Zinc: An important cofactor in haemostasis and thrombosis

Trang T. Vu; James C. Fredenburgh; Jeffrey I. Weitz

doi:10.1160/TH12-07-0465

Thrombosis and Haemostasis, Table of Contents

Thromb Haemost 2013; 109(03): 421-430
DOI: 10.1160/TH12-07-0465

Review Article

Schattauer GmbH

Zinc: An important cofactor in haemostasis and thrombosis

Trang T. Vu

¹Thrombosis and Atherosclerosis Research Institute, Hamilton, Ontario, Canada

²Department of Medical Sciences, McMaster University, Hamilton, Ontario, Canada

,

James C. Fredenburgh

¹Thrombosis and Atherosclerosis Research Institute, Hamilton, Ontario, Canada

³Department of Medicine, McMaster University, Hamilton, Ontario, Canada

,

Jeffrey I. Weitz

¹Thrombosis and Atherosclerosis Research Institute, Hamilton, Ontario, Canada

²Department of Medical Sciences, McMaster University, Hamilton, Ontario, Canada

³Department of Medicine, McMaster University, Hamilton, Ontario, Canada

⁴Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, Ontario, Canada

› Author Affiliations

Abstract

Summary

There is mounting evidence that zinc, the second most abundant transition metal in blood, is an important mediator of haemostasis and thrombosis. Prompted by the observation that zinc deficiency is associated with bleeding and clotting abnormalities, there now is evidence that zinc serves as an effector of coagulation, anticoagulation and fibrinolysis. Zinc binds numerous plasma proteins and modulates their structure and function. Because activated platelets secrete zinc into the local microenvironment, the concentration of zinc increases in the vicinity of a thrombus. Consequently, the role of zinc varies depending on the microenvironment; a feature that endows zinc with the capacity to spatially and temporally regulate haemostasis and thrombosis. This paper reviews the mechanisms by which zinc regulates coagulation, platelet aggregation, anticoagulation and fibrinolysis and outlines how zinc serves as a ubiquitous modulator of haemostasis and thrombosis.

