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.
