New Antiplatelet Agents: Platelet GPIIb/llla Antagonists

The GPIIb/IIIa (α IIb β 3 ) receptor plays a crucial role in platelet aggregation and platelet thrombus formation. Inhibition of GPIIb/IIIa with the Fab fragment of the mouse/human chimeric monoclonal antibody 7E3, snake venom peptides containing the arginine-glycine-aspartic acid (RGD) sequence, or peptides or peptidomimetics based on the RGD sequence results in abolition of platelet aggregation and platelet thrombus formation. This results in profound inhibition of thrombotic occlusions in animal models. The Phase III EPIC study demonstrated that c7E3 Fab, given as bolus followed by a 12 h infusion, reduced the risk of acute ischemic complications after coronary angioplasty by ∼35 % in patients at high risk of suffering such complications. Treated patients had an ∼2-fold increased risk of major bleeding, but no increase in cerebral hemorrhage or lethal bleeding. Treatment with c7E3 Fab may have had a beneficial effect on clinical restenosis at 6 months, but this needs to be confirmed. A possible anticoagulant effect of c7E3 Fab was also identified in EPIC, and in vitro studies support this possibility. With the approval of c7E3 Fab (abciximab ; ReoPro) for patients undergoing high-risk angioplasty in the US and several European and Scandinavian countries, GPIIb/IIIa inhibition joins the armamentarium of antithrombotic agents.

[1]  H. Deckmyn,et al.  Inhibition of integrin function by a cyclic RGD-containing peptide prevents neointima formation. , 1994, Circulation.

[2]  R. Califf,et al.  Pharmacodynamics of chimeric glycoprotein IIb/IIIa integrin antiplatelet antibody Fab 7E3 in high-risk coronary angioplasty. , 1994, Circulation.

[3]  B. Coller,et al.  Glanzmann thrombasthenia: new insights from an historical perspective. , 1994, Seminars in hematology.

[4]  R. Califf,et al.  Randomised trial of coronary intervention with antibody against platelet IIb/IIIa iritegrin for reduction of clinical restenosis: results at six months , 1994, The Lancet.

[5]  Epic Investigators,et al.  Use of a monoclonal antibody directed against the platelet glycoprotein IIb/IIIa receptor in high-risk coronary angioplasty. , 1994, The New England journal of medicine.

[6]  H. Weisman,et al.  Randomized Trial of a GPIIb/IIIa Platelet Receptor Blocker in Refractory Unstable Angina , 1994, Circulation.

[7]  Walker,et al.  Collaborative overview of randomised trials of antiplatelet therapy Prevention of death, myocardial infarction, and stroke by prolonged antiplatelet therapy in various categories of patients , 1994 .

[8]  J. Kutok,et al.  Studies of activated GPIIb/IIIa receptors on the luminal surface of adherent platelets. Paradoxical loss of luminal receptors when platelets adhere to high density fibrinogen. , 1993, The Journal of clinical investigation.

[9]  H. Hemker,et al.  Continuous Registration of Thrombin Generation in Plasma, Its Use for the Determination of the Thrombin Potential , 1993, Thrombosis and Haemostasis.

[10]  D. Cheresh,et al.  Vitronectin and its receptors. , 1993, Current opinion in cell biology.

[11]  B. Coller.  Inhibitors of the platelet glycoprotein IIb/IIIa receptor as conjunctive therapy for coronary artery thromboiysis , 1992 .

[12]  Richard O. Hynes,et al.  Integrins: Versatility, modulation, and signaling in cell adhesion , 1992, Cell.

[13]  J. George,et al.  Glanzmann's thrombasthenia: the spectrum of clinical disease. , 1990, Blood.

[14]  B. Coller.  Platelets and thrombolytic therapy. , 1990, The New England journal of medicine.

[15]  L. Parise,et al.  The platelet membrane glycoprotein IIb-IIIa complex. , 1988, Blood.

[16]  E Ruoslahti,et al.  Platelet membrane glycoprotein IIb/IIIa: member of a family of Arg-Gly-Asp--specific adhesion receptors. , 1986, Science.

[17]  B. Coller.  A new murine monoclonal antibody reports an activation-dependent change in the conformation and/or microenvironment of the platelet glycoprotein IIb/IIIa complex. , 1985, The Journal of clinical investigation.

[18]  F. Werf,et al.  A heparin-controlled study of MK-383 in unstable angina , 1994 .

[19]  A. Callow,et al.  Inhibition of neointimal hyperplasia by blocking αvβ3 integrin with a small peptide antagonist GpenGRGDSPCA , 1994 .

[20]  S. Schwartz.  Serum-derived growth factor is thrombin? , 1993, The Journal of clinical investigation.

[21]  B. Coller.  Antiplatelet agents in the prevention and therapy of thrombosis. , 1992, Annual review of medicine.

[22]  B. Coller,et al.  Platelet vitronectin receptor expression differentiates Iraqi-Jewish from Arab patients with Glanzmann thrombasthenia in Israel. , 1991, Blood.

[23]  E. Haber,et al.  The heart and cardiovascular system , 1986 .