Download PDF
Thromb Haemost 2016; 115(03): 533-542
DOI: 10.1160/th15-06-0462
Coagulation and Fibrinolysis
Schattauer GmbH

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

Sara J. Henderson
1   Thrombosis and Atherosclerosis Research Institute, McMaster University, Hamilton, Ontario, Canada
2   Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, Ontario, Canada
,
Jing Xia
5   School of Engineering and Applied Sciences, Harvard University, Cambridge, Massachusetts, USA
,
Huayin Wu
5   School of Engineering and Applied Sciences, Harvard University, Cambridge, Massachusetts, USA
,
Alan R. Stafford
1   Thrombosis and Atherosclerosis Research Institute, McMaster University, Hamilton, Ontario, Canada
3   Department of Medicine, McMaster University, Hamilton, Ontario, Canada
,
Beverly A. Leslie
1   Thrombosis and Atherosclerosis Research Institute, McMaster University, Hamilton, Ontario, Canada
3   Department of Medicine, McMaster University, Hamilton, Ontario, Canada
,
James C. Fredenburgh
1   Thrombosis and Atherosclerosis Research Institute, McMaster University, Hamilton, Ontario, Canada
3   Department of Medicine, McMaster University, Hamilton, Ontario, Canada
,
David A. Weitz
5   School of Engineering and Applied Sciences, Harvard University, Cambridge, Massachusetts, USA
,
Jeffrey I. Weitz
1   Thrombosis and Atherosclerosis Research Institute, McMaster University, Hamilton, Ontario, Canada
2   Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, Ontario, Canada
3   Department of Medicine, McMaster University, Hamilton, Ontario, Canada
4   Department of Medical Sciences, McMaster University, Hamilton, Ontario, Canada
› Author Affiliations Financial support: This work was supported in part by the Canadian Institutes of Health Research and the Heart and Stroke Foundation. J.I.W. holds the Heart and Stroke Foundation J. Fraser Mustard Endowed Chair in Cardiovascular Research and the Canada Research Chair (Tier 1) in Thrombosis. The work by J. X., H. W., and D. A. W. was supported in part by the Harvard MRSEC (DMR 14–20570).
Further Information

Publication History

Received: 08 June 2015

Accepted after major revision: 14 September 2015

Publication Date:
20 March 2018 (online)

    Permissions and Reprints

Summary

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 twofold 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.

