Redox modification of platelet glycoproteins.

Platelets contain several glycoprotein receptors including the adhesion receptor glycoprotein Ib and the fibrinogen receptor glycoprotein IIbIIIa, also know as the alphaIIb betaIIIa integrin. Both of these receptors contain thiol groups and vicinal thiols representing redox sensitive sites are present in alphaIIb betaIIIa. Disulfide isomerases such as protein disulfide isomerase (PDI) that are on or recruited to the platelet surface have a role in platelet aggregation. Dynamic rearrangement of disulfide bonds in receptor signaling and platelet activation is a developing concept that requires an attacking thiol. Biochemically, a role for disulfide isomerization is suggested as the alphaIIb betaIIIa integrin undergoes major structural changes upon activation centered around a disulfide knot in the integrin. Additionally, the P2Y12 ADP receptor is involved in platelet activation by most platelet agonists and contains extracellular thiols, making it a possible site for redox modification of platelet aggregation. Various forms of redox modulation of thiols or disulfides in platelet glycoproteins exist. These include modification by low molecular weight thiols such as reduced glutathione or homocysteine, oxidized glutathione or by nitric oxide (NO) derived from s-nitrosothiols. Levels of these redox compounds change in various disease states and in some cases physiologic concentrations of these compounds have been shown to modify platelet responsiveness. Additionally, platelets themselves contain a transplasma membrane redox system capable of reducing extracellular disulfide bonds. It is likely that a redox homeostasis exists in blood with the redox environment being controlled in a way analogous to the control of ionized calcium levels or the pH of blood. Changes in this homeostasis induced by disease states or pharmacologic agents that modify the platelet redox environment will modify platelet function.