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DOI: 10.1055/s-0037-1615839
Fibrinolysis and the Contact System: A Role for Factor XI in the Down-Regulation of Fibrinolysis
Publication History
Publication Date:
09 December 2017 (online)
![](https://www.thieme-connect.de/media/10.1055-s-00035024/199902/lookinside/thumbnails/10-1055-s-0037-1615839-1.jpg)
Introduction
Exposure of blood to negatively-charged surfaces, such as collagen, kaolin, or glass, results in the activation of the contact system of the intrinsic pathway of coagulation. Prekallikrein, factor XII, high molecular weight kininogen, and factor XI are the proteins involved in this contact reaction. The assembly of these components on a negatively-charged surface leads to the activation of factor XI, thereby propagating the intrinsic coagulation pathway. Simultaneously, several other reactions occur, such as the activation of factor VII and the initiation of the fibrinolytic system, kinin-forming pathway, and renin-angiotensin pathway.
The first step in the contact phase is to bind factor XII to the negatively-charged surface, making it highly susceptible for proteolysis by kallikrein.1-3 Activated factor XII (α-factor XIIa) is formed in a process that may involve autoactivation.4-7 Prekallikrein is bound to high molecular weight kininogen in plasma. High molecular weight kininogen associates with a negatively-charged surface, thereby localizing prekallikrein to the surface. Limited proteolysis by α-factor XIIa converts prekallikrein to kallikrein. Kallikrein can dissociate from the surface and act on surface-bound factor XII at distant sites, thereby propagating the reciprocal cycle.7 Factor XI circulates plasma in a complex with high molcular weight kininogen. High molecular weight kininogen links factor XI to a negatively charged surface where it is activated by surface bound:α-factor XIIa. Although the in vivo, activating, negatively-charged surface is unknown, assembly and activation of the contact system on biological membranes of endothelial cells, platelets, neutrophils, and monocytes can take place, suggesting that these surfaces are the actual activating surfaces in vivo.8
The physiological significance of the contact system in blood coagulation remains unclear, however, because a deficiency of factor XII, prekallikrein, and high molecular weight kininogen does not result in a bleeding disorder. In contrast, patients deficient in factor XI, most common among Ashkenazi Jews, do suffer from variable bleeding abnormalities, especially from tissues with high local fibrinolytic activity (e.g., urinary tract, nose, oral cavity, tonsils).9,10 This suggested that there was an alternative route for the activation of factor XI, and recently, such a route was described.11,12 Thrombin was found to activate factor XI even in the absence of a negatively-charged surface,11-15 and factor XI was shown to play a role in the downregulation of fibrinolysis.16 In this article, the role of the contact system, with an emphasis on factor XI in the regulation of the fibrinolytic system, will be described.
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References
- 1 Bagdasarian A, Talamo RC, Colman RW. Isolation of high-molecular weight activators of prekallikrein. J Biol Chem. 1973; 248: 3456-3463.
- 2 Cochrane CG, Revak SD, Wuepper KD. Activation of Hageman factor in solid and fluid phases. A critical role of kallikrein. J Exp Med. 1973; 138: 1564-1583.
- 3 Griffin JH. The role of surface in the surface-dependent activation of Hageman factor (blood coagulation factor XII). Proc Natl Acad Sci USA. 1978; 75: 1998-2002.
- 4 Tankersley DL, Finlayson JS. Kinetics of activation and autoactivation of human factor XII. Biochemistry. 1984; 23: 273-279.
- 5 Wiggins RC, Cochrane CG. The autoactivation of rabbit Hageman factor. J Exp Med. 1979; 150: 1122-1133.
- 6 Dunn JT, Silverberg M, Kaplan AP. The cleavage and formation of activated human Hageman factor by autodigestion and by kallikrein. J Biol Chem. 1982; 257: 1779-1784.
- 7 Cochrane CG, Revak SD. Dissemination of contact activation in plasma by plasma kallikrein. J Exp Med. 1980; 152: 608-619.
- 8 Colman RW, Schmaier AH. Contact system: a vascular biology modulator with anticoagulant, profibrinolytic, antiadhesive, and proinflammatory attributes. Blood 1997; 90: 3819-3843.
- 9 Asakai R, Chung DW, Davie EW, Seligsohn U. Factor XI deficiency in Ashkenazi Jews in Israel. N Engl J Med. 1991; 325: 153-158.
