Therapeutische Inhibition von Thrombozyten

  • K. Peter
  • C. Bode
Conference paper

Zusammenfassung

Ischämische kardiovaskuläre Erkrankungen stellen die häufigste Todesursache in industrialisierten Ländern dar. Thrombozyten spielen dabei, insbesondere im Rahmen akuter ischämischer Komplikationen, eine zentrale Rolle. Die Arteriosklerose beginnt oft bereits im 2. Lebens jähr zehnt. Auf der Grundlage der allmählich fortschreitenden arteriosklerotischen Veränderungen kommt es zur Fissur arteriosklerotischer Plaques mit der Exposition einer thrombogenen Oberfläche. Dies führt zur Adhäsion und Aggregation von Thrombozyten und dadurch beispielsweise zu akuten ischämischen Koronarsyndromen wie Myokardinfarkt oder instabiler Angina pectoris. Thrombozyten spielen zudem bei therapeutischen Interventionen, wie beispielsweise der Angioplastie, eine wichtige Rolle. Die therapeutische Aufweitung von Koro- narstenosen führt zum Aufbrechen arteriosklerotischer Plaques und dadurch zur Exposition einer thrombogenen Oberfläche. Die resultierende Thrombo- zytenadhäsion und -aggregation ist dabei sowohl für den akuten Gefäßverschluß als auch für die leider oft entstehende Restenose entscheidend.

