Sphingosine inhibits monocyte tissue factor-initiated coagulation by altering factor VII binding.
Tissue factor is a lipoprotein, expressed on the surface of cells, which binds coagulation Factor VII or VIIa, leading to activation of Factors X and IX with subsequent fibrin generation. Cellular tissue factor activity is important in pathophysiologic processes such as inflammation and disseminated intravascular coagulation. In this study, the long-chain base sphingosine inhibited coagulation initiated by lipopolysaccharide-stimulated intact human monocytes. Sphingosine (5-100 microM) also profoundly inhibited thromboplastin-initiated coagulation (greater than 90% decrease in thromboplastin activity). This inhibition was dose- and time-dependent. Sphingosine inhibited neither the intrinsic pathway of coagulation nor thrombin generation of fibrin. The sphingosine analogues sphingomyelin, ceramide, or N-acetylsphingosine did not affect thromboplastin activity, suggesting that the polar head of sphingosine was necessary for interaction of the molecule with the coagulation system. Investigation of the biochemical mechanism revealed that sphingosine (5-50 microM), but neither sphingomyelin nor ceramide, inhibited specific binding of radiolabeled Factor VII to lipopolysaccharide-stimulated intact monocytes. The results suggest that sphingosine may regulate monocyte tissue factor-initiated coagulation by modulating Factor VII binding to tissue factor. Sphingosine may represent a new class of inhibitors of hemostasis.
Conkling
P R
PR
Department of Medicine, Veterans Administration Medical Center, Durham, North Carolina 27705.
Patton
K L
KL
Hannun
Y A
YA
Greenberg
C S
CS
Weinberg
J B
JB
D001777:Blood Coagulation / Q000187:drug effects* / Q000502:physiology; D002518:Ceramides / Q000494:pharmacology; D005167:Factor VII / Q000378:metabolism*; D006801:Humans; D007700:Kinetics; D008070:Lipopolysaccharides / Q000494:pharmacology; D009000:Monocytes / Q000502:physiology*; D010314:Partial Thromboplastin Time; D013109:Sphingomyelins / Q000494:pharmacology; D013110:Sphingosine / Q000494:pharmacology*; D013925:Thromboplastin / Q000494:pharmacology*
D002518:Ceramides; D008070:Lipopolysaccharides; D013109:Sphingomyelins; D005167:Factor VII; D013925:Thromboplastin; D013110:Sphingosine