- 10 Berliner S, Horowitz I, Martinowitz U, Brenner B, Seligsohn U. Dental surgery in patients with severe factor XI deficiency without plasma replacement. Blood Coagul Fibrinolysis. 1991; 3: 465-468.
- 11 Naito K, Fujikawa K. Activation of human blood coagulation factor XI independent of factor XII. Factor XI is activated by thrombin and factor XIa in the presence of negatively-charged surfaces. J Biol Chem. 1991; 266: 7353-7358.
- 12 Gailani D, Broze GJ. Factor XI activation in a revised model of coagulation. Science 1991; 253: 909-912.
- 13 von dem Borne PAKr, Koppelman SJ, Bouma BN, Meijers JCM. Surface independent factor XI activation by thrombin in the presence of high molecular weight kininogen. Thromb Haemost. 1994; 72: 397-402.
- 14 Cawthern KM, van’t Veer C, Lock JB, DiLorenzo ME, Branda RF, Mann KG. Blood: coagulation in hemophilia A and hemophilia C. Blood 1998; 15: 4581-4592.
- 15 Oliver JA, Monroe DM, Roberts HR, Hoffman M. Thrombin activates factor XI on activated platelets in the absence of factor XII. Arterioscler Thromb Vasc Biol. 1999; 19: 170-177.
- 16 von dem Borne PAKr, Meijers JCM, Bouma BN. Feedback activation of factor XI by thrombin results in additional formation of thrombin that protects fibrin clots from fibrinolysis. Blood 1995; 86: 3035-3042.
- 17 Niewiarowski S, Prou-Wartell O. Rolede facteur contact (Facteur Hageman) dens le fibrinolyse. Thromb Diath Haemorraghica. 1959; 3: 593-603.
- 18 Iatridis SG, Ferguson JH. Effect of surface and Hageman factor on the endogenous or spontaneous activation of the fibrinolytic system. Thromb Diath Haemorrhagica. 1961; 6: 411-423.
- 19 Saito H, Ratnoff OD, Donaldson VH. Defective activation of clotting, fibrinolytic and permeability enhancing systems in human Fletcher trait plasma. Circ Res. 1974; 34: 641-651.
- 20 Saito H, Ratnoff OD, Waldman R, Abraham P. Fitzgerald trait: deficiency of a hitherto unrecognised agent, Fitzgerald factor, participating in surface-mediated reaction of clotting, fibrinolysis, generation of kinins and the property of diluted plasma enhancing vascular permeability (PF/dil). J Clin Invest. 1975; 55: 1082-1089.
- 21 Weiss AS, Gallin JI, Kaplan AP. Fletcher factor deficiency. A diminished rate of Hageman factor activation caused by absence of prekallikrein with abnormalities of coagulation, fibrinolysis, chemotactic activity and kinin generation. J Clin Invest. 1974; 53: 622-633.
- 22 Wuepper KD, Miller DR, Lacombe MJ. Flaujeac trait. Deficiency of human plasma kininogen. J Clin Invest. 1975; 56: 1663-1672.
- 23 Colman RW, Bagdasarian A, Talamo RC, Scott CF, Seavey M, Guimaeras JA, Pierce JV, Kaplan AP. Williams trait: Human Kininogen dificiency with diminished levels of plasminogen proactivator and prekallikrein associated with abnormalities of the Hageman dependent pathways. J Clin Invest 1975; 56: 1650-1662.
- 24 Colman RW. Activation of plasminogen by human plasma kallikrein. Biochem Biophys Res Commun. 1969; 35: 273-278.
- 25 Miles LA, Greengard JS, Griffin JH. A comparison of the abilities of plasma kallikrein, α-factor XIIa, factor XIa and urokinase to activate plasminogen. Thromb Res. 1983; 9: 407-417.
- 26 Goldsmith GH, Saito H, Ratnoff OD. The activation of plasminogen by Hageman factor (factor XII) and Hageman factor fragments. J Clin Invest. 1978; 62: 54-60.
- 27 Mandle Jr. RJ, Kaplan AP. Hageman-factor-dependent fibrinolysis: Generation of fibrinolytic activity by the interaction of human factor XII and plasminogen. Blood 1979; 54: 850-862.
- 28 Mandle Jr. RJ, Kaplan AP. Human plasma prekallikrein: Mechanism of activation by Hageman factor and participation in Hageman-factor-dependent fibrinolysis. J Biol Chem. 1977; 252: 6097-6104.
