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INTRODUCTION

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The hemostatic system is composed of vascular endothelium, platelets, and the coagulation and fibrinolytic system. An injury to the vessel sets off a chain reaction of events which prevent excessive bleeding but maintains a balance with blood fluidity. An imbalance can cause thrombosis, such as stroke, myocardial infarction, or pulmonary embolus.

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Platelets make up the initial response for adequate hemostasis during vascular injury via three steps: adhesion, amplification, and aggregation. The initial injury attracts circulating platelets to adhere to the subendothelial matrix as the primary hemostasis phase. Platelets express a series of receptors (GPVI, GPIbα, GPIIb/IIIa) that are exposed on its surface for collagen and von Willebrand factors (vWF) to dock at the injured site. The adhesion produces a signaling pathway that activates platelets, causing a conformational shape change and release of mediators to recruit additional platelets during the amplification phase. These mediators are synthesized through the COX-1 and COX-2 pathways to generate thromboxane A2, a potent vasodilator, and ADP. Both molecules locally activate ambient platelets. In the final step of thrombus formation, the GP IIb/IIIa receptors of activated platelets bind to free floating fibrinogen and vWF. Bound fibrinogen then bridges adjacent platelets to form linkages. Antiplatelet agents target different receptors to limit the adhesion, activation, and aggregation.

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INHIBITORS OF PLATELET ADHESION

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Platelets binding to vascular collagen require the interaction of glycoprotein (GP) Ib/IX/V on the platelets with the collagen receptors (α2β1 and GPVI). Therefore, antagonizing GPIb or collagen binding would interfere with platelet activation and secretion of modulators, which in turn prevent possible restenosis. Different categories of GP1b antagonists have been utilized ranging from the purification of snake venom protein to isolated recombinant peptides specific to the GPIb docking protein. Although the in vitro use of snake venom toxin has antiplatelets effect, its in vivo use causes serious thrombocytopenia limiting clinical approval.

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On the other hand, antagonized recombinant peptides to the GPIb-mediated platelet adhesion receptor cause the lack of adhesion and minimal bleeding in various animal studies. The drawback is the short plasma half-life of the peptide thus requiring a continuous infusion. The newest therapy to emerge is the use of monoclonal antibodies to GPIb. Specifically, humanized Fab fragment of 6B4 has demonstrated promising preliminary results in animal model with no effect on platelet count or bleeding time.

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INHIBITORS OF PLATELET ACTIVATION AND AMPLIFICATION

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Activation of platelets causes the release of thromboxane A2 (TXA2) and other mediators to allow recruitment at the vascular injury site. Aspirin, the most widely used antiplatelet drug, blocks TXA2 synthesis by irreversible acetylating amino acid of arachidonate cyclooxygenase (COX-1, COX-2). This ultimately reduces TXA2 synthesis by 98%. A small dose of 30 mg is effective and there does not seem to be any additional benefit on platelet activity at doses greater than 300 mg.

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