Blood, 1 April 2001, Vol. 97, No. 7, pp. 1905-1905
Plasma glycolipids levels: new factors regulating the protein
C anticoagulant pathway and determining thrombotic risk
Deguchi and colleagues (page 1907) have identified the
plasma glucosylceramide (GlcCer), but not other similar glycolipids, as
a novel source for supporting the activity of the natural anticoagulant activated protein C (APC). They show that patients below the 10th percentile in GlcCer had an increased incidence of venous thrombosis. Interestingly, subgroup analysis revealed that this relationship only
held with the younger patients (younger than 45 years of age).
Furthermore, the anticoagulant response to APC correlated with GlcCer
concentration in male, but not female, thrombosis patients. These
findings raise important clinical and basic questions.
Both the procoagulant and anticoagulant vitamin K-dependent complexes
utilize negatively charged phospholipids to assemble the relevant
functional complexes. Because the vitamin K domains of the protease
components were relatively conserved, it was always assumed that they
shared similar lipid determinants. Recently, it has been shown that the
phospholipid specificities of the anticoagulant complexes differ
markedly from the procoagulant complexes, with phosphatidylethanolamine
and lipid oxidation augmenting the anticoagulant responses quite
significantly. The present study indicates that plasma glycolipids
increase the anticoagulant response to APC markedly. Previous studies
by Bertina and colleagues have shown that low anticoagulant
responsiveness to APC, regardless of the basis for the poor response,
is associated with increased thrombotic risk. The present study may
have provided one of the mechanisms responsible for this low response
to APC in some of these patients. Another interesting quandary
is that platelets support APC activity poorly in vitro, yet in vivo APC
has been shown to be a potent inhibitor of thrombin-mediated platelet
thrombus formation, suggesting that there are major differences between
the platelet dependent functions of APC in vivo and in vitro. In vitro
studies with platelet anticoagulant functions are usually done in the
absence of plasma. Hence, plasma GlcCer augmentation of APC function
may provide one of the explanations for this quandary. Assuming that
the clinical linkage between low GlcCer plasma levels and increased
risk of thrombosis in young patients is confirmed in additional
studies, the results of the present study suggest that there are both
age- and sex-related differences that determine the importance of
GlcCer in the anticoagulant response. If GlcCer levels do not influence the anticoagulant response in young thrombotic women, it suggests major
gender-based differences in the control of the APC anticoagulant response. As the authors note, GlcCer synthase levels are reduced by
estradiol and hence may provide a mechanism contributing to the
increased risk of thrombosis associated with pregnancy or the use of
oral contraceptives. This is a particularly interesting question since
thrombosis in females with factor V Leiden (APC resistance due to a
mutation in factor V) is increased markedly with the use of oral
contraceptives. One might suggest then that there are other
undiscovered factors that modulate the protein C anticoagulant pathway
since the in vitro anticoagulant response to APC in thrombotic young
women is not correlated with GlcCer levels. Understanding the
mechanistic basis for gender- and age-related differences in the
control of the protein C anticoagulant pathway may open new diagnostic
and therapeutic regimens for thrombosis patients.
Charles T. Esmon
Howard Hughes Medical Institute
