Effects of oral anticoagulant therapy and haplotype 1 of the endothelial protein C receptor gene on activated protein C levels

Pilar Medina; Elena Bonet; Silvia Navarro; Laura Martos; Amparo Estellés; Fernando Ferrando; Vicente Vicente; Rogier M. Bertina; Francisco España

doi:10.1160/TH11-07-0510

Thrombosis and Haemostasis, Table of Contents

Thromb Haemost 2012; 107(03): 448-457
DOI: 10.1160/TH11-07-0510

Blood Coagulation, Fibrinolysis and Cellular Haemostasis

Schattauer GmbH

Effects of oral anticoagulant therapy and haplotype 1 of the endothelial protein C receptor gene on activated protein C levels

Pilar Medina

¹Research Center, La Fe University Hospital, Valencia, Spain

,

Elena Bonet

¹Research Center, La Fe University Hospital, Valencia, Spain

,

Silvia Navarro

¹Research Center, La Fe University Hospital, Valencia, Spain

,

Laura Martos

¹Research Center, La Fe University Hospital, Valencia, Spain

,

Amparo Estellés

¹Research Center, La Fe University Hospital, Valencia, Spain

,

Fernando Ferrando

²Hemostasis and Thrombosis Unit, La Fe University Hospital, Valencia, Spain

,

Vicente Vicente

³Centro Regional de Hemodonación, Universidad de Murcia, Spain

,

Rogier M. Bertina

⁴Department of Thrombosis and Haemostasis, Leiden University Medical Centre, Leiden, The Netherlands

,

Francisco España

¹Research Center, La Fe University Hospital, Valencia, Spain

› Author Affiliations

Abstract

Summary

Oral anticoagulants (OACs) reduce activated protein C (APC) plasma levels less than those of protein C (PC) in lupus erythematosus and cardiac patients. Carriers of the H1 haplotype of the endothelial PC receptor gene (PROCR) have higher APC levels than non-carriers. We aimed to confirm these results in a large group of patients treated with OACs because of venous thromboembolism (VTE) and to assess whether the effect is influenced by the PROCR H1 haplotype. We evaluated APC, PC, and factor (F)II levels in 502 VTE patients (158 with and 344 without OACs) and in 322 healthy individuals. Mean APC, PC and FII levels were significantly lower in OAC patients than in patients not taking OACs. During anticoagulant therapy, the FII/PC ratios were independent of the PC values, whereas APC/FII and APC/PC ratios significantly increased when FII and PC levels decreased. Of the 22 OAC patients carrying the H1H1genotype, 11 (50%) showed APC/PCag ≥2.0 and 10 (45%) APC/ FIIag ratios ≥2.0, whereas for the 49 OAC patients non-carrying the H1 haplotype these figures were 6 (12%) and 4 (8%), respectively (p<0.001). Barium citrate adsorption of plasma from OAC patients showed that most of the circulating free and complexed APC, but only part of PCag, is fully carboxylated. In conclusion, during anticoagulant therapy VT patients have APC levels disproportionately higher than the corresponding PC levels, mainly due to the presence of the PROCR H1 haplotype. Furthermore, a sufficiently carboxylated PC Gla-domain seems to be essential for PC activation in vivo.

Keywords

Activated protein C - endothelial protein C receptor - factor II - oral anti-coagulation - venous thrombosis

Full Text

References

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