title: In-vitro efficacy of different platelet glycoprotein IIb/IIIa antagonists and thrombolytics on platelet/fibrin-mediated clot dynamics in human whole blood using thrombelastography.
abstract: Suppressing platelet activation improves efficacy of thrombolytic therapy for stroke and acute myocardial infarction. Combination treatment with recombinant tissue plasminogen activator (r-tPA) and glycoprotein IIb/IIIa (GPIIb/IIIa) inhibitor that binds with high affinity to platelets may therefore improve the efficacy of thrombolytic therapy. The effect of platelet GPIIb/IIIa antagonists and/or r-tPA on the dynamics of platelet/fibrin clot formation, strength, and lysis was determined using thrombelastography in human blood under thrombin or tissue factor stimulation. The study utilized platelet GPIIb/IIIa antagonists with high affinity and slow off-rate (Class I) from resting and activated platelets in comparison with Class II antagonists (lower affinity and fast off-rate from platelet GPIIb/IIIa receptors). The combination of the active form of roxifiban (XV459; Class I) or the active form of orbofiban (Class II) with a subeffective concentration of r-tPA resulted in a synergistic effect in clot lysis with roxifiban active form XV459 but not with that of orbofiban at therapeutically achievable concentrations that inhibit human platelet aggregation. These data indicate differential enhanced thrombolysis of low levels of r-tPA with high-affinity Class I but not with low-affinity Class II GPIIb/IIIa antagonists in the absence of anticoagulants.
authors.affiliation: The Pharmaceutical Research Institute at Albany College of Pharmacy, Albany, New York 12208, USA. mousas@acp.edu
authors.forename: Shaker A
authors.initials: SA
authors.lastname: Mousa
mesh_terms: D000925:Anticoagulants / Q000494:pharmacology; D001769:Blood / Q000187:drug effects; D001777:Blood Coagulation / Q000187:drug effects*; D001792:Blood Platelets / Q000502:physiology*; D005337:Fibrin / Q000502:physiology*; D005343:Fibrinolytic Agents / Q000494:pharmacology*; D006801:Humans; D007700:Kinetics; D015539:Platelet Activation; D019039:Platelet Glycoprotein GPIIb-IIIa Complex / Q000037:antagonists & inhibitors*; D013916:Thrombelastography / Q000379:methods*; D010959:Tissue Plasminogen Activator / Q000494:pharmacology
chemical_list: D000925:Anticoagulants; D005343:Fibrinolytic Agents; D019039:Platelet Glycoprotein GPIIb-IIIa Complex; D005337:Fibrin; D010959:Tissue Plasminogen Activator