CLINICAL CHARACTERISTICS

Prothrombin thrombophilia is characterized by venous thromboembolism (VTE) manifest most commonly in adults as deep-vein thrombosis (DVT) in the legs or pulmonary embolism. The clinical expression of prothrombin thrombophilia is variable; many individuals heterozygous or homozygous for the 20210G>A variant never develop thrombosis, and while most heterozygotes who develop thrombotic complications remain asymptomatic until adulthood, some have recurrent thromboembolism before age 30 years. The relative risk for DVT in adults heterozygous for the 20210G>A variant is two- to fivefold increased; in children, the relative risk for thrombosis is three- to fourfold increased. Heterozygosity for 20210G>A has at most a modest effect on recurrence risk after a first episode. Although prothrombin thrombophilia may increase the risk for pregnancy loss, its association with preeclampsia and other complications of pregnancy such as intrauterine growth restriction and placental abruption remains controversial. Factors that predispose to thrombosis in prothrombin thrombophilia include: the number of 20210G>A alleles; presence of coexisting genetic abnormalities including factor V Leiden; and acquired thrombophilic disorders (e.g., antiphospholipid antibodies). Circumstantial risk factors for thrombosis include pregnancy and oral contraceptive use. Some evidence suggests that the risk for VTE in 20210G>A heterozygotes increases after air travel.

DIAGNOSIS/TESTING: The diagnosis of prothrombin thrombophilia is established in a proband by identification of a heterozygous or homozygous 20210G>A variant (also known as c.*97G>A) in , the gene encoding prothrombin.

MANAGEMENT

Management depends on the clinical circumstances. The first acute thrombosis is treated according to standard guidelines. The duration of anticoagulation therapy is determined by assessment of the risks for VTE recurrence and anticoagulant-related bleeding. 20210G>A heterozygosity alone is not an indication for long-term anticoagulation in the absence of other risk factors. Individuals receiving long-term anticoagulation require periodic reevaluation to confirm that the benefits of anticoagulation continue to outweigh the risk of bleeding. 20210G>A heterozygotes who do not require long-term anticoagulation may benefit from evaluation prior to exposure to circumstantial risk factors such as surgery or pregnancy. Women heterozygous for 20210G>A with a history of VTE and women homozygous for 20210G>A with or without prior VTE should avoid estrogen-containing contraception and hormone replacement therapy (HRT). No consensus exists on the optimal management of prothrombin thrombophilia during pregnancy; guidelines for treatment of VTE are derived from studies in non-pregnant individuals.

GENETIC COUNSELING

Prothrombin thrombophilia is inherited in an autosomal dominant manner: heterozygosity for the 20210G>A variant results in an increased risk for thrombosis; homozygosity for this variant confers a higher risk for thrombosis than heterozygosity. Occasionally (because of the relatively high frequency of the 20210G>A variant in the general population) one parent is homozygous for the 20210G>A variant or both parents are heterozygous for the 20210G>A variant. The genetic status of both parents and/or the reproductive partner of an affected individual needs to be evaluated before information regarding potential risks to sibs or offspring can be provided. If one parent of a heterozygous proband is heterozygous for the 20210G>A variant, the sibs of the proband are at 50% risk of being heterozygous; if one parent is homozygous, the sibs of the proband will be heterozygous. Once the 20210G>A variant has been identified in a family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing are possible.