Keywords

Zinc - coagulation - contact system - fibrinolysis - platelets

Full Text

References

References
1 Andreini C, Banci L, Bertini I. et al. Counting the zinc-proteins encoded in the human genome. J Proteome Res 2006; 5: 196-201.
2 Vallee BL, Falchuk KH. The biochemical basis of zinc physiology. Physiol Rev 1993; 73: 79-118.
3 Maret W, Li Y. Coordination dynamics of zinc in proteins. Chem Rev 2009; 109: 4682-4707.
4 Tubek S. Zinc supplementation or regulation of its homeostasis: advantages and threats. Biol Trace Elem Res 2007; 119: 1-9.
5 Tubek S, Grzanka P, Tubek I. Role of zinc in hemostasis: a review. Biol Trace Elem Res 2008; 121: 1-8.
6 Foote JW, Delves HT. Albumin bound and alpha 2-macroglobulin bound zinc concentrations in the sera of healthy adults. J Clin Pathol 1984; 37: 1050-1054.
7 Stewart AJ, Blindauer CA, Sadler PJ. Plasma fatty acid levels may regulate the Zn(2+)-dependent activities of histidine-rich glycoprotein. Biochimie 2009; 91: 1518-1522.
8 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.
9 Mahdi F, Madar ZS, Figueroa CD. et al. Factor XII interacts with the multiprotein assembly of urokinase plasminogen activator receptor, gC1qR, and cytokeratin 1 on endothelial cell membranes. Blood 2002; 99: 3585-3596.
10 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.
11 Bernardo MM, Day DE, Halvorson HR. et al. Surface-independent acceleration of factor XII activation by zinc ions. II. Direct binding and fluorescence studies. J Biol Chem 1993; 268: 12477-12483.
12 Bernardo MM, Day DE, Olson ST. et al. Surface-independent acceleration of factor XII activation by zinc ions. I. Kinetic characterisation of the metal ion rate enhancement. J Biol Chem 1993; 268: 12468-12476.
13 Borza DB, Morgan WT. Histidine-proline-rich glycoprotein as a plasma pH sensor. Modulation of its interaction with glycosaminoglycans by pH and metals. J Biol Chem 1998; 273: 5493-5499.
14 Leszczyszyn OI, Schmid R, Blindauer CA. Toward a property/function relationship for metallothioneins: histidine coordination and unusual cluster composition in a zinc-metallothionein from plants. Proteins 2007; 68: 922-935.
15 Jones AL, Hulett MD, Parish CR. Histidine-rich glycoprotein: A novel adaptor protein in plasma that modulates the immune, vascular and coagulation systems. Immunol Cell Biol 2005; 83: 106-118.
16 Gordon PR, Woodruff CW, Anderson HL. et al. Effect of acute zinc deprivation on plasma zinc and platelet aggregation in adult males. Am J Clin Nutr 1982; 35: 113-119.
17 Emery MP, Browning JD, O’Dell BL. Impaired hemostasis and platelet function in rats fed low zinc diets based on egg white protein. J Nutr 1990; 120: 1062-1067.
18 Emery MP, O’Dell BL. Low zinc status in rats impairs calcium uptake and aggregation of platelets stimulated by fluoride. Proc Soc Exp Biol Med 1993; 203: 480-484.
19 Stefanini M. Cutaneous bleeding related to zinc deficiency in two cases of advanced cancer. Cancer 1999; 86: 866-870.
20 Greengard JS, Griffin JH. Receptors for high molecular weight kininogen on stimulated washed human platelets. Biochemistry 1984; 23: 6863-6869.
21 Mann KG, Whelihan MF, Butenas S. et al. Citrate anticoagulation and the dynamics of thrombin generation. J Thromb Haemost 2007; 5: 2055-2061.
22 Renne T, Pozgajova M, Gruner S. et al. Defective thrombus formation in mice lacking coagulation factor XII. J Exp Med 2005; 202: 271-281.
23 Muller F, Gailani D, Renne T. Factor XI and XII as antithrombotic targets. Curr Opin Hematol 2011; 18: 349-355.
24 Gailani D, Renne T. The intrinsic pathway of coagulation: a target for treating thromboembolic disease?. J Thromb Haemost 2007; 5: 1106-1112.
25 Rojkjaer R, Schousboe I. The surface-dependent autoactivation mechanism of factor XII. Eur J Biochem 1997; 243: 160-166.
26 Rojkaer R, Schousboe I. Partial identification of the Zn(2+)-binding sites in factor XII and its activation derivatives. Eur J Biochem 1997; 247: 491-496.
27 Schousboe I. Contact activation in human plasma is triggered by zinc ion modulation of factor XII (Hageman factor). Blood Coagul Fibrinolysis 1993; 4: 671-678.
