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INTRODUCTION

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  • Venous thromboembolism (VTE) results from clot formation in the venous circulation and is manifested as deep vein thrombosis (DVT) and pulmonary embolism (PE).

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PATHOPHYSIOLOGY

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  • Risk factors for VTE include increasing age, history of VTE, and aspects related to Virchow’s triad: (1) blood stasis (eg, immobility and obesity); (2) vascular injury (eg, surgery, trauma, and venous catheters); and (3) hypercoagulability (eg, malignancy, coagulation factor abnormalities, antiphospholipid antibodies, and certain drugs).

  • The most common inherited hypercoagulability disorder is activated protein C (aPC) resistance (Caucasian prevalence 2%–7%), which increases the risk of VTE threefold. Most aPC resistance results from a factor V gene mutation (known as factor V Leiden) that renders it resistant to degradation by aPC.

  • The prothrombin G20210A mutation is the second most frequent inherited hypercoagulability disorder (Caucasian prevalence 2%–4%) and imparts a threefold increased risk of VTE. The mutation increases circulating prothrombin and may enhance thrombin generation.

  • Inherited deficiencies of protein C, protein S, and antithrombin occur in less than 1% of the population and may increase the lifetime VTE risk by as much as sevenfold.

  • Normal hemostasis maintains integrity of the circulatory system after blood vessel damage. Disruption of the endothelial cell lining with injury results in platelet activation and tissue-factor–mediated initiation of the clotting factor cascade, culminating in formation of thrombin and ultimately a fibrin clot. In contrast to physiologic hemostasis, pathologic VTE occurs in the absence of gross vessel wall damage and may be triggered by tissue factor (TF) brought to the clot formation site by circulating microparticles. Clots causing VTE impair blood flow and often cause complete vessel occlusion.

  • Exposure of blood to damaged vessel endothelium causes platelets to become activated after binding to adhesion proteins (eg, von Willebrand factor and collagen). Activated platelets recruit additional platelets, causing formation of a platelet thrombus. Activated platelets change shape and release components that sustain further thrombus formation at the site. Activated platelets accumulating in the thrombus express the adhesion molecule P-selectin, which facilitates capture of blood-borne microparticles bearing tissue-factor, thereby triggering fibrin clot formation via the coagulation cascade.

  • The conceptual model for the coagulation cascade involves reactions that occur on cell surfaces in three overlapping phases (Fig. 14–1):

    • Initiation: A TF/VIIa complex (known as extrinsic tenase or X-ase) on cells bearing TF that have been exposed after vessel injury or captured via P-selectin activates limited amounts of factors IX and X. The resulting factor Xa then associates with factor Va to form the prothrombinase complex, which cleaves prothrombin (factor II) to generate a small amount of thrombin (factor IIa). Factor IXa moves to the surface of activated platelets in the growing platelet thrombus. Tissue factor pathway inhibitor (TFPI) regulates TF/VIIa-induced coagulation, rapidly terminating the initiation phase.

    • Amplification: Thrombin produced during initiation activates factors V and VIII, which bind to platelet surfaces and support the large-scale thrombin generation occurring during the propagation phase. Platelet-bound factor XI is also activated ...

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