Primary Hypercoagulable States
Activated protein C resistance (factor V Leiden mutation)
Factor V is a procoagulant factor that amplifies thrombin production. Most patients with APC resistance harbor a single specific point mutation in the factor V gene, termed factor V Leiden, which renders both forms of factor V (active and inactive) insensitive to APC proteolysis. This mutation occurs with remarkable frequency (3%–7%) in healthy white populations but appears to be far less prevalent or even absent in certain black and Asian populations. The major clinical manifestation of the heterozygous form is deep venous thrombosis or pulmonary embolism, for which there is a lifetime risk of 5% in the general population but up to 20% in families with history of thrombophilia. Asymptomatic heterozygotes with no history of thromboembolic events do not need to be routinely screened for other thrombophilias or treated with anticoagulants except in high-risk situations such as surgery or pregnancy.
Prothrombin G20210A gene mutation
The G20210A mutation in the prothrombin gene has been associated with elevated plasma levels of prothrombin. It is second only to factor V Leiden as a genetic risk factor for venous thrombosis and is also a risk factor for premature cardiovascular disease. It is much more common among white populations than in other populations. The risk of venous thromboembolism (VTE) increases 20-fold when both prothrombin G20210A and factor V Leiden mutation are present in the same individual.
Antithrombin deficiency is rare. It leads to increased thrombin generation and, hence, fibrin accumulation with a lifelong propensity for thrombosis. A meta-analysis of case control and cohort studies showed a 16-fold increased risk of developing VTE in patients with antithrombin deficiency. This mutation may be acquired or hereditary.
Protein C deficiency
Protein C deficiency is also rare, affecting between 0.2% and 0.5% of the general population. This disorder leads to unregulated fibrin generation due to impaired inactivation of factors VIIIa and Va. The risk of VTE in patients who have protein C deficiency is increased 7-fold compared to that of persons without this deficiency.
Protein S deficiency
Protein S is the principal cofactor of APC; therefore, its deficiency mimics that of protein C. The prevalence of this condition in patients presenting with VTE is about 1%, and patients with protein S deficiency have 5 times the risk of developing VTE than those without this deficiency.
Screening for inherited thrombophilia
Screening for these conditions in the unselected general population is not recommended because of the low prevalence, low and variable penetrance among carriers, and lack of safe and cost-effective prophylaxis. Screening would be appropriate in the following groups:
pedigrees that include multiple first-degree relatives with inherited thrombophilia and VTE onset before age 50
family members of probands with symptomatic thrombophilia, particularly those who have protein C, protein S, or antithrombin deficiency
women who plan to use oral contraceptives or hormone replacement therapy and have a family history of VTE with thrombophilia
Screening for methylenetetrahydrofolate reductase (MTHFR) gene variants, assaying homocysteine levels, or seeking plasminogen activator/promoter variants is not recommended, as there is no evidence that risk for blood clots is significantly higher or that prophylactic anticoagulation reduces risk.
Hyperhomocysteinemia, which is caused by elevated blood levels of homocysteine, leads to severe neurologic developmental abnormalities in the homozygous state. Adults with the heterozygous state may have only thrombotic tendencies. Acquired causes of hyperhomocysteinemia in adults commonly involve nutritional deficiencies of pyridoxine, vitamin B12, and folate, all of which are cofactors in homocysteine metabolism. High blood concentration of homocysteine constitutes an independent risk factor for both venous and arterial thrombosis; in contrast, all of the other primary hypercoagulable states are associated only with venous thromboembolic complications, usually involving the lower extremities. The initial treatment of acute venous thrombosis in these patients does not differ from that in patients without genetic defects.
Excerpted from BCSC 2020-2021 series: Section 1 - Update on General Medicine. For more information and to purchase the entire series, please visit https://www.aao.org/bcsc.