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

摘要: 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 act by inhibiting the pro-survival function one or more Bcl-2-related proteins. Agents inhibit Bcl-x(L) induce rapid platelet death leads to thrombocytopenia; however, their impact on residual circulating platelets remains unclear. In this study, we demonstrate mimetics, ABT-737 ABT-263, time- dose-dependent decrease adhesive correlates with ectodomain shedding major adhesion receptors, glycoprotein Ibα VI, functional down-regulation integrin α(IIb)β(3). Analysis from mice treated higher doses revealed presence subpopulation undergoing cell impaired activation responses soluble agonists. Functional analysis intravital microscopy time-dependent defect aggregation at sites vascular injury correlated an increase tail bleeding time. Overall, these studies Bcl-x(L)-inhibitory not only thrombocytopenia but also transient thrombocytopathy can undermine hemostatic platelets.