Plasma glucosylceramide deficiency as potential risk factor for venous thrombosis and modulator of anticoagulant protein C pathway.
To assess the relationship between venous thrombosis and plasma glucosylceramide (GlcCer) or phosphatidylethanolamine (PE), plasma levels of GlcCer and PE were determined for 70 venous thrombosis patients referred for evaluation and 70 healthy blood donors. The mean GlcCer level, but not the PE level, was lower in patients versus controls (4.9 vs 6.5 microg/mL [P =.0007] and 66 vs 71 microg/mL [P =.48], respectively). As a measure of relative risk, the odds ratio for deep vein thrombosis in subjects with GlcCer levels below the 10th percentile of controls was 5.7 (95% CI, 2.3-14). To assess the influence of glycolipids on anticoagulant response to activated protein C (APC):protein S in modified prothrombin time assays, the effects of depleting endogenous plasma GlcCer by glucocerebrosidase treatment or of adding exogenous purified GlcCer or other neutral glycolipids to plasma were tested. Glucocerebrosidase treatment reduced plasma sensitivity to APC:protein S in parallel with GlcCer reduction. Exogenously added GlcCer and the homologous Glc-containing globotriaosylceramide (Gb3Cer), but not galactosylceramide, dose-dependently prolonged clotting times of normal plasma in the presence, but not absence, of APC:protein S, which suggests that GlcCer or Gb3Cer can enhance protein C pathway anticoagulant activity. In studies using purified proteins, inactivation of factor Va by APC:protein S was enhanced by GlcCer alone and by GlcCer in multicomponent vesicles containing phosphatidylserine and phosphatidylcholine. These results suggest that the neutral glycolipids GlcCer and Gb3Cer may directly contribute to the anticoagulant activity of the protein C pathway and that deficiency of plasma GlcCer may be a risk factor for venous thrombosis. (Blood. 2001;97:1907-1914)
Deguchi
H
H
Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, CA 92037, USA.
Fernández
J A
JA
Pabinger
I
I
Heit
J A
JA
Griffin
J H
JH
D020016:Activated Protein C Resistance / Q000097:blood*; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001777:Blood Coagulation / Q000187:drug effects; D002851:Chromatography, High Pressure Liquid; D015897:Comorbidity; D003278:Contraceptives, Oral, Hormonal / Q000009:adverse effects; D015943:Factor Va / Q000032:analysis; D005260:Female; D005699:Galactosylceramides / Q000494:pharmacology; D005962:Glucosylceramidase / Q000494:pharmacology; D005963:Glucosylceramides / Q000097:blood* / Q000172:deficiency / Q000494:pharmacology / Q000502:physiology; D006801:Humans; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000453:epidemiology; D016017:Odds Ratio; D010714:Phosphatidylethanolamines / Q000097:blood; D011183:Postoperative Complications / Q000453:epidemiology; D011486:Protein C / Q000502:physiology*; D017293:Protein S / Q000502:physiology; D011655:Pulmonary Embolism / Q000097:blood* / Q000453:epidemiology / Q000209:etiology; D012306:Risk; D019851:Thrombophilia / Q000097:blood* / Q000209:etiology; D014281:Trihexosylceramides / Q000494:pharmacology; D020246:Venous Thrombosis / Q000097:blood* / Q000453:epidemiology / Q000209:etiology; D044465:White People; D014947:Wounds and Injuries / Q000453:epidemiology
D003278:Contraceptives, Oral, Hormonal; D005699:Galactosylceramides; D005963:Glucosylceramides; D010714:Phosphatidylethanolamines; D011486:Protein C; D017293:Protein S; D014281:Trihexosylceramides; D015943:Factor Va; C018549:globotriaosylceramide; D005962:Glucosylceramidase