Platelets Function and Cardiovascular Events in Patients With End Stage Renal Disease

Background Platelets play an important role in cardiovascular disease both in the pathogenesis of atherosclerosis and in the development of acute thrombotic events. Their importance in coronary disease and in acute coronary syndromes is indirectly confirmed by the benefit of antiplatelet agents (particularly aspirin, clopidogrel, ticlopidine, and the glycoprotein IIb/IIIa inhibitors) in these disorders. Cardiovascular disease is the single best predictor of mortality in patients with end-stage renal disease, as it accounts for almost 50 percent of deaths. Patients with end stage renal disease (ESRD) have an increased tendency to bleeding due to platelet dysfunction that can be partly corrected by either hemodialysis or peritoneal dialysis in approximately two-thirds of cases. Currently there is only scant data concerning the relations between platelet function and cardiovascular risk in patients with ESRD.

Platelets, platelet products, and thrombosis play important and proximate causal roles in the occurrence of acute occlusive vascular events such as MI and ischemic stroke. The disruption of platelet and fibrin rich atherosclerotic plaques may lead to enhanced platelet deposition, and ultimately the formation of a thrombus that can precipitate an acute clinical event. The following observations are compatible with the importance of platelet thrombus formation in acute ischemic syndromes:

• Thrombus formation within a coronary vessel is the acute precipitating event in most unstable ischemic coronary syndromes, as documented by angiographic and pathologic studies . Among patients with sudden death due to coronary thrombosis, the thrombi typically have a layered appearance indicative of episodic growth. Episodic growth may alternate with intermittent fragmentation of the thrombus, leading to distal embolization of both thrombus and platelet aggregates and microinfarction.
• Increased platelet-derived thromboxane A2 and other prostaglandin metabolites have been found in patients with acute myocardial infarction and unstable angina, providing biochemical support for platelet activation as the cause of these events.
• Patients with unstable angina have elevated levels of P-selectin, an integral membrane protein involved in platelet adhesion. Pulsatile shear stress, as occurs in stenotic arteries, can cause platelet aggregation via an increased expression of P-selectin. Hydrodynamic shear stress, resulting from plaque rupture, can activate platelets and cause both platelet aggregation (via glycoprotein IIb/IIIa and von Willebrand factor) and platelet-mediated neutrophil aggregation via upregulation of P-selectin. Although levels of P-selectin decrease during the first month after treatment, levels remain higher than normal even with therapy with glycoprotein IIb/IIIa inhibitors, suggesting continued platelet activation.
• Aggregating platelets from patients with acute coronary syndromes produce less nitric oxide than those from patients with stable or no angina. Why this might occur is not known, but impaired nitric oxide production can enhance platelet aggregation and thrombus formation.

Another platelet-related factor believed to contribute to cardiovascular thrombosis is the presence of larger, more reactive platelets in patients with acute ischemic events (19-21). The increase in platelet size, which is in compensation for a persistent decrease in platelet count, results from the ongoing consumption of platelets in unstable angina; this is not seen in an acute myocardial infarction. In addition, platelets from patients with unstable angina, as determined by studying platelet aggregability ex vivo, are hyperaggregable. These effects promote thrombus growth, limitation of blood flow, and acute ischemia.

Except for the important of platelets in occlusive vascular events several studies suggests that they may also have a role in the evolutionary phase of the atherosclerotic plaque. After adhesion to exposed subendothelium following endothelial injury they release vasoactive substances that induce smooth muscle cell migration and proliferation. Platelets may serve as a lipid source in the development of the fatty streak and can promote foam cell formation even in the absence of hyperlipidemia. However, currently there is no clear clinical evidence that platelets contribute to coronary atherosclerosis. In addition, prophylactic therapy with aspirin has not been clearly shown to decrease the atherosclerotic burden.