Effects of divalent cations on the conversion of fibrinogen to fibrin and fibrin polymerization

Kobayashi, Hideo; Uranishi, Takako; Nakamura, Motoomi

doi:10.1002/ajh.2830130306

Cited by 10 publications

(10 citation statements)

References 20 publications

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“…Thus, it is possible that the fibrin monomers bind to Zn+2, thereby leading to more effective generation of fibrin gels. Such a model has been proposed for the accelerating effect of relatively high concentrations (2.5 mM) of Ca+2, Mg+', Ba+2, and Sr+2 [29] on the polymerization of fibrin. However, such work has not been reported with Zn+'.…”

Section: Discussionmentioning

confidence: 98%

The procoagulant effect of zinc on fibrin clot formation

Marx

Eldor

1985

American J Hematol

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The influence of Zn+2 on fibrin clot formation was investigated by measuring its effect on the clotting times of fibrinogen exposed to thrombin. It was observed with either human or bovine thrombin that 0.01-0.1 mM Zn+2 induced significant reductions of clotting times in a concentration-dependent manner. The procoagulant effect of Zn+2 occurred in the presence of Ca+2 but was inhibited by metal chelating agents. Higher levels of Zn+2 (greater than 0.2 mM final concentration) were required to accelerate thrombin-induced clot formation in the presence of citrate or oxalate. Similarly with oxalated human plasma, greater than 0.2 mM Zn+2 decreased the clotting time. Cations such as Mg+2 and Mn+2 caused little change in clotting times. As an extension of these findings, we examined the effect of Zn+2 on the inhibition of thrombin by antithrombin-III (AT-III). The presence of as little as 0.006 mM Zn+2 in an incubating mixture of thrombin and AT-III severely reduced the inhibitory activity of AT-III towards thrombin. It was observed that the relative intrinsic fluorescence emission of human thrombin decreased upon exposure to Zn+2 but was unaffected by Mg+2 or Mn+2. It is suggested that Zn+2 can form a complex with thrombin, which results in altered reactivity towards fibrinogen and decreased inhibition by AT-III.

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Section: Discussionmentioning

confidence: 98%

The procoagulant effect of zinc on fibrin clot formation

Marx

Eldor

1985

American J Hematol

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“…When thick fibers are dominant within the fibrin clot, it is less stiff, more porous; therefore, a fibrin clot can change easily the size and form, depending on the actual shear stress [62]. Several studies showed the multiple effects of Zn 2+ and Ca 2+ on fibrin clot formation because fibrinogen contains several binding sites for both cations [66,67]. Binding of fibrinogen to Ca 2+ enhances the kinetics of fibrin clot formation and also modifies the structure of the fibrin network; more thick fibers were polymerized [68].…”

Section: Zn2+-dependent Hemostasis and Fibrin Clot Formationmentioning

confidence: 99%

“…Interestingly, binding sites of Zn 2+ are mapped in the lateral D-globular domains, but not in the central E-domain and sites are distinct from those of Ca 2+ [74,75,76], indicating an alternative regulatory mechanism of fibrin formation. Similar to Ca 2+ , Zn 2+ also accelerates the rate of thrombin-induced fibrin clot formation, whereas this effect was not observed in the presence of magnesium (Mg 2+ ) or manganese (Mn 2+ ) [66,67], suggesting that modulation of thrombin-induced fibrin formation is specific to Zn 2+ and Ca 2+ . It has been shown that the lateral association of fibrin monomers to protofibrils is enhanced by Zn 2+ to a greater extent than Ca 2+ , and Zn 2+ induces a fibrin clot that has reduced fiber stiffness, compared to Ca 2+ -induced fibrin clot [66,75,77,78].…”

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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“…In particular, the thrombin concentration and ionic conditions influence clot structure (7). Calcium (Ca 2+ ) facilitates Fn monomer polymerisation, thereby increasing fibre thickness (7)(8)(9), whereas chlorine opposes lateral aggregation and promotes thin fibre formation (10). These observations suggest that the ionic milieu influences Fn monomer polymerisation.…”

Section: Introductionmentioning

confidence: 99%

Zinc promotes clot stability by accelerating clot formation and modifying fibrin structure

Henderson¹,

Xia²,

Wu³

et al. 2016

Thromb Haemost

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Zinc released from activated platelets binds fibrin(ogen) and attenuates fibrinolysis. Although zinc also affects clot formation, the mechanism and consequences are poorly understood. To address these gaps, the effect of zinc on clot formation and structure was examined in the absence or presence of factor (F) XIII. Zinc accelerated a) plasma clotting by 1.4-fold, b) fibrinogen clotting by 3.5- and 2.3-fold in the absence or presence of FXIII, respectively, c) fragment X clotting by 1.3-fold, and d) polymerisation of fibrin monomers generated with thrombin or batroxobin by 2.5- and 1.8-fold, respectively. Whereas absorbance increased up to 3.3-fold when fibrinogen was clotted in the presence of zinc, absorbance of fragment X clots was unaffected by zinc, consistent with reports that zinc binds to the αC-domain of fibrin(ogen). Scanning electron microscopic analysis revealed a two-fold increase in fibre diameter in the presence of zinc and in permeability studies, zinc increased clot porosity by 30-fold with or without FXIII. Whereas FXIII increased clot stiffness from 128 ± 19 Pa to 415 ± 27 Pa in rheological analyses, zinc reduced clot stiffness by 10- and 8.5-fold in the absence and presence of FXIII, respectively. Clots formed in the presence of zinc were more stable and resisted rupture with or without FXIII. Therefore, zinc accelerates clotting and reduces fibrin clot stiffness in a FXIII-independent manner, suggesting that zinc may work in concert with FXIII to modulate clot strength and stability.

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Effects of divalent cations on the conversion of fibrinogen to fibrin and fibrin polymerization

Cited by 10 publications

References 20 publications

The procoagulant effect of zinc on fibrin clot formation

The procoagulant effect of zinc on fibrin clot formation

Zinc Homeostasis in Platelet-Related Diseases

Zinc promotes clot stability by accelerating clot formation and modifying fibrin structure

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