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

literatur

  1. Bennett JS, Vilaire G (1979) Exposure of platelet fibrinogen receptors by ADP and epinephrine. J Clin Invest 64: 1393PubMedCrossRefGoogle Scholar
  2. Calvete JJ (1993) Clues for understanding the structure and function of a prototypic human integrin: The platelet glycoprotein IIb/IIIa complex. Thromb Haemost 72: 1Google Scholar
  3. CAPRIE (1996) A randomised, blinded, trial of clopidogrel versus aspirin in patients at risk of ischemic events. Lancet 348: 1329CrossRefGoogle Scholar
  4. Coller BS, Scudder LE (1985) Inhibition of dog platelet function by in vivo infusion of F(ab’)2 Fragments of a monoclonal antibody to the platelet glycoprotein IIb/IIIa receptor. Blood 66: 1456PubMedGoogle Scholar
  5. The CAPTURE investigators (1997) Randomised placebo-controlled trial of abciximab before and during coronary intervention in refractory unstable angina: the CAPTURE study. Lancet 349: 1429CrossRefGoogle Scholar
  6. Coller BS (1985) A new murine monoclonal antibody reports an activation-dependent change in the conformation of the platelet glycoprotein IIb/IIIa complex. J Clin Invest 76: 101PubMedCrossRefGoogle Scholar
  7. Coller BS (1986) Activation affects access to the platelet receptor for adhesive glycoproteins. J Cell Biol 103: 451PubMedCrossRefGoogle Scholar
  8. Coller BS (1995) Blockade of platelet GP IIb/IIIa receptors as an antithrombotic strategy. Circulation 92: 2373PubMedGoogle Scholar
  9. Coller BS (1997) Platelet GP IIb/IIIa Antagonists: The first anti-integrin receptor therapeutics. J Clin Invest 100:1467 The EPIC investigators (1994) Use of a monoclonal antibody directed against the platelet glycoprotein IIb/IIIa receptor in high-risk coronary angioplasty. N Engl J Med 330: 956Google Scholar
  10. The EPILOG investigators (1997) Platelet glycoprotein IIb/IIIa receptor blockade and low- dose heparin during percutaneous coronary revascularization. N Engl J Med 336: 1689CrossRefGoogle Scholar
  11. Du X, Plow EF, Freelinger III AL, O’Toole TE, Loftus JC, Ginsberg MH (1991) Ligands activate integrin a„αIIBß3 (platelet GP Ilb-IIIa). Cell 65: 409PubMedCrossRefGoogle Scholar
  12. Frishman WH, Burns B, Atac B, Alturk N, Altajar B, Lerrick K (1995) Novel antiplatelet therapies for treatment of patients with ischemic heart disease: inhibitors of the platelet glycoprotein IIb/IIIa integrin receptor. Am Heart J 130: 877PubMedCrossRefGoogle Scholar
  13. Gold HK, Gimple LW, Yasuda T etal. (1990) Pharmacodynamic study of F(ab)2-Fragments of murine monoclonal antibody 7E3 directed against human platelet glycoprotein lib/ Ilia in patients with unstable angina pectoris. J Clin Invest 86: 651PubMedCrossRefGoogle Scholar
  14. Hynes RO (1992) Integrins: Versatility, modulation, and signalling in cell adhesion. Cell 69: 11PubMedCrossRefGoogle Scholar
  15. Knight DM, Wagner C, Jordan R etal. (1995) The immunogenicity of the 7E3 murine monoclonal Fab antibody fragment variable is dramatically reduced in humans by substitution of human for murine constant regions. Mol Immunol 32: 1271PubMedCrossRefGoogle Scholar
  16. Lefkovits J, Plow EF, Topol E (1995) Platelet glycoprotein IIb/IIIa receptors in cardiovascular medicine. N Engl J Med 23: 1553Google Scholar
  17. Marguerie GA, Plow EF, Edgington TS (1979) Human platelets possess an inducible and saturable receptor specific for fibrinogen. J Biol Chem 254: 5357PubMedGoogle Scholar
  18. O’Toole TE, Katagieri Y, Faull RJ etal. (1994) Integrin cytoplasmic domains mediate inside- out signal transduction. J Cell Biol 124: 104Google Scholar
  19. Patrono C (1994) Aspirin as an antiplatelet drug. N Engl J Med 330: 1287PubMedCrossRefGoogle Scholar
  20. Peter K, O’Toole TE (1995) Modulation of cell adhesion by changes in aLp2 (LFA-1, CD 11 a/ CD 18) cytoplasmic domain/cytoskeleton interaction. J Exp Med 181: 315PubMedCrossRefGoogle Scholar
  21. Peter K, Schwarz M, Majer P, Kohler B, Nordt T, Bode C (1997) The antibody fragment c7E3 (Reo-Pro) binds to activated and nonactivated Mac-1 on granulo- and monocytes and blocks Mac-1-mediated cell adhesion and aggregation. J Am Coll Cardiol 29: 241Google Scholar
  22. A Plow EF, Pierschbacher MB, Ruoslathi E, Marguerie GA, Ginsberg MH (1985) The effect of Arg-Gly-Asp-containing peptides on fibrinogen and von Willebrand factor binding to platelets. Proc Natl Acad Sci USA 82: 8057PubMedCrossRefGoogle Scholar
  23. Pytela R, Pierschbacher MB, Ginsberg MH, Plow EF, Ruoslathi E (1986) Platelet membrane glycoprotein IIb/IIIa: member of a family of Arg-Gly-Asp-specific adhesion receptors. Science 231: 1559PubMedCrossRefGoogle Scholar
  24. Roth GJ, Calverley DC (1994) Aspirin, platelets, and thrombosis: theory and practice. Blood 83: 885PubMedGoogle Scholar
  25. Theroux P, Kouz S, Roy L etal. (1996) Platelet membrane receptor glycoprotein IIb/IIIa antagonism in unstable angina; the Canadian lamifiban study. Circulation 94: 899PubMedGoogle Scholar
  26. Topol EJ (1996) Platelet glycoprotein IIb/IIIa receptor antagonists in coronary artery disease. Eur Heart J 17: 9PubMedGoogle Scholar
  27. Topol EJ, Califf RM, Weisman HF etal. (1994) Randomized trial of coronary intervention with antibody against platelet IIb/IIIa integrin for reduction of clinical restenosis: results at six months. Lancet 343: 881PubMedCrossRefGoogle Scholar
  28. Tscheng JE, Harrington RI, Kottke-Marchant K etal., for the IMPACT investigators (1995) Multicenter, randomized, double-blind, placebo-controlled trial of the platelet integrin glycoprotein IIb/IIIa blocker integrelin in elective coronary intervention. Circulation 91: 2151Google Scholar
  29. Ylanne J, Chen Y, O’Toole TE etal. (1993) Distinct functions of integrin alpha and beta sub- unit cytoplasmic domains in cell spreading and formation of focal adhesions. J Cell Biol 122: 223PubMedCrossRefGoogle Scholar
  30. Wagner CL, Mascelli MA, Neblock DS, Weisman HF, Coller BS, Jordan RE (1996) Analysis of GP IIb/IIIa receptor number by quantification of 7E3 binding to human platelets. Blood 88: 907PubMedGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 1998

Authors and Affiliations

  • K. Peter
  • C. Bode

There are no affiliations available

Personalised recommendations