Thrombophilias are inherited or acquired disorders that are associated with increased risk of thrombosis. Inherited thrombophilias include deficiencies of antithrombin, protein C and protein S, as well as the factor V Leiden and the prothrombin G20210A mutations. While the inherited thrombophilias are generally associated with a propensity to VTE, positivity for the presence of an APLA, an acquired thrombophilia, has been linked to arterial, as well as venous events.
Factor V Leiden Mutation
The factor V Leiden mutation, the most common inherited thrombophilia, is a gain-of-function mutation in which there is impaired cleavage and inactivation of activated factor V (factor Va) resulting in resistance to the action of activated protein C. Heterozygosity for this mutation is associated with a fivefold increased risk of VTE, while homozygotes have an approximately 50-fold increased risk.
Prothrombin G20210A Mutation
The prothrombin G20210A mutation is another gain-of-function mutation in the 3' untranslated region of the prothrombin gene (position 20210) that results in increased amounts of plasma prothrombin. The highest frequencies of the prothrombin gene mutation are seen in individuals of southern European descent (4%). Individuals heterozygous for this mutation have a two to three-fold increase in the risk of VTE.
Antithrombin is a serine protease inhibitor that inhibits thrombin, activated factor Xa and several other activated clotting factors, thereby playing a central role in the control of coagulation. Inherited antithrombin deficiency is relatively rare, occurring in approximately one in 2500 persons. In general, this is considered a high-risk thrombophilia. Homozygous deficiency is exceedingly uncommon, while heterozygous antithrombin deficiency is associated with a ten- to 25-fold increase in the risk of VTE.
Protein S & Protein C Deficiency
Activated protein C, along with its cofactor, protein S, binds to and degrades activated factors V and VIII. Like antithrombin deficiency, deficiencies of these natural anticoagulants are also uncommon.
APLAs are autoantibodies directed against phospholipid binding proteins.[27,32] Lupus anticoagulants (nonspecific inhibitors) and anticardiolipin antibodies (ACLA) are commonly the most assayed of these antibodies in clinical practice; however, some centers also test for anti-β2 glycoprotein 1 and other less common ALPAs.[27,33]
Expert Rev Hematol. 2013;6(3):287-300. © 2013 Expert Reviews Ltd.