FLOW CYTOMETRIC STUDIES ON DRUG INTERACTIONS BETWEEN ANTI‐XA, ANTI‐IIA, AND ANTIPLATELET AGENTS

Abstract

There is a growing trend in using combined modalities to treat thrombotic and cardiovascular disorders. Argatroban, Bay 59-7939, and Integrelin represent anti-IIa, anti-Xa, and antiplatelet agents, respectively. In certain indications, all of these agents are combined to manage cardiovascular disorders. To investigate the potential interaction between these three drugs, each was tested individually and in combination for their effects on thromboplastin-induced activation of human platelets as studied in whole native blood employing flow cytometric methods. Platelet aggregation and p-selectin expression were measured using CD 61 and CD 62 antibodies respectively. The combination of Argatroban and Bay produced a concentration dependent inhibition of platelet aggregation and P-selectin expression, which was greater than the effects of either drug alone. Integrilin did not augment the inhibition by Bay and Argatroban (11.49 % aggregation at 0.5 μg/ml of Argatroban and Bay 59-7939 vs. 11.81 % aggregation at 0.5 μg/ml each of Argatroban, Bay 59-7939, and Integrilin). Interestingly, Integrilin was found to enhance P-selectin expression, however supplementation of Bay 59-7939 and Argatroban blunted this response (12.69 median value of P-selectin expression at 0.5 μg/ml of Integrilin vs. 2.51 median value of P-selectin expression at 0.5 μg/ml each of Argatroban, Bay 59-7939, and Integrilin). These studies indicate that antiplatelet agents do not augment the inhibition of thromboplastin mediated activation of platelets, but antithrombin and anti-Xa agents do augment the effects of antiplatelet drugs. These observations underscore the importance of simultaneous administration of antiplatelet and antiprotease agents to inhibit thrombogenesis in indications where both systems are activated.