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


METHODS
Jurkat 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.


RESULTS
Untreated 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.


CONCLUSIONS
Our 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.
Department of Hematology, The Second Affiliated Hospital, Harbin Medical University, Harbin, 150086, China.
Xiushuai
X
Dong
Jialan
J
Shi
Jin
J
Zhou
Xi
X
Chen
Yinglan
Y
Jin
Xiaomin
X
Zhang
Xiaoyun
X
Li
Haibin
H
Dai
Jinghua
J
Wang
D000293:Adolescent; D000328:Adult; D000970:Antineoplastic Agents / Q000009:adverse effects*; D001215:Asparaginase / Q000009:adverse effects*; D001777:Blood Coagulation / Q000187:drug effects; D001780:Blood Coagulation Tests; D045744:Cell Line, Tumor; D003630:Daunorubicin / Q000009:adverse effects*; D005260:Female; D006801:Humans; D008297:Male; D010718:Phosphatidylserines / Q000378:metabolism*; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000150:complications / Q000188:drug therapy*; D013927:Thrombosis / Q000139:chemically induced* / Q000378:metabolism; D055815:Young Adult
D000970:Antineoplastic Agents; D010718:Phosphatidylserines; D001215:Asparaginase; D003630:Daunorubicin
ALL; APL; Acute lymphoblastic leukemia; BSA; Chemotherapy; DNR; L-ASP; L-asparaginase; Lactadherin; MNCs; PCA; PPP; PS; Phosphatidylserine; acute lymphoblastic leukemia; acute promyelocytic leukemia; bovine serum albumin; daunorubicin; mononuclear cells; phosphatidylserine; platelet-poor plasma; procoagulant activity