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Mol Med. 1998 September; 4(9): 629–637.
PMCID: PMC2230314

Decreased fibrinolytic activity in porcine-to-primate cardiac xenotransplantation.


BACKGROUND: One major barrier to successful xenotransplantation is acute vascular rejection, a process pathologically characterized by microvascular thrombosis and diffuse fibrin deposition in transplant blood vessels. This pathologic picture may result from a disturbance in the coagulant or fibrinolytic pathways that regulate normal vascular patency. This study evaluated the regulation of fibrinolytic activity defined by tissue plasminogen activator and plasminogen activator inhibitor-1 as it may exist in the setting of acute vascular rejection. MATERIALS AND METHODS, RESULTS: Serial biopsies from cardiac xenotransplants evaluated by immunofluorescence microscopy demonstrated progressive decreases in tissue plasminogen activator and increases in plasminogen activator inhibitor-1. In vitro studies measuring fibrinolytic activity of cell culture medium from porcine aortic endothelial cells stimulated with human serum or autologous porcine serum revealed that human serum triggered as much as 93% increase in antifibrinolytic activity. CONCLUSIONS: These findings demonstrate that porcine vascular endothelial cells change toward an antifibrinolytic state following stimulation with human xenoreactive antibodies and complement. The shift is at least partly explained by an increased ratio of plasminogen activator inhibitor-1 to tissue plasminogen activator, and is at least in part mediated by the activation of complement. This increased antifibrinolytic activity may contribute to the thrombotic diathesis seen in acute vascular rejection in pig-to-primate xenografts.

