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

Zinc (Zn²⁺) is an essential micronutrient and the second most abundant trace metal in the human body. The important role that Zn²⁺ plays in hemostasis is exemplified by platelet-related bleeding phenotypes coinciding with dietary Zn²⁺ deficiency. These phenotypes are rectified upon Zn²⁺ supplementation. Labile (unbound) Zn²⁺ 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 Zn²⁺ concentrations are higher at sites of thrombosis and hemostasis. Exogenous Zn²⁺ is a regulator of the hemostatic responses, with roles during coagulation and platelet activation. Extracellular Zn²⁺ 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. Zn²⁺-induced platelet activation is dependent on PKC and integrin α_IIbβ₃, and is associated with tyrosine phosphorylation of platelet proteins. Agonist evoked platelet activation results in intracellular Zn²⁺ ([Zn²⁺]_i) fluctuations that are sensitive to the platelet redox state. Increases in [Zn²⁺]_i correlate with activation responses, including shape change, granule release, α_IIbβ₃ 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 Zn²⁺ in platelet function during thrombosis and hemostasis, highlighting its increasing acceptance as an intracellular and extracellular platelet regulatory agent.