Ponatinib treatment promotes arterial thrombosis and hyperactive platelets

Abstract

Key Points Ponatinib therapy heightens arterial thrombosis and platelet reactivity. Concurrent pioglitazone treatment reverses heightened thrombosis risk and platelet reactivity induced by ponatinib.

Ponatinib and other CML Tyrosine Kinase Inhibitors in Thrombosis

“…Drug levels for ponatinib at 3 mg/kg/po bid were obtained by LC/MS/MS assay on day four, 2 and 24 h after starting treatment. They were 176 ± 47 and 11.4 ± 3.4 ng/mL, respectively, which translates to maximal final in vivo concentrations of 33 to 2 nM, respectively [100]. These concentrations are similar to those achieved in man by oral administration [102].…”

“…Vessel wall apoptosis is associated with thrombosis [107]. In murine tissue investigations, we found significantly increased expression of caspase3 in vessel adventitia including adipose tissue [100]. We also identified increased reactive oxygen species (ROS) using the antibody to nitrotyrosine in the ponatinib−treated vessel wall [100].…”

“…The mechanism of how ponatinib induces thrombosis is not completely understood [96,99,100]. Loren and colleagues investigated the possible prothrombotic effect of ponatinib in 2015.…”

“…Having the result of the PACE trial, we independently examined the prothrombotic effect of ponatinib [100]. When these investigations began, we were aware of the Loren et al study and we chose to create an in vivo model that mimics a steady state of ponatinib use with plasma concentration of the agent in wild−type C57 mice similar to that seen in man.…”

“…These data indicate that blood coagulation proteins were not aberrant in ponatinib−treated mice. Additionally, ponatinib−treated mice have a normal complete blood count including platelet count and normal white blood cell differential cell count [100].…”