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  • Platt JL, Vercellotti GM, Dalmasso AP, Matas AJ, Bolman RM, Najarian JS, Bach FH. Transplantation of discordant xenografts: a review of progress. Immunol Today. 1990 Dec;11(12):450–457. [PubMed]
  • Auchincloss H., Jr Xenogeneic transplantation. A review. Transplantation. 1988 Jul;46(1):1–20. [PubMed]
  • Platt JL, Fischel RJ, Matas AJ, Reif SA, Bolman RM, Bach FH. Immunopathology of hyperacute xenograft rejection in a swine-to-primate model. Transplantation. 1991 Aug;52(2):214–220. [PubMed]
  • Parker W, Saadi S, Lin SS, Holzknecht ZE, Bustos M, Platt JL. Transplantation of discordant xenografts: a challenge revisited. Immunol Today. 1996 Aug;17(8):373–378. [PubMed]
  • Cooper DK, Human PA, Lexer G, Rose AG, Rees J, Keraan M, Du Toit E. Effects of cyclosporine and antibody adsorption on pig cardiac xenograft survival in the baboon. J Heart Transplant. 1988 May-Jun;7(3):238–246. [PubMed]
  • Leventhal JR, Dalmasso AP, Cromwell JW, Platt JL, Manivel CJ, Bolman RM, 3rd, Matas AJ. Prolongation of cardiac xenograft survival by depletion of complement. Transplantation. 1993 Apr;55(4):857–866. [PubMed]
  • Pruitt SK, Kirk AD, Bollinger RR, Marsh HC, Jr, Collins BH, Levin JL, Mault JR, Heinle JS, Ibrahim S, Rudolph AR, et al. The effect of soluble complement receptor type 1 on hyperacute rejection of porcine xenografts. Transplantation. 1994 Feb;57(3):363–370. [PubMed]
  • McCurry KR, Kooyman DL, Alvarado CG, Cotterell AH, Martin MJ, Logan JS, Platt JL. Human complement regulatory proteins protect swine-to-primate cardiac xenografts from humoral injury. Nat Med. 1995 May;1(5):423–427. [PubMed]
  • Magee JC, Collins BH, Harland RC, Lindman BJ, Bollinger RR, Frank MM, Platt JL. Immunoglobulin prevents complement-mediated hyperacute rejection in swine-to-primate xenotransplantation. J Clin Invest. 1995 Nov;96(5):2404–2412. [PMC free article] [PubMed]
  • Lin SS, Kooyman DL, Daniels LJ, Daggett CW, Parker W, Lawson JH, Hoopes CW, Gullotto C, Li L, Birch P, et al. The role of natural anti-Gal alpha 1-3Gal antibodies in hyperacute rejection of pig-to-baboon cardiac xenotransplants. Transpl Immunol. 1997 Sep;5(3):212–218. [PubMed]
  • Leventhal JR, Matas AJ, Sun LH, Reif S, Bolman RM, 3rd, Dalmasso AP, Platt JL. The immunopathology of cardiac xenograft rejection in the guinea pig-to-rat model. Transplantation. 1993 Jul;56(1):1–8. [PubMed]
  • Levin EG, Loskutoff DJ. Cultured bovine endothelial cells produce both urokinase and tissue-type plasminogen activators. J Cell Biol. 1982 Sep;94(3):631–636. [PMC free article] [PubMed]
  • Kristensen P, Larsson LI, Nielsen LS, Grøndahl-Hansen J, Andreasen PA, Danø K. Human endothelial cells contain one type of plasminogen activator. FEBS Lett. 1984 Mar 12;168(1):33–37. [PubMed]
  • Collen D, Lijnen HR. Basic and clinical aspects of fibrinolysis and thrombolysis. Blood. 1991 Dec 15;78(12):3114–3124. [PubMed]
  • Schleef RR, Loskutoff DJ. Fibrinolytic system of vascular endothelial cells. Role of plasminogen activator inhibitors. Haemostasis. 1988;18(4-6):328–341. [PubMed]
  • Sprengers ED, Kluft C. Plasminogen activator inhibitors. Blood. 1987 Feb;69(2):381–387. [PubMed]
  • Lijnen HR, Collen D. Endothelium in hemostasis and thrombosis. Prog Cardiovasc Dis. 1997 Jan-Feb;39(4):343–350. [PubMed]
  • Wiman B, Ljungberg B, Chmielewska J, Urdén G, Blombäck M, Johnsson H. The role of the fibrinolytic system in deep vein thrombosis. J Lab Clin Med. 1985 Feb;105(2):265–270. [PubMed]
  • Nilsson IM, Ljungnér H, Tengborn L. Two different mechanisms in patients with venous thrombosis and defective fibrinolysis: low concentration of plasminogen activator or increased concentration of plasminogen activator inhibitor. Br Med J (Clin Res Ed) 1985 May 18;290(6480):1453–1456. [PMC free article] [PubMed]
  • Hamsten A, Wiman B, de Faire U, Blombäck M. Increased plasma levels of a rapid inhibitor of tissue plasminogen activator in young survivors of myocardial infarction. N Engl J Med. 1985 Dec 19;313(25):1557–1563. [PubMed]
  • Aznar J, Estellés A, Tormo G, Sapena P, Tormo V, Blanch S, España F. Plasminogen activator inhibitor activity and other fibrinolytic variables in patients with coronary artery disease. Br Heart J. 1988 May;59(5):535–541. [PMC free article] [PubMed]
  • Labarrere CA, Pitts D, Nelson DR, Faulk WP. Vascular tissue plasminogen activator and the development of coronary artery disease in heart-transplant recipients. N Engl J Med. 1995 Oct 26;333(17):1111–1116. [PubMed]
  • Booth NA, Bennett B, Wijngaards G, Grieve JH. A new life-long hemorrhagic disorder due to excess plasminogen activator. Blood. 1983 Feb;61(2):267–275. [PubMed]
  • Byrne GW, McCurry KR, Martin MJ, McClellan SM, Platt JL, Logan JS. Transgenic pigs expressing human CD59 and decay-accelerating factor produce an intrinsic barrier to complement-mediated damage. Transplantation. 1997 Jan 15;63(1):149–155. [PubMed]
  • Platt JL, LeBien TW, Michael AF. Interstitial mononuclear cell populations in renal graft rejection. Identification by monoclonal antibodies in tissue sections. J Exp Med. 1982 Jan 1;155(1):17–30. [PMC free article] [PubMed]
  • Soeda S, Kakiki M, Shimeno H, Nagamatsu A. Rapid and high-yield purification of porcine heart tissue-type plasminogen activator by heparin-sepharose choromatography. Life Sci. 1986 Oct 13;39(15):1317–1324. [PubMed]
  • Hanss M, Collen D. Secretion of tissue-type plasminogen activator and plasminogen activator inhibitor by cultured human endothelial cells: modulation by thrombin, endotoxin, and histamine. J Lab Clin Med. 1987 Jan;109(1):97–104. [PubMed]
  • Lawson JH, Platt JL. Molecular barriers to xenotransplantation. Transplantation. 1996 Aug 15;62(3):303–310. [PubMed]
  • Saadi S, Holzknecht RA, Patte CP, Stern DM, Platt JL. Complement-mediated regulation of tissue factor activity in endothelium. J Exp Med. 1995 Dec 1;182(6):1807–1814. [PMC free article] [PubMed]
  • Platt JL, Vercellotti GM, Lindman BJ, Oegema TR, Jr, Bach FH, Dalmasso AP. Release of heparan sulfate from endothelial cells. Implications for pathogenesis of hyperacute rejection. J Exp Med. 1990 Apr 1;171(4):1363–1368. [PMC free article] [PubMed]
  • Moore KL, Andreoli SP, Esmon NL, Esmon CT, Bang NU. Endotoxin enhances tissue factor and suppresses thrombomodulin expression of human vascular endothelium in vitro. J Clin Invest. 1987 Jan;79(1):124–130. [PMC free article] [PubMed]
  • Lawson JH, Daniels LJ, Platt JL. The evaluation of thrombomodulin activity in porcine to human xenotransplantation. Transplant Proc. 1997 Feb-Mar;29(1-2):884–885. [PubMed]
  • van Hinsbergh VW, Kooistra T, Emeis JJ, Koolwijk P. Regulation of plasminogen activator production by endothelial cells: role in fibrinolysis and local proteolysis. Int J Radiat Biol. 1991 Jul-Aug;60(1-2):261–272. [PubMed]
  • Diamond SL, Eskin SG, McIntire LV. Fluid flow stimulates tissue plasminogen activator secretion by cultured human endothelial cells. Science. 1989 Mar 17;243(4897):1483–1485. [PubMed]
  • Levin EG, Marzec U, Anderson J, Harker LA. Thrombin stimulates tissue plasminogen activator release from cultured human endothelial cells. J Clin Invest. 1984 Dec;74(6):1988–1995. [PMC free article] [PubMed]
  • Schleef RR, Bevilacqua MP, Sawdey M, Gimbrone MA, Jr, Loskutoff DJ. Cytokine activation of vascular endothelium. Effects on tissue-type plasminogen activator and type 1 plasminogen activator inhibitor. J Biol Chem. 1988 Apr 25;263(12):5797–5803. [PubMed]
  • Emeis JJ, Kooistra T. Interleukin 1 and lipopolysaccharide induce an inhibitor of tissue-type plasminogen activator in vivo and in cultured endothelial cells. J Exp Med. 1986 May 1;163(5):1260–1266. [PMC free article] [PubMed]

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