Novel anticoagulant activity of polybrene: inhibition of monocytic tissue factor hypercoagulation following bacterial endotoxin induction.
The enhanced extrinsic coagulation in response to inflammation could contribute to disseminated intravascular coagulation, often manifesting cardiovascular complications. The complex mechanism remains unclear. Nor is the effective anticoagulation well established. The search for arresting hypercoagulation is of antithrombotic relevance. The ability of polybrene (PB) to inhibit tissue factor (TF)-initiated extrinsic blood coagulation was demonstrated at the protein and cellular levels as well as in human plasma samples. In a single-stage clotting assay, PB dose-dependently offset bacterial endotoxin (lipopolysaccharide)-induced monocytic TF (mTF) hypercoagulation and inhibited rabbit brain thromboplastin (rbTF) procoagulation. Consistent with these findings, the significantly prolonged prothrombin time indicated the depressed extrinsic coagulation by PB. However, PB showed no effect on thrombin time. We dissected the extrinsic pathway to further determine the inhibitory site(s) of PB. A two-stage chromogenic assay monitoring S-2288 hydrolysis showed that PB readily blocked mTF-dependent or rbTF-dependent FVII activation, which was verified by the diminished activated factor VII (FVIIa) formation derived from the proteolytic cleavage of its zymogen factor VII on Western blotting analyses. PB had no effect on FVIIa and activated factor X amidolytic activity. Nor was the dissected TF/FVIIa-catalyzed factor X activation affected. In conclusion, the preferential downregulation of factor VII activation was responsible for the depressed extrinsic coagulation. PB could present a novel anticoagulant antagonizing the extrinsic hypercoagulation for the prevention of thrombotic complication following sepsis and inflammations.
Chu
A J
AJ
Department of Surgery, School of Medicine, Wayne State University, Detroit, Michigan, USA. ad5742@wayne.edu
Rauci
M
M
Nwobi
O I
OI
Mathews
S T
ST
Beydoun
S
S
D000925:Anticoagulants / Q000494:pharmacology*; D001777:Blood Coagulation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004336:Drug Antagonism; D004731:Endotoxins / Q000494:pharmacology*; D005169:Factor VIII / Q000037:antagonists & inhibitors / Q000378:metabolism; D006583:Hexadimethrine Bromide / Q000494:pharmacology*; D006801:Humans; D008070:Lipopolysaccharides / Q000494:pharmacology; D009000:Monocytes / Q000378:metabolism; D019851:Thrombophilia / Q000209:etiology / Q000517:prevention & control*; D013925:Thromboplastin / Q000037:antagonists & inhibitors*; D014407:Tumor Cells, Cultured
D000925:Anticoagulants; D004731:Endotoxins; D008070:Lipopolysaccharides; D006583:Hexadimethrine Bromide; C044101:endotoxin, Escherichia coli; D005169:Factor VIII; D013925:Thromboplastin