Blood Coagulation and the Risk of Atherothrombosis

H.   M.H.   Spronk; H.   T.   Cate

Abstract

Atherosclerosis is a multifactorial disease that is caused by many years of exposure to atherogenic stimuli that already at a young age lead to early lesions, the so-called "fatty streaks". One of the mechanisms involved in atherogenesis is the activated blood coagulation system, but its primary role in this process has not been established. From the fatty streak onwards, evidence of activated coagulation is histologically present in the form of fibrin/fibrinogen molecules. With advancing lesions, the presence of tissue factor protein, introduced by invading macrophages or locally expressed by vascular smooth muscle cells (VSMC) becomes more prominent. Tissue factor has been shown to be an important agonist of arterial thrombosis upon erosion of the luminal plaque surface or frank rupture of plaques. Recent data indicate the production of factor VII, probably expressed by VSMC in plaque lesions, which raises the possibility that formation of a catalytic tissue factor/factor VIIa complex occurs in the atherosclerotic vessel wall. Theoretically, such a complex could then induce local generation of thrombin and fibrin molecules, but its precise role is still unknown. While fibrinogen/fibrin molecules participate in early plaque lesions, increased activity of systemic coagulation is of no major influence on the risk of arterial thrombosis, except in rare cases where a number of specific procoagulant forces collide. Despite the presence of tissue factor - factor VII complex it is unlikely that all fibrin in the atherosclerotic plaque is the direct result from local clotting activity. Evidence is accumulating that the tissue factor/factor VII complex is involved in important coagulation-independent biological processes (inflammation, cell migration, apoptosis), either via direct signal transduction through tissue factor or by (in)direct activation of protease activated receptors. The presence of localized vascular "mini-cascades" of coagulation proteins may target a new role of coagulation in vessel wall remodeling and plaque vulnerability.

Keywords: Coagulation, atherothrombosis, atherosclerosis, thrombin, fibrinogen

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