The procoagulant effect of zinc on fibrin clot formation

Marx, Gerard; Eldor, A

doi:10.1002/ajh.2830190207

Cited by 33 publications

(24 citation statements)

References 25 publications

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“…It is known that platelet-released Zn 2+ can modulate local coagulant reactions, including contact activation and fibrin clotting 9,10,20 . Therefore, we considered that a defective granule biogenesis or granule secretion altering platelet Zn 2+ release, may also affect the fibrin clotting process.…”

Section: Resultsmentioning

confidence: 99%

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

Gotru

Geffen

Nagy

et al. 2019

Sci Rep

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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.

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Section: Resultsmentioning

confidence: 99%

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

Gotru

Geffen

Nagy

et al. 2019

Sci Rep

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“…Initial studies showed that Zn 2+ can inhibit amidolytic activity of thrombin [71,72] and diminishes thrombin-mediated fibrinopeptide A release [73]. Studies by Marx also demonstrated that Zn 2+ can bind fibrinogen and fibrin with Kd values ranging from 8 to 18 µM and with a ratio of six Zn 2+ atoms per fibrin/fibrinogen molecule [66].…”

Section: Zn2+-dependent Hemostasis and Fibrin Clot Formationmentioning

confidence: 99%

Zinc Homeostasis in Platelet-Related Diseases

Mammadova‐Bach

Braun

2019

IJMS

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Zn2+ deficiency in the human population is frequent in underdeveloped countries. Worldwide, approximatively 2 billion people consume Zn2+-deficient diets, accounting for 1–4% of deaths each year, mainly in infants with a compromised immune system. Depending on the severity of Zn2+ deficiency, clinical symptoms are associated with impaired wound healing, alopecia, diarrhea, poor growth, dysfunction of the immune and nervous system with congenital abnormalities and bleeding disorders. Poor nutritional Zn2+ status in patients with metastatic squamous cell carcinoma or with advanced non-Hodgkin lymphoma, was accompanied by cutaneous bleeding and platelet dysfunction. Forcing Zn2+ uptake in the gut using different nutritional supplementation of Zn2+ could ameliorate many of these pathological symptoms in humans. Feeding adult rodents with a low Zn2+ diet caused poor platelet aggregation and increased bleeding tendency, thereby attracting great scientific interest in investigating the role of Zn2+ in hemostasis. Storage protein metallothionein maintains or releases Zn2+ in the cytoplasm, and the dynamic change of this cytoplasmic Zn2+ pool is regulated by the redox status of the cell. An increase of labile Zn2+ pool can be toxic for the cells, and therefore cytoplasmic Zn2+ levels are tightly regulated by several Zn2+ transporters located on the cell surface and also on the intracellular membrane of Zn2+ storage organelles, such as secretory vesicles, endoplasmic reticulum or Golgi apparatus. Although Zn2+ is a critical cofactor for more than 2000 transcription factors and 300 enzymes, regulating cell differentiation, proliferation, and basic metabolic functions of the cells, the molecular mechanisms of Zn2+ transport and the physiological role of Zn2+ store in megakaryocyte and platelet function remain elusive. In this review, we summarize the contribution of extracellular or intracellular Zn2+ to megakaryocyte and platelet function and discuss the consequences of dysregulated Zn2+ homeostasis in platelet-related diseases by focusing on thrombosis, ischemic stroke and storage pool diseases.

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“…Thrombocytes accumulate zinc ions, mainly in cytoplasm and in α-granules, up to 30-60 times more than its normal concentration in serum, which fluctuates within the range of 12.2 to 21.4 µM, whereas free zinc ions concentration varies between 0.15-0.5 µM [2,[21][22][23]. For that reason, platelet stimulation during blood clotting involves a considerable local increase of the zinc concentration at the site of blood-vessel injury.…”

Section: Introductionmentioning

confidence: 99%

Role of Zinc in Hemostasis: A Review

Tubek

Grzanka

Tubek

2007

Biol Trace Elem Res

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Zinc is a multi-functional element that is found in almost 300 enzymes where it performs catalytic, co-catalytic, and/or structural functions. In 1982, Gordon et al. (Am J Clin Ntr 35:849-857, 1982) found that a low zinc diet caused poor platelet aggregation and increased bleeding tendency in adult males. This fact drew interest to the role of zinc in blood clotting. It has been shown that hyperzincemia predisposes to increased coagulability, and hypozincemia to poor platelet aggregation and increased bleeding time. The blood clotting disturbances can be regressed by appropriate zinc intake management. Considering the importance of zinc as an essential element, its participation in regulation of the equilibrium between pro- and anti-thrombotic factors originating in platelets and endothelium prompted further investigations.

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The procoagulant effect of zinc on fibrin clot formation

Cited by 33 publications

References 25 publications

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

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

Zinc Homeostasis in Platelet-Related Diseases

Role of Zinc in Hemostasis: A Review

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