Endothelial damage and a thin intercellular fibrin network promote haemorrhage in acute promyelocytic leukaemia

Chunxu Wang, Muxin Yu, Peng Zhou, Baorong Li, Yingmiao Liu, Lixiu Wang, Xiaojing Chen, Jingwen Du, Yufeng Wang, Jinming Zhang, Haijiao Jing, Yiming Feng, Yue Zhang, Yueyue Li, Zengxiang Dong, Shaohong Fang, Valerie A Novakovic, Jin Zhou, Jialan Shi
EBioMedicine 2020 September 16, 60: 102992

BACKGROUND: The role of vascular endothelium in acute promyelocytic leukaemia (APL) remains unknown. We aimed to investigate the mechanisms by which APL cells interact with endothelial cells (ECs) and to further explore how the endothelium affects bleeding as well as therapeutic interventions.

METHOD: APL cells and an original APL cell line, NB4 cells, were used for experiments. The effects of leukaemic cells on ECs were analyzed in vitro and in vivo. Moreover, the endothelial barrier function and procoagulant activity were detected. An APL mouse model was established for in vivo studies.

FINDINGS: APL cells interacted with ECs via ICAM-1 and VCAM-1 receptors to disrupt endothelial integrity. This binding activated MLCK signaling, resulting in the trans-endothelial passage of protein and red blood cells (RBCs). Combined treatment with asiatic acid or anti-adhesion receptor antibody inhibited the response of ECs to APL cells, thereby preventing APL-associated haemorrhage in vitro and in vivo. Activated ECs exhibited a procoagulant phenotype after phosphatidylserine exposure. Plasma from APL patients formed a thin fibrin network between procoagulant ECs, and this intercellular fibrin decreased the passage of albumin and RBCs. Ex vivo addition of fibrinogen further enhanced this barrier function in a dose-dependent manner.

INTERPRETATION: Endothelial damage induced by leukaemic cell adherence promotes haemorrhaging in APL. Stabilization of ECs, decreasing adhesion receptor expression, and increasing fibrinogen transfusion levels may be a new therapeutic avenue to alleviate this fatal bleeding complication.

FUNDING: National Science Foundation of China (81670128, 81873433).

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