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Acute coronary artery occlusion is a dynamic process that involves three essential processes: compromise of vascular integrity, platelet activation and aggregation, and acceleration of the coagulation cascade with fibrin formation. Although the role of thrombin (factor IIa) is well documented in blood coagulation, fibrin formation, and thrombus stabilization, it is also central to interplay among these processes. Angiographic, intravascular ultrasound (IVUS), and pathologic studies during acute coronary syndromes (ACS) have helped delineate the pathophysiology of coronary artery occlusion: atherosclerotic plaque rupture leads to release of tissue factor (TF), which has broad impact to stimulate platelets and generate thrombin. TF activates factor VII, which activates the common pathway via the extrinsic pathway, and also activates factor IX, activating the intrinsic pathway (Fig. 15-1).1 Subsequent generation of factor Xa leads to thrombin activation.


Coagulation cascade with sites of action of common antithrombin therapies. LMWH, low-molecular-weight heparin; UFH, unfractionated heparin. (Modified with permission from Alquwaizani M, Buckley L, Adams C, Fanikos J. Anticoagulants: A review of the pharmacology, dosing and complications. Curr Emerg Hosp Med Rep. 2013;1:83-97.)

Inhibition of thrombin, along with the other serine proteases, is crucial in breaking this cycle and allowing either endogenous or exogenous fibrinolysis to occur. Thrombin is a well-suited target for therapeutics given its central role in arterial thrombosis. Current clinically available anticoagulants work via direct inhibition of either thrombin or an immediate upstream target, largely factor Xa.


Mechanisms of Action

Heparin was first studied in ACS in 1988 and has been a mainstay for acute ischemic heart disease therapy since then. Heparins represent a heterogeneous group of negatively charged, heavily sulfated glycosaminoglycans. Heparins have a heterogeneous effect on the coagulation cascade, although most of the effect is mediated through binding with antithrombin, causing a conformational change leading to inactivation of multiple enzymes in the coagulation cascade. While factors IXa, XIa, and XIIa are targets as well, thrombin (factor IIa) and factor Xa are the most clinically relevant. As mentioned, thrombin inhibition leads to inhibition of fibrin formation and factors needed for its cross-linking and stabilization. Heparins also have an impact on arterial and venous thrombosis by increasing vessel wall permeability and binding to von Willebrand factor, leading to some inhibition in platelet activation. Unfractionated heparin (UFH) represents a heterogeneous compound with some important limitations:

  • Propensity to bind to plasma proteins

  • Inability to inhibit clot-bound thrombin

  • Does not inhibit thrombin’s activation of platelets via protease-activated receptor-1 (PAR-1)

  • Can induce an immune-mediated response, leading to heparin-induced thrombocytopenia

Low-molecular-weight heparins (LMWHs) are modified derivatives of UFH created by depolymerizing the larger heparin molecules. LMWH exert most of their anticoagulant effect via antithrombin-mediated inhibition of coagulation factors. Factor Xa is more affected than factor IIa in a ratio of ...

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