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Development and Use of Platelet Glycoprotein Antagonists in Heart Disease

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Cardiac Drug Development Guide

Part of the book series: Methods in Pharmacology and Toxicology ((MIPT))

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Abstract

Platelets are not only responsible for primary hemostasis (1), but also for the thrombi that produce the morbidity and mortality of arterial vascular disease (2). Although considerable effort has been expended to associate augmented platelet function with arterial thrombosis, it is more likely that the formation of platelet thrombi simply represents normal platelet function in the wrong location. It follows then that a rational approach to treating atherosclerotic disease is to prevent the development of vascular lesions in the first place. Nonetheless, the administration of platelet-inhibitory drugs, such as aspirin (3), has been of proven benefit to individuals with established vascular disease, providing the impetus to identify more effective clinically useful platelet function inhibitors. Moreover, there has been substantial progress in understanding the biochemical basis of platelet function, providing additional targets for drug development. However, clinical experience has shown that the therapeutic index for the existing potent platelet inhibitors is narrow, suggesting that new and novel approaches to impairing platelet function will be required.

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REFERENCES

  1. Sixma, J. J. and Wester, J. (1977) The hemostatic plug. Semin. Hematol. 14, 265–299.

    PubMed  CAS  Google Scholar 

  2. Lefkovits, J., Plow, E. and Topol, E. (1995) Platelet glycoprotein IIb/IIIa receptors in cardiovascular medicine. N. Engl. J. Med. 332, 1553–1559.

    Article  PubMed  CAS  Google Scholar 

  3. Patrono, C. (1994) Aspirin as an antiplatelet drug. N. Engl. J. Med. 330, 1287–1294.

    Article  PubMed  CAS  Google Scholar 

  4. Hemler, M. E., Crouse, C., Takada, Y. and Sonnenberg, A. (1988) Multiple very late antigen (VLA) heterodimers on platelets. Evidence for distinct VLA-2, VLA-5 (fibronectin receptor), and VLA-6 structures. J. Biol. Chem. 263, 7660–7665.

    PubMed  CAS  Google Scholar 

  5. Turitto, V. T., Weiss, H. J., Zimmerman, T. S., and Sussman, II. (1985) Factor VIII/von Willebrand factor in subendothelium mediates platelet adhesion. Blood 65, 823–831.

    PubMed  CAS  Google Scholar 

  6. Wagner, D. D. and Marder, V. J. (1984) Biosynthesis of von Willebrand protein by human endothelial cells: Processing steps and their intracellular localization. J. Cell Biol. 99, 2123–2130.

    Article  PubMed  CAS  Google Scholar 

  7. Sporn, L. A., Chavin, S. I., Marder, V. J., and Wagner, D. D. (1985) Biosynthesis of von Willebrand protein by human megakaryocytes. J. Clin. Invest. 76, 1102–1106.

    Article  PubMed  CAS  Google Scholar 

  8. Coller, B. S., Peerschke, E. I., Scudder, L. E. and Sullivan, C. A. (1983) Studies with a murine monoclonal antibody that abolishes ristocetin-induced binding of von Willebrand factor to platelets: Additional evidence in support of GPIb as a platelet receptor for von Willebrand factor. Blood 61, 99–110.

    PubMed  CAS  Google Scholar 

  9. Ruggeri, Z. M., DeMarco, L., Gatti, L., Bader, R. and Montgomery, R. R. (1983) Platelets have more than one binding site for von Willebrand factor. J. Clin. Invest. 72, 1–12.

    Article  PubMed  CAS  Google Scholar 

  10. Ruggeri, Z. M. and Zimmerman, T. S. (1987) von Willebrand factor and von Willebrand disease. Blood 70, 895–904.

    PubMed  CAS  Google Scholar 

  11. Savage, B., Saldivar, E., and Ruggeri, Z. M. (1996) Initiation of platelet adhesion by arrest onto fibrinogen or translocation on von Willebrand factor. Cell 84, 289–297.

    Article  PubMed  CAS  Google Scholar 

  12. Roth, G. J. (1991) Developing relationships: Arterial platelet adhesion, glycoprotein Ib, and leucine-rich glycoproteins. Blood 77, 5–19.

    PubMed  CAS  Google Scholar 

  13. Weiss, H. J., Tschopp, T. B., Baumgartner, H. R., Sussman, I. I., Johnson, M. M., and Egan, J. J. (1974) Decreased adhesion of giant (Bernard-Soulier) platelets to subendothelium. Further implications on the role of von Willebrand factor in hemostasis. Am. J. Med. 57, 920–925.

