Defective Zn2+ 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 Fluo...

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Bibliographic Details
Published in:Scientific reports 2019-06, Vol.9 (1), p.8333-8333, Article 8333
Main Authors: Kiran Gotru, Sanjeev, van Geffen, Johanna P., Nagy, Magdolna, Mammadova-Bach, Elmina, Eilenberger, Julia, Volz, Julia, Manukjan, Georgi, Schulze, Harald, Wagner, Leonard, Eber, Stefan, Schambeck, Christian, Deppermann, Carsten, Brouns, Sanne, Nurden, Paquita, Greinacher, Andreas, Sachs, Ulrich, Nieswandt, Bernhard, Hermanns, Heike M., Heemskerk, Johan W. M., Braun, Attila
Format: Article
Language:English
Subjects:
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14/19
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631/45/321
Dyes
Fibrin
Fluorescent indicators
Hermansky-Pudlak syndrome
Homeostasis
Humanities and Social Sciences
Megakaryocytes
Mimicry
multidisciplinary
Platelets
Science
Science (multidisciplinary)
Secretory vesicles
Turbidity
Zinc
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Summary: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.
ISSN:2045-2322
2045-2322
DOI:10.1038/s41598-019-44751-w