Thrombotic microangiopathy as a cause of 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, Jonathan R. Lindner

Research output: Contribution to journalArticle

16 Scopus citations

Abstract

The third-generation tyrosine kinase inhibitor (TKI) ponatinib has been associated with 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 ApoE2/2 mice on a Western diet, ultrasound molecular imaging of the thoracic aorta for VWF A1-domain and glycoprotein-Iba was performed to quantify endothelial-associated VWF and platelet adhesion. After treatment of wild-type mice for 7 days, aortic molecular signal for endothelial-associated VWF and platelet adhesion were five- to sixfold higher in ponatinib vs sham therapy (P < .001), whereas dasatinib had no effect. In ApoE2/2 mice, aortic VWF and platelet signals were two- to fourfold higher for ponatinib-treated compared with sham-treated mice (P < .05) and were significantly higher than in treated wild-type mice (P < .05). Platelet and VWF signals 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 ApoE2/2 mice and corresponding patchy perfusion defects, yet coronary arteries were normal on angiography. Instead, a global microvascular angiopathy was detected 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.

Original languageEnglish (US)
Pages (from-to)1597-1606
Number of pages10
JournalBlood
Volume133
Issue number14
DOIs
StatePublished - Apr 4 2019

ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

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    Latifi, Y., Moccetti, F., Wu, M., Xie, A., Packwood, W., Qi, Y., Ozawa, K., Shentu, W., Brown, E., Shirai, T., McCarty, O. J., Ruggeri, Z., Moslehi, J., Chen, J., Druker, B. J., López, J. A., & Lindner, J. R. (2019). Thrombotic microangiopathy as a cause of cardiovascular toxicity from the BCR-ABL1 tyrosine kinase inhibitor ponatinib. Blood, 133(14), 1597-1606. https://doi.org/10.1182/blood-2018-10-881557