Dapsone hydroxylamine, an active metabolite of dapsone, can promote the procoagulant activity of red blood cells and thrombosis.

Abstract

Dapsone hydroxylamine (DDS-NHOH), N-hydroxylated metabolite of a sulfonamide antibiotic, dapsone, is responsible for various adverse effects of dapsone that include methemoglobinemia, hemolytic anemia, and thrombosis. However, the mechanism underlying DDS-NHOH-induced thrombosis remains unclear. Here, we demonstrated that DDS-NHOH, but not dapsone, could increase prothrombotic risks through inducing the procoagulant activity of RBCs. In freshly isolated human RBCs in vitro, sub-hemolytic concentrations of DDS-NHOH (10 to 50\u2009μM) increased phosphatidylserine (PS) exposure and augmented the formation of PS-bearing microvesicles (MV). Reactive oxygen species (ROS) generation and the subsequent dysregulation of enzymes maintaining membrane phospholipid asymmetry, were found to induce the procoagulant activity of DDS-NHOH. DDS-NHOH also accelerated thrombin generation and enhanced RBC self-aggregation and adherence of RBCs to endothelial cells in vitro. Most importantly, both the single dose of 50 or 100\u2009mg/kg (i.p.) DDS-NHOH and repeated doses of 10\u2009mg/kg per day (i.p.) for 4 days increased thrombus formation in rats (6 rats per dose) in vivo, substantiating a potential prothrombotic risk of DDS-NHOH. Collectively, these results demonstrated the central role of RBC procoagulant activity induced by DDS-NHOH in the thrombotic risk of dapsone.