Defective Zn(2+) homeostasis in mouse and human platelets with α- and δ-storage pool diseases

Zinc (Zn(2+)) can modulate platelet and coagulation activation pathways, including fibrin formation. Here, we studied the (patho)physiological consequences of abnormal platelet Zn(2+) storage and release. To visualize Zn(2+) storage in human and mouse platelets, the Zn(2+) specific fluorescent dye FluoZin3 was used. In resting platelets, the dye transiently accumulated into distinct cytosolic puncta, which were lost upon platelet activation. Platelets isolated from Unc13d(−/−) mice, characterized by combined defects of α/δ granular release, showed a markedly impaired Zn(2+) release upon activation. Platelets from Nbeal2(−/−) mice mimicking Gray platelet syndrome (GPS), characterized by primarily loss of the α-granule content, had strongly reduced Zn(2+) levels, which was also confirmed in primary megakaryocytes. In human platelets isolated from patients with GPS, Hermansky-Pudlak Syndrome (HPS) and Storage Pool Disease (SPD) altered Zn(2+) homeostasis was detected. In turbidity and flow based assays, platelet-dependent fibrin formation was impaired in both Nbeal2(−/−) and Unc13d(−/−) mice, and the impairment could be partially restored by extracellular Zn(2+). Altogether, we conclude that the release of ionic Zn(2+) store from secretory granules upon platelet activation contributes to the procoagulant role of Zn(2+) in platelet-dependent fibrin formation.