TY - JOUR
T1 - Defective Zn2+ homeostasis in mouse and human platelets with α- and δ-storage pool diseases
AU - Gotru, Sanjeev Kiran
AU - van Geffen, Johanna P.
AU - Nagy, Magdolna
AU - Mammadova-Bach, Elmina
AU - Eilenberger, Julia
AU - Volz, Julia
AU - Manukjan, Georgi
AU - Schulze, Harald
AU - Wagner, Leonard
AU - Eber, Stefan
AU - Schambeck, Christian
AU - Deppermann, Carsten
AU - Brouns, Sanne
AU - Nurden, Paquita
AU - Greinacher, Andreas
AU - Sachs, Ulrich
AU - Nieswandt, Bernhard
AU - Hermanns, Heike M.
AU - Heemskerk, Johan W. M.
AU - Braun, Attila
N1 - Funding Information:
The authors thank Mike Friedrich from the Bioimaging center (Rudolf Virchow Center, Würzburg) for excellent technical support. This work was supported by grants from This study was supported by the Interreg Euregio Meuse Rhine programme PolyValve to M.N., S.B. and J.W.M.H.; and by the Deutsche Forschungsgemeinschaft project number 374031971-TRR 240/A09 to A.B. and H.M.H.
Publisher Copyright:
© 2019, The Author(s).
PY - 2019/6/6
Y1 - 2019/6/6
N2 - 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.
AB - 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.
KW - ZINC
KW - METALLOTHIONEIN
KW - HEMOSTASIS
KW - ACTIVATION
KW - SECRETION
KW - NBEAL2
KW - PLASMA
KW - ROLES
U2 - 10.1038/s41598-019-44751-w
DO - 10.1038/s41598-019-44751-w
M3 - Article
C2 - 31171812
SN - 2045-2322
VL - 9
JO - Scientific Reports
JF - Scientific Reports
M1 - 8333
ER -