Abstract 384: The Prothrombotic Profile of BCR-ABL Inhibitors Ponatinib, Nilotinib and Imatinib

Abstract

Background: Thrombotic complications observed in patients treated with the tyrosine kinase inhibitor ponatinib resulted in the temporary suspension of the drug by the FDA in late 2013. Ponatinib is a pan-BCR-ABL inhibitor designed for treatment of chronic myelogenous leukemia and Philadelphia chromosome-positive acute lymphoblastic leukemia. Ponatinib has been shown to inhibit a subset of the class III/IV family of receptor tyrosine kinases. The pathogenic mechanism underlying the prothrombotic phenotype associated with ponatinib remains ill-defined. Hypothesis: We tested the hypothesis that BCR-ABL inhibitors regulate platelet activation, spreading, and aggregation. Methods & Results: Our results show that treatment of platelets with ponatinib (1 μM) abrogated platelet spreading on fibrinogen (50 μg/ml) or collagen (100 μg/ml). Both nilotinib and imatinib inhibited platelet spreading, although not to the same extent as ponatinib at equimolar concentrations. We next examined the effects of BCR-ABL inhibitors on platelet activation and aggregation in response to the GPVI-agonist, CRP, which mediates platelet activation in a receptor tyrosine kinase-dependent manner. Intriguingly, our results show that ponatinib abrogated platelet aggregation in response to CRP (1 μg/ml), whereas equimolar concentrations of nilotinib or imatinib had minimal effects on CRP-induced platelet aggregation. Conclusions: While tyrosine kinase inhibitors are generally associated with bleeding diathesis, thrombotic complications have been observed in patients treated with ponatinib. Our results indicate that ponatinib, nilotinib, and imatinib inhibit platelet spreading and aggregation, with ponatinib having the most significant effect, suggesting that ponatinib may act as a platelet antagonist. Our future work will be focused on identifying platelet proteins affected by the BCR-ABL inhibitors as well as the pathogenic mechanisms underlying the prothrombotic phenotype associated with ponatinib.