28 Samuel M, Pixley RA, Villanueva MA. et al. Human factor XII (Hageman factor) autoactivation by dextran sulfate. Circular dichroism, fluorescence, and ultraviolet difference spectroscopic studies. J Biol Chem 1992; 267: 19691-19697.
29 Shore JD, Day DE, Bock PE. et al. Acceleration of surface-dependent autocatalytic activation of blood coagulation factor XII by divalent metal ions. Biochemistry 1987; 26: 2250-2258.
30 Kannemeier C, Shibamiya A, Nakazawa F. et al. Extracellular RNA constitutes a natural procoagulant cofactor in blood coagulation. Proc Natl Acad Sci USA 2007; 104: 6388-6393.
31 Smith SA, Mutch NJ, Baskar D. et al. Polyphosphate modulates blood coagulation and fibrinolysis. Proc Natl Acad Sci USA 2006; 103: 903-908.
32 Loiseau C, Randriamahazaka HN, Nigretto JM. Influence of Zn(2+) on the kinetic events that contribute to the 50465-kDa dextran-sulfate-dependent activation of factor XII (Hageman factor). Eur J Biochem 1997; 246: 204-210.
33 Citarella F, te Velthuis H, Helmer-Citterich M. et al. Identification of a putative binding site for negatively charged surfaces in the fibronectin type II domain of human factor XII--an immunochemical and homology modeling approach. Thromb Haemost 2000; 84: 1057-1065.
34 Citarella F, Ravon DM, Pascucci B. et al. Structure/function analysis of human factor XII using recombinant deletion mutants. Evidence for an additional region involved in the binding to negatively charged surfaces. Eur J Biochem 1996; 238: 240-249.
35 Shimada T, Kato H, Iwanaga S. Accelerating effect of zinc ions on the surface-mediated activation of factor XII and prekallikrein. J Biochem 1987; 102: 913-921.
36 Gustafson EJ, Schutsky D, Knight LC. et al. High molecular weight kininogen binds to unstimulated platelets. J Clin Invest 1986; 78: 310-318.
37 DeLa Cadena RA, Colman RW. The sequence HGLGHGHEQQHGLGHGH in the light chain of high molecular weight kininogen serves as a primary structural feature for zinc-dependent binding to an anionic surface. Protein Sci 1992; 1: 151-160.
38 Schmaier AH, Kuo A, Lundberg D. et al. The expression of high molecular weight kininogen on human umbilical vein endothelial cells. J Biol Chem 1988; 263: 16327-16333.
39 Reddigari SR, Shibayama Y, Brunnee T. et al. Human Hageman factor (factor XII) and high molecular weight kininogen compete for the same binding site on human umbilical vein endothelial cells. J Biol Chem 1993; 268: 11982-11987.
40 Reddigari SR, Kuna P, Miragliotta G. et al. Human high molecular weight kininogen binds to human umbilical vein endothelial cells via its heavy and light chains. Blood 1993; 81: 1306-1311.
41 Schousboe I. Rapid and cooperative binding of factor XII to human umbilical vein endothelial cells. Eur J Biochem 2001; 268: 3958-3963.
42 Pixley RA, Espinola RG, Ghebrehiwet B. et al. Interaction of high-molecular-weight kininogen with endothelial cell binding proteins suPAR, gC1qR and cytokeratin 1 determined by surface plasmon resonance (BiaCore). Thromb Haemost 2011; 105: 1053-1059.
43 Thompson RE, Mandle Jr. R, Kaplan AP. Association of factor XI and high molecular weight kininogen in human plasma. J Clin Invest 1977; 60: 1376-1380.
44 Zhao Y, Qiu Q, Mahdi F. et al. Assembly and activation of HK-PK complex on endothelial cells results in bradykinin liberation and NO formation. Am J Physiol Heart Circ Physiol 2001; 280: H1821-H1829.
45 Rojkjaer R, Hasan AA, Motta G. et al. Factor XII does not initiate prekallikrein activation on endothelial cells. Thromb Haemost 1998; 80: 74-81.
46 Schmaier AH. The plasma kallikrein-kinin system counterbalances the renin-angiotensin system. J Clin Invest 2002; 109: 1007-1009.
47 Shariat-Madar Z, Mahdi F, Schmaier AH. Factor XI assembly and activation on human umbilical vein endothelial cells in culture. Thromb Haemost 2001; 85: 544-551.
48 Mahdi F, Shariat-Madar Z, Schmaier AH. The relative priority of prekallikrein and factors XI/XIa assembly on cultured endothelial cells. J Biol Chem 2003; 278: 43983-43990.
49 Shariat-Madar Z, Mahdi F, Warnock M. et al. Bradykinin B2 receptor knockout mice are protected from thrombosis by increased nitric oxide and prostacyclin. Blood 2006; 108: 192-199.
