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

Abstract

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.

Fibrin Formation, Structure and Properties

“…Based on the in vitro effects of zinc that reduces fibrin clot stiffness, it was suggested that zinc released from activated platelets may modulate clot strength and stability in cooperation with Factor XIIIa. Fibrin elasticity can be modulated by other physical influences (Kotlarchyk et al 2011; Munster et al 2013) or biochemical modifications as well as by blood components and cells incorporated into the fibrin network (Rojas et al 2009; Weigandt et al 2012; Lauricella et al 2013; Jansen et al 2013; Henderson et al 2015). …”

Fibrinogen and Fibrin in Hemostasis and Thrombosis

“…These include the concentrations of procoagulants, anticoagulants, fibrin(ogen)-binding proteins, molecules 12–20 , and metal ions 21,22 , as well as contributions of blood and vascular cells, and cell-derived microvesicles 23–30 , and presence of blood flow 31,32 (Figure 2). Many of these mechanisms have been reviewed.…”

Fibrin mechanical properties and their structural origins

“…Clot rigidity correlates strongly with the structure of fibrin networks, namely with fiber size and branching that varied upon conditions of clotting [52]. Based on the in vitro effects of zinc that reduces fibrin clot stiffness, it was suggested that zinc released from activated platelets may modulate clot strength and stability in cooperation with factor XIIIa [53]. Fibrin polymerized under continuous mechanical perturbation was shown to form a rigid clot with dramatically altered viscoelastic properties [54].…”