Yale: Acute Coronary Syndromes: Platelet Pathobiology

CONTENTS

Yale University
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Yale

Platelet Pathobiology

In the mid- to late 1980’s, the results of the GISI, TIMI-1 and ISIS-2 trials were reported, forever changing the treatment of acute myocardial infarction (AMI). Treatment of patients presenting to the emergency department with symptoms of myocardial ischemia and appropriate ECG criteria could now be treated proactively with fibrinolytic agents in an attempt to restore patency to the infarct related artery (IRA). The role of aspirin was sometimes less appreciated than the newer, sexier fibrinolytic agents. However, treatment with aspirin itself was associated with a 23% reduction in 5 week vascular mortality in ISIS-2, an effect essentially equal to that of treatment with Streptokinase (SK) alone. Furthermore, the combination of aspirin and streptokinase was 65% more effective than either agent alone at reducing the risk of 5 week vascular mortality. Similar findings were demonstrated in trials of therapeutic regimens for the treatment of NQWMI and unstable angina. In 1990, RISC demonstrated a 57% reduction in relative risk of death or MI in patients with USA or NQWMI. Aspirin quickly became a standard part of treatment protocols for AMI and acute coronary syndromes (ACS).

Aspirin (ASA), acetylsalicylic acid, acts by selectively and irreversibly acetylating platelet cyclooxygenase, blocking the synthesis of prostaglandins and thromboxane A2 (TXA2) from arachadonic acid. TXA2 is a moderately potent agonist of platelet aggregation. It is synthesized and released by activated platelets, inducing further platelet aggregation and constriction of arterial smooth muscle. Inhibition of TXA2 with ASA increases the bleeding time of normal volunteers by 2-3min. However, in the absence of TXA2, platelets will still aggregate in response to thrombin or collagen, the first of which is likely a critical player in the pathogenesis of ACS and reocclusion after successful fibrinolysis.

Members of the newer class of platelet antagonists, the thienopyridines, are thought to inhibit platelet aggregation by blocking the ADP receptor. Ticlopidine and Clopidogrel have an onset of action that is delayed approximately 2-4 days after beginning therapy and are believed to effect the intracellular processing of ADP as well. They do not affect platelet aggregation induced by stimuli such as collagen or thrombin. Whereas typical pharmacoligic doses of ASA inhibit ex-vivo platelet aggregation by approximately 10%, the thienopyridines reduce aggregation by approximately 30%.

The cascade of platelet aggregation begins with exposure of sub-endothelial matrix elements such as collagen or tissue factor. Platelets mediate the primary hemostasis at the injury site by forming a monolayer of platelets bound via their GP Ib receptors to Von Willebrand factor. The platelets become activated, changing shape from smooth discs to spiculated forms, degranulate their alpha and dense granules which contain TXA2, serotonin and other proaggregatory and chemoattractant molecules, and express activated GPIIb/IIIa receptors on their surfaces, ready to bind fibrinogen.

The binding of the dimeric fibrinogen molecule is the final common pathway of platelet aggregation. Fibrinogen binds to the platelet membrane receptor GPIIb/IIIa. GPIIb/IIIa is a calcium dependent heterodimeric glycoprotein of MW 265,000 that is a member of the integrin superfamily of receptors that mediate cell-cell interactions. The receptor is comprised of 2 sub-units, the aIIb and bIII chains. The bIII subunit contains the binding site for fibrinogen, fibronectin and Von Willebrand factor which is a four amino acid sequence, beginning with arginine-glycine-aspartic acid (abbreviated RGD) with a varying fourth amino acid. GPIIb/IIIa is the most densely populated receptor on the platelet surface with approximately 50-80,000 copies per platelet. In the platelet’s basal state, the receptors on the platelet surface are inactive with a lower binding affinity. When the platelet is stimulated, the receptor is more highly expressed on the platelet surface and attains an activated state where it binds fibrinogen and its other ligands much more avidly.

Several therapeutic agents discussed on this site have been developed to inhibit platelet aggregation by blocking the binding of fibrinogen to the GPIIb/IIIa receptor. These GPIIb/IIIa receptor blockers fall into three broad categories: 1) The monoclonal antibodies to the GPIIb/IIIa receptor (abciximab), 2) the intravenous peptide and non-peptide GPIIb/IIIa receptor blockers, and 3) the oral GPIIb/IIIa receptor blockers. Therapeutic doses of these agents are expected to result in 80% inhibition of platelet aggregation, making them almost 10 times as potent as ASA. A final point to consider is the role of thrombin in platelet aggregation. Not only is thrombin the most potent agonist of platelet aggregation known, but a positive feedback loop is present as further thrombin is generated on the surface of activated platelets. Thrombin binds a receptor on the platelet surface, the thrombin receptor substrate, with resultant cleavage of 41amino acids from the n-terminus. The resulting amino terminus is identical to the thrombin receptor agonist peptide (TRAP). TRAP participates in intracellular signalling and an autocatalytic cascade that results in exponential increases in thrombin production. Therefore, as well as being potently stimulated to aggregate by thrombin, platelets participate in its production as well. In the setting of ACS and post fibrinolysis where local thrombin concentrations are likely to be elevated, these pathways could be extremely important.