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INTRODUCTION

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Most patients who develop an arterial or venous thrombosis do so because of local factors (e.g., a focal atherosclerotic lesion producing a thrombus in an coronary artery) or major systemic events (e.g., trauma, surgery, or prolonged immobilization). However, several inherited genetic mutations predispose patients to venous thromboembolism with some studies finding up to 50% of patients with venous thromboembolism having a thrombophilia (Table 234-1).1 Importantly, risk for clotting from genetic, acquired, and environmental factors is additive or even multiplicative; a patient with mild deficiency may develop a deep venous thrombosis when started on estrogen.2

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TABLE 234-1Hypercoagulable States
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PATHOPHYSIOLOGY

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Several physiologic systems ensure that blood clots do not extend beyond the necessary area. The two most clinically important pathways involve antithrombin and protein C (see Figures 232-1 and 232-2 and Table 234-2). Antithrombin is a plasma-based protein that inhibits several activated coagulation factors, primarily thrombin, factor Xa, and factor IXa. Both unfractionated heparin and low-molecular-weight heparin possess anticoagulant activity by increasing the rate by which antithrombin inhibits these factors: approximately 2000- to 4000-fold for thrombin, about 500- to 1000-fold for factor Xa, and about a million-fold for factor IXa. Protein C is a vitamin K–dependent plasma protein that binds to the endothelial cell surface and is activated by thrombin. Activated protein C cleaves both factor Va and factor VIIIa, inhibiting both the common pathway and the intrinsic pathway. Protein S, another vitamin K–dependent plasma protein, is a cofactor that increases the inhibitory action of activated protein C by about 20-fold.

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TABLE 234-2Functions of Coagulation Proteins in Protein C and Antithrombin Systems

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