very rare disorder caused by mutations in the F2 gene that generate hypoprothrombinemia or dysprothrombinemia and is characterized by bleeding manifestations that can vary from clinically irrelevant to life-threatening."

Attributes both biochemical forms of the disease to F2 mutation, which is the claim this initiating node makes.

PMID:15892853 SUPPORT Human Clinical

"Five different causative mutations including four (80%) missense and an in-frame deletion (20%) were identified."

Documents the mutation classes found in a consecutive patient series, supporting the missense-dominant spectrum described here.

Reduced Hepatic Prothrombin Output

In type I disease the hepatocyte makes, secretes, or maintains less prothrombin, so plasma antigen and coagulant activity fall together. The liver is otherwise structurally normal and no other coagulation factor is affected.

hepatocyte CL:0000182

blood coagulation GO:0007596 ↓ DECREASED

Downstream

Impaired Prothrombinase-Mediated Thrombin Generation Less substrate is available to the prothrombinase complex, so less thrombin can be generated per unit time.

Show evidence (1 reference)

PMID:19598065 SUPPORT Human Clinical

"hypoprothrombinemia (type I deficiency), characterized by concomitantly low levels of activity and antigen"

The concordant fall in antigen and activity is what identifies this node as a reduction in the amount of circulating protein.

Circulating Dysfunctional Prothrombin

In type II disease a normal or near-normal quantity of prothrombin circulates but cannot do its job. Documented mechanisms include failure of the zymogen-to-proteinase transition, perturbation of the Na+-binding site that governs activation, and loss of substrate recognition once thrombin is formed. The consequence is a large activity-to-antigen gap.

serine-type endopeptidase activity of thrombin GO:0004252 ⇓ LOSS OF FUNCTION

Downstream

Impaired Prothrombinase-Mediated Thrombin Generation The mutant zymogen is a poor substrate for prothrombinase or yields a catalytically impaired thrombin, so functional thrombin generation falls despite a normal substrate concentration.

Show evidence (2 references)

PMID:25242243 SUPPORT Human Clinical

"The homozygous patient had a markedly prolonged prothrombin time, strongly reduced FII activity (0.82%) but normal antigen levels."

A worked case of a dysfunctional protein present at normal concentration, which is exactly what this node asserts.

PMID:28196451 SUPPORT Human Clinical

"Bioinformatics and model analyses illuminated that the mutation will be probably damaging and perturbing the structure of Na+-binding site, which will affect the activation of prothrombin."

Gives a structural mechanism by which a secreted, antigenically normal prothrombin fails to be activated.

Defective Vitamin K-Dependent Gla-Domain Membrane Binding

Prothrombin is a vitamin K-dependent protein. Gamma-carboxylation of the glutamate residues of its Gla domain creates the calcium-dependent conformation that docks the zymogen onto the anionic phospholipid surface where prothrombinase assembles. Variants that block propeptide cleavage - the step that presents the Gla domain correctly - remove that anchoring. The same step is what acquired vitamin K deficiency, vitamin K antagonists, and the hereditary combined vitamin K-dependent factor deficiencies interrupt, which is why those conditions phenocopy this disease.

peptidyl-glutamic acid carboxylation GO:0017187

calcium-dependent phospholipid membrane binding by the Gla domain GO:0005543 ↓ DECREASED

Downstream

Impaired Prothrombinase-Mediated Thrombin Generation A zymogen that cannot be presented on the phospholipid surface is not efficiently converted by the membrane-assembled prothrombinase complex.

Show evidence (2 references)

PMID:28394285 SUPPORT Human Clinical

"Prothrombin is a plasma glycoprotein and zymogen of a serine protease requiring vitamin K for normal biosynthesis."

Establishes that prothrombin's normal biosynthesis is vitamin K-dependent, the premise of this node.

PMID:19141161 SUPPORT Other

"Once carboxylated, the proteins have a calcium-dependent conformation that allows binding to phospholipids and/or endothelial cells."

States why gamma-carboxylation is required for membrane binding, which is the functional consequence this node models.

Impaired Prothrombinase-Mediated Thrombin Generation

The prothrombinase complex - factor Xa with factor Va as its cofactor, assembled on an anionic phospholipid membrane in the presence of calcium ions - is what converts prothrombin to thrombin at a physiologically useful rate. Whether the lesion is too little substrate (type I), a substrate that cannot be activated (type II), or a substrate that cannot reach the membrane, the rate-limiting step is the same one, and the measurable consequence is a reduced and slowed thrombin generation curve.

platelet CL:0000233

zymogen activation of prothrombin by prothrombinase GO:0031638 ↓ DECREASED

Downstream

Deficient Thrombin Activity at the Site of Injury Reduced conversion of the zymogen leaves too little active thrombin where and when the haemostatic response needs it.

Show evidence (3 references)

PMID:31102425 SUPPORT Other

"In the presence of an anionic phospholipid membrane and calcium ions, factors Va and Xa assemble into the prothrombinase complex."

Establishes the composition and membrane/calcium requirement of the complex named in this node.

PMID:31102425 SUPPORT Other

"Following formation of the ternary complex with the macromolecular zymogen substrate prothrombin, the latter is rapidly converted into thrombin, the key regulatory enzyme of coagulation."

States the reaction this node describes as impaired, and that prothrombin is the substrate of the complex.

PMID:41443372 SUPPORT INDIRECT Human Clinical

"Overall, thrombin generation in patients was significantly reduced compared with controls, with decreased thrombin potentials (median 58%) and prolonged lag times (150%), resulting in reduced TP/LT ratios (45%)."

Measures the reduced and delayed thrombin generation predicted by this node in a cross-sectional cohort of rare factor deficiencies that included factor II deficiency.

Deficient Thrombin Activity at the Site of Injury

Thrombin is the hub of the haemostatic response, and this node is where the single upstream lesion fans out. Thrombin converts fibrinogen to fibrin, activates platelets through protease-activated receptors, feeds back to activate factors V, VIII and XI so that its own generation becomes a burst, activates factor XIII to cross-link the fibrin mesh, and - complexed with thrombomodulin - switches on protein C. Losing one enzyme therefore removes five distinct outputs at once.

blood coagulation GO:0007596 ↓ DECREASED

Animal models

Prothrombin-null mouse (F2 knockout) Mouse partially recapitulates Complete genetic ablation of prothrombin, producing total loss of thrombin generation and fatal haemorrhage.

Downstream

Impaired Fibrinogen-to-Fibrin Conversion

Impaired Thrombin-Mediated Platelet Activation

Loss of Thrombin Feedback Amplification of Factors V, VIII and XI

Impaired Factor XIII Activation and Fibrin Cross-Linking

Reduced Thrombomodulin-Dependent Protein C Activation

Show evidence (2 references)

PMID:9636195 SUPPORT Model Organism

"The conversion of prothrombin (FII) to the serine protease, thrombin (FIIa), is a key step in the coagulation cascade because FIIa triggers platelet activation, converts fibrinogen to fibrin, and activates regulatory pathways that both promote and ultimately suppress coagulation."

Names the multiple downstream outputs of thrombin that this hub node fans out into.

PMID:28394285 SUPPORT Human Clinical

"It triggers platelet aggregation and promote coagulation by activating regulatory pathways and generating fibrin monomers by cleavage of a specific peptide bond in fibrinogen α- and β- subunits at N-termini"

A review of this disease states the same multi-output role for thrombin, anchoring the hub to the disease rather than to general biochemistry.

Impaired Fibrinogen-to-Fibrin Conversion

Thrombin's canonical substrate reaction, cleavage of fibrinopeptides from fibrinogen to release fibrin monomers, proceeds too slowly and too little fibrin is deposited.

blood coagulation, fibrin clot formation GO:0072378 ↓ DECREASED

Downstream

Weak, Poorly Cross-Linked Hemostatic Clot

Show evidence (2 references)

PMID:34154000 SUPPORT Other

"plays a key role in hemostasis by converting fibrinogen to fibrin and activating coagulation factor XIII whereby the fibrin clot is stabilized"

Establishes fibrinogen cleavage as a thrombin-dependent step, so a thrombin deficit impairs it.

PMID:32132579 SUPPORT Model Organism

"Human prothrombin engineered with the equivalent mutation exhibits a severe reduction in secretion, thrombin generation, and fibrinogen cleavage."

Shows experimentally that a prothrombin variant reduces fibrinogen cleavage, connecting the prothrombin lesion to this specific output.

Impaired Thrombin-Mediated Platelet Activation

Thrombin is among the most potent physiological platelet agonists, acting through the protease-activated receptors PAR1 and PAR4 on the human platelet surface. With less thrombin, platelet recruitment and the procoagulant platelet surface that prothrombinase itself needs are both blunted, so the defect is not confined to the plasma phase of coagulation.

platelet CL:0000233

thrombin-activated receptor signaling pathway GO:0070493 ↓ DECREASED platelet activation GO:0030168 ↓ DECREASED

Downstream

Weak, Poorly Cross-Linked Hemostatic Clot Fewer recruited and activated platelets means a smaller platelet-fibrin mass and less catalytic membrane surface at the wound.

Show evidence (1 reference)

PMID:34154000 SUPPORT Other

"Furthermore, thrombin activates platelets through protease-activated receptors on the platelet surface."

Establishes the protease-activated-receptor route by which thrombin recruits platelets, the step lost here.

Loss of Thrombin Feedback Amplification of Factors V, VIII and XI

Thrombin activates factors V, VIII and XI, converting the initial trace of enzyme into a burst. When thrombin is scarce from the outset the loop never engages, so the deficit is amplified rather than merely proportional - which is part of why bleeding is out of proportion to a single-factor lesion.

regulation of blood coagulation GO:0030193 ↓ DECREASED

Downstream

Weak, Poorly Cross-Linked Hemostatic Clot

Show evidence (1 reference)

PMID:10528826 SUPPORT Other

"It regulates its own generation by activating coagulation factors V, VIII and even XI resulting in a burst of thrombin formation."

Names the exact feedback substrates and the burst behaviour that is lost when thrombin generation is deficient.

Impaired Factor XIII Activation and Fibrin Cross-Linking

Thrombin activates factor XIII, the transglutaminase that covalently cross-links fibrin monomers and binds alpha-2-antiplasmin into the mesh. Less thrombin means less factor XIIIa, so the fibrin that does form is mechanically weak and abnormally susceptible to fibrinolysis.

blood coagulation, fibrin clot formation GO:0072378 ↓ DECREASED

Downstream

Weak, Poorly Cross-Linked Hemostatic Clot

Show evidence (1 reference)

PMID:10528826 SUPPORT Other

"Thrombin not only cleaves fibrinogen to fibrin, but also through the activation of factor XIII effects the cross-linking of fibrin monomers to produce a firm fibrin clot."

States that clot firmness depends on thrombin-driven factor XIII activation, the step this node models as impaired.

Reduced Thrombomodulin-Dependent Protein C Activation

Thrombin bound to endothelial thrombomodulin activates protein C, the principal physiological brake on further thrombin generation. This anticoagulant output is lost alongside the procoagulant ones, so the net haemostatic consequence of prothrombin deficiency is not a simple subtraction, and the offset is a plausible contributor to the weak correlation between residual factor II activity and bleeding severity. It is not the explanation for the rare dysprothrombin variants that present with thrombosis: those escape inhibition by antithrombin, which is a separate mechanism acting on the mutant thrombin itself rather than on this thrombomodulin-protein C arm.

endothelial cell CL:0000115

regulation of blood coagulation GO:0030193 ↓ DECREASED

Show evidence (1 reference)

PMID:34154000 SUPPORT Other

"Conversely, thrombin also exerts anticoagulant effects, enhancing the protein C activity while complexed with thrombomodulin."

Establishes the thrombomodulin-protein C arm as a thrombin output, so it is lost together with the procoagulant outputs.

Weak, Poorly Cross-Linked Hemostatic Clot

The clot that forms at a site of injury is small, slow to form, deficient in cross-linked fibrin, and under-populated with recruited platelets. It is the convergence point of every downstream thrombin branch and the immediate substrate of the clinical bleeding.

blood coagulation, fibrin clot formation GO:0072378 ↓ DECREASED

Animal models

Zebrafish prothrombin kringle-1 deletion (f2) Zebrafish partially recapitulates Homozygous mutants cannot form occlusive venous or arterial thrombi after endothelial injury and die of internal haemorrhage by two months.

Downstream

Systemic Bleeding Diathesis

Show evidence (1 reference)

PMID:32132579 SUPPORT Model Organism

"Mutants are unable to form occlusive venous and arterial thrombi in response to endothelial injury, a defect that was phenocopied using direct oral anticoagulants."

In vivo demonstration that prothrombin loss prevents formation of an occlusive clot after endothelial injury.

Systemic Bleeding Diathesis

A lifelong, episodic bleeding tendency whose severity tracks residual factor II activity: below about 5% patients bleed with little or no trauma, 5-10% is moderate, and above 10% is usually mild and may be silent until a haemostatic challenge. Because the mechanism is systemic rather than tissue-specific, any vascular bed can be the site.

