Inherited Thrombophilias

Secondary hemostasis, or blood coagulation, is initiated by interaction of blood with vascular subendothelium or tissue factor exposed on cell surfaces after cellular injury. Intrinsic and extrinsic coagulation pathways converge through a series of steps to form a common pathway, ultimately leading to thrombin generation. The coagulation cascade rapidly transduces small initiating stimuli into large fibrin clots. Endogenous anticoagulant mechanisms offset the potentially explosive nature of this cascade by carefully regulating extent of coagulation serine protease generation. The natural anticoagulants permit coagulation to proceed locally while preventing it from becoming a systemic process. Congenital and acquired hypercoagulable states arise when imbalance develops between prothrombotic and anticoagulant plasma activities in favor of thrombosis. In most inherited thrombophilias, genetic variations of proteins regulating hemostasis ultimately lead to increased generation, or impaired neutralization of thrombin, predisposing to thrombotic events. Hypercoagulable states are more clinically relevant as causes of venous thromboembolism (VTE) than thrombotic arterial disease.

Antithrombin III, Protein S, and Protein C Deficiencies. These are the three most important natural anticoagulants. Antithrombin III (ATIII) inhibits the activity of several serine proteases of intrinsic and common coagulation pathways, particularly thrombin. In the presence of heparin sulfate, the rate of inactivation is increased by several 1000-fold. Protein C and protein S form the second regulatory system. When linked to the endothelial membrane protein thrombomodulin, thrombin activates protein C, which, in turn, cleaves factors VIIIa and Va. Protein S serves as a cofactor accelerating this reaction. Although gene mutations in these natural anticoagulants are uncommon, when present they lead to venous and arterial thrombosis in early adulthood. If these occur in homozygosity, severe thrombogenesis occurs during infancy and childhood that is often incompatible with life.

Factor V Leiden (FVL). This is the most common genetic defect related to venous thrombosis, present in 10% to 50% of affected individuals. Worldwide carrier frequencies range from 1% to 15%; it is highly prevalent among Caucasians. This point mutation in the coagulation factor V gene renders the mutant factor V resistant to proteolytic degradation by activated protein C, a characteristic denominated activated protein C resistance. This leads to increased thrombin generation and a procoagulant state. FVL heterozygosity increases VTE risk threefold to eightfold; homozygosity is associated with a 50 to 100 times higher risk. Its role in arterial thrombosis is debated. Because it interacts synergistically with smoking, oral contraceptives, and other inherited thrombophilias, it is a potential risk factor for ischemic stroke in young patients with additional vascular risk factors.

Prothrombin Gene Mutation. Prothrombin is a vitamin K–dependent zymogen that in its activated form (thrombin) converts fibrinogen into fibrin. A prothrombin gene G-to-A substitution in the 3′- untranslated region is associated with elevated plasma prothrombin levels and increased thrombotic risk. This is the second most common inherited thrombophilia; it leads to a twofold to fivefold increased VTE risk. The prevalence of heterozygosity is 2% in Caucasians. The relationship with arterial thrombosis and stroke remains controversial; although this mutation is associated with a moderate increase in arterial thrombotic disease, it assumes particular importance in certain subgroups, including young women taking oral contraceptives and children.

Hyperhomocysteinemia. Homocysteine is a sulfurcontaining amino acid formed as an intermediary compound during methionine metabolism and metabolized by both remethylation and trans-sulfuration. Vitamins B₁₂, B₆, and folate are essential cofactors in these pathways. Plasma homocysteine elevations can be caused by genetic (mutations in the methylenetetrahydrofolate reductase [MTHFR] and cystathionine β-synthase [CBS] genes), nutritional (vitamin B and folate deficiencies), and acquired factors (e.g., renal failure). Deleterious effects of hyperhomocysteinemia include endothelial dysfunction, platelet activation, and arterial and venous thrombus formation. Nutritional factors and homozygosity of the MTHFR polymorphism lead to mild forms of hyperhomocysteinemia with modestly increased thrombotic risk. CBS gene mutations lead to severe hyperhomocysteinemia manifested clinically with premature, severe atherosclerosis, early thromboembolic events, mental retardation, skeletal deformities, and ectopia lentis.

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