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

Sanjeev Kiran Gotru, Johanna P. van Geffen, Magdolna Nagy, Elmina Mammadova-Bach, Julia Eilenberger, Julia Volz, Georgi Manukjan, Harald Schulze, Leonard Wagner, Stefan Eber, Christian Schambeck, Carsten Deppermann, Sanne Brouns, Paquita Nurden, Andreas Greinacher, Ulrich Sachs, Bernhard Nieswandt, Heike M. Hermanns, Johan W. M. Heemskerk, Attila Braun*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

12 Citations (Web of Science)

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 alpha/delta 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 alpha-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.

Original languageEnglish
Article number8333
Number of pages7
JournalScientific Reports
Volume9
DOIs
Publication statusPublished - 6 Jun 2019

Keywords

  • ZINC
  • METALLOTHIONEIN
  • HEMOSTASIS
  • ACTIVATION
  • SECRETION
  • NBEAL2
  • PLASMA
  • ROLES

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