Effect of fibrinogen concentration and platelet count on the inhibitory effect of abciximab and tirofiban

Giulia Renda; Bianca Rocca; Roberto Crocchiolo; Raimondo De Cristofaro; Raffaele Landolfi

doi:10.1055/s-0037-1613452

Thrombosis and Haemostasis, Inhaltsverzeichnis

Thromb Haemost 2003; 89(02): 348-354
DOI: 10.1055/s-0037-1613452

Platelets and Blood Cells

Schattauer GmbH

Effect of fibrinogen concentration and platelet count on the inhibitory effect of abciximab and tirofiban

Autoren

Giulia Renda

²Chair of Cardiology, University of Chieti “G. D'Annunzio”, Italy
Bianca Rocca

¹Research Center on Pathophysiology of Haemostasis, Catholic University School of Medicine, Rome
Roberto Crocchiolo

¹Research Center on Pathophysiology of Haemostasis, Catholic University School of Medicine, Rome
Raimondo De Cristofaro

¹Research Center on Pathophysiology of Haemostasis, Catholic University School of Medicine, Rome
Raffaele Landolfi

¹Research Center on Pathophysiology of Haemostasis, Catholic University School of Medicine, Rome

Abstract

Summary

Glycoprotein (Gp) IIb/IIIa blockers are powerful antithrombotic agents, but display a wide variability of their effect using weight-adjusted dosing. We investigated whether some hemostatic variables affected in vitro platelet inhibition exerted by the antibody abciximab and the peptidomimetic tirofiban. High fibrinogen concentrations reduced platelet inhibition by tirofiban, assessed in whole blood (r = –0.85, n = 10, p <0.01) and in platelet rich plasma (r = –0.89, n = 10, p <0.01) through PFA 100 and Born’s aggregometry assay, respectively. Both drugs were unaffected by von Willebrand factor levels, while platelet count was inversely related to their inhibitory effect (tirofiban: r = –0.9, n = 7, p <0.01; abciximab: r = –0.81, n = 9, p <0.01). Analysis of GpIIb-IIIa blockade showed that receptor occupancy at a fixed abciximab dose was inversely related to platelet counts. These experimental data were in agreement with the classical model of receptor saturation by a tight binding inhibitor.

A role for fibrinogen and/or platelet count in influencing the antithrombotic properties of platelet GpIIb-IIIa antagonists can be hypothesized.

Keywords

Platelet - GpIIb-IIIa blockers - fibrinogen - receptor occupancy - inhibition

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Referenzen

References
1 Scarborough RM, Kleiman NS, Phillips DR. Platelet glycoprotein IIb/IIIa antagonists. What are the relevant issues concerning their pharmacology and clinical use?. Circulation 1999; 100: 437-44.
2 Braunwald E, Antman EM, Beasley JW, Califf RM, Cheitlin MD, Hochman JS, Jones RH, Kereiakes D, Kupersmith J, Levin TN, Pepine CJ, Schaeffer JW, Smith EE, 3rd Stewart DE, Theroux P, Alpert JS, Eagle KA, Faxon DP, Fuster V, Gardner TJ, Gregoratos G, Russell RO, Smith Jr SC. ACC/AHA guidelines for the management of patients with unstable angina and non-ST segment elevation myocardial infarction: a report from the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol 2000; 36: 970-1062.
3 Steinhubl SR, Kottke-Marchant K, Moliterno DJ, Rosenthal ML, Godfrey NK, Coller BS, Topol EJ, Lincoff AM.. Attainment and maintenance of platelet inhibition through standard dosing of abciximab in diabetic and non-diabetic patients undergoing percutaneous coronary intervention. Circulation 1999; 100: 1977-82.
4 Steinhubl SR, Talley D, Braden GA, Tcheng JE, Casterella PJ, Moliterno DJ, Navetta FI, Berger PB, Popma JJ, Dangas G, Gallo R, Sane DC, Saucedo JF, Jia G, Lincoff AM, Theroux P, Holmes DR, Teirstein PS, Kereiakes DJ. Point of care measured platelet inhibition correlates with a reduced risk of an adverse cardiac event after percutaneous coronary intervention. Results of the GOLD (AU-Assessing Ultegra) Multicenter study. Circulation 2001; 103: 2572-8.
5 Kereiakes DJ, Broderick TM, Roth EM, Whang D, Mueller M, Lacock P, Anderson LC, Howard W, Blanck C, Schneider J, Abbottsmith CA. High platelet count in platelet-rich plasma reduces measured platelet inhibition by abcix-imab but not tirofiban nor eptifibatide glyco-protein IIb/IIIa receptor antagonists. J Thromb Thrombolysis 2000; 9: 149-55.
6 Simoons ML, de Boer MJ, van den BrandMJ, van MiltenburgAJ, Hoorntje JC, Heyndrickx GR, van der WiekenLR, de BonoD, Rutsch W, Schaible TF. for the European Cooperative Study Group. Randomized trial of GpIIb-IIIa platelet receptor blocker in refractory unstable angina. Circulation 1994; 89: 596-603.
7 Holmes MB, Sobel BE, Schneider DJ. Variable responses to inhibition of fibrinogen binding induced by tirofiban and eptifibatide in blood from healthy subjects. Am J Cardiol 1999; 84: 203-7.
8 Kundu SK, Heilmann EJ, Sio R, Garcia C, Davidson RM, Ostgaard RA. Description of an in vitro platelet function analyzer-PFA-100. Semin Thromb Haemost 1995; 21: 106-12.
9 Landolfi R, De Cristofaro R, De Candia E, Rocca B, Bizzi B. Effect of fibrinogen concentration on the velocity of platelet aggregation. Blood 1991; 78: 377-81.
10 Quinn M, Deering A, Stewart M, Cox D, Foley B, Fitzgerald D. Quantifying GP IIb/IIIa receptor binding using 2 monoclonal antibodies. Discriminating abciximab and small molecular weight antagonists. Circulation 1999; 99: 2231-38.
11 Cha S. Tight-binding inhibitors. Biochem Pharmacol 1975; 24: 2177-85.
12 Hezard N, Metz D, Tassan-Mangina S, Potron G, Nguyen P. Unexpected flow cytometric results with two small GpIIb-IIIa blockers: eptifibatide and tirofiban. Thromb Haemost 2001; 85: 561-2.
13 Osende JI, Fuster V, Lev EI, Shimbo D, Rauch U, Marmur JD, Richard M, Varon DBadimon. JJ. Testing platelet activation with a shear-dependent platelet function test versus aggregation-based tests: relevance for monitoring long-term glycoprotein IIb/IIIa inhibition. Circulation 2001; 103: 1488-91.
14 Wu KK, Willerson JT. Monitoring Platelet function in Glycoprotein IIb-IIIa Inhibitor therapy. Circulation 2001; 103: 2528-30.
15 Li YF, Spencer FA, Becker RC. Comparative efficacy of fibrinogen and platelet supplementation on the in vitro reversibility of competitive glycoprotein IIb/IIIa (aII/b3) receptor-directed platelet inhibition. Am Heart J 2001; 142: 204-10.
16 Tcheng JE. Clinical challenges of platelet glycoprotein IIb/IIIa receptor inhibitor therapy: Bleeding, reversal, thrombocytopenia and retreatment. Am Heart J 2000; 139: S38-S45.