Paul A. Gurbel, and Udaya S. Tantry JCHF 2014;2:1-14 Antithtrombotic Therapy Targets in Heart Failure During arterial thrombosis, at the site of “altered” vessel wall, exposure of the subendothelial matrix leads to adhesion and activation of platelets and subsequent release of secondary agonists, thromboxane A2 (TxA2) and adenosine diphosphate (ADP). These 2 locally-generated secondary agonists play a critical role in the sustained activation of glycoprotein (GP) IIb/IIIa receptors and stable platelet aggregation. During venous thrombosis, tissue factor (TF) delivered by microparticles to the site of vessel wall injury binds to autoactivated factor (F) VII (VIIa) to form TF-FVIIa complex, which in turn activates factor X to Xa. Initial formation of small amounts of Xa initiates the coagulation process on the surface of activated platelets and leukocytes, where large amounts of thrombin are generated. During arterial thrombosis, TF is exposed at the site of plaque rupture and initiates the coagulation process. Xa along with Va converts FII to FIIa. Simultaneously, trace amounts of thrombin activate FVIII and FV, which dramatically enhances catalytic activity of FIX and FX, respectively. Thrombin-activated FXIIIa catalyzes the formation of covalent cross-links between adjacent fibrin chains to form polymerized fibrin. Finally, together with aggregated platelets, the polymerized fibrin network leads to the formation of a stable, occlusive, platelet-fibrin clot and subsequent ischemic events. In venous thrombosis, the coagulation pathway plays a major role resulting in fibrin-rich clot formation, whereas in arterial thrombosis, platelet activation and aggregation play a major role resulting in platelet-rich thrombus formation. Therefore, the management of venous thrombosis is mainly centered around anticoagulation strategies whereas management of arterial thrombosis is focused on antiplatelet strategies. Vitamin K is a cofactor that promotes the biosynthesis of γ-carboxyglutamic acid residues in coagulation factor proteins that are essential for biological activity. Anticoagulation strategies include warfarin that acts by inhibiting the synthesis of vitamin K-dependent clotting factors, II, VII, IX, and X, and the anticoagulant proteins C and S. Warfarin inhibits clotting factor synthesis by inhibition of vitamin K epoxide reductase (VKORC1), thereby reducing the regeneration of vitamin K1 epoxide. Other anticoagulants include direct thrombin inhibitors such as bivalirudin and dabigatran; direct Xa inhibitors such as rivaroxaban and apixaban; LMWH, heparin, and fondaparinux bind to antithrombin (AT), facilitating its inhibition of coagulation factors. Fondaparinux and LMWH preferentially inhibit Xa as compared to heparin, which more greatly inhibits IIa. Antiplatelet strategies include inhibition of platelet cyclooxygenase-1 enzyme by aspirin resulting in the inhibition of generation of TxA2 and TxA2-induced platelet aggregation; inhibition of ADP receptor, P2Y12, by clopidogrel, prasugrel, ticagrelor, and cangrelor; inhibition of activated GPIIb/IIIa receptor by abciximab, eptifibatide, and tirofiban; and vorapaxar that inhibits thrombin receptor protease activated receptor (PAR)-1. Factor II = prothrombin; Factor IIa = thrombin; LMWH = low molecular weight heparin; TP = thromboxane A2 receptor; vWF = von Willebrand factor. Paul A. Gurbel, and Udaya S. Tantry JCHF 2014;2:1-14 American College of Cardiology Foundation