Platelet physiology and antiplatelet agents

Abstract

Apart from the central beneficial role platelets play in hemostasis, they are also involved in atherothrombotic diseases. Here, we review the current knowledge of platelet intracellular signal transduction pathways involved in platelet adhesion, activation, amplification of the activation signal and aggregation, as well as pathways limiting platelet aggregation. A thorough understanding of these pathways allows explanation of the mechanism of action of existing antiplatelet agents, but also helps to identify targets for novel drug development.

Model systems of genetically modified platelets

“…3 The subsequent rise in intracellular calcium triggers conformational changes in integrin receptors, degranulation, exposition of a procoagulant surface, and generation and release of secondary agonists resulting in a thrombus that will cover the site of injury and prevent further blood loss. 4 Platelets are furthermore an important factor in thrombotic events, such as stroke and myocardial infarction. 5 To identify more proteins regulating platelet function that may serve as new targets for the development of anti-thrombotics or in the prevention of bleeding, the platelet research community has seen the completion of several large-scale screening programs and the spectacular rise in the "platelet-omics" field.…”

Antiplatelet therapy: present status and its future directions

“…In high-shear conditions of arterioles, for effectively adhering, platelets require another receptor of collagen, i.e., GPIb which form a complex with factors V and IX along with its main ligand, von Willebrand Factor (vWF). 6 Binding of platelets through its direct collagen receptors triggers tyrosine kinase activity and induce the platelet activation cascade. This induces the conformational change in the platelets, causing the release of chemical mediators such as ADP, TXA2, 5HT, PAF, and thrombin.…”

“…Thrombin, or activated factor II, being a serine protease, hydrolyses fi brinogen to fi brin & forms a plug. [4][5][6] Figure 1: The receptors present on the surface of platelets.…”

“…Ticlopidine is associated with neutropenia and TTP hence not preferred much. 6 Since clopidogrel requires hepatic cytochrome P450 metabolism to release its active metabolite, there is considerable inter individual variability in response to clopidogrel, with 5-10% of patients not responding to its effects, and as many as 25% being only partially responsive to the drug. As with aspirin, the mechanisms underlying variability in response for clopidogrel are multifactorial such as inadequate dosing, non-compliance, gene polymorphisms of the CYP3A4 system, polymorphisms of the P2Y12 receptor, etc.…”

“…vWF forms a bridge between the exposed collagen and interact with the platelets, causing their adhesion to take place to the sub endothelium in the damaged blood vessel wall. 5,6 Therefore, the monoclonal antibodies which target this collagen-vWF-GPIb interaction or which can inhibit another receptor of collagen, i.e., GPVI are being developed for their use in inhibition of platelet aggregation. GPVI is the most attractive target as it was seen that either its inhibition or absence offered huge protection from the development and progression of arterial thrombosis, with no major bleeding in mice.…”