Clinical Guidance

No genotype-phenotype correlations have been identified for other F2 variants.

Source: GeneReviews — "Prothrombin Thrombophilia"

Diagnostic Criteria

Suggestive Findings

No clinical features are specific for prothrombin thrombophilia. The diagnosis should be suspected in individuals with at least one of the following more specific findings:

• A first unprovoked venous thromboembolism (VTE) before age 50 years

• A history of recurrent VTE

• Venous thrombosis at certain unusual sites such as the cerebral, mesenteric, portal, or hepatic veins

• VTE during pregnancy or the puerperium

• VTE associated with the use of estrogen-containing oral contraceptives or hormone replacement therapy (HRT)

• An unprovoked VTE at any age in an individual with a first-degree family member with a VTE before age 50 years

Prothrombin thrombophilia testing may be considered in individuals who have less specific findings, including the following:

Source: GeneReviews — "Prothrombin Thrombophilia"

Differential Diagnosis

The differential diagnosis of venous thromboembolism (VTE) includes several other inherited thrombophilic disorders (discussed here) and acquired thrombophilic disorders (outside of the scope of this GeneReview). Factor V Leiden refers to the specific G-to-A substitution in F5 that predicts a single amino-acid replacement (Arg506Gln) that destroys a cleavage site for activated protein C. Factor V Leiden thrombophilia (the most common inherited form of thrombophilia) is characterized by a poor anticoagulant response to activated protein C and an increased risk for VTE. Deep vein thrombosis (DVT) is the most common VTE, with the legs being the most common site.

Source: GeneReviews — "Prothrombin Thrombophilia"

Management Guidelines

Evaluations Following Initial Diagnosis

To assess the risk for venous thromboembolism (VTE) in an individual found to have the F2 variant, the following are recommended:

• An activated protein C resistance or DNA assay for factor V Leiden

• Serologic assays for anticardiolipin antibodies and anti-beta2 glycoprotein 1 antibodies

• Multiple phospholipid-dependent coagulation assays for a lupus inhibitor

For high-risk individuals (e.g., those with a history of recurrent VTE, especially at a young age, or those with strong family history of VTE at a young age), evaluation should also include assays of the following:

• Protein C activity

• Antithrombin activity

• Protein S activity or free protein S antigen

Note: Measurement of the following is NOT recommended:

• Plasma concentration of homocysteine, since no data support a change in duration of anticoagulation or the use of vitamin supplementation in individuals with hyperhomocysteinemia and a history of VTE

• MTHFR variants, as no clinical rationale for this testing exists

• Factor VIII and other clotting factor levels

Treatment of Manifestations

Treatment of VTE in Adults

The management of thrombosis in individuals with prothrombin thrombophilia depends on the clinical circumstances. The first acute thrombosis should be treated according to standard guidelines . For initial treatment of VTE, current guidelines suggest a direct oral anticoagulant (dabigatran, edoxaban, rivaroxaban, or apixaban) over warfarin because of a lower bleeding risk and greater co...

Source: GeneReviews — "Prothrombin Thrombophilia"

Clinical Guidance

Women with a history of VTE who are heterozygous for 20210GA should avoid estrogen-containing contraception and hormone replacement therapy (HRT). Women homozygous for 20210GA with or without prior VTE should avoid estrogen-containing contraception and HRT. Asymptomatic women heterozygous for 20210GA:

• Should be counseled on the risks of estrogen-containing contraception and HRT use and should be encouraged to consider alternative forms of contraception and control of menopausal symptoms;

• Electing to use oral contraceptives should avoid third-generation and other progestins with a higher thrombotic risk;

• Electing short-term hormone replacement therapy for severe menopausal symptoms should use a low-dose transdermal preparation, which has a lower thrombotic risk than oral formulations .

Source: GeneReviews — "Prothrombin Thrombophilia"

Therapies Under Investigation

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions.

Source: GeneReviews — "Prothrombin Thrombophilia"

Surveillance Guidelines

Individuals receiving long-term anticoagulation require periodic reevaluation to confirm that the benefits of anticoagulation continue to outweigh the risk of bleeding. 20210GA heterozygotes who do not require long-term anticoagulation may benefit from evaluation prior to exposure to circumstantial risk factors such as surgery or pregnancy .

Source: GeneReviews — "Prothrombin Thrombophilia"