i(3)so3-galactosylceramide and Venous-Thrombosis

In 1961, Wago et al. reported a potential anticoagulant role for sulfatide using animal experiments. Since then there have been many studies of sulfatide in the field of thrombogenesis/haemostasis, yielding contradictory conclusions. Some report that sulfatide has anti-thrombotic activity because it prolongs clotting time, inhibits platelet adhesion, and prolongs bleeding. Others report that sulfatide induces thrombosis in animal models. This mini-review is a chronologic review of reports examining the role of sulfatide in thrombogenesis/haemostasis together with the introduction of data from our laboratory and a discussion of the possible mechanisms underlying these curious phenomena.

Topics: Animals; Anticoagulants; Blood Coagulation; Disease Models, Animal; Hemostasis; Humans; Platelet Adhesiveness; Sulfoglycosphingolipids; Thrombosis; Venous Thrombosis

We previously reported that the sulfatide (galactosylceramide I3-sulfate) may have contradictory functions, namely both coagulant and anticoagulant roles in vivo: sulfatide induced giant thrombi formation when injected into rats with vein ligation, whereas no thrombi were formed when sulfatide was injected into rats without vein ligation. Rather it prolonged bleeding time. To investigate the structural features of sulfatide for both functions, a synthetic sulfatide (galactosylceramide I6-sulfate) which does not occur naturally, cholesterol 3-sulfate and ganglioside GM4 were examined together with naturally occurring sulfatide. Both sulfatides and cholesterol 3-sulfate induced giant thrombi in the rats with vein ligation within ten minutes of injection, although cholesterol 3-sulfate exhibited weaker coagulant activity than the sulfatides. On the contrary, both sulfatides significantly prolonged bleeding time but cholesterol 3-sulfate barely prolonged it when injected without vein ligation. GM4 exhibited neither coagulant nor anticoagulant activity. These results suggested that sulfate moiety in the sulfatides is essential for coagulant activity and that galactose residue enhances the activity, whereas both galactose and sulfate residues seem to be important for anticoagulant activity. This is because the sulfatides possess both residues but GM4 possesses galactose without sulfate and cholesterol 3-sulfate possesses sulfate without galactose. We previously reported that the possible mechanism of anticoagulation by sulfatide was due to its binding to fibrinogen, thereby inhibiting the conversion to fibrin. In this paper we reveal that both sulfatides inhibited thrombin activity independent of heparin cofactor II, thus providing evidence of another anticoagulation mechanism for the sulfatides.

Topics: Animals; Anticoagulants; Blood Coagulation; Calcium Chloride; Cattle; Cholesterol; Coagulants; Disease Models, Animal; Dose-Response Relationship, Drug; Galactose; Gangliosides; Humans; Male; Plasma; Rats; Rats, Sprague-Dawley; Sulfates; Sulfoglycosphingolipids; Swine; Thrombin; Venous Thrombosis

Although sulfatide (galactosylceramide I3-sulfate) has been reported to activate blood coagulation factor XII (Hageman factor), it has been administered to animals without subsequent thrombus formation. We recently found that sulfatide binds to fibrinogen and thus disturbs fibrin formation in vitro, suggesting its possible role as an anticoagulant rather than as a coagulant. We therefore examined the in vivo effects of sulfatide on thrombogenesis by using a rat deep vein thrombosis model in which thrombus is induced by ligating the inferior vena cava. Sulfatide and gangliosides were each separately administered to rats 1 min before the vein ligation, and after 3 h, sulfatide but not gangliosides markedly (P < .001) enhanced the thrombogenesis. A kinetic turbidmetric assay of plasma coagulation initiated by CaCl2 in the wells of a microtiter plate revealed that coagulation was also markedly accelerated in the presence of sulfatide but not gangliosides, the results of which seemed to be very consistent with those of the in vivo experiments. Because sulfatide could not induce thrombosis without vein ligation in rats, the enhancement of thrombogenesis by sulfatide in the in vivo model might require endothelial damage and/or venous congestion, both of which could be induced by vein ligation.

Topics: Animals; Blood Coagulation; Calcium Chloride; Disease Models, Animal; Factor XII; Fibrinogen; Gangliosides; Kinetics; Male; Protein Binding; Prothrombin Time; Rats; Rats, Sprague-Dawley; Sulfoglycosphingolipids; Venous Thrombosis