    Article  PubMed  CAS  Google Scholar 

  14. Matsuno, H., Kozawa, O., Niwa, M., and Uematsu, T. (1997) Inhibition of von Willebrand factor binding to platelet GP Ib by a fractionated aurintricarboxylic acid prevents restenosis after vascular injury in hamster carotid artery. Circulation 96, 1299–1304.

    PubMed  CAS  Google Scholar 

  15. Okada, N. and Koizumi, S. (1995) A neuroprotective compound, aurin tricarboxylic acid, stimulates the tyrosine phosphorylation cascade in PC12 cells. J. Biol. Chem. 270, 16,464–16,469.

    Article  PubMed  CAS  Google Scholar 

  16. Rui, H., Xu, J., Mehta, S., Fang, H., Williams, J., Dong, F., and Grimley, P. M. (1998) Activation of the Jak2-Stat5 signaling pathway in Nb2 lymphoma cells by an anti-apoptotic agent, aurintricarboxylic acid. J. Biol. Chem. 273, 28–32.

    Article  PubMed  CAS  Google Scholar 

  17. Azzam, K., Cisse-Thiam, M., and Drouet, L. (1996) The antithrombotic effect of aurin tricarboxylic acid in the guinea pig is not solely due to its interaction with the von Willebrand factor-GPIb axis. Thromb. Haemost. 75, 203–210.

    PubMed  CAS  Google Scholar 

  18. Kageyama, S., Yamamoto, H., Nakazawa, H., Matsushita, J., Kouyama, T., Gonsho, A., et al. (2002) Pharmacokinetics and pharmacodynamics of AJW200, a humanized monoclonal antibody to von Willebrand factor, in monkeys. Arterioscler. Thromb. Vasc. Biol. 22, 187–192.

    Article  PubMed  CAS  Google Scholar 

  19. Peng, M., Lu, W., Beviglia, L., Niewiarowski, S., and Kirby, E. P. (1993) Echicetin: A snake venom protein that inhibits binding of vonWillebrand factor and alboaggregins to platelet glycoprotein Ib. Blood 81, 2321–2328.

    PubMed  CAS  Google Scholar 

  20. Chang, M. C., Lin, H. K., Peng, H. C., and Huang, T. F. (1998) Antithrombotic effect of crotalin, a platelet membrane glycoprotein Ib antagonist from venom of Crotalus atrox. Blood 91, 1582–1589.

    PubMed  CAS  Google Scholar 

  21. Yeh, C. H., Chang, M. C., Peng, H. C., and Huang, T. F. (2001) Pharmacological characterization and antithrombotic effect of agkistin, a platelet glycoprotein Ib antagonist. Br. J. Pharmacol. 132, 843–850.

    Article  PubMed  CAS  Google Scholar 

  22. Savage, B., Almus-Jacobs, F., and Ruggeri, Z. M. (1998) Specific synergy of multiple substrate-receptor interactions in platelet thrombus formation under flow. Cell 94, 657–666.

    Article  PubMed  CAS  Google Scholar 

  23. Charo, I. F., Feinman, R. D., and Detwiler, T. C. (1977) Interrelations of platelet aggregation and secretion. J. Clin. Invest. 60, 866–873.

    Article  PubMed  CAS  Google Scholar 

  24. Clemetson, J. M., Polgar, J., Magnenat, E., Wells, T. N., and Clemetson, K. J. (1999) The platelet collagen receptor glycoprotein VI is a member of the immunoglobulin superfamily closely related to FcαR and the natural killer receptors. J. Biol. Chem. 274, 29,019–29,024.

    Article  PubMed  CAS  Google Scholar 

  25. Moroi, M., Jung, S. M., Okuma, M., and Shinmyozu, K. (1989) A patient with platelets deficient in glycoprotein VI that lack both collagen-induced aggregation and adhesion. J. Clin. Invest. 84, 1440–1445.

    Article  PubMed  CAS  Google Scholar 

  26. Nieuwenhuis, H. K., Akkerman, J. W. N., Houdijk, W. P. M., and Sixma, J. J. (1985) Human blood platelets showing no response to collagen fail to express surface glycoprotein Ia. Nature 318, 470–472.

