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Promyelocytic extracellular chromatin exacerbates coagulation and fibrinolysis in
acute promyelocytic leukemia
#MMPMID28053193
Cao M
; Li T
; He Z
; Wang L
; Yang X
; Kou Y
; Zou L
; Dong X
; Novakovic VA
; Bi Y
; Kou J
; Yu B
; Fang S
; Wang J
; Zhou J
; Shi J
Blood
2017[Mar]; 129
(13
): 1855-1864
PMID28053193
show ga
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.
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