We examined the in vivo influence of ponatinib on murine arterial thrombosis and platelet reactivity. Our investigations reveal that ponatinib increases in vivo arterial thrombosis risk and platelet hyperreactivity, but concurrent pioglitazone administration reverses both. Ponatinib has the widest inhibitory spectrum of CML tyrosine kinases.3 It inhibits ABL1 (T315I),fibroblast growth factor receptors 1 to 4, vascular endothelial growth factor receptors 1 to 3, FLT3,KIT, platelet-derived growth factor receptor, SRC, MEKK3, and Tie2, which are important vascular and myeloid cell receptors involved in cell growth, proliferation, angiogenesis, and repair. These combined investigations indicate that ponatinib at human therapeutic concentrations in mice exhibited deleterious effects on the vessel wall and selectively modulated agonist-induced platelet reactivity. Pioglitazone has the ability to neutralize these deleterious effects. This finding suggests that pioglitazone, along with its possible ability to increase mol. remission in CML, may be a useful adjunct in some patients with cardiovascular risk factors receiving ponatinib therapy.