    Article  PubMed  CAS  Google Scholar 

  27. Arai, M., Yamamoto, N., Moroi, M., Akamatsu, N., Fukutake, K., and Tanoue, K. (1995) Platelets with 10% of the normal amount of glycoprotein VI have an impaired response to collagen that results in a mild bleeding tendency. Br. J. Haematol. 89, 124–130.

    PubMed  CAS  Google Scholar 

  28. Nieuwenhuis, H. K., Sakariassen, K. S., Houdijk, W. P. M., Nievelstein, P. F. E. M., and Sixma, J. J. (1986) Deficiency of platelet membrane glycoprotein Ia associated with a decreased platelet adhesion to subendothelium: A defect in platelet spreading. Blood 68, 692–695.

    PubMed  CAS  Google Scholar 

  29. Kehrel, B., Balleisen, L., Kokott, R., Mesters, R., Stenzinger, W., Clemetson, K. J., and van de Loo, J. (1988) Deficiency of intact thrombospondin and membrane glycoprotein Ia in platelets with defective collagen-induced aggregation and spontaneous loss of disorder. Blood 71, 1074–1078.

    PubMed  CAS  Google Scholar 

  30. Santoso, S., Kunicki, T. J., Kroll, H., Haberbosch, W., and Gardemann, A. (1999) Association of the platelet glycoprotein Ia C807T gene polymorphism with nonfatal myocardial infarction in younger patients. Blood 93, 2449–2453.

    PubMed  CAS  Google Scholar 

  31. Carlsson, L. E., Santoso, S., Spitzer, C., Kessler, C., and Greinacher, A. (1999) The alpha2 gene coding sequence T807/A873 of the platelet collagen receptor integrin alpha2beta1 might be a genetic risk factor for the development of stroke in younger patients. Blood 93, 3583–3586.

    PubMed  CAS  Google Scholar 

  32. Corral, J., Gonzalez-Conejero, R., Rivera, J., Ortuno, F., Aparicio, P., and Vicente, V. (1999) Role of the 807 C/T polymorphism of the alpha2 gene in platelet GP Ia collagen receptor expression and function—effect in thromboembolic diseases. Thromb. Haemost. 81, 951–956.

    PubMed  CAS  Google Scholar 

  33. Holtkotter, O., Nieswandt, B., Smyth, N., Muller, W., Hafner, M., Schulte, V., et al. (2002) Integrin alpha 2-deficient mice develop normally, are fertile, but display partially defective platelet interaction with collagen. J. Biol. Chem. 277, 10,789–10,794.

    Article  PubMed  CAS  Google Scholar 

  34. Nieswandt, B., Brakebusch, C., Bergmeier, W., Schulte, V., Bouvard, D., et al. (2001) Glycoprotein VI but not alpha2beta1 integrin is essential for platelet interaction with collagen. EMBO J. 20, 2120–2130.

    Article  PubMed  CAS  Google Scholar 

  35. Jandrot-Perrus, M., Busfield, S., Lagrue, A. H., Xiong, X., Debili, N., Chickering, T., et al. (2000) Cloning, characterization, and functional studies of human and mouse glycoprotein VI: A platelet-specific collagen receptor from the immunoglobulin superfamily. Blood 96, 1798–1807.

    PubMed  CAS  Google Scholar 

  36. Bennett, J. S. (1996) Structural biology of glycoprotein IIb-IIIa. Trends Cardiovasc. Med. 6, 31–37.

    Article  PubMed  CAS  Google Scholar 

  37. Poncz, M., Eisman, R., Heidenreich, R., Silver, S. M., Vilaire, G., Surrey, S., et al. (1987) Structure of the platelet membrane glycoprotein IIb. J. Biol. Chem. 262, 8476–8482.

    PubMed  CAS  Google Scholar 

  38. Wagner, C. L., Mascelli, M. A., Neblock, D. S., Weisman, H. F., Coller, B. S., and Jordan, R. E. (1996) Analysis of GPIIb/IIIa receptor number by quantitation of 7E3 binding to human platelets. Blood 88, 907–914.

    PubMed  CAS  Google Scholar 

  39. Weisel, J. W., Nagaswami, C., Vilaire, G., and Bennett, J. S. (1992) Examination of the platelet membrane glycoprotein IIb/IIIa complex and its interaction with fibrinogen and other ligands by electron microscopy. J. Biol. Chem. 267, 16,637–16,643.