Downstream

Recurrent mucocutaneous bleeding

Menorrhagia

Joint hemorrhage

Intramuscular hematoma

Intracranial hemorrhage

Prolonged bleeding after surgery

Show evidence (2 references)

PMID:38601422 SUPPORT Human Clinical

"Patients with prothrombin activity of less than 5% have severe symptoms presenting earlier in life; patients with 5-10% have moderate symptoms; and patients with greater than 10% have mild symptoms."

Gives the activity-to-severity gradation stated in this node's description.

PMID:28394285 SUPPORT Human Clinical

"severe defects (FII plasma levels <5%) is characterized by different symptoms, with recurrent muco-cutaneous and gynaecological bleeding and more rarely haemarthroses and muscle bleeds"

Describes the clinical spectrum of the severe end of the diathesis in this specific disease.

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Pathograph

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Phenotypes

Blood 8

Recurrent mucocutaneous bleeding FREQUENT Abnormal bleeding HP:0001892

Temporal: RECURRENT

Show evidence (1 reference)

PMID:28394285 SUPPORT Human Clinical

"severe defects (FII plasma levels <5%) is characterized by different symptoms, with recurrent muco-cutaneous and gynaecological bleeding and more rarely haemarthroses and muscle bleeds"

Names recurrent mucocutaneous bleeding as the leading symptom of severe prothrombin deficiency.

Menorrhagia FREQUENT HP:0000132

Show evidence (2 references)

PMID:39022653 SUPPORT Human Clinical

"Menorrhagia is a frequent manifestation in deficient women and, when severe, can be controlled by prophylaxis"

Stated in the review's factor II section, supporting both the phenotype and the FREQUENT band.

PMID:23439950 SUPPORT Human Clinical

"We report a case of inherited hypoprothrombinemia (factor II deficiency), a rare bleeding disorder as the cause of life-threatening menorrhagia."

A documented case in which menorrhagia was the presenting and life-threatening manifestation of inherited factor II deficiency.

Joint hemorrhage OCCASIONAL HP:0005261

Show evidence (2 references)

PMID:40747195 SUPPORT Human Clinical

"In contrast, hemarthroses and deep hematomas are primarily associated with factor II and X deficiencies."

Identifies haemarthrosis as characteristic of factor II deficiency relative to the other rare bleeding disorders.

PMID:28394285 SUPPORT Human Clinical

"more rarely haemarthroses and muscle bleeds"

Supports the OCCASIONAL frequency band by placing haemarthrosis below mucocutaneous bleeding within this disease.

Intracranial hemorrhage OCCASIONAL HP:0002170

Show evidence (1 reference)

PMID:21692854 SUPPORT Human Clinical

"a three-month-old boy with non-consanguineous parents was referred for convulsions because of intracerebral hemorrhage"

Documents intracranial haemorrhage as the presenting event in a genetically confirmed prothrombin-deficient infant.

Prolonged bleeding after surgery FREQUENT HP:0004846

Show evidence (2 references)

PMID:40747195 SUPPORT Human Clinical

"Homozygous and compound heterozygous forms are symptomatic, while heterozygotes are usually asymptomatic but may bleed during surgery, childbirth, or dental extractions"

Names surgery, childbirth and dental extraction as the challenges that provoke bleeding in this disorder.

PMID:38601422 SUPPORT Human Clinical

"Mild coagulation defects are often clinically silent and are evident after significant trauma or while screening for invasive procedures or surgery with a baseline coagulation screening profile."

Supports the claim that procedural bleeding is how mild disease typically comes to attention.

Prolonged prothrombin time VERY_FREQUENT HP:0008151

Show evidence (1 reference)

PMID:40747195 SUPPORT Human Clinical

"In patients with hypo- or dysprothrombinemia, routine coagulation tests such as PT and aPTT are often variably prolonged."

States that the PT is prolonged in both biochemical forms of the disorder.

Prolonged partial thromboplastin time VERY_FREQUENT HP:0003645

Show evidence (2 references)

PMID:40747195 SUPPORT Human Clinical

"In patients with hypo- or dysprothrombinemia, routine coagulation tests such as PT and aPTT are often variably prolonged."

States that the aPTT is prolonged in both biochemical forms of the disorder.

PMID:15892853 SUPPORT Human Clinical

"The diagnosis was based on prolonged prothrombin (PT) and activated partial thromboplastin times and low factor II coagulant activity (FII: C) measured using a PT based assay."

Documents the prolonged aPTT alongside the prolonged PT in confirmed cases.

Reduced prothrombin antigen HP:0040250

Show evidence (1 reference)

PMID:19598065 SUPPORT Human Clinical

"hypoprothrombinemia (type I deficiency), characterized by concomitantly low levels of activity and antigen"

States that the antigen is reduced concomitantly with activity in type I disease.

Musculoskeletal 1

Intramuscular hematoma OCCASIONAL HP:0012233

Show evidence (2 references)

PMID:28394285 SUPPORT Human Clinical

"more rarely haemarthroses and muscle bleeds"

Names muscle bleeding among the manifestations of severe factor II deficiency and places it in the less-common tier.

PMID:40747195 SUPPORT Human Clinical

"In contrast, hemarthroses and deep hematomas are primarily associated with factor II and X deficiencies."

Identifies deep haematoma as characteristic of factor II deficiency within the rare bleeding disorders.

🧬

Genetic Associations

F2 (Causative)

Gene: F2 hgnc:3535 relationship_type: CAUSATIVE variant_origin: GERMLINE

Autosomal recessive inheritance

Show evidence (2 references)

PMID:25242243 SUPPORT Human Clinical

Names F2 as the causal gene for both biochemical forms of the disease.

PMID:23852823 SUPPORT Human Clinical

"Thirty-nine different mutations have been identified and characterized in prothrombin deficiency."

Establishes an allelic series in the single causal gene, consistent with a monogenic recessive disorder.

Variants (2)

Prothrombin Vellore 1 (p.Ala362Thr)

A novel missense change affecting the B chain of alpha-thrombin, found in compound heterozygosity with a propeptide-cleavage-site variant in an Indian patient with 17.5% residual coagulant activity. Modelling places it adjacent to the catalytic-triad histidine.

Show evidence (1 reference)

PMID:15892853 SUPPORT Human Clinical

"Molecular modeling of this mutation was found to cause a conformational change around the region involving a catalytic triad residue His363 and a cysteine residue at codon 364."

Reports the structural consequence attributed to this named variant in the paper that described it.

p.Val322Glu

A homozygous missense variant causing severe dysprothrombinaemia. The mutant zymogen cannot complete the zymogen-to-proteinase transition; ecarin-driven activation accumulates the meizothrombin intermediate, which retains some fibrinogen-degrading activity and may explain the patient's mild clinical phenotype despite activity below 1%.

Show evidence (1 reference)

PMID:25242243 SUPPORT Human Clinical

"prothrombin activation by ecarin was defective, with a massive accumulation of the meizothrombin intermediate"

Documents the specific activation defect assigned to this variant.

💊

Medical Actions

Prothrombin Complex Concentrate Replacement

Action: Pharmacotherapy NCIT:C15986

Agent: prothrombin complex concentrate

Platform: Protein replacement

The mainstay of treatment. No purified factor II concentrate exists, so replacement uses 3- or 4-factor prothrombin complex concentrate, which also carries factors IX and X and variably factor VII. Given on demand for bleeding and as cover for surgery; long-term prophylaxis is used in the small number of patients with recurrent life-threatening bleeding. Because the product supplies several long-half-life vitamin K-dependent factors, repeated dosing carries a thrombotic risk that has to be monitored.

Mechanism Target:

RESTORES Deficient Thrombin Activity at the Site of Injury — Infused prothrombin restores substrate for the prothrombinase complex and so restores thrombin generation; it does not correct the underlying F2 lesion, and the effect decays with prothrombin's roughly three-day plasma half-life.

Show evidence (1 reference)

PMID:38601422 SUPPORT Human Clinical

"Treatment to manage the condition includes the administration of prothrombin complex concentrates or fresh frozen plasma, which may be required as per the short three-day half-life of prothrombin"

States both the replacement strategy and the half-life that governs re-dosing.

Show evidence (4 references)

PMID:28394285 SUPPORT Human Clinical

"No FII concentrate exists, in fact treatment involves the use of prothrombin complex concentrates (PCCs), that contain other vitamin K-dependent coagulation factors (FIX, FX and not systematically FVII)."

Establishes PCC as the replacement product and the reason a single-factor alternative is unavailable.

PMID:28394285 SUPPORT Human Clinical

"The recommended treatment is administration of PCC at doses of 20–30 IU/kg, to be repeated as needed to maintain haemostatic levels 20%–30%."

Names prothrombin complex concentrate as the recommended treatment and the dosing basis used in practice.

PMID:23152198 SUPPORT Human Clinical

"on demand therapy with administration of prothrombin complex concentrates (PCCs) or fresh frozen plasma is generally performed, and prophylactic therapy for FII deficiency has been reported in only three cases"

Supports on-demand PCC as the usual approach and the rarity of long-term prophylaxis.

+ 1 more reference

Fresh Frozen Plasma Transfusion

Action: Fresh Frozen Plasma Transfusion NCIT:C116475

Agent: fresh frozen plasma

Used where prothrombin complex concentrate is unavailable, and in practice the treatment actually given in resource-limited settings. Plasma raises factor II activity less predictably than concentrate and carries a volume load, so it is a second choice rather than an equivalent.

Mechanism Target:

RESTORES Deficient Thrombin Activity at the Site of Injury — Donor plasma supplies intact prothrombin, restoring substrate for thrombin generation.

Show evidence (2 references)

PMID:39022653 SUPPORT Human Clinical

"If PCC is not available, FFP or SD-FFP at a dose of 15 to 25 mL/kg is anticipated to raise FII activity to 30 to 40 IU/dL"

Positions plasma as the alternative when concentrate is unavailable and quantifies the expected rise in factor II.

PMID:23190616 SUPPORT Human Clinical

"The treatment consisted of transfusion with fresh frozen plasma in all cases."

Documents plasma as the treatment actually delivered to a whole case series.

Tranexamic Acid

Action: Pharmacotherapy NCIT:C15986

Agent: tranexamic acid CHEBI:48669

Platform: Small molecule

An antifibrinolytic used for mucosal, dental and menstrual bleeding and as cover for minor procedures. It does not correct the common-pathway defect; it protects the weak, poorly cross-linked clot that does form from premature lysis, so it is adjunctive and inadequate on its own for major bleeding.

Mechanism Target:

MODULATES Weak, Poorly Cross-Linked Hemostatic Clot — Inhibiting plasminogen activation prolongs the survival of a clot that is already deficient in cross-linked fibrin. The mechanism acts on clot persistence, not on thrombin generation, which is why it is adjunctive.

Show evidence (2 references)

PMID:39022653 SUPPORT Human Clinical

"For mild bleeding or surgery, tranexamic acid at a dose of 15 to 20 mg/kg or 1 g every 6 hours is enough for hemostasis"

States the indication and dosing for tranexamic acid in the factor II deficiency section of the review.

PMID:38601422 SUPPORT Human Clinical

"The patient then underwent surgery under the cover of tranexamic acid and strict hemostatic measures."

Documents tranexamic acid used as procedural cover in a patient with mild factor II deficiency.

🔬

Biochemical Markers

Factor II coagulant activity (DECREASED)

Pathograph Readouts

Readout Of Impaired Prothrombinase-Mediated Thrombin Generation Negative Diagnostic

The functional assay reports how much thrombin-generating capacity the circulating prothrombin pool retains. It is reduced in both subtypes and so cannot on its own distinguish them.

Reference Ranges

– % (Patients with congenital prothrombin deficiency)

Severe deficiency (–5.0 %) Moderate deficiency (5.0–10.0 %) Mild deficiency (10.0– %)

Severe deficiency: Severe symptoms presenting earlier in life, including bleeding with little or no trauma.

Moderate deficiency: Moderate symptoms.

Mild deficiency: Mild symptoms; often clinically silent until trauma, surgery, or a pre-procedural coagulation screen.

Bands are clinical severity tiers expressed as percent of normal factor II coagulant activity. They are drawn from a narrative review and are not prospectively validated diagnostic thresholds.

Show evidence (1 reference)

PMID:38601422 SUPPORT Human Clinical

Source of the three severity bands recorded here.

Show evidence (1 reference)

PMID:15892853 SUPPORT Human Clinical

"FII: C levels ranged between 4.7% and 17.5%."

Reports the measured residual coagulant activity across a consecutive series of genetically confirmed patients.

Prothrombin antigen concentration in type I disease (DECREASED)

Pathograph Readouts

Readout Of Reduced Hepatic Prothrombin Output Negative Diagnostic

A reduced antigen concentration is the direct measure of how much prothrombin protein reaches the circulation.

Show evidence (1 reference)

PMID:40747195 SUPPORT Human Clinical

"Type I (hypoprothrombinemia), a quantitative deficiency with severely reduced prothrombin activity and antigen (<5% of normal), causing severe bleeding symptoms even without trauma."

