Platelets
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Prasugrel is a third-generation thienopyridine that inhibits ADP-induced platelet activation by irreversibly blocking the P2Y12 receptor. Given in healthy volunteers in dosages used clinically, it invariably inhibits platelet aggregation. ⋯ However, cases of inadequate platelet inhibition or of the so-called 'resistance' to prasugrel have been occasionally reported. The focus of this review is prasugrel resistance prevalence, mechanisms and potential clinical implications.
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Although there are many new and effective anti-P2Y(12) drugs available, clopidogrel in its original or generic forms will probably remain the most widely used and cheaper option. As clopidogrel is a pro-drug, there is marked heterogeneity in drug responsiveness between individuals and lack of responsiveness is associated with poorer clinical outcomes. ⋯ Monitoring of P2Y(12) inhibition and/or identification of loss of function cytochrome P-450 genotypes could, therefore, offer the potential of tailoring therapy by identifying poor responders to clopidogrel and optimizing the levels of platelet inhibition using, for example, alternative drugs such as prasugrel or ticagrelor. The question remains whether any of these tests have prognostic utility with a defined therapeutic window to reliably identify hypo or hyper-responsive patients who may have an increased risk of thrombosis or bleeding, respectively? Once such patients are identified, can the tests then be subsequently used to demonstrate a change or improvement in platelet reactivity by using alternative therapies and equate this with improved clinical outcome? In this review, we describe an overview of the current platelet and genetic tests available and discuss whether these tests will ever become used routinely.
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Described 40 years ago as cell dust, microparticles (MPs) are now considered a key component in the haemostatic response. Owing to their plasma membrane reactivity, platelets are believed to constitute the main source of circulating procoagulant microparticles and behave as true sensors for the haemostatic response. Erythrocytes, leukocytes and endothelial cells are also able to shed MPs in the blood flow, their respective contribution varying with the pathophysiologic circumstances and extent of the cellular damage. ⋯ In specific pathophysiologic contents with elevated levels of circulating TF+-MPs, accessible TFPI at the MP surface would be overwhelmed. Beyond their procoagulant properties demonstrated in vitro, a number of pieces of evidence points to procoagulant MPs as efficient effectors in the haemostatic response, and as pathogenic markers of thrombotic disorders and vascular damage. This review will focus on the pathophysiological significance of platelet-derived MPs and their interaction with vascular cells.
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Essential thrombocythaemia (ET) is associated with a broad spectrum of microvascular circulation disturbances including erythromelalgia and its ischaemic complications, episodic neurological symptoms of atypical and typical transient ischaemic attacks (TIAs), transient ocular ischaemic attacks, acute coronary syndromes, and superficial 'thrombophlebitis'. The microvascular circulation disturbances are caused by spontaneous activation and aggregation of hypersensitive thrombocythaemic platelets at high shear stress in the endarterial microcirculation involving the peripheral, cerebral and coronary circulation. As this microvascular syndrome is a pathognomonic feature of essential thrombocythaemia and of thrombocythaemia associated with polycythaemia vera (PV) in complete remission with normal haematocrit, we have labelled these two variants of thrombocythaemia as thrombocythaemia vera. ⋯ On top of this, major arterial and venous thrombotic events and haemorrhages are related to increased haematocrit, red cell mass and its concomitant increased blood viscosity. Correction of increased blood viscosity and haematocrit to normal values (0.40-0.44) by bloodletting alone will significantly reduce the risk of major thrombotic complications, but does not prevent the microvascular circulation disturbances because thrombocythaemia persists. The microvascular syndrome associated with thrombocythaemia in PV patients in remission after bloodletting is best controlled by low-dose aspirin (50-100 mg/day) or by reduction of platelet count to normal (< 350 x 10(9)/l).