    PubMed  CAS  Google Scholar 

  40. Bennett, J. S. and Vilaire, G. (1979) Exposure of platelet fibrinogen receptors by ADP and epinephrine. J. Clin. Invest. 64, 1393–1401.

    Article  PubMed  CAS  Google Scholar 

  41. Litvinov, R. I., Shuman, H., Bennett, J. S., and Weisel, J. W. (2002) Binding strength and activation state of single fibrinogen-integrin pairs on living cells. Proc. Natl. Acad. Sci. USA 99, 7423–7431.

    Article  CAS  Google Scholar 

  42. O’Toole, T. E., Katagiri, Y., Faull, R. J., Peter, K., Tamura, R., Quaranta, V., et al. (1994) Integrin cytoplasmic domains mediate inside-out signal transduction. J. Cell. Biol.O′124, 1047–1059.

    Google Scholar 

  43. Hillery, C. A., Smyth, S. S., and Parise, L. V. (1991) Phosphorylation of human platelet glycoprotein IIIa (GPIIIa) Dissociation from fibrinogen receptor activation and phosphorylation of GPIIIa in vitro. J. Biol. Chem. 266, 14,663–14,669.

    PubMed  CAS  Google Scholar 

  44. Hughes, P. E., Diaz-Gonzales, F., Leong, L., Wu, C., McDonald, J. A., Shattil, S. J., et al. (1996) Breaking the integrin hinge. A defined structural constraint regulates integrin signaling. J. Biol. Chem. 271, 6571–6574.

    Article  PubMed  CAS  Google Scholar 

  45. Li, R., Babu, C. R., Lear, J. D., Wand, A. J., Bennett, J. S., and DeGrado, W. F. (2001) Oligomerization of the integrin alphaIIbbeta3: Roles of the transmembrane and cytoplasmic domains. Proc. Natl. Acad. Sci. USA 98, 12,462–12,467.

    Article  PubMed  CAS  Google Scholar 

  46. Shattil, S. J., O’Toole, T., Eigenthaler, M., Thon, V., Williams, M., Babior, B. M., Ginsberg, M. H. (1995) β3-endonexin, a novel polypeptide that interacts specifically with the cytoplasmic tail of the integrin β3 subunit. J. Cell. Biol. 131, 807–816.

    Article  PubMed  CAS  Google Scholar 

  47. Hannigan, G. E., Leung-Hagesteijn, C., Fitz-Gibbon, L., Coppolino, M. G., Redeva, G., Filmus, J., et al. (1996) Regulation of cell adhesion and anchorage-dependent growth by a new β1-integrin-linked protein kinase. Nature 379, 91–95.

    Article  PubMed  CAS  Google Scholar 

  48. Naik, U. P., Patel, P. M., and Parise, L. V. (1997) Identification of a novel calcium-binding protein that interacts with the integrin αIIβ cytoplasmic domain. J. Biol. Chem. 272, 4651–4654.

    Article  PubMed  CAS  Google Scholar 

  49. Kashiwagi, H., Schwartz, M. A., Eigenthaler, M., Davis, K. A., Ginsberg, M. H., and Shattil, S. J. (1997) Affinity modulation of platelet integrin αIIbβ by β3-endonexin, a selective binding partner of the β3 integrin cytoplasmic tail. J. Cell Biol. 137, 1433–1443.

    Article  PubMed  CAS  Google Scholar 

  50. Tsuboi, S. (2002) Calcium integrin-binding protein activates platelet integrin alpha IIbbeta 3. J. Biol. Chem. 277, 1919–1923.

    Article  PubMed  CAS  Google Scholar 

  51. Pfaff, M., Liu, S., Erle, D. J., and Ginsberg, M. H. (1998) Integrin beta cytoplasmic domains differentially bind to cytoskeletal proteins. J. Biol. Chem. 273, 6104–6109.

    Article  PubMed  CAS  Google Scholar 

  52. Calderwood, D. A., Shattil, S. J., and Ginsberg, M. H. (2000) Integrins and actin filaments: Reciprocal regulation of cell adhesion and signaling. J. Biol. Chem. 275, 22,607–22,610.

    Article  PubMed  CAS  Google Scholar 

  53. Reddy, K. B., Bialkowska, K., and Fox, J. E. (2001) Dynamic modulation of cytoskeletal proteins linking integrins to signaling complexes in spreading cells. Role of skelemin in initial integrin-induced spreading. J. Biol. Chem. 276, 28,300–28,308.