Keywords

Zinc - fibrinogen - fibrin - FXIII - clot structure
 

  • References

  • 1 Weisel JW, Litvinov RI. Mechanisms of fibrin polymerisation and clinical implications. Blood 2013; 121: 1712-1719.
    CrossrefPubMedGoogle Scholar
  • 2 Kurniawan NA, Grimbergen J, Koopman J. et al. Factor XIII stiffens fibrin clots by causing fibre compaction. J Thromb Haemost 2014; 12: 1687-1696.
    CrossrefPubMedGoogle Scholar
  • 3 Weisel JW. Structure of fibrin: impact on clot stability. J Thromb Haemost 2007; 5 (Suppl. 01) 116-124.
    CrossrefPubMedGoogle Scholar
  • 4 Weisel JW. The mechanical properties of fibrin for basic scientists and clinicians. Biophys Chem 2004; 112: 267-276.
    CrossrefPubMedGoogle Scholar
  • 5 Gabriel DA, Muga K, Boothroyd EM. The effect of fibrin structure on fibrinoly-sis. J Biol Chem 1992; 267: 24259-24263.
    PubMedGoogle Scholar
  • 6 Carr ME. Fibrin formed in plasma is composed of fibres more massive than those formed from purified fibrinogen. Thromb Haemost 1988; 59: 535-539.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 7 Ryan EA, Mockros LF, Weisel JW. et al. Structural origins of fibrin clot rheology. Biophys J 1999; 77: 2813-2826.
    CrossrefPubMedGoogle Scholar
  • 8 Kanaide H, Uranishi T, Nakamura M. Effects of divalent cations on the conversion of fibrinogen to fibrin and fibrin polymerisation. Am J Hematol 1982; 13: 229-237.
    CrossrefPubMedGoogle Scholar
  • 9 Marx G. Elasticity of fibrin and protofibrin gels is differentially modulated by calcium and zinc. Thromb Haemost 1988; 59: 500-503.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 10 Di Stasio E, Nagaswami C, Weisel JW. et al. Cl- regulates the structure of the fibrin clot. Biophys J 1998; 75: 1973-1979.
    CrossrefPubMedGoogle Scholar
  • 11 Carr ME, Powers PL. Differential effects of divalent cations on fibrin structure. Blood Coagul Fibrinolysis 1991; 2: 741-747.
    CrossrefPubMedGoogle Scholar
  • 12 Fatah K, Hessel B. Effect of zinc ions on fibrin network structure. Blood Coagul Fibrinolysis 1998; 9: 629-635.
    CrossrefPubMedGoogle Scholar
  • 13 Marx G, Eldor A. The procoagulant effect of zinc on fibrin clot formation. Am J Hematol 1985; 19: 151-159.
    CrossrefPubMedGoogle Scholar
  • 14 Marx G, Hopmeier P, Gurfel D. Zinc alters fibrin ultrastructure. Thromb Haemost 1987; 57: 73-76.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 15 Suzuki K, Hashimoto S. The influences of divalent metal ions on fibrin monomer polymerisation. Biochim Biophys Acta 1976; 439: 310-315.
    CrossrefPubMedGoogle Scholar
  • 16 Gorodetsky R, Mou X, Blankenfeld A. et al. Platelet multielemental composition, lability, and subcellular localisation. Am J Hematol 1993; 42: 278-283.
    CrossrefPubMedGoogle Scholar
  • 17 Henderson SJ, Stafford AR, Leslie BA. et al. Zinc delays clot lysis by attenuating plasminogen activation and plasmin-mediated fibrin degradation. Thromb Haemost 2015; 113: 1278-1288.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 18 Lu J, Stewart AJ, Sadler PJ. et al. Albumin as a zinc carrier: properties of its high-affinity zinc-binding site. Biochem Soc Trans 2008; 36: 1317-1321.
    CrossrefPubMedGoogle Scholar
  • 19 Whitehouse RC, Prasad AS, Rabbani PI. et al. Zinc in plasma, neutrophils, lymphocytes, and erythrocytes as determined by flameless atomic absorption spectrophotometry. Clin Chem 1982; 28: 475-480.
    PubMedGoogle Scholar
  • 20 Marx G, Korner G, Mou X. et al. Packaging zinc, fibrinogen, and factor XIII in platelet alpha-granules. J Cell Physiol 1993; 156: 437-442.
    CrossrefPubMedGoogle Scholar
  • 21 Vu TT, Fredenburgh JC, Weitz JI. Zinc: an important cofactor in haemostasis and thrombosis. Thromb Haemost 2013; 109: 421-430.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 22 Fredenburgh JC, Leslie BA, Stafford AR. et al. Zn2+ mediates high affinity binding of heparin to the alphaC domain of fibrinogen. J Biol Chem 2013; 288: 29394-29402.
    CrossrefPubMedGoogle Scholar
  • 23 Fredenburgh JC, Stafford AR, Leslie BA. et al. Bivalent binding to gammaA/ gamma‘-fibrin engages both exosites of thrombin and protects it from inhibition by the antithrombin-heparin complex. J Biol Chem 2008; 283: 2470-2477.
    CrossrefPubMedGoogle Scholar
  • 24 Walker JB, Nesheim ME. The molecular weights, mass distribution, chain composition, and structure of soluble fibrin degradation products released from a fibrin clot perfused with plasmin. J Biol Chem 1999; 274: 5201-5212.
    CrossrefPubMedGoogle Scholar
  • 25 Schaefer AV, Leslie BA, Rischke JA. et al. Incorporation of fragment X into fibrin clots renders them more susceptible to lysis by plasmin. Biochemistry 2006; 45: 4257-4265.
    CrossrefPubMedGoogle Scholar
  • 26 Ariens RA, Philippou H, Nagaswami C. et al. The factor XIII V34L polymorphism accelerates thrombin activation of factor XIII and affects cross-linked fibrin structure. Blood 2000; 96: 988-995.
    CrossrefPubMedGoogle Scholar
  • 27 Collet JP, Moen JL, Veklich YI. et al. The alphaC domains of fibrinogen affect the structure of the fibrin clot, its physical properties, and its susceptibility to fibrinolysis. Blood 2005; 106: 3824-3830.
    CrossrefPubMedGoogle Scholar
  • 28 Hethershaw EL, Cilia La Corte AL, Duval C. et al. The effect of blood coagulation factor XIII on fibrin clot structure and fibrinolysis. J Thromb Haemost 2014; 12: 197-205.
    CrossrefPubMedGoogle Scholar
  • 29 Schroeder V, Kohler HP. New developments in the area of factor XIII. J Thromb Haemost 2013; 11: 234-244.
    CrossrefPubMedGoogle Scholar
  • 30 Levy JH, Greenberg C. Biology of Factor XIII and clinical manifestations of Factor XIII deficiency. Transfusion 2013; 53: 1120-1131.
    CrossrefPubMedGoogle Scholar
  • 31 Bagoly Z, Koncz Z, Harsfalvi J. et al. Factor XIII clot structure, thrombosis. Thromb Res 2012; 129: 382-387.
    CrossrefPubMedGoogle Scholar