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Blood, 1 April 2001, Vol. 97, No. 7, pp. 1907-1914
PLENARY PAPER
Plasma glucosylceramide deficiency as potential risk factor for
venous thrombosis and modulator of anticoagulant protein C
pathway
Hiroshi Deguchi,
José
A. Fernández,
Ingrid Pabinger,
John A. Heit, and
John H. Griffin
From the Department of Molecular and Experimental
Medicine, The Scripps Research Institute, La Jolla, CA; the First
Department of Medicine, University of Vienna, Austria; and the
Department of Medicine, Mayo Clinic, Rochester, MN.
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 µg/mL [P = .0007] and 66 vs 71 µg/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.
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