title: Bcl-xL-inhibitory BH3 mimetics can induce a transient thrombocytopathy that undermines the hemostatic function of platelets.
abstract: BH3 mimetics are a new class of proapo-ptotic anticancer agents that have shown considerable promise in preclinical animal models and early-stage human trials. These agents act by inhibiting the pro-survival function of one or more Bcl-2-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 Ibα and glycoprotein VI, and functional down-regulation of integrin α(IIb)β(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.
authors.affiliation: Australian Centre for Blood Diseases, Monash University, Melbourne, Australia.
authors.forename: Simone M
authors.initials: SM
authors.lastname: Schoenwaelder
authors.forename: Kate E
authors.initials: KE
authors.lastname: Jarman
authors.forename: Elizabeth E
authors.initials: EE
authors.lastname: Gardiner
authors.forename: My
authors.initials: M
authors.lastname: Hua
authors.forename: Jianlin
authors.initials: J
authors.lastname: Qiao
authors.forename: Michael J
authors.initials: MJ
authors.lastname: White
authors.forename: Emma C
authors.initials: EC
authors.lastname: Josefsson
authors.forename: Imala
authors.initials: I
authors.lastname: Alwis
authors.forename: Akiko
authors.initials: A
authors.lastname: Ono
authors.forename: Abbey
authors.initials: A
authors.lastname: Willcox
authors.forename: Robert K
authors.initials: RK
authors.lastname: Andrews
authors.forename: Kylie D
authors.initials: KD
authors.lastname: Mason
authors.forename: Hatem H
authors.initials: HH
authors.lastname: Salem
authors.forename: David C S
authors.initials: DC
authors.lastname: Huang
authors.forename: Benjamin T
authors.initials: BT
authors.lastname: Kile
authors.forename: Andrew W
authors.initials: AW
authors.lastname: Roberts
authors.forename: Shaun P
authors.initials: SP
authors.lastname: Jackson
mesh_terms: D000814:Aniline Compounds / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001713:Biphenyl Compounds / Q000494:pharmacology; D001792:Blood Platelets / Q000378:metabolism / Q000502:physiology* / Q000648:ultrastructure; D015153:Blotting, Western; D003094:Collagen / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation / Q000187:drug effects; D006487:Hemostasis / Q000187:drug effects / Q000502:physiology*; D008562:Membrane Glycoproteins / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008855:Microscopy, Electron, Scanning; D009596:Nitrophenols / Q000494:pharmacology; D010718:Phosphatidylserines / Q000378:metabolism; D010879:Piperazines / Q000494:pharmacology; D010973:Platelet Adhesiveness / Q000187:drug effects; D010974:Platelet Aggregation / Q000187:drug effects; D010976:Platelet Count; D019039:Platelet Glycoprotein GPIIb-IIIa Complex / Q000378:metabolism; D019038:Platelet Glycoprotein GPIb-IX Complex; D010980:Platelet Membrane Glycoproteins / Q000378:metabolism; D013449:Sulfonamides / Q000494:pharmacology; D013921:Thrombocytopenia / Q000139:chemically induced / Q000503:physiopathology*; D013997:Time Factors; D051020:bcl-X Protein / Q000037:antagonists & inhibitors / Q000378:metabolism*
chemical_list: C501332:ABT-737; D000814:Aniline Compounds; D001713:Biphenyl Compounds; D008562:Membrane Glycoproteins; D009596:Nitrophenols; D010718:Phosphatidylserines; D010879:Piperazines; D019039:Platelet Glycoprotein GPIIb-IIIa Complex; D019038:Platelet Glycoprotein GPIb-IX Complex; D010980:Platelet Membrane Glycoproteins; D013449:Sulfonamides; C094990:adhesion receptor; D051020:bcl-X Protein; C098341:platelet membrane glycoprotein VI; D003094:Collagen; C528561:navitoclax