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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
1   Research Center, La Fe University Hospital, Valencia, Spain
,
Elena Bonet
1   Research Center, La Fe University Hospital, Valencia, Spain
,
Silvia Navarro
1   Research Center, La Fe University Hospital, Valencia, Spain
,
Laura Martos
1   Research Center, La Fe University Hospital, Valencia, Spain
,
Amparo Estellés
1   Research Center, La Fe University Hospital, Valencia, Spain
,
Fernando Ferrando
2   Hemostasis and Thrombosis Unit, La Fe University Hospital, Valencia, Spain
,
Vicente Vicente
3   Centro Regional de Hemodonación, Universidad de Murcia, Spain
,
Rogier M. Bertina
4   Department of Thrombosis and Haemostasis, Leiden University Medical Centre, Leiden, The Netherlands
,
Francisco España
1   Research Center, La Fe University Hospital, Valencia, Spain
› Author Affiliations Financial support: This work was supported by grants from the PN de I+D+I 2008–20011, ISCIII, and FEDER (PS09/00610 to FE, Red RECAVA RD06/0014/0004 to FE, and RD06/0014/0016 to JF), the Consellería de Educación Generalitat Valenciana (Prometeo/2011/027 to FE), and the Fundación para la Investigación del Hospital Universitario La Fe (2007–0185 to FE), Spain. Pilar Medina is a Miguel Servet Researcher (ISCIII CP09/00065) and Silvia Navarro is a RECAVA Researcher (ISCIII RD06/0014/0004).
Further Information

Publication History

Received: 22 July 2011

Accepted after major revision: 05 January 2011

Publication Date:
22 November 2017 (online)

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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
 

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