Effects of Glycoprotein IIb/IIIa Inhibitors on Platelet Function

S. Harder; C. M. Kirchmaier; H. K. Breddin

doi:10.1055/s-0038-1660391

Hämostaseologie, Table of Contents

Hamostaseologie 1999; 19(03): 108-111
DOI: 10.1055/s-0038-1660391

Übersichts- und Originalarbeiten/Review and Original Articles

Schattauer GmbH

Effects of Glycoprotein IIb/IIIa Inhibitors on Platelet Function

Authors

S. Harder

¹Institute of Clinical Pharmacology of the J. W. Goethe University, Frankfurt a.M.
C. M. Kirchmaier

²Deutsche Klinik für Diagnostik, Wiesbaden
H. K. Breddin

³International Institute of Thrombosis and Vascular Diseases, Frankfurt a. M., Germany

Abstract

Summary

We have studied the effect of two monoclonal antibodies against the G PI Ib/IIIa-receptor (abciximab and YM 337) on different platelet functions in healthy male volunteers. Platelet aggregation (1, 5 and 20 μM ADP), platelet adhesion, fibrinogen binding, bleeding time and platelet induced thrombin generation (PITT) were studied after an i.v. bolus of different doses of YM337 and after a bolus (0.35 mg/kg) plus 6 h infusion at different dose levels of YM337 or after a bolus of 0.25 mg/kg abciximab followed by a six hour infusion of 0,125 μg/kg/min. After 0.2 mg/kg and 0.4 mg/kg bolus of YM337 fibrinogen binding was reduced by >80%, coinciding with a prolongation of bleeding time to approx. 60 min. Platelet aggregation returned to normal within 24 h and adhesion within 48 h. Bleeding times returned to normal already 4 h after cessation of the infusion. YM337 and abciximab effectively inhibit GPIIb/IIIa mediated platelet aggregation and adhesion in volunteers. In parallel, platelet induced thrombin generation is markedly reduced. The best method to monitor treatment with GPIIb/IIIa inhibitors still has to be defined.

Keywords

Platelet aggregation inhibitors - antibodies - GPIIb/IIIa - YM337 - abciximab

Full Text

References

References
1 Coller B.S. Platelet GPIIb/IIIa antagonists: the first anti-integrin receptor therapeutics. J Clin Invest 1997; 100 (Suppl. 11) S57-60.
2 Tcheng J.E, Ellis S.G, George B.S, Kereiakes D.J, Kleiman N.S, Talley J.D, Wang A.L, Weisman H.F, Califf R.M, Topol E.J. Pharmacodynamics of chimeric glycoprotein IIb/IIIa integrin antiplatelet antibody FAB 7E3 in high-risk coronary angioplasty. Circulation 1994; 90: 1757-64.
3 Harder S, Kirchmaier C.M, Krzywanek H.J, Westrup D, Bae J.W, Breddin H.K. Pharmacokinetics and pharmacodynamic effects of a new antibody glycoprotein IIb/IIIa inhibitor (YM337) in healthy subjects. Circulation 1999,100:in press.
4 Born G.V.R. Quantitative investigations into the aggregation of blood platelets. J Phys 1962; 162: 67-8.
5 Breddin H.K, Ziemen M, Bauer O, Harmann W, Schaudinn L, Schlosser V, Winterhagen A, Krzywanek H.J. Time and temperature dependent changes of ADP and collagen induced and spontaneous’ aggregation. Thrombosis Res 1980; 19: 621-38.
6 Faraday N, Goldschmidt-Clermont P, Dise K, Bray P.F. Quantitation of soluble fibrinogen binding to platelets by fluorescence-activated flow cytometry. J Lab Clin Med 1994; 123: 728-40.
7 Breddin K. Zur Messung der Thrombo-zytenadhäsivität. Thromb Diath Haemorrh 1964; 12: 269-80.
8 Basic-Micic M, Roman C, Herpel U, Kling E, Scholz B, Breddin H.K. Platelet-induced thrombin generation time: A new sensitive global assay for platelet function and coagulation. Haemostasis 1992; 22: 309-21.
9 Mascelli M.A, Worley S, Veriabo N.J, Lance E.T, Mack S, Schaible T, Weisman H.F, Jordan R.E. Rapid assessment of platelet function with a modified whole-blood aggre-gometer in percutaneous transluminal coronary angioplasty patients receiving anti-GP IIb/IIIa therapy. Circulation 1997; 38: 60-6.
10 Harrington R.A, Kleiman N.S, Kottke-Marchant K, Lincoff A.M, Tcheng J.E, Sigmon K.N, Joseph D, Rios G, Trainor K, Rose D. Immediate and reversible platelet inhibition after intravenous administration of a peptide glycoprotein IIb/IIIa inhibitor during percutaneous coronary intervention. Am J Cardiol 1995; 76: 1222-7.
11 Meyer M, Kirchmaier C.M, Schirmer A, Spangenberg P, Strohl C, Breddin H.K. Aquired disorder of platelet function associated with autoantibodies against glycoprotein IIb-IIIa complex. Thromb Haemost 1991; 65: 491-6.
12 Hagcndorff K.B, Westrup D, Müller M, Breddin H.K, Seifried E, Kirchmaier C.M. Platelet adhesion in patients with thrombasthenia Glanzmann, giant platelet throm-bocytopathy and storage pool disease on extracellular matrix. Thromb Haemostas 1997; Suppl: 67 (abstract PS269).
13 Breddin H.K, Breddin H, Kirchmaier C.M, Keppler S. Methods to monitor the effects of GP IIb-IIIa -inhibitors and their interactions with other antithrombotic agents. Thromb Haemost 1995; 73: 1446 (abstract 2087).
14 Hérault J.P, Peyrou V, Savi P, Bernât A, Herbert J.M. Effect of SR 12.1566A, a potent GP IIb-IIIa antagonist on platelet-mediated thrombin generation in vitro and in vivo. Thromb Haemost 1998; 79: 383-8.
15 Animar T, Scudder L.E, Coller B.S. In vitro effects of the platelet glycoprotein IIb/IIIa receptor antagonist c7E3 Fab on the activated clotting time. Circulation 1997; 4 (95) 614-7.
16 Coller B.S, Lang D, Scudder L.E. Rapid and simple platelet function assay to assess glycoprotein IIb/IIIa receptor blockade. Circulation. 1997; 95: 860-7.