Bcl-x(L)-inhibitory BH3 mimetics can induce a transient thrombocytopathy that undermines the hemostatic function of platelets

Schoenwaelder, SM; Jarman, KE; Gardiner, EE; Hua, M; Qiao, JL; White, MJ; Josefsson, EC; Alwis, I; Ono, A; Willcox, A; Andrews, RK; Mason, KD; Salem, HH; Huang, DCS; Kile, BT; Roberts, AW; Jackson, SP

Author(s): Schoenwaelder, SM; Jarman, KE; Gardiner, EE; Hua, M; Qiao, JL; White, MJ; Josefsson, EC; Alwis, I; Ono, A; Willcox, A; Andrews, RK; Mason, KD; Salem, HH; Huang, DCS; Kile, BT; Roberts, AW; Jackson, SP;
Details: Publication Year 2011-08-11,Volume 118,Issue #6,Page 1663-1674
Journal Title: BLOOD
Publication Type: Journal Article
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 Bcl2-related proteins. Agents that inhibit Bcl-x(L) 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 Ib alpha and glycoprotein VI, and functional down-regulation of integrin alpha(IIb)beta(3). 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-x(L)-inhibitory BH3 mimetics not only induce thrombocytopenia but also a transient thrombocytopathy that can undermine the hemostatic function of platelets. (Blood. 2011;118(6):1663-1674)
Publisher: AMER SOC HEMATOLOGY
Keywords: SMALL-MOLECULE INHIBITOR; BCL-2 FAMILY INHIBITOR; IN-VIVO; PROTEIN-KINASE; SHAPE CHANGE; CANCER; APOPTOSIS; ABT-737; VITRO; PHOSPHORYLATION
Publisher's Version: https://doi.org/10.1182/blood-2011-04-347849
Terms of Use/Rights Notice: Refer to copyright notice on published article.

Creation Date: 2011-08-11 12:00:00