- 29 Bouma BN, Miles LA, Beretta Griffin JH. Human plasma prekallikrein. Studies of its activation by activated factor XII and of its inactivation by Diisopropyl phosphofluoridate. Biochemistry. 1980; 19: 1151-1160.
- 30 Ichinose A, Fujikawa K, Suyama T. The activation of prourokinase by plasma kallikrein and its inactivation by thrombin. J Biol Chem. 1986; 261: 3486-3490.
- 31 Lenich C, Pannell R, Gurewich V. Assembly and activation of the intrinsic fibrinolytic pathway on the surface of human endothelial cells in culture. Thromb Haemost. 1995; 74: 698-703.
- 32 Loza JP, Gurewich V, Johnstone M, Pannell R. Platelet bound prekallikrein promotes pro-urokinase-induced clot lysis: a mechanism for targeting the factor XII dependent intrinsic pathway of fibrinolysis. Thromb Haemost. 1994; 71: 347-352.
- 33 Gurewich V, Johnstone M, Loza JP, Pannell R. Pro-urokinase and prekallikrein are both associated with platelets. Implications for the intrinsic pathway of fibrinolysis and for therapeutic thrombolysis. FEBS Lett. 1993; 318: 317-321.
- 34 Motta G, Rojkjaer R, Hasan AAK, Cines DB, Schmaier AH. High molecular weight kininogen regulates prekallikrein assembly and activation on endothelial cells. Blood 1998; 91: 516-528.
- 35 Brown NJ, Nadeau JH, Vaughan DE. Selective stimulation of tissue-type plasminogen activator (t-PA) in vivo by infusion of bradykinin. Thromb Haemost. 1997; 77: 522-525.
- 36 Levi M, Hack CE, de Boer JP, Brandjes DPM, Büller HR, ten Cate JW. Reduction of contact activation related fibrinolytic activity in factor XII-deficient patients: further evidence for the role of the contact system in fibrinolysis in vivo. J Clin Invest. 1991; 88: 1155-1160.
- 37 Lämmle B, Wuillemin WA, Huber I, Krauskopf M, Zurcher R, Pflugshaupt R, Furlan M. Thromboembolism and bleeding tendency in congenital factor XII deficiency: a study on 74 subjects from 14 Swiss families. Thromb Haemost. 1991; 65: 117-121.
- 38 Scott CF, Colman RW. Fibrinogen blocks the autoactivation and thrombin-mediated activation of factor XI on dextran sulfate. Proc Natl Acad Sci USA. 1992; 89: 11189-11193.
- 39 Brunnee T, La Porta C, Reddigari SR, Salerno VM, Kaplan AP, Silverberg M. Activation of factor XI in plasma is dependent on factor XII. Blood 1993; 81: 580-586.
- 40 von dem Borne PAKr, Meijers JCM, Bouma BN. Effect of heparin on the activation of factor XI by fibrin bound thrombin. Thromb Haemost. 1996; 76: 347-353.
- 41 Gailani D, Broze GJ. Factor XII-independent activation of factor XI in plasma: effects of sulfatides on tissue factor-induced coagulation. Blood 1993; 82: 813-819.
- 42 Lawson JH, Kalafatis M, Stram S, Mann KG. A model for the tissue factor pathway to thrombin. An empirical study. J Biol Chem. 1994; 269: 23357-23366.
- 43 Minnema MC, Pajkrt D, Wuillemin WA, Roem D, Bleeker WK, Levi M, van Deventer SJH, Hack CE, ten Cate H. Activation of clotting factor XI without detectable contact activation in experimental human endotoxemia. Blood 1998; 92: 3294-3301.
- 44 von dem Borne PAKr, Mosnier LO, Tans G, Meijers JCM, Bouma BN. Factor XI activation by meizothrombin: stimulation by phospholipids vesicles containing both phosphatidylserine and phosphatidylethanolamine. Thromb Haemost. 1997; 78: 834-839.
- 45 Kessels H, Beguin S, Andree H, Hemker HC. Measurement of thrombin generation in whole blood—the effect of heparin and aspirin. Thromb Haemost. 1994; 72: 78-83.
- 46 Bajzar L, Manuel R, Nesheim ME. Purification and characterization of TAFI, a thrombin activatable fibrinolysis inhibitor. J Biol Chem. 1995; 270: 14477-14484.
