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Thrombotic microangipathy as a cause for cardiovascular toxicity from the BCR-ABL1 tyrosine kinase inhibitor ponatinib

Yllka Latifi, Federico Moccetti, Melinda Wu, Aris Xie, William Packwood, Yue Qi, Koya Ozawa, Weihui Shentu, Eran Brown, Toshiaki Shirai, Owen J. McCarty, Zaverio Ruggeri, Javid Moslehi, Junmei Chen, Brian J. Druker, Jose A. López and Jonathan R. Lindner

Key points

  • Ponatinib therapy can result in VWF-mediated platelet adhesion to the microvascular endothelium.

  • Ponatinib-related microangiopathy can reduce segmental LV dysfunction.

Abstract

The third generation tyrosine kinase inhibitor (TKI) ponatinib is effective against drug-resistant chronic myelogenous leukemia, but has been plagued by high rates of acute ischemic events. The pathophysiology responsible for these events is unknown. We hypothesized that ponatinib produces an endothelial angiopathy involving excessive endothelial-associated von Willebrand factor (VWF) and secondary platelet adhesion. In wild-type mice and ApoE-/- mice on Western diet, contrast-enhanced ultrasound molecular imaging of the thoracic aorta for VWF A1-domain and glycoprotein-Ibα was performed to quantify endothelial-associated VWF and platelet adhesion. After treatment of wild-type mice for seven days, aortic molecular imaging signal for endothelial-associated VWF and platelet adhesion were 5-6-fold higher in ponatinib versus sham-therapy (p<0.001), whereas dasatinib had no effect. In ApoE-/- mice, aortic VWF and platelet signal were 2-4-fold higher for ponatinib compared to sham-treated mice (p<0.05), and were significantly higher than in treated wild-type mice (p<0.05). Platelet and VWF signal in ponatinib-treated mice were significantly reduced by n-acetylcysteine and completely eliminated by recombinant ADAMTS13. Ponatinib produced segmental left-ventricular wall-motion abnormalities in 33% of wild-type and 45% of ApoE-/- mice, and corresponding patchy perfusion defects; yet coronary arterial anatomy was normal on angiography. Instead, a global microvascular angiopathy was detected both by immunohistochemistry and by intravital microscopy observation of platelet aggregates and nets associated with endothelial cells and leukocytes. Our findings reveal a new form of vascular toxicity for the TKI ponatinib that involves VWF-mediated platelet adhesion and a secondary microvascular angiopathy that produces ischemic wall-motion abnormalities. These processes can be mitigated by interventions known to reduce VWF multimer size.

  • Submitted October 19, 2018.
  • Accepted January 16, 2019.