States that both antigen and activity are reduced in type I disease.

Prothrombin antigen concentration in type II disease (NORMAL)

Pathograph Readouts

Readout Of Circulating Dysfunctional Prothrombin Present Absent Diagnostic

A preserved antigen concentration establishes that the circulating protein is present but non-functional.

Show evidence (1 reference)

PMID:40747195 SUPPORT Human Clinical

"Type II (dysprothrombinemia) is a qualitative deficiency where prothrombin activity is decreased (around 10% of normal) but antigen levels remain normal or slightly reduced."

States that the antigen concentration is preserved in type II disease.

Activity-to-antigen discrepancy (PRESENT)

Pathograph Readouts

Readout Of Circulating Dysfunctional Prothrombin Present Absent Diagnostic

The discrepancy is the observable that establishes a qualitative rather than a quantitative defect.

Show evidence (2 references)

PMID:25242243 SUPPORT Human Clinical

"The homozygous patient had a markedly prolonged prothrombin time, strongly reduced FII activity (0.82%) but normal antigen levels."

A worked measurement of the discrepancy: activity below 1% against a normal antigen concentration.

PMID:28196451 SUPPORT Human Clinical

"Phenotypic analysis revealed that the proband had an obviously prolonged PT, APTT, reduced prothrombin activity but normal antigen levels."

A second independent case showing the same activity-antigen dissociation that defines type II.

📊

Prevalence

Worldwide

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

Approximately 1 in 2,000,000, i.e. 0.05 cases per 100,000. Reported prevalence is higher where consanguineous marriage is common, and ascertainment of mild cases is incomplete.

Show evidence (2 references)

PMID:23852823 SUPPORT Human Clinical

"Prothrombin (factor II [FII]) deficiency is a rare inherited coagulation disorder, having a prevalence of approximately 1 in 2,000,000."

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

PMID:38601422 SUPPORT Human Clinical

"Congenital prothrombin deficiency is a rare hemorrhagic disorder, frequent in areas with high degrees of consanguinity as it is autosomal recessive in nature."

Supports the note that the observed prevalence is concentrated in populations with a high rate of consanguinity.

🔀

Differential Diagnoses

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

Lupus anticoagulant-hypoprothrombinaemia syndrome

Overlapping Features An acquired, antibody-mediated hypoprothrombinaemia that presents with the same screening pattern as the congenital disorder - prolonged PT and aPTT with a reduced factor II level - but has a completely different mechanism. Non-neutralizing antiprothrombin antibodies accelerate clearance of the prothrombin-antibody complex from the circulation rather than any F2 lesion, and the syndrome is triggered by autoimmune disease or infection. It is frequently the reason a low factor II level in a previously well patient is not congenital, and it must not be curated as a subtype of this disease.

Distinguishing Features

Lupus anticoagulant positive in essentially all cases, which is definitional for the acquired syndrome
High-titre anticardiolipin and anti-beta-2-glycoprotein I antibodies
Acquired onset, frequently post-infectious or autoimmune, in a previously unaffected person
Other coagulation factors usually normal
Responds to immunosuppression, which has no role in the congenital disorder

Show evidence (2 references)

PMID:40719111 SUPPORT Human Clinical

"the laboratory profile is characterized by a prolongation of prothrombin time (PT) and activated partial thromboplastin time (aPTT) with a mild to severe reduction in factor II levels"

Documents the laboratory profile that this acquired syndrome shares with congenital prothrombin deficiency, which is why it is the key differential.

PMID:40719111 SUPPORT Human Clinical

"Lupus anticoagulant (LA) is positive in 100% of cases, as this represents a defining feature."

Gives the discriminating test: lupus anticoagulant positivity is definitional for the acquired syndrome and absent in the congenital disorder.

Hereditary combined vitamin K-dependent coagulation factor deficiency

Overlapping Features Biallelic GGCX or VKORC1 defects impair gamma-carboxylation of every vitamin K-dependent protein, so factor II falls together with factors VII, IX and X and with proteins C and S. The overlap with congenital prothrombin deficiency is mechanistic as well as clinical: both act on the Gla-domain membrane-binding step, but the combined deficiency does so for the whole vitamin K-dependent family rather than for prothrombin alone.

Distinguishing Features

Proportionate reduction of factors II, VII, IX and X plus proteins C and S, rather than an isolated factor II defect
Frequently at least partially responsive to vitamin K

Show evidence (1 reference)

PMID:19141161 SUPPORT Human Clinical

"found to have immunologically recognizable coagulation factors II, VII, IX, and X that lacked γ-carboxyglutamic acid residues"

Documents the multi-factor pattern that separates the combined deficiency from an isolated factor II defect.

🐁

Animal Models

Prothrombin-null mouse (F2 knockout)

Targeted inactivation of the murine prothrombin gene. Roughly half the null embryos die between embryonic days 9.5 and 11.5 with bleeding into the yolk sac cavity; those that reach term die of haemorrhage within days of birth. The model is the principal evidence that complete prothrombin loss is incompatible with survival, and so bounds what the human disease can be.

Species

Mouse

Genotype

F2 homozygous null (FII-/-)

Publication

PMID:9636195

Pathograph links

Deficient Thrombin Activity at the Site of Injury partially recapitulates fidelity: moderate observes: organism Complete genetic ablation of prothrombin, producing total loss of thrombin generation and fatal haemorrhage.

Limitations: The model is a complete null. Every described human patient retains measurable residual prothrombin activity, and no living human with undetectable prothrombin has been reported, so the mouse models the lethal limit of the disease rather than any clinically observed genotype. Its embryonic and neonatal lethality also prevents study of the chronic, episodic bleeding that defines the human disorder.

Readouts

Survival of homozygous null neonates

Direction: DECREASED

Interpretation: Null neonates that reach term die of haemorrhage within days, showing that prothrombin is required postnatally and not only developmentally.

Show evidence (1 reference)

PMID:9636195 SUPPORT Model Organism

"at least one-quarter of the FII-/- mice survived to term, but ultimately they, too, developed fatal hemorrhagic events and died within a few days of birth"

Reports the postnatal survival and cause of death measured in this model.

Show evidence (1 reference)

PMID:9636195 SUPPORT Model Organism

"Inactivation of the FII gene leads to partial embryonic lethality with more than one-half of the FII-/- embryos dying between embryonic days 9.5 and 11.5."

Establishes the embryonic lethality that makes complete prothrombin loss the boundary condition on the human disease model.

Show evidence (1 reference)

PMID:9636196 SUPPORT Model Organism

"The rare Cf2(-/-) neonates died of hemorrhage on the first postnatal day."

An independently generated prothrombin-null mouse line reproduces the lethal haemorrhagic phenotype, which is why this model is treated as informative rather than line-specific.

Zebrafish prothrombin kringle-1 deletion (f2)

A targeted deletion in the kringle 1 domain of zebrafish prothrombin. Unlike the mouse null, homozygotes develop normally into the mid-juvenile stage, so the model exposes severe prothrombin deficiency beyond the window in which mammals die, at the cost of a very different physiological setting.

Species

Zebrafish

Genotype

f2 kringle 1 domain targeted deletion, homozygous

Publication

PMID:32132579

Pathograph links

Weak, Poorly Cross-Linked Hemostatic Clot partially recapitulates fidelity: moderate observes: organism Homozygous mutants cannot form occlusive venous or arterial thrombi after endothelial injury and die of internal haemorrhage by two months.

Limitations: A fish model of a mammalian bleeding disorder: blood pressure, aquatic development and the absence of birth trauma all differ, and the lesion is a single engineered kringle-1 deletion rather than an allele observed in patients. Zebrafish tolerate haemostatic defects that are lethal in mammals, so the survival phenotype does not transfer.

Readouts

Occlusive thrombus formation after endothelial injury

Direction: ABOLISHED

Interpretation: Loss of occlusive thrombus formation in vivo is the direct functional correlate of the failed haemostatic clot node.

Show evidence (1 reference)

PMID:32132579 SUPPORT Model Organism

"Mutants are unable to form occlusive venous and arterial thrombi in response to endothelial injury, a defect that was phenocopied using direct oral anticoagulants."

Reports the injury-response measurement behind this readout.

Show evidence (1 reference)

PMID:32132579 SUPPORT Model Organism

"Homozygous mutant embryos develop normally into the mid-juvenile stage but demonstrate complete mortality by 2 months of age primarily due to internal hemorrhage."

Reports the haemorrhagic phenotype that makes this model informative for the failed-clot node.

