The Role of the Platelet Glycoprotein IIb / IIIa in Thrombosis and Haemostasis

Haemostasis is a finely balanced and complex process ideally initiated only in response to disruption of the vascular endothelium as a means of preventing loss of blood from an injured vessel. Deviations from the ideal can lead to serious disease. Firstly, thrombosis, which arises as a consequence of inappropriate platelet-platelet interactions at a region of vessel damaged by atherosclerosis, can lead to occlusion of the affected vessel as in myocardial infarction or stroke. Secondly, loss of the ability of platelets to form aggregates leads to Glanzmann's thrombasthenia (GT) with a tendency to bleed for prolonged periods following injury. Glycoprotein IIb/IIIa (GPIIb/IIIa) plays a major role in the regulation of platelet adhesion and aggregation during haemostasis. Upon platelet activation by an agonist a signalling process is initiated, termed "inside-out" signalling, which gives rise to conformational changes within GPIIb/IIIa. These conformational changes increase the affinity of the receptor for its primary ligand, fibrinogen. Bound fibrinogen then acts as a bridging molecule facilitating the interaction of adjacent platelets. Upon fibrinogen binding GPIIb/IIIa undergoes further conformational changes and through a process termed "outside-in" signalling the receptor signals in to the platelet ultimately resulting in acceleration of the aggregation process. Qualitative or quantitative abnormalities in GPIIb/IIIa give rise to GT, a recessive bleeding disorder, and analysis of affected individuals has provided invaluable insights into the structure/function relationship of this receptor. Due to its critical role in mediating platelet aggregate formation GPIIb/IIIa has become a primary target for the development of antithrombotic agents.