Elevated factor VIII levels and the risk of thrombosis.

In vivo, a delicate balance exists between fibrin formation and fibrinolysis. Reduced blood flow, changes in the vessel wall, and changes in blood composition (hypercoagulability)1 may all result in a disturbance of this balance, which favors fibrin formation and ultimately may lead to the formation of occlusive thrombi. Venous thromboembolism is the result of clot formation in a vein at sites of reduced blood flow. Arterial thrombosis involves the formation of platelet aggregates at high shear rates at sites of vessel-wall injury. Classic acquired risk factors for venous thrombosis include trauma, immobilization, pregnancy, surgery, malignancy, and infection. These are all factors that may cause tissue damage, stasis of the blood, or changes in blood composition. Inherited risk factors for venous thrombosis,2–5 most of which concern defects in the procoagulant and anticoagulant pathways, account for a substantial proportion of all thrombotic events. Table 1 summarizes prevalences and relative risks of established genetic risk factors.6–9 These risk factors include factor V Leiden (resistance to activated protein C [APC]),9 prothrombin 20210A,8 and deficiencies in antithrombin,2 protein C,3,4 and protein S.5,10,11 Elevated fibrinogen,12 antiphospholipid antibodies,13 and mild hyperhomocysteinemia14 are examples of laboratory phenotypes associated with venous thrombosis. Some of these phenotypes have also been found to be associated with arterial thrombosis.15–17 Whether this is also true for genetic risk factors such as factor V Leiden or the prothrombin 20210A allele is still uncertain.18–26 Despite growing insight in the pathogenesis of thrombophilia, the cause of many thrombotic episodes remains unknown. Recently, new laboratory phenotypes that are associated with an increased risk of venous thrombosis have been reported .27–29 One of these is an elevated factor VIII level. High factor VIII levels are a common risk factor for venous thrombosis27,30,31 and may also be associated with the risk of arterial thrombosis in coronary heart disease32,33 and stroke.34 The regulation of plasma factor VIII levels is complex. Most factor VIII circulates as a complex with von Willebrand factor (vWF),35,36 the levels of which are known to be dependent on factors such as blood group37–39 and endothelial stimulation.40,41 This highly complicates the study of the molecular basis of elevated factor VIII levels. In the present review, we will summarize the present knowledge on the relation between factor VIII and thrombosis and discuss the possible determinants of elevated factor VIII levels in plasma.