{ }

Source YAML

click to show

name: Congenital Prothrombin Deficiency
creation_date: "2026-09-05T00:00:00Z"
category: Genetic
parents:
- Bleeding Disorder
- Coagulation Disorder
- Rare Bleeding Disorder
disease_term:
  preferred_term: congenital prothrombin deficiency
  term:
    id: MONDO:0013361
    label: congenital prothrombin deficiency
synonyms:
- factor II deficiency
- congenital factor II deficiency
- hereditary prothrombin deficiency
- hypoprothrombinemia
- dysprothrombinemia
description: >-
  Congenital prothrombin (factor II) deficiency is the rarest of the inherited
  coagulation factor deficiencies, caused by biallelic pathogenic variants in
  F2. Prothrombin sits at the convergence point of the coagulation cascade: the
  prothrombinase complex - factor Xa with factor Va as cofactor, assembled on an
  anionic phospholipid surface in the presence of calcium - cleaves the zymogen
  to thrombin, and thrombin is the effector that converts fibrinogen to fibrin,
  activates platelets through protease-activated receptors, feeds back on
  factors V, VIII and XI, activates factor XIII to cross-link the fibrin mesh,
  and, complexed with thrombomodulin, switches on the protein C anticoagulant
  arm. Because a single defect removes all of those outputs at once, the
  bleeding is out of proportion to what a single-pathway lesion would predict.
  Two biochemical forms are distinguished by the relationship between antigen
  and activity: type I (hypoprothrombinaemia) reduces both roughly in parallel,
  while type II (dysprothrombinaemia) leaves a normal or near-normal amount of a
  dysfunctional protein, so activity falls disproportionately. That
  antigen-versus-activity discrepancy is the diagnostic signature. Prothrombin
  is vitamin K-dependent, and gamma-carboxylation of its Gla domain is what
  allows it to dock on the procoagulant membrane surface, which is why the
  acquired vitamin K-related deficiencies phenocopy the congenital disorder.
  Complete absence of prothrombin has never been observed in a living human and
  appears to be incompatible with life; every described patient retains some
  residual activity.
prevalence:
- population: Worldwide
  measure_type: POINT_PREVALENCE
  prevalence_class: BELOW_1_IN_1000000
  rate_per_100000: 0.05
  rate_denominator: POPULATION
  notes: >-
    Approximately 1 in 2,000,000, i.e. 0.05 cases per 100,000. Reported
    prevalence is higher where consanguineous marriage is common, and
    ascertainment of mild cases is incomplete.
  evidence:
  - reference: PMID:23852823
    reference_title: "Congenital prothrombin deficiency: an update."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Prothrombin (factor II [FII]) deficiency is a rare inherited coagulation disorder, having a prevalence of approximately 1 in 2,000,000."
    explanation: >-
      States the worldwide prevalence estimate that this record normalizes to
      0.05 per 100,000.
  - reference: PMID:38601422
    reference_title: "Isolated Prothrombin Deficiency: A Case Report of a Rare Coagulation Disorder and Review of Literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Congenital prothrombin deficiency is a rare hemorrhagic disorder, frequent in areas with high degrees of consanguinity as it is autosomal recessive in nature."
    explanation: >-
      Supports the note that the observed prevalence is concentrated in
      populations with a high rate of consanguinity.
has_subtypes:
- name: Type I
  display_name: Type I (Hypoprothrombinaemia)
  description: >-
    True quantitative deficiency: prothrombin coagulant activity and prothrombin
    antigen are reduced concordantly, because less normal protein is made,
    secreted, or retained in the circulation. Severe cases (activity below about
    5% of normal) can bleed without trauma.
  evidence:
  - reference: PMID:19598065
    reference_title: Congenital prothrombin deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "hypoprothrombinemia (type I deficiency), characterized by concomitantly low levels of activity and antigen"
    explanation: >-
      Defines type I as the form in which activity and antigen fall together,
      which is the discriminator this subtype is keyed on.
  - reference: PMID:40747195
    reference_title: Molecular Aspects of Rare Coagulation Factor Deficiencies.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Type I (hypoprothrombinemia), a quantitative deficiency with severely reduced prothrombin activity and antigen (<5% of normal), causing severe bleeding symptoms even without trauma."
    explanation: >-
      Gives the quantitative character of type I and the activity range at which
      spontaneous bleeding is described.
- name: Type II
  display_name: Type II (Dysprothrombinaemia)
  description: >-
    Qualitative defect: a normal or near-normal amount of a dysfunctional
    prothrombin is synthesized and secreted, so the antigen concentration is
    preserved while coagulant activity is disproportionately low. The resulting
    activity-to-antigen discrepancy is what distinguishes this subtype at the
    bench.
  evidence:
  - reference: PMID:23852823
    reference_title: "Congenital prothrombin deficiency: an update."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "dysprothrombinemia (type II deficiency), characterized by the normal or near-normal synthesis of a dysfunctional protein"
    explanation: >-
      Defines type II as normal or near-normal synthesis of a dysfunctional
      protein, the defining feature of this subtype.
  - reference: PMID:40747195
    reference_title: Molecular Aspects of Rare Coagulation Factor Deficiencies.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Type II (dysprothrombinemia) is a qualitative deficiency where prothrombin activity is decreased (around 10% of normal) but antigen levels remain normal or slightly reduced."
    explanation: >-
      States the activity-versus-antigen dissociation that defines the
      qualitative subtype.
inheritance:
- name: Autosomal recessive inheritance
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  description: >-
    Homozygotes and compound heterozygotes for F2 pathogenic variants are
    symptomatic; single heterozygotes usually remain asymptomatic and are
    detected only incidentally or after a haemostatic challenge.
  evidence:
  - reference: PMID:23190616
    reference_title: "Congenital factor II deficiency: moroccan cases."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Inherited factor II deficiency is an extremely rare autosomal recessive disorder affecting both genders: clinical bleeding can vary widely in homozygous individuals, and heterozygotes often remain clinically asymptomatic."
    explanation: >-
      A four-patient series states the recessive inheritance pattern and the
      asymptomatic heterozygote state directly.
  - reference: PMID:40747195
    reference_title: Molecular Aspects of Rare Coagulation Factor Deficiencies.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Homozygous and compound heterozygous forms are symptomatic, while heterozygotes are usually asymptomatic but may bleed during surgery, childbirth, or dental extractions"
    explanation: >-
      Supports the biallelic requirement and the challenge-dependent expression
      seen in carriers.
pathophysiology:
- name: Biallelic F2 Pathogenic Variants
  biological_scale: MOLECULAR
  description: >-
    Homozygous or compound heterozygous pathogenic variants in F2, on chromosome
    11, are the initiating lesion. Most are missense; nonsense, frameshift,
    splice-site and small in-frame deletions are also described. Variants
    distribute between the catalytic domain, the anion-binding exosite, the
    Na+-binding loop, the kringle domains, and the propeptide/Gla processing
    region, and the domain hit is what determines whether the result is a
    quantitative or a qualitative defect.
  molecular_functions:
  - preferred_term: serine-type endopeptidase activity of thrombin
    modifier: DECREASED
    term:
      id: GO:0004252
      label: serine-type endopeptidase activity
  cell_types:
  - preferred_term: hepatocyte
    term:
      id: CL:0000182
      label: hepatocyte
  evidence:
  - reference: PMID:25242243
    reference_title: A novel congenital dysprothrombinemia leading to defective prothrombin maturation.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Prothrombin deficiency is a very rare disorder caused by mutations in the F2 gene that generate hypoprothrombinemia or dysprothrombinemia and is characterized by bleeding manifestations that can vary from clinically irrelevant to life-threatening."
    explanation: >-
      Attributes both biochemical forms of the disease to F2 mutation, which is
      the claim this initiating node makes.
  - reference: PMID:15892853
    reference_title: "Molecular genetics of hereditary prothrombin deficiency in Indian patients: identification of a novel Ala362 --> Thr (Prothrombin Vellore 1) mutation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Five different causative mutations including four (80%) missense and an in-frame deletion (20%) were identified."
    explanation: >-
      Documents the mutation classes found in a consecutive patient series,
      supporting the missense-dominant spectrum described here.
  downstream:
  - target: Reduced Hepatic Prothrombin Output
    causal_link_type: DIRECT
    description: >-
      Null, hypomorphic and secretion-impairing alleles reduce the amount of
      prothrombin reaching the circulation, producing the type I phenotype.
  - target: Circulating Dysfunctional Prothrombin
    causal_link_type: DIRECT
    description: >-
      Missense alleles in the catalytic, exosite, Na+-loop and kringle regions
      allow a normal quantity of protein to be secreted but leave it unable to
      be activated or to act normally once activated, producing the type II
      phenotype.
  - target: Defective Vitamin K-Dependent Gla-Domain Membrane Binding
    causal_link_type: DIRECT
    description: >-
      Variants at the propeptide cleavage site prevent the propeptide from being
      removed from the Gla domain, so the mature protein cannot present a normal
      calcium-dependent membrane-binding surface.
    evidence:
    - reference: PMID:21692854
      reference_title: A severe neonatal presentation of factor II deficiency.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "the resulting mutations were inferred to respectively affect the cleavage of the propeptide from the Gla domain, and the stability of the kringle-2 domain, both resulting in a severe hypoprothrombinemia"
      explanation: >-
        Traces a specific propeptide variant to failure of propeptide cleavage
        from the Gla domain, which is the edge asserted here.
- name: Reduced Hepatic Prothrombin Output
  biological_scale: CELLULAR
  description: >-
    In type I disease the hepatocyte makes, secretes, or maintains less
    prothrombin, so plasma antigen and coagulant activity fall together. The
    liver is otherwise structurally normal and no other coagulation factor is
    affected.
  cell_types:
  - preferred_term: hepatocyte
    term:
      id: CL:0000182
      label: hepatocyte
  biological_processes:
  - preferred_term: blood coagulation
    modifier: DECREASED
    term:
      id: GO:0007596
      label: blood coagulation
  evidence:
  - reference: PMID:19598065
    reference_title: Congenital prothrombin deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "hypoprothrombinemia (type I deficiency), characterized by concomitantly low levels of activity and antigen"
    explanation: >-
      The concordant fall in antigen and activity is what identifies this node
      as a reduction in the amount of circulating protein.
  downstream:
  - target: Impaired Prothrombinase-Mediated Thrombin Generation
    causal_link_type: DIRECT
    description: >-
      Less substrate is available to the prothrombinase complex, so less
      thrombin can be generated per unit time.
- name: Circulating Dysfunctional Prothrombin
  biological_scale: MOLECULAR
  description: >-
    In type II disease a normal or near-normal quantity of prothrombin
    circulates but cannot do its job. Documented mechanisms include failure of
    the zymogen-to-proteinase transition, perturbation of the Na+-binding site
    that governs activation, and loss of substrate recognition once thrombin is
    formed. The consequence is a large activity-to-antigen gap.
  molecular_functions:
  - preferred_term: serine-type endopeptidase activity of thrombin
    modifier: LOSS_OF_FUNCTION
    term:
      id: GO:0004252
      label: serine-type endopeptidase activity
  evidence:
  - reference: PMID:25242243
    reference_title: A novel congenital dysprothrombinemia leading to defective prothrombin maturation.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The homozygous patient had a markedly prolonged prothrombin time, strongly reduced FII activity (0.82%) but normal antigen levels."
    explanation: >-
      A worked case of a dysfunctional protein present at normal concentration,
      which is exactly what this node asserts.
  - reference: PMID:28196451
    reference_title: Phenotypic and genetic analysis of dysprothrombinemia due to a novel homozygous mutation.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Bioinformatics and model analyses illuminated that the mutation will be probably damaging and perturbing the structure of Na+-binding site, which will affect the activation of prothrombin."
    explanation: >-
      Gives a structural mechanism by which a secreted, antigenically normal
      prothrombin fails to be activated.
  downstream:
  - target: Impaired Prothrombinase-Mediated Thrombin Generation
    causal_link_type: DIRECT
    description: >-
      The mutant zymogen is a poor substrate for prothrombinase or yields a
      catalytically impaired thrombin, so functional thrombin generation falls
      despite a normal substrate concentration.
    evidence:
    - reference: PMID:25242243
      reference_title: A novel congenital dysprothrombinemia leading to defective prothrombin maturation.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "In the thrombin generation assay the lag time and the peak height were unmeasurable, suggesting that the Val322Glu mutation results in the inability of the mutant prothrombin to be fully activated to thrombin."
      explanation: >-
        Directly links the dysfunctional protein to failed thrombin generation
        in the same patient's plasma.
- name: Defective Vitamin K-Dependent Gla-Domain Membrane Binding
  biological_scale: MOLECULAR
  description: >-
    Prothrombin is a vitamin K-dependent protein. Gamma-carboxylation of the
    glutamate residues of its Gla domain creates the calcium-dependent
    conformation that docks the zymogen onto the anionic phospholipid surface
    where prothrombinase assembles. Variants that block propeptide cleavage - the
    step that presents the Gla domain correctly - remove that anchoring. The same
    step is what acquired vitamin K deficiency, vitamin K antagonists, and the
    hereditary combined vitamin K-dependent factor deficiencies interrupt, which
    is why those conditions phenocopy this disease.
  molecular_functions:
  - preferred_term: calcium-dependent phospholipid membrane binding by the Gla domain
    modifier: DECREASED
    term:
      id: GO:0005543
      label: phospholipid binding
  biological_processes:
  - preferred_term: peptidyl-glutamic acid carboxylation
    term:
      id: GO:0017187
      label: peptidyl-glutamic acid carboxylation
  evidence:
  - reference: PMID:28394285
    reference_title: Diagnosis and Treatment of von Willebrand Disease and Rare Bleeding Disorders.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Prothrombin is a plasma glycoprotein and zymogen of a serine protease requiring vitamin K for normal biosynthesis."
    explanation: >-
      Establishes that prothrombin's normal biosynthesis is vitamin K-dependent,
      the premise of this node.
  - reference: PMID:19141161
    reference_title: Familial deficiency of vitamin K-dependent clotting factors.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Once carboxylated, the proteins have a calcium-dependent conformation that allows binding to phospholipids and/or endothelial cells."
    explanation: >-
      States why gamma-carboxylation is required for membrane binding, which is
      the functional consequence this node models.
  downstream:
  - target: Impaired Prothrombinase-Mediated Thrombin Generation
    causal_link_type: DIRECT
    description: >-
      A zymogen that cannot be presented on the phospholipid surface is not
      efficiently converted by the membrane-assembled prothrombinase complex.
- name: Impaired Prothrombinase-Mediated Thrombin Generation
  biological_scale: MOLECULAR
  description: >-
    The prothrombinase complex - factor Xa with factor Va as its cofactor,
    assembled on an anionic phospholipid membrane in the presence of calcium
    ions - is what converts prothrombin to thrombin at a physiologically useful
    rate. Whether the lesion is too little substrate (type I), a substrate that
    cannot be activated (type II), or a substrate that cannot reach the membrane,
    the rate-limiting step is the same one, and the measurable consequence is a
    reduced and slowed thrombin generation curve.
  biological_processes:
  - preferred_term: zymogen activation of prothrombin by prothrombinase
    modifier: DECREASED
    term:
      id: GO:0031638
      label: zymogen activation
  cell_types:
  - preferred_term: platelet
    term:
      id: CL:0000233
      label: platelet
  evidence:
  - reference: PMID:31102425
    reference_title: Blood coagulation factor Va's key interactive residues and regions for prothrombinase assembly and prothrombin binding.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "In the presence of an anionic phospholipid membrane and calcium ions, factors Va and Xa assemble into the prothrombinase complex."
    explanation: >-
      Establishes the composition and membrane/calcium requirement of the
      complex named in this node.
  - reference: PMID:31102425
    reference_title: Blood coagulation factor Va's key interactive residues and regions for prothrombinase assembly and prothrombin binding.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Following formation of the ternary complex with the macromolecular zymogen substrate prothrombin, the latter is rapidly converted into thrombin, the key regulatory enzyme of coagulation."
    explanation: >-
      States the reaction this node describes as impaired, and that prothrombin
      is the substrate of the complex.
  - reference: PMID:41443372
    reference_title: "Thrombin generation profiling in rare coagulation factor deficiencies: associations with bleeding severity and potential for screening."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "Overall, thrombin generation in patients was significantly reduced compared with controls, with decreased thrombin potentials (median 58%) and prolonged lag times (150%), resulting in reduced TP/LT ratios (45%)."
    explanation: >-
      Measures the reduced and delayed thrombin generation predicted by this
      node in a cross-sectional cohort of rare factor deficiencies that included
