13.02.2 Platelet Aggregation and Anti-Platelet Drugs

When a blood vessel is damaged, this exposes underlying collagen, and platelets stick to collagen. The local mediator responsible for this is thromboxane-A₂ (TXA₂). Thus, there is activation of COX-1 in the platelets, and the intermediates from this, in the presence of thromboxanes synthase form TXA₂. In turn, TXA₂ stimulates TP receptors on platelets to decrease the activity of adenylate cyclase, leading to decreased cAMP, which promotes platelet aggregation (Figure 13.7).

Figure 13.7 Thromboxane and platelet aggregation (Copyright QUT, Sheila Doggrell)

Platelets do not have a nucleus, and therefore cannot synthesise COX-1. Platelets only have a small supply of COX-1, and once this is used up, there is no more. Low dose aspirin irreversible inhibits COX-1 in platelets, decreasing the amount of intermediates available to be converted to TXA₂. This leads to decreased platelet aggregation.

In contrast, endothelial cells have a plentiful supply of COX-1, and can synthesise more COX-1. Thus, low dose aspirin has no significant effect on the COX-1 in the endothelial cells or on the production of PGI₂ from the endothelial cells, and PGI₂-mediated inhibition of platelet aggregation. Overall, low dose aspirin only leads to decreased TXA₂ and decreased platelet-platelet aggregation. Low dose aspirin selectively inhibits TXA₂ formation to reduce platelet aggregation. Low dose aspirin is used to prevent myocardial infarction and stroke. High dose aspirin inhibits both PGI₂ and TXA₂ formation and has NO EFFECT on platelet aggregation, and will not be useful in the prevention of myocardial infarction or stroke.

Thromboxane is not the only mediator of platelet aggregation. ADP is a potent promoter of platelet aggregation, and this effect of ADP is mediated by purinergic P2Y receptors. Clopidogrel is an antagonist at P2Y receptors and inhibits ADP-induced platelet aggregation (Figure 13.8).

Figure 13.8 Mechanism of action of clopidogrel (Copyright QUT, Sheila Doggrell)

Clopidogrel reduces cardiovascular events in patients with unstable angina, which often leads to coronary artery stenting. Clopidogrel reduces cardiovascular events in patients with unstable angina. As clopidogrel and aspirin inhibit platelet aggregation by different mechanisms, they have an additive effect. Clopidogrel is commonly used in combination with aspirin to prevent vascular events in subjects with unstable angina, recent myocardial infarction, and in stenting.

Activated platelets develop glycoprotein IIb/IIIa receptors, which are receptors for fibrinogen, and mediate aggregation. The GPIIb/IIIa receptor is the final step in platelet aggregation (Figure 13.9). Inhibiting this receptor will reduce platelet aggregation, regardless of what is causing the aggregation (ADP, TXA₂).

Figure 13.9 GPIIb/IIIa receptors (Copyright QUT, Sheila Doggrell)

Abciximab is an antibody to the GPIIb/IIIa receptor, and prevents platelet aggregation. Abciximab is used in combination with aspirin and the anti-coagulant heparin, when angioplasty or stenting is undertaken for coronary thrombosis. Used during these procedures, abciximab decreases the incidence of recurrent myocardial infarction and death. Abciximab is administered intravenously, as a bolus, followed by a continuous infusion of a lower dose for 12 hours. The major side effect of abciximab, like all anti-thrombotic drugs is an increased incidence of bleeding.