title: Effects of oral anticoagulant therapy and haplotype 1 of the endothelial protein C receptor gene on activated protein C levels.
abstract: 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.
authors.affiliation: Research Center, La Fe University Hospital, Valencia, Spain.
authors.forename: Pilar
authors.initials: P
authors.lastname: Medina
authors.forename: Elena
authors.initials: E
authors.lastname: Bonet
authors.forename: Silvia
authors.initials: S
authors.lastname: Navarro
authors.forename: Laura
authors.initials: L
authors.lastname: Martos
authors.forename: Amparo
authors.initials: A
authors.lastname: Estellés
authors.forename: Fernando
authors.initials: F
authors.lastname: Ferrando
authors.forename: Vicente
authors.initials: V
authors.lastname: Vicente
authors.forename: Rogier M
authors.initials: RM
authors.lastname: Bertina
authors.forename: Francisco
authors.initials: F
authors.lastname: España
mesh_terms: D000328:Adult; D000925:Anticoagulants / Q000008:administration & dosage* / Q000009:adverse effects; D015703:Antigens, CD / Q000235:genetics / Q000378:metabolism*; D004252:DNA Mutational Analysis; D000074283:Endothelial Protein C Receptor; D005260:Female; D005500:Follow-Up Studies; D006239:Haplotypes; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics; D011486:Protein C / Q000378:metabolism*; D011516:Prothrombin / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000235:genetics / Q000378:metabolism*; D054556:Venous Thromboembolism / Q000097:blood / Q000188:drug therapy* / Q000235:genetics*; D055815:Young Adult
chemical_list: D000925:Anticoagulants; D015703:Antigens, CD; D000074283:Endothelial Protein C Receptor; C478370:PROCR protein, human; D011486:Protein C; D011956:Receptors, Cell Surface; D011516:Prothrombin