50 Schmaier AH. Assembly, activation, and physiologic influence of the plasma kallikrein/kinin system. Int Immunopharmacol 2008; 8: 161-165.
51 Colman RW, Schmaier AH. Contact system: a vascular biology modulator with anticoagulant, profibrinolytic, antiadhesive, and proinflammatory attributes. Blood 1997; 90: 3819-3843.
52 Moreau ME, Garbacki N, Molinaro G. et al. The kallikrein-kinin system: current and future pharmacological targets. J Pharmacol Sci 2005; 99: 6-38.
53 Sainz IM, Pixley RA, Colman RW. Fifty years of research on the plasma kallikrein-kinin system: from protein structure and function to cell biology and in-vivo pathophysiology. Thromb Haemost 2007; 98: 77-83.
54 Monroe DM, Hoffman M. What does it take to make the perfect clot?. Arterioscler Thromb Vasc Biol 2006; 26: 41-48.
55 Baglia FA, Badellino KO, Li CQ. et al. Factor XI binding to the platelet glycoprotein Ib-IX-V complex promotes factor XI activation by thrombin. J Biol Chem 2002; 277: 1662-1668.
56 Baglia FA, Gailani D, Lopez JA. et al. Identification of a binding site for glycoprotein Ibalpha in the Apple 3 domain of factor XI. J Biol Chem 2004; 279: 45470-45476.
57 Van Nostrand WE. Zinc (II) selectively enhances the inhibition of coagulation factor XIa by protease nexin-2/amyloid beta-protein precursor. Thromb Res 1995; 78: 43-53.
58 Woodruff RS, Sullenger B, Becker RC. The many faces of the contact pathway and their role in thrombosis. J Thromb Thrombolysis 2011; 32: 9-20.
59 Heyns AP, Eldor A, Yarom R. et al. Zinc-induced platelet aggregation is mediated by the fibrinogen receptor and is not accompanied by release or by thromboxane synthesis. Blood 1985; 66: 213-219.
60 Kowalska MA, Juliano D, Trybulec M. et al. Zinc ions potentiate adenosine diphosphate-induced platelet aggregation by activation of protein kinase C. J Lab Clin Med 1994; 123: 102-1029.
61 Trybulec M, Kowalska MA, McLane MA. et al. Exposure of platelet fibrinogen receptors by zinc ions: role of protein kinase C. Proc Soc Exp Biol Med 1993; 203: 108-116.
62 Calvete JJ. On the structure and function of platelet integrin alpha IIb beta 3, the fibrinogen receptor. Proc Soc Exp Biol Med 1995; 208: 346-360.
63 Nesbitt WS, Giuliano S, Kulkarni S. et al. Intercellular calcium communication regulates platelet aggregation and thrombus growth. J Cell Biol 2003; 160: 1151-1161.
64 O’Dell BL. Role of zinc in plasma membrane function. J Nutr 2000; 130: 1432S-1436S.
65 Vasdev S, Gill V, Singal PK. Beneficial effect of low ethanol intake on the cardiovascular system: possible biochemical mechanisms. Vasc Health Risk Manag 2006; 2: 263-276.
66 O’Dell BL, Emery M, Xia J. et al. In vitro addition of glutathione to blood from zinc-deficient rats corrects platelet defects: impaired aggregation and calcium uptake. J Nutr Biochem 2007; 8: 346-350.
67 Margaritis A, Priora R, Frosali S. et al. The role of protein sulfhydryl groups and protein disulfides of the platelet surface in aggregation processes involving thiol exchange reactions. Pharmacol Res 2011; 63: 77-84.
68 Del Principe D, Frega G, Savini I. et al. The plasma membrane redox system in human platelet functions and platelet-leukocyte interactions. Thromb Haemost 2009; 101: 284-289.
69 Solovyov A, Gilbert HF. Zinc-dependent dimerisation of the folding catalyst, protein disulfide isomerase. Protein Sci 2004; 13: 1902-1907.
70 Korichneva I, Hoyos B, Chua R. et al. Zinc release from protein kinase C as the common event during activation by lipid second messenger or reactive oxygen. J Biol Chem 2002; 277: 44327-44331.
71 Pula G, Schuh K, Nakayama K. et al. PKCdelta regulates collagen-induced platelet aggregation through inhibition of VASP-mediated filopodia formation. Blood 2006; 108: 4035-4044.
72 Marx G, Eldor A. The procoagulant effect of zinc on fibrin clot formation. Am J Hematol 1985; 19: 151-159.
73 Marx G. Modulation of thrombin activity by zinc. Ann NY Acad Sci 1986; 485: 421-424.
74 Marx G, Hopmeier P. Zinc inhibits FPA release and increases fibrin turbidity. Am J Hematol 1986; 22: 347-353.
75 Marx G. Zinc binding to fibrinogen and fibrin. Arch Biochem Biophys 1988; 266: 285-288.
76 Scully MF, Kakkar VV. Structural features of fibrinogen associated with binding to chelated zinc. Biochim Biophys Acta 1982; 700: 130-135.