    Article  PubMed  CAS  Google Scholar 

  54. Shattil, S. J., Kashiwagi, H., and Pampori, N. (1998) Integrin signaling: the platelet paradigm. Blood 91, 2645–2657.

    PubMed  CAS  Google Scholar 

  55. Calderwood, D. A., Zent, R., Grant, R., Rees, D. J., Hynes, R. O., and Ginsberg, M. H. (1999) The Talin head domain binds to integrin beta subunit cytoplasmic tails and regulates integrin activation. J. Biol. Chem. 274, 28,071–28,074.

    Article  PubMed  CAS  Google Scholar 

  56. Hawiger, J., Kloczewiak, M., Bednarek, M. A., and Timmons, S. (1989) Platelet receptor recognition domains on the a chain of human fibrinogen: Structure-function analysis. Biochemistry 28, 2929–2914.

    Article  Google Scholar 

  57. Gartner, T. K. and Bennett, J. S. (1985) The tetrapeptide analogue of the cell attachment site of fibronectin inhibits platelet aggregation and fibrinogen binding to activated platelets. J. Biol. Chem. 260, 11,891–11,894.

    PubMed  CAS  Google Scholar 

  58. Farrell, D. H., Thiagarajan, P., Chung, D. W., and Davie, E. W. (1992) Role of fibrinogen α and γ chain sites in platelet aggregation. Proc. Natl. Acad. Sci. USA 89, 10729–10732.

    Article  PubMed  CAS  Google Scholar 

  59. Farrell, D. H. and Thiagarajan, P. (1994) Binding of recombinant fibrinogen mutants to platelets. J. Biol. Chem. 269, 226–231.

    PubMed  CAS  Google Scholar 

  60. Bennett, J. S., Shattil, S. J., Power, J. W., and Gartner, T. K. (1988) Interaction of fibrinogen with its platelet receptor. Differential effects of a and g chain fibrinogen peptides on the glycoprotein IIb-IIIa complex. J. Biol. Chem. 263, 12,948–12,953.

    PubMed  CAS  Google Scholar 

  61. Hu, D. D., White, C. A., Panzer-Knodle, S., Page, J. D., Nicholson, N., and Smith, J. W. (1999) A new model of dual interacting ligand binding sites on integrin αIIbβ3. J. Biol. Chem. 274, 4633–4639.

    Article  PubMed  CAS  Google Scholar 

  62. Puzon-McLaughlin, W., Kamata, T., and Takada, Y. (2000) Multiple discontinuous ligand-mimetic antibody binding sites define a ligand binding pocket in integrin αaIIbβ3. J. Biol. Chem. 275, 7795–7802.

    Article  PubMed  CAS  Google Scholar 

  63. Lin, E. C. K., Ratnikov, B. I., Tsai, P. M., Carron, C. P., Myers, D. M., Barbas, C. F., III, and Smith, J. W. (1997) Identification of a region in the integrin β3 subunit that confers ligand binding specificity. J. Biol. Chem. 272, 23,912–23,920.

    Article  PubMed  CAS  Google Scholar 

  64. D’Souza, S. E., Ginsberg, M. H., Lam, S. C, and Plow, E. F. (1988) Chemical crosslinking of arginyl-glycyl-aspartic acid peptides to an adhesion receptor on platelets. J. Biol. Chem. 263, 3943–3951.

    CAS  Google Scholar 

  65. Xiong, J. P., Stehle, T., Diefenbach, B., Zhang, R., Dunker, R., Scott, D. L., et al. (2001) Crystal structure of the extracellular segment of integrin alpha Vbeta3. Science 294, 339–345.

    Article  PubMed  CAS  Google Scholar 

  66. Basani, R. B., French, D. L., Vilaire, G., Brown, D. L., Chen, F., Coller, B. S., et al. (2000) A naturally occurring mutation near the amino terminus of aIIb defines a new region involved in ligand binding to aαibβ3. Blood 95, 180–188.

    PubMed  CAS  Google Scholar 

  67. Kamata, T., Tieu, K. K., Irie, A., Springer, T. A., and Takada, Y. (2001) Amino acid residues in the alpha IIb subunit that are critical for ligand binding to integrin alpha IIbbeta 3 are clustered in the beta-propeller model. J. Biol. Chem. 276, 44,275–44,283.

    Article  PubMed  CAS  Google Scholar 

  68. Coller, B. S. (1985) A new murine monoclonal antibody reports an activation-dependent change in the conformation and/or microenvironment of the platelet glycoprotein IIb–IIIa complex. J. Clin. Invest. 76, 101–108.

