Protein C is the major natural anticoagulant and a complete deficiency leads to a severe thrombotic tendency shortly after birth. It is activated by thrombin when it is bound to thrombomodulin on the endothelial surface. Since thrombin is the central procoagulant, this constitutes a strong regulatory system to keep coagulation limited and localized. Activated protein C (APC) inhibits coagulation, in the presence of its cofactor protein S, by proteolytic cleavage of procoagulant factors Va and VIIIa. Reduced performance of this system, such as in partial (heterozygous) deficiencies of protein C or protein S, or in an amino acid change at one of the cleavage sites of factor V, as in factor V Leiden, results in thrombophilia (ie, an increased risk of venous thrombosis).

The endothelial protein C receptor (EPCR), discovered in 1994, has been reported to enhance the activation of protein C by thrombin bound to thrombomodulin.1,2  It is logical to postulate that abnormalities in this receptor play a role in the etiology of venous thrombosis. Because the receptor is bound to the endothelial cells of the blood vessels, its function cannot be readily assessed in vivo. However, a soluble form of EPCR (sEPCR) can be measured in plasma, which is probably a degradation product of EPCR, but still has some of the functions of EPCR, such as binding to protein C. Interestingly, levels of sEPCR have a strikingly bimodal distribution in plasma, suggestive of single locus genetic control.3 

Poor function of EPCR could cause thrombosis because of less efficient activation of protein C. Recently, a mutation in the EPCR gene was described that consisted of a 23–base pair insertion that leads to an early stop codon.4  Since such a mutation is likely to lead to loss of function due to less expression or lowered functionality, this opened a possibility to study the relevance of EPCR in vivo. The mutation was found in a few individuals with thrombophilia, but firm conclusions could not be reached due to its rarity (population prevalence estimated at less than 5 per 1000).5 

In this issue, Saposnik and colleagues (page 1311) describe extensive screening of the EPCR gene, which led to the identification of a haplotype that is strongly related to sEPCR plasma levels, with over 6-fold increased levels in those homozygous for the haplotype. In addition, they report that the haplotype is associated with a 1.7-fold increased risk of venous thrombosis (95% confidence interval, 1.2-2.4) in a case control study including 338 patients and 338 controls. Even though this is a moderately increased risk, it may be highly relevant because of the high frequency of the haplotype in the population (18%), which implies that over 20% of all thrombotic events could be attributed to this variant (population attributable risk). However, since the same genotype was not associated with thrombosis in previous studies, the results on this association need confirmation.

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