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Sci Rep. 2019 Jun 6;9(1):8333. doi: 10.1038/s41598-019-44751-w.

Defective Zn2+ homeostasis in mouse and human platelets with α- and δ-storage pool diseases.

Author information

1
Institute of Experimental Biomedicine, University Hospital and Rudolf Virchow Center, University of Würzburg, Würzburg, Germany.
2
Department of Biochemistry, CARIM, Maastricht University, Maastricht, The Netherlands.
3
Practice for Pediatric Hematology and Hemostaseology, Munich, Germany.
4
Medical Clinic and Policlinic II, Division of Hepatology, University Hospital Würzburg, Würzburg, Germany.
5
Haemostasikum, Munich, Germany.
6
Institut Hospitalo-Universitaire LIRYC, Plateforme Technologique d'Innovation Biomédicale, Hôpital Xavier Arnozan, Pessac, France.
7
Institute for Immunology and Transfusion Medicine, University Medicine Greifswald, Greifswald, Germany.
8
Institute for Clinical Immunology and Transfusion Medicine, Justus Liebig University, Giessen, Germany.
9
Institute of Experimental Biomedicine, University Hospital and Rudolf Virchow Center, University of Würzburg, Würzburg, Germany. attila.braun@virchow.uni-wuerzburg.de.

Abstract

Zinc (Zn2+) can modulate platelet and coagulation activation pathways, including fibrin formation. Here, we studied the (patho)physiological consequences of abnormal platelet Zn2+ storage and release. To visualize Zn2+ storage in human and mouse platelets, the Zn2+ 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 Zn2+ release upon activation. Platelets from Nbeal2-/- mice mimicking Gray platelet syndrome (GPS), characterized by primarily loss of the α-granule content, had strongly reduced Zn2+ 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 Zn2+ 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 Zn2+. Altogether, we conclude that the release of ionic Zn2+ store from secretory granules upon platelet activation contributes to the procoagulant role of Zn2+ in platelet-dependent fibrin formation.

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