    Article  PubMed  CAS  Google Scholar 

  69. Coller, B. S. (1999) Binding of abciximab to αVβ3 and activated αMβ2 receptors: With a review of platelet-leukocyte interactions. Thromb. Haemost. 82, 326–336.

    PubMed  CAS  Google Scholar 

  70. Tcheng, J., Ellis, S., George, B., Kereiakes, D., Kleiman, N., Talley, J., et al. (1994) Pharmacodynamics of chimeric glycoprotein IIb/IIIa integrin antiplatelet antibody Fab 7E3 in high-risk coronary angioplasty. Circulation 90, 1757–1764.

    PubMed  CAS  Google Scholar 

  71. Mascelli, M. A., Lance, E. T., Damaraju, L., Wagner, C. L., Weisman, H. F., and Jordan, R. E. (1998) Pharmacodynamic profile of short-term abciximab treatment demonstrates prolonged platelet inhibition with gradual recovery from GP IIb/IIIa receptor blockade. Circulation 97, 1680–1688.

    PubMed  CAS  Google Scholar 

  72. 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, 956–961.

    Article  Google Scholar 

  73. EPILOG Investigators. (1997) Platelet glycoprotein IIb/IIIa receptor blockade and low-dose heparin during percutaneous coronary revascularization. The EPILOG Investigators. N. Engl. J. Med. 336, 1689–1696.

    Article  Google Scholar 

  74. CAPTURE Investigators. (1997) Randomised placebo-controlled trial of abciximab before and during coronary intervention in refractory unstable angina: the CAPTURE Study. Lancet 349, 1429–1435.

    Article  Google Scholar 

  75. EPISTENT Investigators. (1998) Randomised placebo-controlled and balloon-angioplasty-controlled trial to assess safety of coronary stenting with use of platelet glycoprotein-IIb/IIIa blockade. Lancet 352, 87–92.

    Article  Google Scholar 

  76. Phillips, D. R. and Scarborough, R. M. (1997) Clinical pharmacology of eptifibatide. Am. J. Cardiol. 80, 11B–20B.

    Article  PubMed  CAS  Google Scholar 

  77. Harrington, R. A., Kleiman, N. S., Kottke-Marchant, K., Lincoff, A. M., Tcheng, J. E., Sigmon, K. N., et al. (1995) Immediate and reversible platelet inhibition after intravenous administration of a peptide glycoprotein IIb/IIIa inhibitor during percutaneous coronary intervention. Am. J. Cardiol. 76, 1222–1227.

    Article  PubMed  CAS  Google Scholar 

  78. Phillips, D. R., Teng, W., Arfsten, A., Nannizzi-Alaimo, L., White, M. M., Longhurst, C., et al. (1997) Effect of Ca2+ on GP IIb-IIIa interactions with integrilin: enhanced GP IIb–IIIa binding and inhibition of platelet aggregation by reductions in the concentration of ionized calcium in plasma anticoagulated with citrate. Circulation 96, 1488–1494.

    PubMed  CAS  Google Scholar 

  79. IMPACT-II Investigators. (1997) Randomised placebo-controlled trial of effect of eptifibatide on complications of percutaneous coronary intervention: IMPACT-II. Lancet 349, 1422–1428.

    Article  Google Scholar 

  80. Harrington, R. A. (1997) Design and methodology of the PURSUIT trial: Evaluating eptifibatide for acute ischemic coronary syndromes. Platelet Glycoprotein IIb–IIIa in Unstable Angina: Receptor Suppression Using Integrilin Therapy. Am. J. Cardiol. 80, 34B–38B.

    Article  PubMed  CAS  Google Scholar 

  81. ESPRIT Investigators. (2000) Novel dosing regimen of eptifibatide in planned coronary stent implantation (ESPRIT): A randomised, placebo-controlled trial. Lancet 356, 2037–2044.

    Article  Google Scholar 

  82. Cook, J. J., Bednar, B., Lynch, J. L., Jr., Gould, R. J., Egbertson, M. S., Halczenko, W., et al. (1999) Tirofiban (Aggrastat®). Cardiovasc. Drug Rev. 17, 199–224.