77 Marx G, Hopmeier P, Gurfel D. Zinc alters fibrin ultrastructure. Thromb Haemost 1987; 57: 73-76.
78 Marx G. Divalent cations induce protofibril gelation. Am J Hematol 1988; 27: 104-109.
79 Fatah K, Hessel B. Effect of zinc ions on fibrin network structure. Blood Coagul Fibrinolysis 1998; 9: 629-635.
80 Marx G, Harari N. Albumin indirectly modulates fibrin and protofibrin ultrastructure. Biochemistry 1989; 28: 8242-8248.
81 Meloni FJ, Schmaier AH. Low molecular weight kininogen binds to platelets to modulate thrombin-induced platelet activation. J Biol Chem 1991; 266: 6786-6794.
82 Bradford HN, DeLa Cadena RA, Kunapuli SP. et al. Human kininogens regulate thrombin binding to platelets through the glycoprotein Ib-IX-V complex. Blood 1997; 90: 1508-1515.
83 Bradford HN, Pixley RA, Colman RW. Human factor XII binding to the glycoprotein Ib-IX-V complex inhibits thrombin-induced platelet aggregation. J Biol Chem 2000; 275: 22756-22763.
84 Kunapuli SP, DeLa Cadena RA, Colman RW. Deletion mutagenesis of high molecular weight kininogen light chain. Identification of two anionic surface binding subdomains. J Biol Chem 1993; 268: 2486-2492.
85 Meloni FJ, Gustafson EJ, Schmaier AH. High molecular weight kininogen binds to platelets by its heavy and light chains and when bound has altered susceptibility to kallikrein cleavage. Blood 1992; 79: 1233-1244.
86 Dormann D, Clemetson KJ, Kehrel BE. The GPIb thrombin-binding site is essential for thrombin-induced platelet procoagulant activity. Blood 2000; 96: 2469-2478.
87 Joseph K, Nakazawa Y, Bahou WF. et al. Platelet glycoprotein Ib: a zinc-dependent binding protein for the heavy chain of high-molecular-weight kininogen. Mol Med 1999; 5: 555-563.
88 Bajaj SP, Schmidt AE, Agah S. et al. High resolution structures of p-aminobenzamidine- and benzamidine-VIIa/soluble tissue factor: unpredicted conformation of the 192-193 peptide bond and mapping of Ca(2+), Mg(2+), Na(+), and Zn(2+) sites in factor VIIa. J Biol Chem 2006; 281: 24873-24888.
89 Petersen LC, Olsen OH, Nielsen LS. et al. Binding of Zn(2+) to a Ca(2+) loop allosterically attenuates the activity of factor VIIa and reduces its affinity for tissue factor. Protein Sci 2000; 9: 859-866.
90 Pedersen AH, Lund-Hansen T, Komiyama Y. et al. Inhibition of recombinant human blood coagulation factor VIIa amidolytic and proteolytic activity by zinc ions. Thromb Haemost 1991; 65: 528-534.
91 Danese S, Vetrano S, Zhang L. et al. The protein C pathway in tissue inflammation and injury: pathogenic role and therapeutic implications. Blood 2010; 115: 1121-1130.
92 Sen P, Sahoo S, Pendurthi UR. et al. Zinc modulates the interaction of protein C and activated protein C with endothelial cell protein C receptor. J Biol Chem 2010; 285: 20410-20420.
93 Esmon CT. The protein C pathway. Chest 2003; 124: 26S-32S.
94 Preston RJ, Ajzner E, Razzari C. et al. Multifunctional specificity of the protein C/activated protein C Gla domain. J Biol Chem 2006; 281: 28850-28857.
95 He X, Shen L, Villoutreix BO. et al. Amino acid residues in thrombin-sensitive region and first epidermal growth factor domain of vitamin K-dependent protein S determining specificity of the activated protein C cofactor function. J Biol Chem 1998; 273: 27449-27458.
96 Zhu T, Ubhayasekera W, Nickolaus N. et al. Zinc ions bind to and inhibit activated protein C. Thromb Haemost 2010; 104: 544-553.
97 Oliver JA, Monroe DM, Church FC. et al. Activated protein C cleaves factor Va more efficiently on endothelium than on platelet surfaces. Blood 2002; 100: 539-546.
98 Burstyn-Cohen T, Heeb MJ, Lemke G. Lack of protein S in mice causes embryonic lethal coagulopathy and vascular dysgenesis. J Clin Invest 2009; 119: 2942-2953.
99 Heeb MJ, Prashun D, Griffin JH. et al. Plasma protein S contains zinc essential for efficient activated protein C-independent anticoagulant activity and binding to factor Xa, but not for efficient binding to tissue factor pathway inhibitor. FASEB J 2009; 23: 2244-2253.
100 Heeb MJ, Rosing J, Bakker HM. et al. Protein S binds to and inhibits factor Xa. Proc Natl Acad Sci USA 1994; 91: 2728-2732.
