Chemotherapy induces enhanced procoagulant activity through phosphatidylserine exposure in acute lymphoblastic leukemia

IntroductionThromboembolism is a serious complication in patients with acute lymphoblastic leukemia (ALL). Coagulation disorders can be induced and worsened by cytotoxic drugs; however, the mechanisms are largely unknown. Our study aims to investigate the effects of daunorubicin (DNR) and L-asparaginase (L-ASP) on phosphatidylserine (PS) exposure and the procoagulant activity (PCA) of Jurkat/ALL cells. The anticoagulant properties of lactadherin were also explored.Materials and MethodsJurkat cells and cells from 10 newly diagnosed patients with ALL were treated with DNR or L-ASP. Flow cytometry and confocal microscopy were used to quantify and locate PS exposure, respectively. PCA was evaluated using coagulation assays and purified coagulation complex assays. Lactadherin, a glycoprotein of the milk fat globule membrane with stereospecific binding to phosphatidyl-L-serine, was used as a probe for the detection of exposed PS.ResultsUntreated Jurkat/ALL cells exhibited higher PS exposure and greater PCA than mononuclear cells (MNCs). The PCA of cells treated with DNR or L-ASP was markedly increased. Flow cytometry and confocal microscopy indicated that the increased PCA occurred in parallel with PS exposure. The blocking of PS with lactadherin prolonged the coagulation time and inhibited approximately 85-90% of the activities of procoagulant enzyme complexes in Jurkat/ALL cells.ConclusionsOur results indicate that DNR and L-ASP increased the PCA of Jurkat/ALL cells through PS exposure and played a critical role in inducing thrombosis in ALL patients. Lactadherin is an ideal probe for PS detection at an early stage and a potential anticoagulant to improve the hypercoagulability of ALL patients.