    Article  CAS  Google Scholar 

  83. RESTORE Investigators. (1997) Effects of platelet glycoprotein IIb/IIIa blockade with tirofiban on adverse cardiac events in patients with unstable angina or acute myocardial infarction undergoing coronary angioplasty. The RESTORE Investigators. Randomized Efficacy Study of Tirofiban for Outcomes and REstenosis. Circulation 96, 1445–1453.

    Google Scholar 

  84. Gibson, C. M., Goel, M., Cohen, D. J., Piana, R. N., Deckelbaum, L. I., Harris, K. E., and King, S. B., 3rd. (1998) Six-month angiographic and clinical follow-up of patients prospectively randomized to receive either tirofiban or placebo during angioplasty in the RESTORE trial. Randomized Efficacy Study of Tirofiban for Outcomes and Restenosis. J. Am. Coll. Cardiol. 32, 28–34.

    Article  PubMed  CAS  Google Scholar 

  85. PRISM Investigators. (1998) A comparison of aspirin plus tirofiban with aspirin plus heparin for unstable angina. N. Engl. J. Med. 338, 1498–1505.

    Article  Google Scholar 

  86. PRISM-PLUS Investigators. (1998) Inhibition of the platelet glycoprotein IIb/IIIa receptor with tirofiban in unstable angina and non-Q-wave myocardial infarction. N. Engl. J. Med. 338, 1488–1497.

    Article  Google Scholar 

  87. Theroux, P. (1998) Oral inhibitors of platelet membrane receptor glycoprotein IIb/IIIa in clinical cardiology: Issues and opportunities. Am. Heart J. 135, S107–S112.

    Article  PubMed  CAS  Google Scholar 

  88. Kereiakes, D. J. (1999) Oral blockade of the platelet glycoprotein IIb/IIIa receptor: Fact or fancy? Am. Heart J. 138, S39–46.

    Article  PubMed  CAS  Google Scholar 

  89. SYMPHONY Investigators. (2000) Comparison of sibrafiban with aspirin for prevention of cardiovascular events after acute coronary syndromes: A randomized trial. Lancet 355, 337–345.

    Article  Google Scholar 

  90. O’Neill, W. W., Serruys, P., Knudtson, M., Van Es, G.-A., Timmis, G. C., van der Zwaan, C., et al. (2000) Long-term treatment with a platelet glycoprotein-receptor antagonist after percutaneous coronary revascularization. N. Engl. J. Med. 342, 1316–1324.

    Article  Google Scholar 

  91. Cannon, C. P., McCabe, C. H., Wilcox, R. G., Langer, A., Caspi, A., Berink, P., et al. (2000) Oral glycoprotein IIb/IIIa inhibition with orbofiban in patients with unstable coronary syndromes (OPUS-TIMI 16) trial. Circulation 102, 149–56.

    PubMed  CAS  Google Scholar 

  92. George, J. N., Caen, J. P., and Nurden, A. T. (1990) Glanzmann’s thrombasthenia: The spectrum of clinical disease. Blood 75, 1383–1395.

    PubMed  CAS  Google Scholar 

  93. Damiano, B. P., Mitchell, J. A., Giardino, E., Corcoran, T., Haertlein, B. J., de Garavilla, L., et al. (2001) Antiplatelet and antithrombotic activity of RWJ-53308, a novel orally active glycoprotein IIb/IIIa antagonist. Thromb. Res. 104, 113–126.

    Article  PubMed  CAS  Google Scholar 

  94. Du, X. P., Plow, E. F., Frelinger, A. L., III, OToole, T. E., Loftus, J. C., and Ginsberg, M. H. (1991) Ligands “activate” integrin alpha IIb beta 3 (platelet GPIIb/IIIa) Cell 65, 409–416.

    Article  PubMed  CAS  Google Scholar 

  95. Harfenist, E. J., Packham, M. A., and Mustard, J. F. (1988) Effects of cell adhesion peptide, Arg-Gly-Asp-Ser, on responses of washed platelets from humans, rabbits, and rats. Blood 71, 132–136.

    PubMed  CAS  Google Scholar 

  96. Jennings, L. K., White, M. M., and Mandrell, T. D. (1995) Interspecies comparison of platelet aggregation, LIBS expression and clot retraction: Observed differences in GPIIb/IIIa functional activity. Thromb. Haemostas. 74, 1551–1556.

    CAS  Google Scholar 

  97. Basani, R. B., D’Andrea, G., Mitra, N., Vilaire, G., Richberg, M., Kowalska, M. A., et al. (2001) RGD-containing peptides inhibit fibrinogen binding to platelet alpha(IIb)beta3 by inducing an allosteric change in the amino-terminal portion of alpha(IIb) J. Biol. Chem. 276, 13,975–13,981.