- 47 Comp PC, Esmon CT. Generation of fibrinolytic activity by infusion of activated protein C into dogs. J Clin Invest. 1981; 68: 1221-1228.
- 48 Sakata Y, Loskutoff DJ, Gladson CL, Hekman CM, Griffin JH. Mechanism of protein C-dependent clot lysis: role of plasminogen activator inhibitor. Blood 1986; 86: 1218-1223.
- 49 de Fouw NJ, Haverkate F, Bertina RM. Protein C and fibrinolysis: a link between coagulation and fibrinolysis. Adv Exp Med Biol. 1990; 281: 235-243.
- 50 Bajzar L, Fredenburgh JC, Nesheim ME. The activated protein C-mediated enhancement of tissue-type plasminogen activator-induced fibrinolysis in a cell-free system. J Biol Chem. 1990; 265: 16948-16954.
- 51 Bajzar L, Nesheim ME. The effect of activated protein C on fibrinolysis in cell free plasma can be attributed specifically to attenuation of prothrombin activation. J Biol Chem. 1993; 268: 8608-8616.
- 52 Tan AK, Eaton DL. Activation and characterization of procarboxypeptidase B from human plasma. Biochemistry. 1995; 34: 5811-5816.
- 53 Redlitz A, Tan AK, Eaton DL, Plow EF. Plasma carboxypeptidases as regulators of the plasminogen system. J Clin Invest. 1995; 96: 2534-2538.
- 54 Wang W, Hendriks DF, Scharpé SS. Carboxypeptidase U, a plasma carboxypeptidase with high affinity for plasminogen. J Biol Chem. 1994; 269: 15937-15944.
- 55 von dem Borne PAKr, Bajzar L, Meijers JCM, Nesheim ME, Bouma BN. Thrombin-mediated activation of factor XI results in a thrombin-activatable fibrinolysis inhibition of fibrinolysis. J Clin Invest. 1997; 99: 2323-2327.
- 56 Mosnier LO, von dem Borne PAKr, Meijers JCM, Bouma BN. Plasma TAFI levels influence the clot lysis time in healthy individuals in the presence of an intact intrinsic pathway of coagulation. Thromb Haemost. 1998; 80: 829-835.
- 57 Minnema MC, Friederich PW, Levi M, von dem Borne PAKr, Mosnier LO, Meijers JCM, Biemond BJ, Hack CE, Bouma BN, ten Cate H. Enhancement of rabbit jugular vein thrombolysis by neutralization of factor XI. In vivo evidence for a role of factor XI as an anti-fibrinolytic factor. J Clin Invest. 1998; 1: 10-14.
- 58 Sakharov DV, Plow EF, Rijken DC. On the mechanism of the antifibrinolytic activity of plasma carboxypeptidase B. J Biol Chem. 1997; 272: 14477-14482.
- 59 Weitz JI, Hudoba D, Massel J, Maraganore J, Hirsh J. 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.
- 60 Kumar R, Beguin S, Hemker HC. The influence of fibrinogen on thrombin generation: evidence for feedback activation of the clotting system by clot bound thrombin. Thromb Haemost. 1994; 72: 713-721.
- 61 Biemond BJ, Friederich PW, Levi M, Vlasuk GP, Buller HR, ten Cate JW. Comparison of sustained antithrombotic effects of inhibitors of thrombin and factor Xa in experimental thrombosis. Circulation. 1996; 93: 153-160.
- 62 Bajzar L, Morser J, Nesheim ME. TAFI, or plasma procarboxypeptidase B, couples the coagulation and fibrinolytic cascades through the thrombin-thrombomodulin complex. J Biol Chem. 1996; 271: 16603-16608.
- 63 Broze GJ, Higuchi DA. Coagulation-dependent inhibition of fibrinolysis: role of carboxypeptidase-U and the premature lysis of clots from hemophilic plasma. Blood 1996; 88: 3815-3823.
- 64 Ichinose A. The physiology and biochemistry of factor XIII. In: Haemostasis and Thrombosis. Bloom AL, Forbes CD, Thomas DP, Tuddenham EGD. eds. Edinburgh: Churchill Livingstone; 1994: 531-546.
- 65 Gurewich V, Pannell R. Inactivation single-chain urokinase (prourokinase) by thrombin and thrombin-like enzymes: relevance of the findings to the interpretation of fibrin binding experiments. Blood 1987; 69: 769-772.
