A 23-bp insertion in the EPCR gene and the risk of venous thrombosis

Abstract number: P0364

Franco^* R. F., Maffei† F. H. A., Piccinatto‡ C. E., Zago‡ M. A., Morelli§ V. M., Lourenço§ D. M., Ferreira‡ A. C. P.

^*Blood Centre of Rib. Preto, Brazil; †School of Medicine of Botucatu – UNESP, Brazil; §UNIFESP, Brazil ‡University of São Paulo, Brazil;

EPCR is a transmembrane protein highly expressed on the endothelium which binds protein C and enhances its activation by the thrombin-thrombomodulin complex. The EPCR gene has been characterized, which opens up the possibility of searching for mutations. Indeed, a 23-base-pair insertion at nucleotide 4031 in exon 3 has been identified, which may predispose patients to venous thrombosis. It was recently demonstrated that the insertion leads to the formation of a truncated EPCR with impaired function. The mutated protein is retained inside the cell, is less stable than the wild-type receptor and has diminished ability to bind activated PC. In spite of these new findings, the clinical importance of the insertion remains uncertain. In the present study we investigated the EPCR 23-bp insertion as a risk factor for venous thrombotic disease by determining its prevalence in 431 consecutive patients (male/female ratio 0.6, median age 44 years, range 2–70 years) with an objective diagnosis (ultrasonography or phlebography) of deep venous thrombosis (DVT) and in 431 age-, gender- and race-matched healthy subjects (male/female ratio 0.6, median age 44 years, range 2–70 years) in a case-control investigation, the Brathros (Brazilian Thrombosis Study). PCR amplification of EPCR exon 3 was used to determine the genotypes. Odds ratio (OR) as a measure of relative risk for DVT and 95% confidence intervals were calculated by standard methods. The EPCR mutation was identified in heterozygous state in 2/431 patients, yielding a carrier frequency of 0.46%. The insertion was detected in 4/431 controls, yielding a carrier frequency of 0.93%. These frequencies yielded an OR for DVT linked to the insertion of 0.5 (95% CI: 0.09–2.73). The present data show that the 23-bp insertion is a rare gene variation in the Brazilian population. In addition, our findings suggest that this mutation is not a major risk factor for venous thrombotic disease.