title: Promyelocytic extracellular chromatin exacerbates coagulation and fibrinolysis in acute promyelocytic leukemia.
abstract: Despite routine treatment of unselected acute promyelocytic leukemia (APL) with all-trans-retinoic acid (ATRA), early death because of hemorrhage remains unacceptably common, and the mechanism underlying this complication remains elusive. We have recently demonstrated that APL cells undergo a novel cell death program, termed ETosis, which involves release of extracellular chromatin. However, the role of promyelocytic extracellular chromatin in APL-associated coagulation remains unclear. Our objectives were to identify the novel role of ATRA-promoted extracellular chromatin in inducing a hypercoagulable and hyperfibrinolytic state in APL and to evaluate its interaction with fibrin and endothelial cells (ECs). Results from a series of coagulation assays have shown that promyelocytic extracellular chromatin increases thrombin and plasmin generation, causes a shortening of plasma clotting time of APL cells, and increases fibrin formation. DNase I but not anti-tissue factor antibody could inhibit these effects. Immunofluorescence staining showed that promyelocytic extracellular chromatin and phosphatidylserine on APL cells provide platforms for fibrin deposition and render clots more resistant to fibrinolysis. Additionally, coincubation assays revealed that promyelocytic extracellular chromatin is cytotoxic to ECs, converting them to a procoagulant phenotype. This cytotoxity was blocked by DNase I by 20% or activated protein C by 31%. Our current results thus delineate the pathogenic role of promyelocytic extracellular chromatin in APL coagulopathy. Furthermore, the remaining coagulation disturbance in high-risk APL patients after ATRA administration may be treatable by intrinsic pathway inhibition via accelerating extracellular chromatin degradation.
authors.affiliation: Department of Hematology, The First Hospital, Harbin Medical University, Harbin, China.|The Key Laboratory of Myocardial Ischemia, Ministry of Education, Heilongjiang Province, Harbin, China.
authors.forename: Muhua
authors.initials: M
authors.lastname: Cao
authors.affiliation: Department of Hematology, The First Hospital, Harbin Medical University, Harbin, China.|The Key Laboratory of Myocardial Ischemia, Ministry of Education, Heilongjiang Province, Harbin, China.
authors.forename: Tao
authors.initials: T
authors.lastname: Li
authors.affiliation: Department of Hematology, The First Hospital, Harbin Medical University, Harbin, China.
authors.forename: Zhangxiu
authors.initials: Z
authors.lastname: He
authors.affiliation: Department of Cardiology, The First Hospital, and.
authors.forename: Lixiu
authors.initials: L
authors.lastname: Wang
authors.affiliation: Department of Hematology, The First Hospital, Harbin Medical University, Harbin, China.
authors.forename: Xiaoyan
authors.initials: X
authors.lastname: Yang
authors.affiliation: Department of Hematology, The First Hospital, Harbin Medical University, Harbin, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Kou
authors.affiliation: Department of Cardiology, The Second Hospital, Harbin Medical University, Harbin, China.
authors.forename: Lili
authors.initials: L
authors.lastname: Zou
authors.affiliation: Department of Hematology, The First Hospital, Harbin Medical University, Harbin, China.
authors.forename: Xue
authors.initials: X
authors.lastname: Dong
authors.affiliation: Department of Research, VA Boston Healthcare System, Boston, MA.
authors.forename: Valerie A
authors.initials: VA
authors.lastname: Novakovic
authors.affiliation: Department of Cardiology, The First Hospital, and.
authors.forename: Yayan
authors.initials: Y
authors.lastname: Bi
authors.affiliation: Department of Cardiology, The Second Hospital, Harbin Medical University, Harbin, China.
authors.forename: Junjie
authors.initials: J
authors.lastname: Kou
authors.affiliation: The Key Laboratory of Myocardial Ischemia, Ministry of Education, Heilongjiang Province, Harbin, China.
authors.forename: Bo
authors.initials: B
authors.lastname: Yu
authors.affiliation: The Key Laboratory of Myocardial Ischemia, Ministry of Education, Heilongjiang Province, Harbin, China.
authors.forename: Shaohong
authors.initials: S
authors.lastname: Fang
authors.affiliation: Department of Hematology, The Second Hospital, Harbin Medical University, Harbin, China; and.
authors.forename: Jinghua
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Hematology, The First Hospital, Harbin Medical University, Harbin, China.
authors.forename: Jin
authors.initials: J
authors.lastname: Zhou
authors.affiliation: Department of Hematology, The First Hospital, Harbin Medical University, Harbin, China.|Department of Surgery, Brigham and Women's Hospital, VA Boston Healthcare System and Harvard Medical School, Boston, MA.
authors.forename: Jialan
authors.initials: J
authors.lastname: Shi
mesh_terms: D001777:Blood Coagulation; D002478:Cells, Cultured; D002843:Chromatin / Q000473:pathology* / Q000502:physiology* / Q000648:ultrastructure; D042783:Endothelial Cells; D005337:Fibrin / Q000378:metabolism; D005342:Fibrinolysis; D042381:Granulocyte Precursor Cells / Q000473:pathology; D006801:Humans; D015473:Leukemia, Promyelocytic, Acute / Q000097:blood / Q000150:complications*; D014212:Tretinoin / Q000494:pharmacology; D014407:Tumor Cells, Cultured
chemical_list: D002843:Chromatin; D014212:Tretinoin; D005337:Fibrin