- 66 Lijnen HR, van Hoef B, Collen D. Activation of with plasmin of two-chain urokinase type plasminogen activator derived from single-chain urokinase-type plasminogen activator by treatment with thrombin. Eur J Biochem. 1987; 169: 359-364.
- 67 Braat EAM, Los P, Rijken DC. The inactivation of single-chain urokinase-type plasminogen activator by thrombin in a plasma milieu: the effect of thrombomodulin. Blood Coag Fibrinolysis. 1998; 9: 419-427.
- 68 Braat EAM, Rijken DC. The inactivation of single-chain urokinase type-plasminogen activator by thrombin may provide an additional explanation for the antifibrinolytic effect of factor XI. Thromb Haemost. 1999; 81: 657.
- 69 Bouma BN, von dem Borne PAKr, Meijers JCM. Factor XI and protection of the fibrin clot against lysis—a role for the intrinsic pathway of coagulation in fibrinolysis. Thromb Haemost. 1998; 80: 24-27.
- 70 Osterud B, Rapaport S. Activation of factor IX by the reaction product of tissue factor and factor VII: an additional pathway for initiating blood coagulation. Proc Natl Acad Sci USA. 1997; 74: 5260-5264.
- 71 Marlar RA, Kleiss AJ, Griffin JH. An alternative pathway of human blood coagulation. Blood 1982; 60: 1353-1358.
- 72 Broze GJ. The role of tissue factor pathway inhibitor in a revised coagulation cascade. Semin Hematol. 1992; 29: 159-169.
- 73 Rand MD, Lock JB, van’t Veer C, Gaffney DP, Mann KG. Blood clotting in minimally altered blood. Blood 1996; 88: 3422-3445.
- 74 Gresele P, Momi S, Berrettini M, Nenci GG, Schwarz HP, Semeraro N, Colucci M. Activated protein C prevents thrombin-induced thromboembolism in mice. Evidence that activated protein C reduces intravascular fibrin accumulation through the inhibition of additional thrombin generation. J Clin Invest. 1998; 101: 667-676.
- 75 Bertina RM, Koeleman BP, Koster T, Rosendaal FR, Dirven RJ, de Ronde H, van der Velden PA, Reitsma PH. Mutation in blood coagulation factor V associated with resistance to activated protein C. Nature 1994; 369: 64-67.
- 76 Bajzar L, Kalafatis M, Simioni P, Tracy PB. An antifibrinolytic mechanism describing the prothrombotic effect associated with factor V Leiden. J Biol Chem. 1996; 271: 22949-22952.
- 77 Griffin JH. Blood coagulation—the thrombin paradox. Nature 1995; 378: 337-338.
- 78 Hanson SR, Griffin JH, Harker LA, Kelly AB, Esmon CT, Gruber A. Antithrombotic effects of thrombin-induced activation of endogenous protein C in primates. J Clin Invest. 1993; 92: 2003-2012.
- 79 Bauer KA, Rosenberg RD. The pathophysiology of the prethrombotic state in humans: insights gained from studies using markers of hemostatic system activation. Blood 1987; 70: 343-350.
- 80 Nuijens JH, Huijbregts CCM, Eerenberg-Belmer AJM, Abbink JJ, Strack van Schijndel RJM, Felt-Bersma RJF, Thijs LG, Hack CE. Quantification of plasma factor XII-C1-inhibitor and kallikrein-C1-inhibitior complexes in sepsis. Blood 1988; 72: 1841-1848.
- 81 Pixley RA, de la Cadena R, Page JD, Kaufman N, Wyshock EG, Colman RW, Chang A, Taylor FB. Activation of the contact system in lethal hypotensive bacteremia in a baboon model. Am J Pathol. 1992; 140: 897-906.
- 82 van der Linden PWG, Hack CE, Eerenberg AJM, Struyvenberg A, van der Zwan JK. Activation of the contact system in insect-sting anaphylaxis: association with the development of angioedema and shock. Blood 1993; 82: 1732-1739.
- 83 Abbink JJ, Kamp AM, Nuijens JH, Eerenberg AJM, Swaak AJF, Hack CE. Relative contribution of contact and complement activation to inflammatory reactions in arthritis joints. Ann Rheum Dis. 1992; 51: 123-128.
- 84 Colman RW. Surface-mediated defense reactions. The plasma contact activation system. J Clin Invest. 1984; 73: 1249-1253.