      factor II deficiency.
  downstream:
  - target: Deficient Thrombin Activity at the Site of Injury
    causal_link_type: DIRECT
    description: >-
      Reduced conversion of the zymogen leaves too little active thrombin where
      and when the haemostatic response needs it.
- name: Deficient Thrombin Activity at the Site of Injury
  biological_scale: ORGANISM
  description: >-
    Thrombin is the hub of the haemostatic response, and this node is where the
    single upstream lesion fans out. Thrombin converts fibrinogen to fibrin,
    activates platelets through protease-activated receptors, feeds back to
    activate factors V, VIII and XI so that its own generation becomes a burst,
    activates factor XIII to cross-link the fibrin mesh, and - complexed with
    thrombomodulin - switches on protein C. Losing one enzyme therefore removes
    five distinct outputs at once.
  biological_processes:
  - preferred_term: blood coagulation
    modifier: DECREASED
    term:
      id: GO:0007596
      label: blood coagulation
  evidence:
  - reference: PMID:9636195
    reference_title: Prothrombin deficiency results in embryonic and neonatal lethality in mice.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "The conversion of prothrombin (FII) to the serine protease, thrombin (FIIa), is a key step in the coagulation cascade because FIIa triggers platelet activation, converts fibrinogen to fibrin, and activates regulatory pathways that both promote and ultimately suppress coagulation."
    explanation: >-
      Names the multiple downstream outputs of thrombin that this hub node fans
      out into.
  - reference: PMID:28394285
    reference_title: Diagnosis and Treatment of von Willebrand Disease and Rare Bleeding Disorders.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "It triggers platelet aggregation and promote coagulation by activating regulatory pathways and generating fibrin monomers by cleavage of a specific peptide bond in fibrinogen α- and β- subunits at N-termini"
    explanation: >-
      A review of this disease states the same multi-output role for thrombin,
      anchoring the hub to the disease rather than to general biochemistry.
  downstream:
  - target: Impaired Fibrinogen-to-Fibrin Conversion
    causal_link_type: DIRECT
  - target: Impaired Thrombin-Mediated Platelet Activation
    causal_link_type: DIRECT
  - target: Loss of Thrombin Feedback Amplification of Factors V, VIII and XI
    causal_link_type: DIRECT
  - target: Impaired Factor XIII Activation and Fibrin Cross-Linking
    causal_link_type: DIRECT
  - target: Reduced Thrombomodulin-Dependent Protein C Activation
    causal_link_type: DIRECT
- name: Impaired Fibrinogen-to-Fibrin Conversion
  biological_scale: MOLECULAR
  description: >-
    Thrombin's canonical substrate reaction, cleavage of fibrinopeptides from
    fibrinogen to release fibrin monomers, proceeds too slowly and too little
    fibrin is deposited.
  biological_processes:
  - preferred_term: "blood coagulation, fibrin clot formation"
    modifier: DECREASED
    term:
      id: GO:0072378
      label: "blood coagulation, fibrin clot formation"
  evidence:
  - reference: PMID:34154000
    reference_title: "Thrombin: A Pivotal Player in Hemostasis and Beyond."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "plays a key role in hemostasis by converting fibrinogen to fibrin and activating coagulation factor XIII whereby the fibrin clot is stabilized"
    explanation: >-
      Establishes fibrinogen cleavage as a thrombin-dependent step, so a
      thrombin deficit impairs it.
  - reference: PMID:32132579
    reference_title: Disruption of the kringle 1 domain of prothrombin leads to late onset mortality in zebrafish.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Human prothrombin engineered with the equivalent mutation exhibits a severe reduction in secretion, thrombin generation, and fibrinogen cleavage."
    explanation: >-
      Shows experimentally that a prothrombin variant reduces fibrinogen
      cleavage, connecting the prothrombin lesion to this specific output.
  downstream:
  - target: Weak, Poorly Cross-Linked Hemostatic Clot
    causal_link_type: DIRECT
- name: Impaired Thrombin-Mediated Platelet Activation
  biological_scale: CELLULAR
  description: >-
    Thrombin is among the most potent physiological platelet agonists, acting
    through the protease-activated receptors PAR1 and PAR4 on the human platelet
    surface. With less thrombin, platelet recruitment and the procoagulant
    platelet surface that prothrombinase itself needs are both blunted, so the
    defect is not confined to the plasma phase of coagulation.
  cell_types:
  - preferred_term: platelet
    term:
      id: CL:0000233
      label: platelet
  biological_processes:
  - preferred_term: thrombin-activated receptor signaling pathway
    modifier: DECREASED
    term:
      id: GO:0070493
      label: thrombin-activated receptor signaling pathway
  - preferred_term: platelet activation
    modifier: DECREASED
    term:
      id: GO:0030168
      label: platelet activation
  evidence:
  - reference: PMID:34154000
    reference_title: "Thrombin: A Pivotal Player in Hemostasis and Beyond."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Furthermore, thrombin activates platelets through protease-activated receptors on the platelet surface."
    explanation: >-
      Establishes the protease-activated-receptor route by which thrombin
      recruits platelets, the step lost here.
  downstream:
  - target: Weak, Poorly Cross-Linked Hemostatic Clot
    causal_link_type: DIRECT
    description: >-
      Fewer recruited and activated platelets means a smaller platelet-fibrin
      mass and less catalytic membrane surface at the wound.
- name: Loss of Thrombin Feedback Amplification of Factors V, VIII and XI
  biological_scale: MOLECULAR
  description: >-
    Thrombin activates factors V, VIII and XI, converting the initial trace of
    enzyme into a burst. When thrombin is scarce from the outset the loop never
    engages, so the deficit is amplified rather than merely proportional - which
    is part of why bleeding is out of proportion to a single-factor lesion.
  biological_processes:
  - preferred_term: regulation of blood coagulation
    modifier: DECREASED
    term:
      id: GO:0030193
      label: regulation of blood coagulation
  evidence:
  - reference: PMID:10528826
    reference_title: Multifunctional roles of thrombin.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "It regulates its own generation by activating coagulation factors V, VIII and even XI resulting in a burst of thrombin formation."
    explanation: >-
      Names the exact feedback substrates and the burst behaviour that is lost
      when thrombin generation is deficient.
  downstream:
  - target: Weak, Poorly Cross-Linked Hemostatic Clot
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - Failure of the thrombin amplification loop leaves thrombin generation slow and low in amplitude
    - Fibrin deposition and platelet recruitment at the wound remain sub-threshold
- name: Impaired Factor XIII Activation and Fibrin Cross-Linking
  biological_scale: MOLECULAR
  description: >-
    Thrombin activates factor XIII, the transglutaminase that covalently
    cross-links fibrin monomers and binds alpha-2-antiplasmin into the mesh. Less
    thrombin means less factor XIIIa, so the fibrin that does form is
    mechanically weak and abnormally susceptible to fibrinolysis.
  biological_processes:
  - preferred_term: "blood coagulation, fibrin clot formation"
    modifier: DECREASED
    term:
      id: GO:0072378
      label: "blood coagulation, fibrin clot formation"
  evidence:
  - reference: PMID:10528826
    reference_title: Multifunctional roles of thrombin.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Thrombin not only cleaves fibrinogen to fibrin, but also through the activation of factor XIII effects the cross-linking of fibrin monomers to produce a firm fibrin clot."
    explanation: >-
      States that clot firmness depends on thrombin-driven factor XIII
      activation, the step this node models as impaired.
  downstream:
  - target: Weak, Poorly Cross-Linked Hemostatic Clot
    causal_link_type: DIRECT
- name: Reduced Thrombomodulin-Dependent Protein C Activation
  biological_scale: MOLECULAR
  description: >-
    Thrombin bound to endothelial thrombomodulin activates protein C, the
    principal physiological brake on further thrombin generation. This
    anticoagulant output is lost alongside the procoagulant ones, so the net
    haemostatic consequence of prothrombin deficiency is not a simple
    subtraction, and the offset is a plausible contributor to the weak
    correlation between residual factor II activity and bleeding severity. It is
    not the explanation for the rare dysprothrombin variants that present with
    thrombosis: those escape inhibition by antithrombin, which is a separate
    mechanism acting on the mutant thrombin itself rather than on this
    thrombomodulin-protein C arm.
  cell_types:
  - preferred_term: endothelial cell
    term:
      id: CL:0000115
      label: endothelial cell
  biological_processes:
  - preferred_term: regulation of blood coagulation
    modifier: DECREASED
    term:
      id: GO:0030193
      label: regulation of blood coagulation
  evidence:
  - reference: PMID:34154000
    reference_title: "Thrombin: A Pivotal Player in Hemostasis and Beyond."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Conversely, thrombin also exerts anticoagulant effects, enhancing the protein C activity while complexed with thrombomodulin."
    explanation: >-
      Establishes the thrombomodulin-protein C arm as a thrombin output, so it
      is lost together with the procoagulant outputs.
  notes: >-
    Deliberately left with no downstream edge. The loss of this arm does not
    contribute to the bleeding phenotype - it opposes it - and no source
    quantifies its net effect in congenital prothrombin deficiency. See the
    `anticoagulant_arm_offset` discussion.
- name: Weak, Poorly Cross-Linked Hemostatic Clot
  biological_scale: TISSUE
  description: >-
    The clot that forms at a site of injury is small, slow to form, deficient in
    cross-linked fibrin, and under-populated with recruited platelets. It is the
    convergence point of every downstream thrombin branch and the immediate
    substrate of the clinical bleeding.
  biological_processes:
  - preferred_term: "blood coagulation, fibrin clot formation"
    modifier: DECREASED
    term:
      id: GO:0072378
      label: "blood coagulation, fibrin clot formation"
  evidence:
  - reference: PMID:32132579
    reference_title: Disruption of the kringle 1 domain of prothrombin leads to late onset mortality in zebrafish.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Mutants are unable to form occlusive venous and arterial thrombi in response to endothelial injury, a defect that was phenocopied using direct oral anticoagulants."
    explanation: >-
      In vivo demonstration that prothrombin loss prevents formation of an
      occlusive clot after endothelial injury.
  downstream:
  - target: Systemic Bleeding Diathesis
    causal_link_type: DIRECT
- name: Systemic Bleeding Diathesis
  biological_scale: ORGANISM
  description: >-
    A lifelong, episodic bleeding tendency whose severity tracks residual factor
    II activity: below about 5% patients bleed with little or no trauma, 5-10%
    is moderate, and above 10% is usually mild and may be silent until a
    haemostatic challenge. Because the mechanism is systemic rather than
    tissue-specific, any vascular bed can be the site.
  evidence:
  - reference: PMID:38601422
    reference_title: "Isolated Prothrombin Deficiency: A Case Report of a Rare Coagulation Disorder and Review of Literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Patients with prothrombin activity of less than 5% have severe symptoms presenting earlier in life; patients with 5-10% have moderate symptoms; and patients with greater than 10% have mild symptoms."
    explanation: >-
      Gives the activity-to-severity gradation stated in this node's
      description.
  - reference: PMID:28394285
    reference_title: Diagnosis and Treatment of von Willebrand Disease and Rare Bleeding Disorders.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "severe defects (FII plasma levels <5%) is characterized by different symptoms, with recurrent muco-cutaneous and gynaecological bleeding and more rarely haemarthroses and muscle bleeds"
    explanation: >-
      Describes the clinical spectrum of the severe end of the diathesis in this
      specific disease.
  downstream:
  - target: Recurrent mucocutaneous bleeding
    causal_link_type: DIRECT
  - target: Menorrhagia
    causal_link_type: DIRECT
  - target: Joint hemorrhage
    causal_link_type: DIRECT
  - target: Intramuscular hematoma
    causal_link_type: DIRECT
  - target: Intracranial hemorrhage
    causal_link_type: DIRECT
  - target: Prolonged bleeding after surgery
    causal_link_type: DIRECT
phenotypes:
- name: Recurrent mucocutaneous bleeding
  category: Hematologic
  frequency: FREQUENT
  description: >-
    The dominant clinical presentation in severe deficiency: recurrent bleeding
    from skin and mucosal surfaces. HPO has no mucocutaneous-bleeding class, so
    this is bound to the parent abnormal-bleeding term and the specificity is
    carried in the preferred term.
  phenotype_term:
    preferred_term: Recurrent mucocutaneous bleeding
    term:
      id: HP:0001892
      label: Abnormal bleeding
    temporality: RECURRENT
  evidence:
  - reference: PMID:28394285
    reference_title: Diagnosis and Treatment of von Willebrand Disease and Rare Bleeding Disorders.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "severe defects (FII plasma levels <5%) is characterized by different symptoms, with recurrent muco-cutaneous and gynaecological bleeding and more rarely haemarthroses and muscle bleeds"
    explanation: >-
      Names recurrent mucocutaneous bleeding as the leading symptom of severe
      prothrombin deficiency.
- name: Menorrhagia
  category: Reproductive
  frequency: FREQUENT
  description: >-
    Heavy menstrual bleeding is a frequent, and sometimes the only, manifestation
    in affected women, and can be severe enough to be life-threatening.
  phenotype_term:
    preferred_term: Menorrhagia
    term:
      id: HP:0000132
      label: Menorrhagia
  evidence:
  - reference: PMID:39022653
    reference_title: "Rare inherited coagulation disorders: no longer orphan and neglected."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Menorrhagia is a frequent manifestation in deficient women and, when severe, can be controlled by prophylaxis"
    explanation: >-
      Stated in the review's factor II section, supporting both the phenotype
      and the FREQUENT band.
  - reference: PMID:23439950
    reference_title: A Rare Case of Inherited Factor-II Deficiency Causing Life-Threatening Menorrhagia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We report a case of inherited hypoprothrombinemia (factor II deficiency), a rare bleeding disorder as the cause of life-threatening menorrhagia."
    explanation: >-
      A documented case in which menorrhagia was the presenting and
      life-threatening manifestation of inherited factor II deficiency.
- name: Joint hemorrhage
  category: Musculoskeletal
  frequency: OCCASIONAL
  description: >-
    Haemarthrosis occurs in severe deficiency. Two things are true at once and
    both are curated here: within the rare bleeding disorders, haemarthrosis and
    deep haematoma are characteristic of factor II and factor X deficiency rather
    than of the group as a whole; but within factor II deficiency itself these
    are less common than mucocutaneous and gynaecological bleeding.
  phenotype_term:
    preferred_term: Hemarthrosis
    term:
      id: HP:0005261
      label: Joint hemorrhage
  evidence:
  - reference: PMID:40747195
    reference_title: Molecular Aspects of Rare Coagulation Factor Deficiencies.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In contrast, hemarthroses and deep hematomas are primarily associated with factor II and X deficiencies."
    explanation: >-
      Identifies haemarthrosis as characteristic of factor II deficiency
      relative to the other rare bleeding disorders.
  - reference: PMID:28394285
    reference_title: Diagnosis and Treatment of von Willebrand Disease and Rare Bleeding Disorders.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "more rarely haemarthroses and muscle bleeds"
    explanation: >-
      Supports the OCCASIONAL frequency band by placing haemarthrosis below
      mucocutaneous bleeding within this disease.
- name: Intramuscular hematoma
  category: Musculoskeletal
  frequency: OCCASIONAL
  description: >-
    Deep muscle haematoma in severe deficiency, occurring alongside
    haemarthrosis and, like it, less often than mucocutaneous bleeding.
  phenotype_term:
    preferred_term: Deep muscle hematoma
    term:
      id: HP:0012233
      label: Intramuscular hematoma
  evidence:
  - reference: PMID:28394285
    reference_title: Diagnosis and Treatment of von Willebrand Disease and Rare Bleeding Disorders.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "more rarely haemarthroses and muscle bleeds"
    explanation: >-
      Names muscle bleeding among the manifestations of severe factor II
      deficiency and places it in the less-common tier.
  - reference: PMID:40747195
    reference_title: Molecular Aspects of Rare Coagulation Factor Deficiencies.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In contrast, hemarthroses and deep hematomas are primarily associated with factor II and X deficiencies."
    explanation: >-
      Identifies deep haematoma as characteristic of factor II deficiency within
      the rare bleeding disorders.
- name: Intracranial hemorrhage
  category: Neurologic
  frequency: OCCASIONAL
  description: >-
    The severe, and in neonates and infants the presenting, manifestation.
    Intracerebral haemorrhage has been the first sign of the disorder in an
    infant with 12% residual prothrombin activity.
  phenotype_term:
    preferred_term: Intracranial hemorrhage
    term:
      id: HP:0002170
      label: Intracranial hemorrhage
  evidence:
  - reference: PMID:21692854
    reference_title: A severe neonatal presentation of factor II deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "a three-month-old boy with non-consanguineous parents was referred for convulsions because of intracerebral hemorrhage"
    explanation: >-
      Documents intracranial haemorrhage as the presenting event in a
      genetically confirmed prothrombin-deficient infant.
- name: Prolonged bleeding after surgery
  category: Hematologic
  frequency: FREQUENT
  description: >-
    Excessive bleeding after surgery, dental extraction, or childbirth. In mild
    disease this is often how the disorder first declares itself, and it is the
    circumstance in which even heterozygotes may bleed.
  phenotype_term:
    preferred_term: Prolonged bleeding after surgery or dental extraction
    term:
      id: HP:0004846
      label: Prolonged bleeding after surgery