    PubMed  CAS  Google Scholar 

  98. Springer, T. A. (1997) Folding of the N-terminal, ligand-binding region of integrin a-subunits into a β-propeller domain. Proc. Natl. Acad. Sci., USA 94, 65–72.

    Article  PubMed  CAS  Google Scholar 

  99. Xiong, J. P., Stehle, T., Zhang, R., Joachimiak, A., Frech, M., Goodman, S. L, and Arnaout, M. A. (2002) Crystal structure of the extracellular segment of integrin alpha Vbeta3 in complex with an Arg-Gly-Asp ligand. Science 296, 151–155.

    Article  PubMed  CAS  Google Scholar 

  100. Kallen, J., Welzenbach, K., Ramage, P., Geyl, D., Kriwacki, R., Legge, G., et al. (1999) Structural basis for LFA-1 inhibition upon lovastatin binding to the CD11a I-domain. J. Mol. Biol. 292, 1–9.

    Article  PubMed  CAS  Google Scholar 

  101. Huth, J. R., Olejniczak, E. T., Mendoza, R., Liang, H., Harris, E. A., Lupher, M. L., Jr., et al. (2000) NMR and mutagenesis evidence for an I domain allosteric site that regulates lymphocyte function-associated antigen 1 ligand binding. Proc. Natl. Acad. Sci. USA 97, 5231–5236.

    Article  PubMed  CAS  Google Scholar 

  102. Furie, B., Furie, B. C., and Flaumenhaft, R. (2001) A journey with platelet P-selectin: The molecular basis of granule secretion, signalling and cell adhesion. Thromb. Haemost. 86, 214–221.

    PubMed  CAS  Google Scholar 

  103. Yang, J., Furie, B. C., and Furie, B. (1999) The biology of P-selectin glycoprotein ligand-1: Its role as a selectin counterreceptor in leukocyte-endothelial and leukocyte-platelet interaction. Thromb. Haemost. 81, 1–7.

    PubMed  CAS  Google Scholar 

  104. McEver, R. P. (2002) P-selectin and PSGL-1: Exploiting connections between inflammation and venous thrombosis. Thromb. Haemost. 87, 364–365.

    PubMed  CAS  Google Scholar 

  105. Mayadas, T. N., Johnson, R. C., Rayburn, H., Hynes, R. O., and Wagner, D. D. (1993) Leukocyte rolling and extravasation are severely compromised in P selectin-deficient mice. Cell 74, 541–554.

    Article  PubMed  CAS  Google Scholar 

  106. Subramaniam, M., Frenette, P. S., Saffaripour, S., Johnson, R. C., Hynes, R. O., and Wagner, D. D. (1996) Defects in hemostasis in P-selectin-deficient mice. Blood 87, 1238–1242.

    PubMed  CAS  Google Scholar 

  107. Henn, V., Slupsky, J. R., Grafe, M., Anagnostopoulos, I., Forster, R., Muller-Berghaus, G., and Kroczek, R. A. (1998) CD40 ligand on activated platelets triggers an inflammatory reaction of endothelial cells. Nature 391, 591–594.

    Article  PubMed  CAS  Google Scholar 

  108. Andre, P., Prasad, K. S., Denis, C. V., He, M., Papalia, J. M., Hynes, R. O., et al. (2002) CD40L stabilizes arterial thrombi by a beta3 integrin-dependent mechanism. Nat. Med. 8, 247–252.

    Article  PubMed  CAS  Google Scholar 

  109. Kawai, T., Andrews, D., Colvin, R. B., Sachs, D. H., and Cosimi, A. B. (2000) Thromboembolic complications after treatment with monoclonal antibody against CD40 ligand. Nat. Med. 6, 114.

    Article  CAS  Google Scholar 

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Bennett, J.S. (2003). Development and Use of Platelet Glycoprotein Antagonists in Heart Disease. In: Pugsley, M.K. (eds) Cardiac Drug Development Guide. Methods in Pharmacology and Toxicology. Humana Press. https://doi.org/10.1385/1-59259-404-2:107

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  • DOI: https://doi.org/10.1385/1-59259-404-2:107

  • Publisher Name: Humana Press

  • Print ISBN: 978-1-58829-097-7

  • Online ISBN: 978-1-59259-404-7

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