Compound 48/80 suppresses monocytic tissue factor-initiated extrinsic blood coagulation induced by bacterial endotoxin.
BACKGROUND
Hypercoagulability is one of the commonly exhibited endotoxemia septic symptoms; it could contribute to the manifestation of disseminated intravascular coagulation presenting threats to cardiovascular functions. The underlying mechanism, however, remains largely complex and unknown.


OBJECTIVE
We herein determine whether bacterial endotoxin (LPS) upregulates the activities of clotting factors in plasma, contributing to extrinsic hypercoagulation. Compound 48/80 (48/80) is also tested for its ability to suppress hypercoagulation.


METHODS
In an in vitro infection model, we exposed whole blood to LPS (Escherichia coli 0111:B04; 100 ng/ml) for 2 h. Thrombin time (TT), prothrombin time (PT), and the activities of clotting factors ( FVII, FIX, FX ) in plasma contributing to the extrinsic coagulation were determined. Peripheral blood monocytes were isolated from Histoplaque 1077 gradient centrifugation, and the procoagulant activity was determined by a single-stage clotting assay on a Fibrometer.


RESULTS
LPS drastically activated monocytic procoagulant activity which was defined as tissue factor (TF) activity, whereas LPS had no effect on TT, PT, and the activities of clotting factors in plasma. 48/80 not only instantaneously offset LPS-induced monocytic TF activation, but also significantly inhibited PT including the activities of clotting factors (FVII, FIX, and FX) in plasma, whereas TT remained unaffected.


CONCLUSIONS
Monocytic TF activation was solely responsible for the extrinsic hypercoagulation in response to LPS. 48/80 effectively suppressed LPS-induced monocyticTF-initiated extrinsic coagulation at multiple sites, possibly presenting a new therapy for an instantaneous relief of hypercoagulation under septic conditions.
Chu
A J
AJ
Department of Surgery, Wayne State University, Detroit, Michigan 48201, USA. ad5742@wayne.edu
Raphael
U O
UO
Prasad
J K
JK
Beydoun
S
S
Ramos
N
N
D001777:Blood Coagulation / Q000187:drug effects*; D005167:Factor VII / Q000502:physiology; D005170:Factor X / Q000502:physiology; D006801:Humans; D008070:Lipopolysaccharides / Q000633:toxicity*; D009000:Monocytes / Q000502:physiology*; D013925:Thromboplastin / Q000502:physiology*; D003189:p-Methoxy-N-methylphenethylamine / Q000494:pharmacology*
D008070:Lipopolysaccharides; D003189:p-Methoxy-N-methylphenethylamine; D005167:Factor VII; D005170:Factor X; D013925:Thromboplastin