  evidence:
  - reference: PMID:40747195
    reference_title: Molecular Aspects of Rare Coagulation Factor Deficiencies.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Homozygous and compound heterozygous forms are symptomatic, while heterozygotes are usually asymptomatic but may bleed during surgery, childbirth, or dental extractions"
    explanation: >-
      Names surgery, childbirth and dental extraction as the challenges that
      provoke bleeding in this disorder.
  - reference: PMID:38601422
    reference_title: "Isolated Prothrombin Deficiency: A Case Report of a Rare Coagulation Disorder and Review of Literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Mild coagulation defects are often clinically silent and are evident after significant trauma or while screening for invasive procedures or surgery with a baseline coagulation screening profile."
    explanation: >-
      Supports the claim that procedural bleeding is how mild disease typically
      comes to attention.
- name: Prolonged prothrombin time
  category: Hematologic
  frequency: VERY_FREQUENT
  description: >-
    Prothrombin sits in the common pathway, so its deficiency prolongs the
    prothrombin time. Prolongation of the PT together with the aPTT, correcting
    on mixing, is the screening pattern that points at this disorder.
  phenotype_term:
    preferred_term: Prolonged prothrombin time
    term:
      id: HP:0008151
      label: Prolonged prothrombin time
  reports_on:
  - target: Impaired Prothrombinase-Mediated Thrombin Generation
    relationship: READOUT_OF
    direction: NEGATIVE
    endpoint_context: DIAGNOSTIC
    interpretation: >-
      A clot-based screening test whose prolongation reflects reduced functional
      prothrombin; it does not distinguish type I from type II and does not
      separate congenital from acquired causes.
    evidence:
    - reference: PMID:15892853
      reference_title: "Molecular genetics of hereditary prothrombin deficiency in Indian patients: identification of a novel Ala362 --> Thr (Prothrombin Vellore 1) mutation."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "The diagnosis was based on prolonged prothrombin (PT) and activated partial thromboplastin times and low factor II coagulant activity (FII: C) measured using a PT based assay."
      explanation: >-
        Ties the prolonged PT to reduced factor II coagulant activity in
        genetically confirmed patients.
  evidence:
  - reference: PMID:40747195
    reference_title: Molecular Aspects of Rare Coagulation Factor Deficiencies.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In patients with hypo- or dysprothrombinemia, routine coagulation tests such as PT and aPTT are often variably prolonged."
    explanation: >-
      States that the PT is prolonged in both biochemical forms of the disorder.
- name: Prolonged partial thromboplastin time
  category: Hematologic
  frequency: VERY_FREQUENT
  description: >-
    The aPTT is prolonged for the same reason as the PT - the lesion is in the
    common pathway, downstream of the point at which the intrinsic and extrinsic
    arms converge.
  phenotype_term:
    preferred_term: Prolonged activated partial thromboplastin time
    term:
      id: HP:0003645
      label: Prolonged partial thromboplastin time
  reports_on:
  - target: Impaired Prothrombinase-Mediated Thrombin Generation
    relationship: READOUT_OF
    direction: NEGATIVE
    endpoint_context: DIAGNOSTIC
    interpretation: >-
      Simultaneous prolongation of the aPTT and the PT localizes the defect to
      the common pathway; a specific factor II assay is needed to identify it.
  evidence:
  - reference: PMID:40747195
    reference_title: Molecular Aspects of Rare Coagulation Factor Deficiencies.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In patients with hypo- or dysprothrombinemia, routine coagulation tests such as PT and aPTT are often variably prolonged."
    explanation: >-
      States that the aPTT is prolonged in both biochemical forms of the
      disorder.
  - reference: PMID:15892853
    reference_title: "Molecular genetics of hereditary prothrombin deficiency in Indian patients: identification of a novel Ala362 --> Thr (Prothrombin Vellore 1) mutation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The diagnosis was based on prolonged prothrombin (PT) and activated partial thromboplastin times and low factor II coagulant activity (FII: C) measured using a PT based assay."
    explanation: >-
      Documents the prolonged aPTT alongside the prolonged PT in confirmed
      cases.
- name: Reduced prothrombin antigen
  category: Hematologic
  subtype: Type I
  description: >-
    Restricted to type I disease. A reduced immunoreactive prothrombin
    concentration, falling in parallel with coagulant activity, is what
    identifies the quantitative form; the antigen is normal or near-normal in
    type II.
  phenotype_term:
    preferred_term: Reduced prothrombin antigen
    term:
      id: HP:0040250
      label: Reduced prothrombin antigen
  evidence:
  - reference: PMID:19598065
    reference_title: Congenital prothrombin deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "hypoprothrombinemia (type I deficiency), characterized by concomitantly low levels of activity and antigen"
    explanation: >-
      States that the antigen is reduced concomitantly with activity in type I
      disease.
biochemical:
- name: Factor II coagulant activity
  presence: DECREASED
  biomarker_term:
    preferred_term: factor II coagulant activity
    term:
      id: NCIT:C82854
      label: Prothrombin
  notes: >-
    Measured by a one-stage PT-based clotting assay against factor II-deficient
    plasma. The interpretation bands below are the symptom-severity tiers used in
    the clinical literature, not a laboratory normal interval; no LOINC code is
    bound because none was verified against an authoritative source during
    curation.
  evidence:
  - reference: PMID:15892853
    reference_title: "Molecular genetics of hereditary prothrombin deficiency in Indian patients: identification of a novel Ala362 --> Thr (Prothrombin Vellore 1) mutation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "FII: C levels ranged between 4.7% and 17.5%."
    explanation: >-
      Reports the measured residual coagulant activity across a consecutive
      series of genetically confirmed patients.
  readouts:
  - target: Impaired Prothrombinase-Mediated Thrombin Generation
    relationship: READOUT_OF
    direction: NEGATIVE
    endpoint_context: DIAGNOSTIC
    interpretation: >-
      The functional assay reports how much thrombin-generating capacity the
      circulating prothrombin pool retains. It is reduced in both subtypes and so
      cannot on its own distinguish them.
  reference_ranges:
  - unit: '%'
    population: Patients with congenital prothrombin deficiency
    notes: >-
      Bands are clinical severity tiers expressed as percent of normal factor II
      coagulant activity. They are drawn from a narrative review and are not
      prospectively validated diagnostic thresholds.
    evidence:
    - reference: PMID:38601422
      reference_title: "Isolated Prothrombin Deficiency: A Case Report of a Rare Coagulation Disorder and Review of Literature."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Patients with prothrombin activity of less than 5% have severe symptoms presenting earlier in life; patients with 5-10% have moderate symptoms; and patients with greater than 10% have mild symptoms."
      explanation: >-
        Source of the three severity bands recorded here.
    interpretation_bands:
    - name: Severe deficiency
      upper_bound: 5.0
      unit: '%'
      abnormal_flag: CRITICAL_LOW
      severity: SEVERE
      interpretation: >-
        Severe symptoms presenting earlier in life, including bleeding with
        little or no trauma.
    - name: Moderate deficiency
      lower_bound: 5.0
      upper_bound: 10.0
      unit: '%'
      abnormal_flag: LOW
      severity: MODERATE
      interpretation: Moderate symptoms.
    - name: Mild deficiency
      lower_bound: 10.0
      unit: '%'
      abnormal_flag: LOW
      severity: MILD
      interpretation: >-
        Mild symptoms; often clinically silent until trauma, surgery, or a
        pre-procedural coagulation screen.
- name: Prothrombin antigen concentration in type I disease
  presence: DECREASED
  subtype: Type I
  biomarker_term:
    preferred_term: prothrombin antigen
    term:
      id: NCIT:C82854
      label: Prothrombin
  notes: >-
    Immunoreactive prothrombin concentration, reduced in parallel with coagulant
    activity. This is the measurement that assigns a patient to type I.
  evidence:
  - reference: PMID:40747195
    reference_title: Molecular Aspects of Rare Coagulation Factor Deficiencies.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Type I (hypoprothrombinemia), a quantitative deficiency with severely reduced prothrombin activity and antigen (<5% of normal), causing severe bleeding symptoms even without trauma."
    explanation: >-
      States that both antigen and activity are reduced in type I disease.
  readouts:
  - target: Reduced Hepatic Prothrombin Output
    relationship: READOUT_OF
    direction: NEGATIVE
    endpoint_context: DIAGNOSTIC
    interpretation: >-
      A reduced antigen concentration is the direct measure of how much
      prothrombin protein reaches the circulation.
- name: Prothrombin antigen concentration in type II disease
  presence: NORMAL
  subtype: Type II
  biomarker_term:
    preferred_term: prothrombin antigen
    term:
      id: NCIT:C82854
      label: Prothrombin
  notes: >-
    Normal or near-normal immunoreactive prothrombin despite reduced coagulant
    activity. This is the measurement that assigns a patient to type II.
  evidence:
  - reference: PMID:40747195
    reference_title: Molecular Aspects of Rare Coagulation Factor Deficiencies.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Type II (dysprothrombinemia) is a qualitative deficiency where prothrombin activity is decreased (around 10% of normal) but antigen levels remain normal or slightly reduced."
    explanation: >-
      States that the antigen concentration is preserved in type II disease.
  readouts:
  - target: Circulating Dysfunctional Prothrombin
    relationship: READOUT_OF
    direction: PRESENT_ABSENT
    endpoint_context: DIAGNOSTIC
    interpretation: >-
      A preserved antigen concentration establishes that the circulating protein
      is present but non-functional.
- name: Activity-to-antigen discrepancy
  presence: PRESENT
  subtype: Type II
  biomarker_term:
    preferred_term: factor II activity-to-antigen ratio
    term:
      id: NCIT:C82854
      label: Prothrombin
  notes: >-
    The diagnostic signature of the disorder. Measuring coagulant activity and
    antigen in the same sample is what separates the quantitative from the
    qualitative form: a large gap between a very low activity and a normal
    antigen identifies dysprothrombinaemia, whereas a proportional fall in both
    identifies hypoprothrombinaemia. Neither the PT, the aPTT, nor the activity
    assay alone can make this call.
  evidence:
  - reference: PMID:25242243
    reference_title: A novel congenital dysprothrombinemia leading to defective prothrombin maturation.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The homozygous patient had a markedly prolonged prothrombin time, strongly reduced FII activity (0.82%) but normal antigen levels."
    explanation: >-
      A worked measurement of the discrepancy: activity below 1% against a
      normal antigen concentration.
  - reference: PMID:28196451
    reference_title: Phenotypic and genetic analysis of dysprothrombinemia due to a novel homozygous mutation.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Phenotypic analysis revealed that the proband had an obviously prolonged PT, APTT, reduced prothrombin activity but normal antigen levels."
    explanation: >-
      A second independent case showing the same activity-antigen dissociation
      that defines type II.
  readouts:
  - target: Circulating Dysfunctional Prothrombin
    relationship: READOUT_OF
    direction: PRESENT_ABSENT
    endpoint_context: DIAGNOSTIC
    interpretation: >-
      The discrepancy is the observable that establishes a qualitative rather
      than a quantitative defect.
genetic:
- name: F2
  gene_term:
    preferred_term: F2
    term:
      id: hgnc:3535
      label: F2
  association: Causative
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  inheritance:
  - name: Autosomal recessive inheritance
    inheritance_term:
      preferred_term: Autosomal recessive inheritance
      term:
        id: HP:0000007
        label: Autosomal recessive inheritance
  notes: >-
    F2 encodes prothrombin and is the only gene in which variants cause this
    disorder. The common F2 c.*97G>A (G20210A) 3' untranslated-region allele is a
    distinct entity: it raises prothrombin and predisposes to venous thrombosis
    rather than causing deficiency, and must not be conflated with the
    loss-of-function alleles curated here.
  evidence:
  - reference: PMID:25242243
    reference_title: A novel congenital dysprothrombinemia leading to defective prothrombin maturation.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Prothrombin deficiency is a very rare disorder caused by mutations in the F2 gene that generate hypoprothrombinemia or dysprothrombinemia and is characterized by bleeding manifestations that can vary from clinically irrelevant to life-threatening."
    explanation: >-
      Names F2 as the causal gene for both biochemical forms of the disease.
  - reference: PMID:23852823
    reference_title: "Congenital prothrombin deficiency: an update."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Thirty-nine different mutations have been identified and characterized in prothrombin deficiency."
    explanation: >-
      Establishes an allelic series in the single causal gene, consistent with a
      monogenic recessive disorder.
  variants:
  - name: Prothrombin Vellore 1 (p.Ala362Thr)
    description: >-
      A novel missense change affecting the B chain of alpha-thrombin, found in
      compound heterozygosity with a propeptide-cleavage-site variant in an
      Indian patient with 17.5% residual coagulant activity. Modelling places it
      adjacent to the catalytic-triad histidine.
    evidence:
    - reference: PMID:15892853
      reference_title: "Molecular genetics of hereditary prothrombin deficiency in Indian patients: identification of a novel Ala362 --> Thr (Prothrombin Vellore 1) mutation."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Molecular modeling of this mutation was found to cause a conformational change around the region involving a catalytic triad residue His363 and a cysteine residue at codon 364."
      explanation: >-
        Reports the structural consequence attributed to this named variant in
        the paper that described it.
  - name: p.Val322Glu
    description: >-
      A homozygous missense variant causing severe dysprothrombinaemia. The
      mutant zymogen cannot complete the zymogen-to-proteinase transition;
      ecarin-driven activation accumulates the meizothrombin intermediate, which
      retains some fibrinogen-degrading activity and may explain the patient's
      mild clinical phenotype despite activity below 1%.
    evidence:
    - reference: PMID:25242243
      reference_title: A novel congenital dysprothrombinemia leading to defective prothrombin maturation.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "prothrombin activation by ecarin was defective, with a massive accumulation of the meizothrombin intermediate"
      explanation: >-
        Documents the specific activation defect assigned to this variant.
treatments:
- name: Prothrombin Complex Concentrate Replacement
  description: >-
    The mainstay of treatment. No purified factor II concentrate exists, so
    replacement uses 3- or 4-factor prothrombin complex concentrate, which also
    carries factors IX and X and variably factor VII. Given on demand for
    bleeding and as cover for surgery; long-term prophylaxis is used in the small
    number of patients with recurrent life-threatening bleeding. Because the
    product supplies several long-half-life vitamin K-dependent factors,
    repeated dosing carries a thrombotic risk that has to be monitored.
  therapeutic_modality: PROTEIN_REPLACEMENT
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: prothrombin complex concentrate
  notes: >-
    The therapeutic agent is deliberately left unbound. The only NCIT match,
    NCIT:C208347 Four-factor Prothrombin Complex Concentrate, is narrower than
    the treatment as practised - the cited sources describe 3-factor products
    too - and binding it would assert a specificity the evidence does not carry.
  target_mechanisms:
  - target: Deficient Thrombin Activity at the Site of Injury
    treatment_effect: RESTORES
    description: >-
      Infused prothrombin restores substrate for the prothrombinase complex and
      so restores thrombin generation; it does not correct the underlying F2
      lesion, and the effect decays with prothrombin's roughly three-day plasma
      half-life.
    evidence:
    - reference: PMID:38601422
      reference_title: "Isolated Prothrombin Deficiency: A Case Report of a Rare Coagulation Disorder and Review of Literature."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Treatment to manage the condition includes the administration of prothrombin complex concentrates or fresh frozen plasma, which may be required as per the short three-day half-life of prothrombin"
      explanation: >-
        States both the replacement strategy and the half-life that governs
        re-dosing.
  evidence:
  - reference: PMID:28394285
    reference_title: Diagnosis and Treatment of von Willebrand Disease and Rare Bleeding Disorders.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "No FII concentrate exists, in fact treatment involves the use of prothrombin complex concentrates (PCCs), that contain other vitamin K-dependent coagulation factors (FIX, FX and not systematically FVII)."
    explanation: >-
      Establishes PCC as the replacement product and the reason a single-factor
      alternative is unavailable.
  - reference: PMID:28394285
    reference_title: Diagnosis and Treatment of von Willebrand Disease and Rare Bleeding Disorders.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The recommended treatment is administration of PCC at doses of 20–30 IU/kg, to be repeated as needed to maintain haemostatic levels 20%–30%."
    explanation: >-
      Names prothrombin complex concentrate as the recommended treatment and the
      dosing basis used in practice.
  - reference: PMID:23152198
    reference_title: Prophylactic administration of prothrombin complex concentrates for congenital prothrombin deficiency with a novel frameshift mutation, prothrombin saitama.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "on demand therapy with administration of prothrombin complex concentrates (PCCs) or fresh frozen plasma is generally performed, and prophylactic therapy for FII deficiency has been reported in only three cases"
    explanation: >-
