Bcl-xL-inhibitory BH3 mimetics can induce a transient thrombocytopathy that undermines the hemostatic function of platelets

Simone M. Schoenwaelder, Kate E. Jarman, Elizabeth E. Gardiner, My Hua, Jianlin Qiao, Michael J. White, Emma C. Josefsson, Imala Alwis, Akiko Ono, Abbey Willcox, Robert K. Andrews, Kylie D. Mason, Hatem H. Salem, David C.S. Huang, Benjamin T. Kile, Andrew W. Roberts, Shaun P. Jackson*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

250 Citations (Scopus)

Abstract

BH3 mimetics are a new class of proapoptotic anticancer agents that have shown considerable promise in preclinical animal models and early-stage human trials. These agents act by inhibiting the prosurvival function of one or more Bcl-2-related proteins. Agents that inhibit Bcl-xL induce rapid platelet death that leads to thrombocytopenia; however, their impact on the function of residual circulating platelets remains unclear. In this study, we demonstrate that the BH3 mimetics, ABT-737 or ABT-263, induce a time- and dose-dependent decrease in platelet adhesive function that correlates with ectodomain shedding of the major platelet adhesion receptors, glycoprotein Ibα and glycoprotein VI, and functional downregulation of integrin β3. Analysis of platelets from mice treated with higher doses of BH3 mimetics revealed the presence of a subpopulation of circulating platelets undergoing cell death that have impaired activation responses to soluble agonists. Functional analysis of platelets by intravital microscopy revealed a time-dependent defect in platelet aggregation at sites of vascular injury that correlated with an increase in tail bleeding time. Overall, these studies demonstrate that Bcl-xL-inhibitory BH3 mimetics not only induce thrombocytopenia but also a transient thrombocytopathy that can undermine the hemostatic function of platelets.

Original languageEnglish
Pages (from-to)1663-1674
Number of pages12
JournalBlood
Volume118
Issue number6
DOIs
Publication statusPublished - 11 Aug 2011
Externally publishedYes

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