Thrombophilia – prothrombin defect

The principal clinical manifestation is venous thromboembolism, with markedly variable clinical expression; many affected individuals never develop thrombosis. Deep-vein thrombosis (typically of the lower extremities, less commonly the upper extremities) and pulmonary embolism predominate; most first thrombotic events occur in adulthood, although recurrent venous thromboembolism before age 30 years has been reported. Cerebral venous thrombosis is a further clinically important manifestation, and hepatic, portal, and pregnancy-associated venous thromboembolism are recognised. By contrast, the F2 20210G>A variant is not a major risk factor for arterial thrombosis, including myocardial infarction or stroke, across all age groups. At least 50% of thrombotic episodes are provoked by additional acquired risk factors, particularly pregnancy and combined oral contraceptive use.

The estimated prevalence is 1/33 to 1/59 , reflecting F2 20210G>A carrier frequency in European and US populations; regional variation ranges from approximately 1.7% (Northern Europe) to 3% (southern Europe), with similar carrier frequencies reported in population-based cohort studies.

Germline pathogenic variants in F2, the gene encoding coagulation factor II (prothrombin), underlie the predisposition to venous thromboembolism. The recurrent variant 20210G>A (HGVS designation c.*97G>A) is located in the 3’ untranslated region and increases the efficiency of mRNA 3’-end processing, resulting in mRNA accumulation and elevated prothrombin synthesis. Heterozygotes show approximately 30% higher plasma prothrombin than healthy controls, contributing to increased thrombin generation and a prothrombotic state; the molecular mechanism is gain of function.

Prothrombin thrombophilia is inherited in an autosomal dominant manner. Each child of an affected individual has a 50% chance of inheriting the F2 20210G>A variant. After identification of the familial pathogenic variant, predictive testing of at-risk adult relatives can be undertaken in the setting of genetic counselling. Prenatal molecular testing is technically possible once the familial pathogenic variant has been identified.

The diagnosis of prothrombin thrombophilia is established primarily through molecular genetic testing for the F2 20210G>A (c.*97G>A) pathogenic variant in the 3’ untranslated region. No clinical diagnostic criteria, biochemical assays, or imaging findings define the diagnosis; indications for and interpretation of thrombophilia testing are addressed in current hematology guidelines.

Main differential diagnoses include:

• : poor anticoagulant response to activated protein C due to the Arg506Gln substitution
• Inherited deficiencies of the natural anticoagulants , , and
• Hereditary dysfibrinogenemia: rare qualitative fibrinogen disorder

• Establishing the diagnosis: a molecular genetic diagnosis confirms the underlying cause in symptomatic individuals and resolves diagnostic uncertainty.
• Informing clinical management: identification of the underlying pathogenic variant is a prerequisite for targeted medical care, with management decisions made by the treating physicians in consultation with the affected individual.
• Family member testing: identification of the familial pathogenic variant enables predictive testing of at-risk relatives after appropriate genetic counselling.

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• Morimont L, Haguet H, Dogné JM, Gaspard U, Douxfils J. Combined oral contraceptives and venous thromboembolism: review and perspective to mitigate the risk. Front Endocrinol (Lausanne). 2021;12:769187. doi:10.3389/fendo.2021.769187. PMID:; PMCID:PMC8697849.