      Supports on-demand PCC as the usual approach and the rarity of long-term
      prophylaxis.
  - reference: PMID:39022653
    reference_title: "Rare inherited coagulation disorders: no longer orphan and neglected."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "PCCs may cause thrombotic complications due to their content of multiple vitamin K–dependent coagulation factors."
    explanation: >-
      Supports the thrombotic-risk caveat attached to repeated PCC dosing.
- name: Fresh Frozen Plasma Transfusion
  description: >-
    Used where prothrombin complex concentrate is unavailable, and in practice
    the treatment actually given in resource-limited settings. Plasma raises
    factor II activity less predictably than concentrate and carries a volume
    load, so it is a second choice rather than an equivalent.
  treatment_term:
    preferred_term: Fresh Frozen Plasma Transfusion
    term:
      id: NCIT:C116475
      label: Fresh Frozen Plasma Transfusion
    therapeutic_agent:
    - preferred_term: fresh frozen plasma
  notes: >-
    The therapeutic agent is left unbound. NCIT:C89783 Fresh Frozen Plasma is a
    biospecimen term, not a pharmacologic substance, so it is not a valid
    ChemicalEntityTerm; the transfusion action itself carries the binding.
  target_mechanisms:
  - target: Deficient Thrombin Activity at the Site of Injury
    treatment_effect: RESTORES
    description: >-
      Donor plasma supplies intact prothrombin, restoring substrate for thrombin
      generation.
  evidence:
  - reference: PMID:39022653
    reference_title: "Rare inherited coagulation disorders: no longer orphan and neglected."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "If PCC is not available, FFP or SD-FFP at a dose of 15 to 25 mL/kg is anticipated to raise FII activity to 30 to 40 IU/dL"
    explanation: >-
      Positions plasma as the alternative when concentrate is unavailable and
      quantifies the expected rise in factor II.
  - reference: PMID:23190616
    reference_title: "Congenital factor II deficiency: moroccan cases."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The treatment consisted of transfusion with fresh frozen plasma in all cases."
    explanation: >-
      Documents plasma as the treatment actually delivered to a whole case
      series.
- name: Tranexamic Acid
  description: >-
    An antifibrinolytic used for mucosal, dental and menstrual bleeding and as
    cover for minor procedures. It does not correct the common-pathway defect; it
    protects the weak, poorly cross-linked clot that does form from premature
    lysis, so it is adjunctive and inadequate on its own for major bleeding.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: tranexamic acid
      term:
        id: CHEBI:48669
        label: tranexamic acid
  target_mechanisms:
  - target: Weak, Poorly Cross-Linked Hemostatic Clot
    treatment_effect: MODULATES
    description: >-
      Inhibiting plasminogen activation prolongs the survival of a clot that is
      already deficient in cross-linked fibrin. The mechanism acts on clot
      persistence, not on thrombin generation, which is why it is adjunctive.
  evidence:
  - reference: PMID:39022653
    reference_title: "Rare inherited coagulation disorders: no longer orphan and neglected."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "For mild bleeding or surgery, tranexamic acid at a dose of 15 to 20 mg/kg or 1 g every 6 hours is enough for hemostasis"
    explanation: >-
      States the indication and dosing for tranexamic acid in the factor II
      deficiency section of the review.
  - reference: PMID:38601422
    reference_title: "Isolated Prothrombin Deficiency: A Case Report of a Rare Coagulation Disorder and Review of Literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The patient then underwent surgery under the cover of tranexamic acid and strict hemostatic measures."
    explanation: >-
      Documents tranexamic acid used as procedural cover in a patient with mild
      factor II deficiency.
animal_models:
- name: Prothrombin-null mouse (F2 knockout)
  species: Mouse
  genotype: F2 homozygous null (FII-/-)
  publication: PMID:9636195
  description: >-
    Targeted inactivation of the murine prothrombin gene. Roughly half the null
    embryos die between embryonic days 9.5 and 11.5 with bleeding into the yolk
    sac cavity; those that reach term die of haemorrhage within days of birth.
    The model is the principal evidence that complete prothrombin loss is
    incompatible with survival, and so bounds what the human disease can be.
  modeled_mechanisms:
  - target: Deficient Thrombin Activity at the Site of Injury
    relationship: PARTIALLY_RECAPITULATES
    fidelity: MODERATE
    model_scale: ORGANISM
    description: >-
      Complete genetic ablation of prothrombin, producing total loss of thrombin
      generation and fatal haemorrhage.
    limitations: >-
      The model is a complete null. Every described human patient retains
      measurable residual prothrombin activity, and no living human with
      undetectable prothrombin has been reported, so the mouse models the lethal
      limit of the disease rather than any clinically observed genotype. Its
      embryonic and neonatal lethality also prevents study of the chronic,
      episodic bleeding that defines the human disorder.
    evidence:
    - reference: PMID:9636195
      reference_title: Prothrombin deficiency results in embryonic and neonatal lethality in mice.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Inactivation of the FII gene leads to partial embryonic lethality with more than one-half of the FII-/- embryos dying between embryonic days 9.5 and 11.5."
      explanation: >-
        Establishes the embryonic lethality that makes complete prothrombin loss
        the boundary condition on the human disease model.
    readouts:
    - name: Survival of homozygous null neonates
      target: Deficient Thrombin Activity at the Site of Injury
      direction: DECREASED
      interpretation: >-
        Null neonates that reach term die of haemorrhage within days, showing
        that prothrombin is required postnatally and not only developmentally.
      evidence:
      - reference: PMID:9636195
        reference_title: Prothrombin deficiency results in embryonic and neonatal lethality in mice.
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "at least one-quarter of the FII-/- mice survived to term, but ultimately they, too, developed fatal hemorrhagic events and died within a few days of birth"
        explanation: >-
          Reports the postnatal survival and cause of death measured in this
          model.
  evidence:
  - reference: PMID:9636196
    reference_title: Incomplete embryonic lethality and fatal neonatal hemorrhage caused by prothrombin deficiency in mice.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "The rare Cf2(-/-) neonates died of hemorrhage on the first postnatal day."
    explanation: >-
      An independently generated prothrombin-null mouse line reproduces the
      lethal haemorrhagic phenotype, which is why this model is treated as
      informative rather than line-specific.
- name: Zebrafish prothrombin kringle-1 deletion (f2)
  species: Zebrafish
  genotype: f2 kringle 1 domain targeted deletion, homozygous
  publication: PMID:32132579
  description: >-
    A targeted deletion in the kringle 1 domain of zebrafish prothrombin. Unlike
    the mouse null, homozygotes develop normally into the mid-juvenile stage, so
    the model exposes severe prothrombin deficiency beyond the window in which
    mammals die, at the cost of a very different physiological setting.
  modeled_mechanisms:
  - target: Weak, Poorly Cross-Linked Hemostatic Clot
    relationship: PARTIALLY_RECAPITULATES
    fidelity: MODERATE
    model_scale: ORGANISM
    description: >-
      Homozygous mutants cannot form occlusive venous or arterial thrombi after
      endothelial injury and die of internal haemorrhage by two months.
    limitations: >-
      A fish model of a mammalian bleeding disorder: blood pressure, aquatic
      development and the absence of birth trauma all differ, and the lesion is a
      single engineered kringle-1 deletion rather than an allele observed in
      patients. Zebrafish tolerate haemostatic defects that are lethal in
      mammals, so the survival phenotype does not transfer.
    evidence:
    - reference: PMID:32132579
      reference_title: Disruption of the kringle 1 domain of prothrombin leads to late onset mortality in zebrafish.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Homozygous mutant embryos develop normally into the mid-juvenile stage but demonstrate complete mortality by 2 months of age primarily due to internal hemorrhage."
      explanation: >-
        Reports the haemorrhagic phenotype that makes this model informative for
        the failed-clot node.
    readouts:
    - name: Occlusive thrombus formation after endothelial injury
      target: Weak, Poorly Cross-Linked Hemostatic Clot
      direction: ABOLISHED
      interpretation: >-
        Loss of occlusive thrombus formation in vivo is the direct functional
        correlate of the failed haemostatic clot node.
      evidence:
      - reference: PMID:32132579
        reference_title: Disruption of the kringle 1 domain of prothrombin leads to late onset mortality in zebrafish.
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "Mutants are unable to form occlusive venous and arterial thrombi in response to endothelial injury, a defect that was phenocopied using direct oral anticoagulants."
        explanation: >-
          Reports the injury-response measurement behind this readout.
differential_diagnoses:
- name: Lupus anticoagulant-hypoprothrombinaemia syndrome
  description: >-
    An acquired, antibody-mediated hypoprothrombinaemia that presents with the
    same screening pattern as the congenital disorder - prolonged PT and aPTT
    with a reduced factor II level - but has a completely different mechanism.
    Non-neutralizing antiprothrombin antibodies accelerate clearance of the
    prothrombin-antibody complex from the circulation rather than any F2 lesion,
    and the syndrome is triggered by autoimmune disease or infection. It is
    frequently the reason a low factor II level in a previously well patient is
    not congenital, and it must not be curated as a subtype of this disease.
  distinguishing_features:
  - Lupus anticoagulant positive in essentially all cases, which is definitional for the acquired syndrome
  - High-titre anticardiolipin and anti-beta-2-glycoprotein I antibodies
  - Acquired onset, frequently post-infectious or autoimmune, in a previously unaffected person
  - Other coagulation factors usually normal
  - Responds to immunosuppression, which has no role in the congenital disorder
  evidence:
  - reference: PMID:40719111
    reference_title: "Lupus Anticoagulant-hypoprothrombinemia Syndrome: A Review Enriched by a New Particular Patient."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "the laboratory profile is characterized by a prolongation of prothrombin time (PT) and activated partial thromboplastin time (aPTT) with a mild to severe reduction in factor II levels"
    explanation: >-
      Documents the laboratory profile that this acquired syndrome shares with
      congenital prothrombin deficiency, which is why it is the key differential.
  - reference: PMID:40719111
    reference_title: "Lupus Anticoagulant-hypoprothrombinemia Syndrome: A Review Enriched by a New Particular Patient."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Lupus anticoagulant (LA) is positive in 100% of cases, as this represents a defining feature."
    explanation: >-
      Gives the discriminating test: lupus anticoagulant positivity is definitional
      for the acquired syndrome and absent in the congenital disorder.
- name: Hereditary combined vitamin K-dependent coagulation factor deficiency
  description: >-
    Biallelic GGCX or VKORC1 defects impair gamma-carboxylation of every vitamin
    K-dependent protein, so factor II falls together with factors VII, IX and X
    and with proteins C and S. The overlap with congenital prothrombin deficiency
    is mechanistic as well as clinical: both act on the Gla-domain membrane-binding
    step, but the combined deficiency does so for the whole vitamin K-dependent
    family rather than for prothrombin alone.
  distinguishing_features:
  - Proportionate reduction of factors II, VII, IX and X plus proteins C and S, rather than an isolated factor II defect
  - Frequently at least partially responsive to vitamin K
  evidence:
  - reference: PMID:19141161
    reference_title: Familial deficiency of vitamin K-dependent clotting factors.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "found to have immunologically recognizable coagulation factors II, VII, IX, and X that lacked γ-carboxyglutamic acid residues"
    explanation: >-
      Documents the multi-factor pattern that separates the combined deficiency
      from an isolated factor II defect.
discussions:
- discussion_id: anticoagulant_arm_offset
  kind: KNOWLEDGE_GAP
  status: OPEN
  prompt: >-
    How much of the variable bleeding severity in congenital prothrombin
    deficiency is explained by the simultaneous loss of the thrombin-thrombomodulin
    protein C anticoagulant arm?
  attaches_to:
  - pathophysiology#Reduced Thrombomodulin-Dependent Protein C Activation
  rationale: >-
    Prothrombin deficiency removes an anticoagulant output at the same time as
    the procoagulant ones, so the net haemostatic deficit is not a simple
    subtraction. Nothing in the curated literature quantifies the offset in this
    disease, and its existence is one candidate explanation for why residual
    factor II activity predicts bleeding severity only loosely and why some
    dysprothrombin variants present with thrombosis instead. The node is
    therefore left without a downstream edge rather than being wired into the
    bleeding chain.
- discussion_id: no_human_null_phenotype
  kind: OPEN_QUESTION
  status: OPEN
  prompt: >-
    What is the human phenotype of complete prothrombin deficiency, and is the
    inference of lethality from animal models safe?
  attaches_to:
  - pathophysiology#Deficient Thrombin Activity at the Site of Injury
  - disease#Congenital Prothrombin Deficiency
  rationale: >-
    No living patient with undetectable plasma prothrombin has ever been
    reported, and every described genotype leaves residual activity. The claim
    that complete absence is incompatible with life is therefore an inference
    from an absence of human observations plus two independent prothrombin-null
    mouse lines and a zebrafish model, not a human finding. This entry states it
    as a constraint on the disease model rather than as an observed human
    phenotype.
  evidence:
  - reference: PMID:23852823
    reference_title: "Congenital prothrombin deficiency: an update."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "No living patient with undetectable plasma prothrombin has been reported to date."
    explanation: >-
      The human side of the claim is an absence of observations, which is what
      makes this an open question rather than a settled phenotype.
  - reference: PMID:32132579
    reference_title: Disruption of the kringle 1 domain of prothrombin leads to late onset mortality in zebrafish.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Complete deficiency of the central clotting enzyme prothrombin has never been observed in humans and is incompatible with postnatal life in mice, thus limiting the ability to study its role in vivo."
    explanation: >-
      States both halves of the inference and the reason it cannot be tested
      directly in humans.
  - reference: PMID:39022653
    reference_title: "Rare inherited coagulation disorders: no longer orphan and neglected."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "No cases of aprothrombinemia have been reported, suggesting incompatibility with life"
    explanation: >-
      An independent review draws the same inference, and its hedged wording
      ("suggesting") is the epistemic status this entry adopts.
references:
- reference: PMID:23852823
  title: "Congenital prothrombin deficiency: an update."
  findings: []
- reference: PMID:19598065
  title: Congenital prothrombin deficiency.
  findings: []
- reference: PMID:40747195
  title: Molecular Aspects of Rare Coagulation Factor Deficiencies.
  findings: []
- reference: PMID:39022653
  title: "Rare inherited coagulation disorders: no longer orphan and neglected."
  findings: []
- reference: PMID:28394285
  title: Diagnosis and Treatment of von Willebrand Disease and Rare Bleeding Disorders.
  findings: []
- reference: PMID:38601422
  title: "Isolated Prothrombin Deficiency: A Case Report of a Rare Coagulation Disorder and Review of Literature."
- reference: PMID:23190616
  title: "Congenital factor II deficiency: moroccan cases."
- reference: PMID:25242243
  title: A novel congenital dysprothrombinemia leading to defective prothrombin maturation.
- reference: PMID:15892853
  title: "Molecular genetics of hereditary prothrombin deficiency in Indian patients: identification of a novel Ala362 --> Thr (Prothrombin Vellore 1) mutation."
- reference: PMID:21692854
  title: A severe neonatal presentation of factor II deficiency.
- reference: PMID:28196451
  title: Phenotypic and genetic analysis of dysprothrombinemia due to a novel homozygous mutation.
- reference: PMID:19141161
  title: Familial deficiency of vitamin K-dependent clotting factors.
- reference: PMID:31102425
  title: "Blood coagulation factor Va's key interactive residues and regions for prothrombinase assembly and prothrombin binding."
- reference: PMID:41443372
  title: "Thrombin generation profiling in rare coagulation factor deficiencies: associations with bleeding severity and potential for screening."
- reference: PMID:9636195
  title: Prothrombin deficiency results in embryonic and neonatal lethality in mice.
- reference: PMID:34154000
  title: "Thrombin: A Pivotal Player in Hemostasis and Beyond."
- reference: PMID:32132579
  title: Disruption of the kringle 1 domain of prothrombin leads to late onset mortality in zebrafish.
- reference: PMID:10528826
  title: Multifunctional roles of thrombin.
- reference: PMID:23439950
  title: A Rare Case of Inherited Factor-II Deficiency Causing Life-Threatening Menorrhagia.
- reference: PMID:23152198
  title: "Prophylactic administration of prothrombin complex concentrates for congenital prothrombin deficiency with a novel frameshift mutation, prothrombin saitama."
- reference: PMID:9636196
  title: Incomplete embryonic lethality and fatal neonatal hemorrhage caused by prothrombin deficiency in mice.
- reference: PMID:40719111
  title: "Lupus Anticoagulant-hypoprothrombinemia Syndrome: A Review Enriched by a New Particular Patient."
notes: >-
  Scope. This entry covers the congenital, F2-linked disorder only. The acquired
  mimic lupus anticoagulant-hypoprothrombinaemia syndrome is antibody-mediated
  and is curated as a differential diagnosis, not a subtype. The common F2
  G20210A thrombophilia allele raises prothrombin and causes thrombosis; it is a
  different disease and is not modelled here.

