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Venous thromboembolism is a multicausal disease involving one or more genetic defects in conjunction with acquired risk factors such as trauma, immobility, malignancy, inflammation, pregnancy, oral contraceptive use, and autoimmune disease. Thrombophilia is defined as a genetically determined increased likelihood of thrombosis. The two most common hereditary defects in whites (found in a substantial proportion of patients presenting with venous thrombosis) include activated protein C resistance caused by replacement of Arg506 by Gln in the factor V gene (factor V Leiden) and a prothrombin single-nucleotide polymorphism (G20210A) that causes elevated plasma prothrombin levels. Also common are hyperhomocysteinemia and increased plasma levels of factor VIII that can result from identified and unidentified genetic defects or from acquired conditions. Less common genetic abnormalities include deficiencies of the anticoagulant proteins, protein C, protein S, and antithrombin. The majority of these thrombophilic defects either enhance procoagulant reactions or hamper anticoagulant mechanisms, thus causing a prothrombotic state resulting from hypercoagulability of the blood. Venous thrombosis or thromboembolism are the most common manifestations of thrombophilia, although a minority of patients, particularly those with other vascular risk factors, also develop arterial thrombosis. Less usual presentations include visceral or cerebral vein thrombosis, second- or third-trimester pregnancy loss, and severe preeclampsia. Laboratory assays are widely available to identify most thrombophilias. Knowledge of these disorders can affect patient management, including the duration of anticoagulant treatment, the use of prophylactic antithrombotic agents, and counseling patients regarding the relative risks of pregnancy and use of oral contraceptives or hormone replacement.

Acronyms and Abbreviations

Acronyms and abbreviations that appear in this chapter include: APC, activated protein C; APCR, activated protein C resistance; aPTT, activated partial thromboplastin time; EPCR, endothelial protein C receptor; IUGR, intrauterine growth restriction; MTHFR, methylenetetrahydrofolate reductase; OR, odds ratio; PAI, plasminogen-activator inhibitor; PCI, protein C inhibitor; PCR, polymerase chain reaction; QTL, quantitative trait loci; sFlt1, soluble fms-like tyrosine kinase 1; TAFI, thrombin-activatable fibrinolysis inhibitor; TFPI, tissue factor pathway inhibitor; VEGF, vascular endothelial growth factor; VTE, venous thrombosis or thromboembolism.

Hereditary thrombophilia hereinafter termed thrombophilia is defined as a genetically determined increased risk of venous thrombosis or thromboembolism (VTE). Table 131–1 lists the major genetic defects associated with VTE and the acquired predisposing risk factors. Increasing age and interaction among inherited thrombophilias coupled with the effects of acquired predisposing factors are the common causes of VTE (Fig. 131–1).

Table 131–1. Thrombophilias and Predisposing Risk Factors for Venous Thromboembolism

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