Role of hemostatic gene polymorphisms in venous and arterial thrombotic disease

Abstract

Venous thromboembolic disorders form a spectrum of conditions characterized by in situ thrombus formation and the variable presence of embolic manifestations. The clinical presentation depends to a large extent on the site and extent of thrombus formation and on the underlying cause. In the absence of genetic deficiencies, thrombosis occurs in the older population, largely in the context of marked environmental influences such as surgery, obesity, and underlying malignancy. In contrast, at the other extreme, familial thrombosis associated with mutations in genes for protein S, protein C, or antithrombin is associated with younger age of onset, lesser environmental stimulus, and thrombus formation often in unusual sites. There is an increasing awareness of the importance of hemostatic mechanisms in the pathogenesis of venous thrombosis. The hemostatic process comprises coagulation and fibrinolytic systems with activators, zymogens, cofactors, surfaces (such as platelets), and inhibitors. The function and regulation of these composite systems and factors have been extensively studied. Understanding their functional integration in vivo, however, still presents a major challenge. A starting point for a simplified model of integration envisages a balance between procoagulant (clot-promoting) and anticoagulant (clot-preventing) mechanisms. This balance serves to prevent an explosive generation of thrombin when coagulation is triggered. The balance is determined by the (functional) levels of all coagulation and fibrinolytic factors, with increases in the levels of coagulation factors and decreases in the levels of both fibrinolytic factors and natural inhibitors being procoagulant. The role of inhibitory mechanisms in preventing venous occlusion was established after the identification of the link between inherited deficiencies of antithrombin, protein C, protein S, and venous thrombosis during the 1960s and the 1970s. The general importance of the anticoagulant pathway involving protein C and protein S was established by the widespread prevalence among white populations and the clinical consequences of the phenotype of activated protein C resistance (APCR) and its main causative gene mutation, factor V G1691A (factor V Arg506Gln, factor V Leiden). There has been slower appreciation of the procoagulant effect of increased levels of coagulation factors in venous disease, but recent work has highlighted the likely importance of prothrombin and factor VIII levels in this regard.