Doxorubicin-induced platelet procoagulant activities: An important clue for chemotherapy-associated thrombosis

Se Hwan Kim, Kyung Min Lim, Ji Yoon Noh, Keunyoung Kim, Seojin Kang, Youn Kyeong Chang, Sue Shin, Jin Ho Chung

Research output: Contribution to journalArticlepeer-review

34 Scopus citations

Abstract

Thrombotic risk associated with chemotherapy including doxorubicin (DOX) has been frequently reported; yet, the exact mechanism is not fully understood. Here, we report that DOX can induce procoagulant activity in platelets, an important contributor to thrombus formation. In human platelets, DOX increased phosphatidylserine (PS) exposure and PS-bearing microparticle (MP) generation. Consistently, DOX-treated platelets and generated MPs induced thrombin generation, a representative marker for procoagulant activity. DOX-induced PS exposure appeared to be from intracellular Ca 2+ increase and ATP depletion, which resulted in the activation of scramblase and inhibition of flippase. Along with this, apoptosis was induced by DOX as determined by the dissipation of mitochondrial membrane potential (Δψ), cytochrome c release, Bax translocation, and caspase-3 activation. A Ca 2+ chelator ethylene glycol tetraacetic acid, caspase inhibitor Q-VD-OPh, and antioxidants (vitamin C and trolox) can attenuate DOX-induced PS exposure and procoagulant activity significantly, suggesting that Ca 2+, apoptosis, and reactive oxygen species (ROS) were involved in DOX-enhanced procoagulant activity. Importantly, rat in vivo thrombosis model demonstrated that DOX could manifest prothrombotic effects through the mediation of platelet procoagulant activity, which was accompanied by increased PS exposure and Δψ dissipation in platelets.

Original languageEnglish
Article numberkfr222
Pages (from-to)215-224
Number of pages10
JournalToxicological Sciences
Volume124
Issue number1
DOIs
StatePublished - Nov 2011

Keywords

  • Doxorubicin
  • Platelets
  • PS exposure
  • Thrombosis

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