Zinc: an endogenous and exogenous regulator of platelet function during hemostasis and thrombosis.

Zinc (Zn) is an essential micronutrient and the second most abundant trace metal in the human body. The important role that Zn plays in hemostasis is exemplified by platelet-related bleeding phenotypes coinciding with dietary Zn deficiency. These phenotypes are rectified upon Zn supplementation. Labile (unbound) Zn is present in the plasma at micromolar levels, but is also detected in atherosclerotic plaques, and released from platelet α granules. Therefore, it is likely that localized Zn concentrations are higher at sites of thrombosis and hemostasis. Exogenous Zn is a regulator of the hemostatic responses, with roles during coagulation and platelet activation. Extracellular Zn gains access to the platelet cytosol and induces full platelet activation at high concentrations, and potentiates platelets to activation by conventional agonists at lower concentrations. Zn-induced platelet activation is dependent on PKC and integrin αβ, and is associated with tyrosine phosphorylation of platelet proteins. Agonist evoked platelet activation results in intracellular Zn ([Zn]) fluctuations that are sensitive to the platelet redox state. Increases in [Zn] correlate with activation responses, including shape change, granule release, αβ activation and phosphatidyl-serine exposure, consistent with a role as a second messenger. This review provides insight into the numerous demonstrated and potential roles for Zn in platelet function during thrombosis and hemostasis, highlighting its increasing acceptance as an intracellular and extracellular platelet regulatory agent.