title: Greater inhibition of platelet procoagulant activity by antibody-derived glycoprotein IIb--IIIa inhibitors than by peptide and peptidomimetic inhibitors.
abstract: Antibody-derived GPIIb-IIIa antagonists, such as the c7E3 Fab fragment abciximab, have been shown to inhibit platelet procoagulant activity as well as platelet aggregation. Whether low-molecular-weight peptide-derived and peptidomimetic antagonists also inhibit platelet procoagulant activity in a similar manner has not been fully investigated. We compared the effects of the antibody-derived antagonists c7E3 Fab and m10E5 IgG, the peptide-derived antagonists eptifibatide, MK-852 and RGDS, and the peptidomimetic RO44--9883 on platelet procoagulant activity and on the stimulated cytosolic calcium increases that promote procoagulant activity. Procoagulant activity was measured as prothrombinase activity in gel-filtered platelets, activated by collagen plus thrombin or collagen alone, with and without stirring. The stimulated increases in cytosolic calcium were measured in parallel samples of platelets loaded with fura-2AM. Both c7E3 and m10E5 inhibited prothrombinase activity by 40--50% under all conditions of activation tested and inhibited cytosolic calcium increases to a similar extent in stirred, but not unstirred, platelets. The low-molecular-weight antagonists caused significantly less inhibition of prothrombinase activity in collagen plus thrombin-stimulated platelets, and produced no inhibition but rather a slight enhancement of activity in platelets stimulated by collagen alone. These antagonists also had little or no effect on the cytosolic calcium increases in stirred platelets. These differential effects of antibody-derived versus non-antibody GPIIb-IIIa antagonists on procoagulant activity may be a factor contributing to the differing anti-thrombotic effects of these antagonists seen in clinical trials.
authors.affiliation: Department of Medicine, Division of Haematology-Oncology, St Luke's-Roosevelt Hospital Centre, and Columbia University College of Physicians and Surgeons, New York, NY, USA. xylum10@ix.netcom.com
authors.forename: B
authors.initials: B
authors.lastname: Lages
authors.forename: H J
authors.initials: HJ
authors.lastname: Weiss
mesh_terms: D000077284:Abciximab; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D001792:Blood Platelets / Q000378:metabolism / Q000502:physiology*; D002118:Calcium / Q000378:metabolism; D003600:Cytosol / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D000077542:Eptifibatide; D016257:Fura-2; D006801:Humans; D007140:Immunoglobulin Fab Fragments / Q000494:pharmacology*; D007128:Immunoglobulin Fragments / Q000494:pharmacology*; D009842:Oligopeptides / Q000494:pharmacology; D010455:Peptides / Q000494:pharmacology; D010456:Peptides, Cyclic / Q000494:pharmacology; D015539:Platelet Activation; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology; D019039:Platelet Glycoprotein GPIIb-IIIa Complex / Q000037:antagonists & inhibitors*; D053778:Thiazolidines; D013925:Thromboplastin / Q000378:metabolism*
chemical_list: D000911:Antibodies, Monoclonal; D004791:Enzyme Inhibitors; D007140:Immunoglobulin Fab Fragments; D007128:Immunoglobulin Fragments; D009842:Oligopeptides; D010455:Peptides; D010456:Peptides, Cyclic; D010975:Platelet Aggregation Inhibitors; D019039:Platelet Glycoprotein GPIIb-IIIa Complex; D053778:Thiazolidines; C083231:MK 0852; D013925:Thromboplastin; C046617:arginyl-glycyl-aspartyl-serine; D000077542:Eptifibatide; D002118:Calcium; D016257:Fura-2; D000077284:Abciximab