101 Hackeng TM, Sere KM, Tans G. et al. Protein S stimulates inhibition of the tissue factor pathway by tissue factor pathway inhibitor. Proc Natl Acad Sci USA 2006; 103: 3106-3111.
102 Hackeng TM, Maurissen LF, Castoldi E. et al. Regulation of TFPI function by protein S. J Thromb Haemost 2009; 7 (Suppl. 01) 165-168.
103 Fernandes N, Mosnier LO, Tonnu L. et al. Zn(2+) -containing protein S inhibits extrinsic factor X-activating complex independently of tissue factor pathway inhibitor. J Thromb Haemost 2010; 8: 1976-1985.
104 Rau JC, Beaulieu LM, Huntington JA. et al. Serpins in thrombosis, hemostasis and fibrinolysis. J Thromb Haemost 2007; 5 (Suppl. 01) 102-115.
105 Chan HH, Leslie BA, Stafford AR. et al. By increasing the affinity of heparin for fibrin, Zn(2+) promotes the formation of a ternary heparin-thrombin-fibrin complex that protects thrombin from inhibition by antithrombin. Biochemistry 2012; 51: 7964-7973.
106 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.
107 Lovely RS, Kazmierczak SC, Massaro JM. et al. Gamma' fibrinogen: evaluation of a new assay for study of associations with cardiovascular disease. Clin Chem 2010; 56: 781-788.
108 van den Herik EG, Cheung EY, de Lau LM. et al. Gamma'/total fibrinogen ratio is associated with short-term outcome in ischaemic stroke. Thromb Haemost 2011; 105: 430-434.
109 Tsuchida-Straeten N, Ensslen S, Schafer C. et al. Enhanced blood coagulation and fibrinolysis in mice lacking histidine-rich glycoprotein (HRG). J Thromb Haemost 2005; 3: 865-872.
110 Morgan WT. Interactions of the histidine-rich glycoprotein of serum with metals. Biochemistry 1981; 20: 1054-1061.
111 Jancso A, Kolozsi A, Gyurcsik B. et al. Probing the Cu(2+) and Zn(2+) binding affinity of histidine-rich glycoprotein. J Inorg Biochem 2009; 103: 1634-1643.
112 MacQuarrie JL, Stafford AR, Yau JW. et al. Histidine-rich glycoprotein binds factor XIIa with high affinity and inhibits contact-initiated coagulation. Blood 2011; 117: 4134-4141.
113 Vu TT, Stafford AR, Leslie BA. et al. Histidine-rich glycoprotein binds fibrin(ogen) with high affinity and competes with thrombin for binding to the gamma'-chain. J Biol Chem 2011; 286: 30314-30323.
114 Peterson CB, Morgan WT, Blackburn MN. Histidine-rich glycoprotein modulation of the anticoagulant activity of heparin. Evidence for a mechanism involving competition with both antithrombin and thrombin for heparin binding. J Biol Chem 1987; 262: 7567-7574.
115 Kluszynski BA, Kim C, Faulk WP. Zinc as a cofactor for heparin neutralisation by histidine-rich glycoprotein. J Biol Chem 1997; 272: 13541-13547.
116 Weitz JI, Hudoba M, Massel D. et al. Clot-bound thrombin is protected from inhibition by heparin-antithrombin III but is susceptible to inactivation by antithrombin III-independent inhibitors. J Clin Invest 1990; 86: 385-391.
117 Cesarman-Maus G, Hajjar KA. Molecular mechanisms of fibrinolysis. Br J Haematol 2005; 129: 307-321.
118 Siddiq MM, Tsirka SE. Modulation of zinc toxicity by tissue plasminogen activator. Mol Cell Neurosci 2004; 25: 162-171.
119 Tu Z, Liang J. Zinc inhibits tumor metastasis by regulating plasminogen activation. Int J Cancer Suppl 2006; 2: 376-382.
120 Husain SS. Fibrin affinity of urokinase-type plasminogen activator. Evidence that Zn(2+) mediates strong and specific interaction of single-chain urokinase with fibrin. J Biol Chem 1993; 268: 8574-8579.
121 Longstaff C, Thelwell C, Williams SC. et al. The interplay between tissue plasminogen activator domains and fibrin structures in the regulation of fibrinolysis: kinetic and microscopic studies. Blood 2011; 117: 661-668.
122 Weisel JW. Structure of fibrin: impact on clot stability. J Thromb Haemost 2007; 5 (Suppl. 01) 116-124.
123 Smith D, Gilbert M, Owen WG. Tissue plasminogen activator release in vivo in response to vasoactive agents. Blood 1985; 66: 835-839.
124 Goldsmith Jr. GH, Saito H, Ratnoff OS. The activation of plasminogen by Hageman factor (Factor XII) and Hageman factor fragments. J Clin Invest 1978; 62: 54-60.
125 Schousboe I. Factor XIIa activation of plasminogen is enhanced by contact activating surfaces and Zn(2+). Blood Coagul Fibrinolysis 1997; 8: 97-104.