Defective Zn homeostasis in mouse and human platelets with α- and δ-storage pool diseases.

Zinc (Zn) can modulate platelet and coagulation activation pathways, including fibrin formation. Here, we studied the (patho)physiological consequences of abnormal platelet Zn storage and release. To visualize Zn storage in human and mouse platelets, the Zn 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 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 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 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. Altogether, we conclude that the release of ionic Zn store from secretory granules upon platelet activation contributes to the procoagulant role of Zn in platelet-dependent fibrin formation.