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Thromb Haemost 2004; 91(05): 905-911
DOI: 10.1160/TH03-10-0657
Blood Coagulation, Fibrinolysis and Cellular Haemostasis
Schattauer GmbH

Contribution of polymorphisms in the endothelial protein C receptor gene to soluble endothelial protein C receptor and circulating activated protein C levels, and thrombotic risk

Pilar Medina
1   Research Center, La Fe University Hospital, Valencia, Spain
,
Silvia Navarro
1   Research Center, La Fe University Hospital, Valencia, Spain
,
Amparo Estellés
1   Research Center, La Fe University Hospital, Valencia, Spain
,
Amparo Vayá
2   Department of Clinical Pathology, La Fe University Hospital, Valencia, Spain
,
Barry Woodhams
3   Serbio (Groupe Stago), Gennevilliers, France
,
Yolanda Mira
2   Department of Clinical Pathology, La Fe University Hospital, Valencia, Spain
,
Piedad Villa
2   Department of Clinical Pathology, La Fe University Hospital, Valencia, Spain
,
Martine Migaud-Fressart
4   Diagnostica Stago, Asnieres, France
,
Fernando Ferrando
2   Department of Clinical Pathology, La Fe University Hospital, Valencia, Spain
,
Justo Aznar
2   Department of Clinical Pathology, La Fe University Hospital, Valencia, Spain
,
Rogier M. Bertina
5   Department of Hematology, Leiden University Medical Centre, Leiden, The Netherlands
,
Francisco España
1   Research Center, La Fe University Hospital, Valencia, Spain
› Author AffiliationsFinancial support: Supported in part by research grants from Plan Nacional de Investigación Científica, Desarrollo e Innovación Tecnológica (I+D+I) e Instituto de Salud Carlos III, Fondo de Investigación Sanitaria (PI020125 and PI020136), Madrid, and from Generalitat Valenciana-Agencia Valenciana de Ciencia y Tecnología (Grupos03/010), Valencia, Spain. S. Navarro was the recipient of a fellowship from Fundación Española de Trombosis y Hemostasia (FETH), Spain.
Further Information

Publication History

Received 28 October 2003

Accepted after resubmission 27 January 2004

Publication Date:
01 December 2017 (online)

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Summary

Endothelial cell protein C receptor (EPCR) enhances the generation of activated protein C (APC) by the thrombin-thrombomodulin complex. A soluble form of EPCR (sEPCR), which is generated by metalloprotease activity, is present in plasma. The distribution of sEPCR levels in healthy populations is bimodal. Previously, we described two polymorphisms in exon 4 of the EPCR gene, 4600A/G that encodes the substitution of Ser219 by Gly in the transmembrane region of EPCR and 4678G/C in the 3’-UT region. The aim of this study was to investigate the relationship between these two polymorphisms and plasma sEPCR and APC levels and risk of venous thrombosis. We genotyped 401 healthy controls from the Spanish population and measured their plasma sEPCR and APC levels. Carriers of the 4600AG genotype had significantly higher sEPCR levels than those with the AA genotype, while the 4678CC genotype was associated, to a lesser extent, with elevated APC levels. To assess the effect of these polymorphisms on the risk of thrombosis, we genotyped 405 patients with venous thromboembolism. The frequency of the 4600AG genotype was very similar in patients and controls (p=0.975), whereas the 4678CC genotype was significantly more frequent in controls than in patients (p=0.008). In multivariate analysis, carriers of the 4678CC genotype had a decreased risk of thrombosis (OR=0.61, p=0.009). These data indicate that individuals carrying the 4600AG genotype have high sEPCR levels but do not have an increased risk of thrombosis, whereas individuals carrying the 4678CC genotype have higher APC levels and lower risk of venous thromboembolism.

Keywords

Protein C - endothelial protein C receptor - polymorphism
 

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