The in vitro effect of eptifibatide, a glycoprotein IIb/IIIa antagonist, on various responses of porcine blood platelets.
The current study systematically evaluates the in vitro effect of eptifibatide, a GPIIb/IIIa blocker, on various responses of porcine platelets evoked by principal physiological stimulators. Eptifibatide at concentrations up to 40 mg/mL did not affect the calcium signal produced by thrombin, partly reduced the procoagulant response evoked by collagen, and strongly inhibited (IC50 approximately 11 mg/mL) adhesion of these cells to fibrinogen coated surfaces. Eptifibatide in a concentration-dependent manner reduced ADP, collagen, and thrombin-induced platelet aggregation (IC50 = 16-27 mg/mL), dense granule secretion (IC50 = 22-31 mg/mL) and lysosome secretion (IC50 = 25-50 mg/mL). Substantial (up to 30-40%) collagen or thrombin-evoked platelet aggregation still occurred at high (52 mg/mL) eptifibatide concentrations. Direct comparison of the susceptibility of platelet aggregation and dense granule secretion to the inhibitory action of eptifibatide indicates that aggregation is appreciably more sensitive than secretion. Eptifibatide (8 mg/mL) added together with a low (70 ng/mL) concentration of bivalirudin (a direct thrombin inhibitor) effectively (approximately 90%) reduced platelet aggregation induced by thrombin (0.2 U/mL). Based on these results, eptifibatide is not expected to reduce efficiently thrombus formation initiated by rapid local production of large amounts of thrombin. One practical consequence of our in vitro studies is the suggestion that the anti-thrombotic efficacy of eptifibatide, especially in preventing acute thrombotic events, may be largely improved by its combination with direct thrombin inhibitors.
Ciborowski
Michał
M
Department of Physical Chemistry, Medical University of Bialystok, 1 Kilińskiego St., 15-089 Białystok, Poland.
Tomasiak
Marian
M
D000244:Adenosine Diphosphate / Q000494:pharmacology; D000818:Animals; D000925:Anticoagulants / Q000494:pharmacology; D001792:Blood Platelets / Q000187:drug effects* / Q000378:metabolism; D020013:Calcium Signaling / Q000187:drug effects; D003094:Collagen / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004359:Drug Therapy, Combination; D000077542:Eptifibatide; D005260:Female; D006629:Hirudins / Q000494:pharmacology; D066298:In Vitro Techniques; D020128:Inhibitory Concentration 50; D008297:Male; D010446:Peptide Fragments / Q000494:pharmacology; D010455:Peptides / Q000008:administration & dosage / Q000494:pharmacology*; D010974:Platelet Aggregation / Q000187:drug effects*; D010975:Platelet Aggregation Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D019039:Platelet Glycoprotein GPIIb-IIIa Complex / Q000037:antagonists & inhibitors; D011994:Recombinant Proteins / Q000494:pharmacology; D013552:Swine; D013917:Thrombin / Q000494:pharmacology
D000925:Anticoagulants; D006629:Hirudins; D010446:Peptide Fragments; D010455:Peptides; D010975:Platelet Aggregation Inhibitors; D019039:Platelet Glycoprotein GPIIb-IIIa Complex; D011994:Recombinant Proteins; D000244:Adenosine Diphosphate; D003094:Collagen; D013917:Thrombin; D000077542:Eptifibatide; C074619:bivalirudin