The platelet fibrinogen receptor: from megakaryocyte to the mortuary

Abstract

Platelets are integral to normal haemostatic function and act to control vascular haemorrhage with the formation of a stable clot. The fibrinogen receptor (glycoprotein IIb/IIIa [GPIIb/IIIa]) is the most abundant platelet integrin and, by binding fibrinogen, facilitates irreversible binding of platelets to the exposed extracellular matrix and enables the cross-linking of adjacent platelets. The vital role of GPIIb/IIIa requires tight control of both its synthesis and function. After transcription from distinct domains on chromosome 17, the two subunits of the heterodimer are carefully directed through organelles with intricate regulatory steps designed to prevent the cellular expression of a dysfunctional receptor. Similarly, exquisite control of platelet activation via bidirectional signalling acts to limit the inappropriate and excessive formation of platelet-mediated thrombus. However, the enormous diversity of genetic mutations in the fibrinogen receptor has resulted in a number of allelic variants becoming established. The Pro(33) polymorphism in GPIIIa is associated with increased cardiovascular risk due to a pathological persistence of outside-in signalling once fibrinogen has dissociated from the receptor. The polymorphism has also been associated with the phenomenon of aspirin resistance, although larger epidemiological studies are required to establish this conclusively. A failure of appropriate receptor function due to a diverse range of mutations in both structural and signalling domains, results in the bleeding diathesis Glanzmann's thrombasthaenia. GPIIb/IIIa inhibitors were the first rationally designed anti-platelet drugs and have proven to be a successful therapeutic option in high-risk primary coronary intervention. As our understanding of bidirectional signalling improves, more subtle and directed therapeutic strategies may be developed.

Figure 1

Synthesis of the fibrinogen receptor. (i) The subunits are transcribed from independent domains of chromosome 17q21.32, resulting in a pro-GPIIb moiety with heavy and light chains and a mature GPIIIa chain. (ii) The pro-GPIIb moiety is glycosylated and associates with the mature GPIIIa chain within the endoplasmic reticulum. (iii) Uncomplexed subunits are degraded by the calnexin cycle. (iv) Proteolytic cleavage of the pro-GPIIb subunit within the Golgi apparatus yields the mature GPIIb/IIIa. (v) Mature GPIIb/IIIa is transported to the plasma membrane or stored in alpha granules. G, glycoslation