  A third biochemical category, sometimes labelled type III, is described in the
  literature: dysprothrombin variants whose defect is resistance to inhibition by
  antithrombin, so they present with thrombosis rather than bleeding. It is not
  curated as a subtype because it is a within-type-II mechanistic subdivision of
  a handful of variants rather than an established third clinical form, and
  because no node in this entry models antithrombin inhibition. Do not confuse it
  with the Reduced Thrombomodulin-Dependent Protein C Activation node, which is a
  different anticoagulant arm.

  Module conformance. No conforms_to is declared. The two candidate modules were
  checked: `primary_hemostatic_plug_failure` explicitly excludes
  coagulation-factor deficiencies from its scope ("mucocutaneous bleeding alone
  is NOT sufficient to infer conformance: coagulation-factor deficiencies
  (hemophilia, plasma von Willebrand disease) ... all produce the same clinical
  output without a platelet primary-hemostatic component being lost"), and
  `thrombogenesis` models pathological intravascular thrombus formation, which is
  this disease's inverse. A shared coagulation-factor-deficiency module covering
  the common-pathway factor deficiencies would be a reasonable future addition;
  it does not exist yet.

  Umbilical stump bleeding was deliberately not curated as a phenotype. It is a
  classic sign of a rare bleeding disorder, but the sources reviewed here assign
  it specifically to factor XIII deficiency and afibrinogenaemia
  ("Bleeding from the umbilical stump shortly after birth is highly suggestive of
  factor XIII deficiency or afibrinogenemia", PMID:40747195), and no source
  reviewed reported it in factor II deficiency. Epistaxis and gingival bleeding
  are almost certainly part of the mucocutaneous picture but are recorded here
  only inside the aggregate "Recurrent mucocutaneous bleeding" phenotype, because
  no reviewed source names them for this disease specifically.

  Bleeding severity correlates only loosely with residual factor II activity.
  Thrombin generation assays outperform the PT and aPTT for detecting rare factor
  deficiencies and track bleeding severity better than factor activity does,
  which is consistent with this entry's model in which a single enzyme deficit
  propagates through five separate downstream branches.

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