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High plasma levels of endothelial protein C receptor are associated with the risk of unexplained fetal death

2005; Elsevier BV; Volume: 3; Issue: 2 Linguagem: Inglês

10.1111/j.1538-7836.2005.01151.x

1538-7933

Géraldine Lavigne-Lissalde, Éva Cochery-Nouvellon, Éric Mercier, P. Marès, Jean‐Christophe Gris,

Cardiovascular Issues in Pregnancy

Journal of Thrombosis and HaemostasisVolume 3, Issue 2 p. 393-395 Free Access High plasma levels of endothelial protein C receptor are associated with the risk of unexplained fetal death G. LAVIGNE-LISSALDE, G. LAVIGNE-LISSALDE Laboratoire d'Hématologie, Centre Hospitalo-Universitaire, Nîmes, FranceSearch for more papers by this authorE. COCHERY-NOUVELLON, E. COCHERY-NOUVELLON Laboratoire d'Hématologie, Centre Hospitalo-Universitaire, Nîmes, FranceSearch for more papers by this authorE. MERCIER, E. MERCIER Laboratoire d'Hématologie, UFR des Sciences Pharmaceutiques et Biologiques, Université de Montpellier, France Equipe d'Accueil, Université de Montpellier, FranceSearch for more papers by this authorP. MARÈS, P. MARÈS Département de Gynécologie et Obstétrique, Centre Hospitalo-Universitaire, Nîmes, FranceSearch for more papers by this authorJ.-C. GRIS, J.-C. GRIS Laboratoire d'Hématologie, UFR des Sciences Pharmaceutiques et Biologiques, Université de Montpellier, France Equipe d'Accueil, Université de Montpellier, FranceSearch for more papers by this author G. LAVIGNE-LISSALDE, G. LAVIGNE-LISSALDE Laboratoire d'Hématologie, Centre Hospitalo-Universitaire, Nîmes, FranceSearch for more papers by this authorE. COCHERY-NOUVELLON, E. COCHERY-NOUVELLON Laboratoire d'Hématologie, Centre Hospitalo-Universitaire, Nîmes, FranceSearch for more papers by this authorE. MERCIER, E. MERCIER Laboratoire d'Hématologie, UFR des Sciences Pharmaceutiques et Biologiques, Université de Montpellier, France Equipe d'Accueil, Université de Montpellier, FranceSearch for more papers by this authorP. MARÈS, P. MARÈS Département de Gynécologie et Obstétrique, Centre Hospitalo-Universitaire, Nîmes, FranceSearch for more papers by this authorJ.-C. GRIS, J.-C. GRIS Laboratoire d'Hématologie, UFR des Sciences Pharmaceutiques et Biologiques, Université de Montpellier, France Equipe d'Accueil, Université de Montpellier, FranceSearch for more papers by this author First published: 25 January 2005 https://doi.org/10.1111/j.1538-7836.2005.01151.xCitations: 6 Géraldine Lavigne-Lissalde MD, Laboratoire d'Hématologie, Groupe Hospitalo-Universitaire Caremeau, Place du Pr. Robert Debré, F-30029 Nîmes cedex 9, France. Tel.: +33 4 66 68 32 11; fax: +33 4 66 68 36 48; e-mail:geraldinelavigne@hotmail.com AboutSectionsPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat Data obtained in knockout mouse models have elegantly shown that the thrombomodulin–protein C system controls the growth and survival of trophoblast cells in the placenta [1], and that the endothelial cell protein C receptor (EPCR) plays a key role in preventing thrombosis at the maternal–embryonic interface [2], both functions being essential for the maintenance of pregnancy. Recently, a case–control study showed that a rare haplotype of the EPCR gene is associated with increased plasma levels of soluble EPCR (sEPCR) and is a candidate risk factor for thrombosis [3]. We thus conducted, in young non-thrombotic women with a first episode of fetal death, a case–control study aiming at analysis of the potential risk factor value of sEPCR plasma concentrations. All the women we studied had given their informed consent for participation in our Abnormal Pregnancy Study Program, based on the recruitment of a vast cohort of patients from the South of France with at least one miscarriage/fetal loss, or with pre-eclampsia or placental abruption, and of healthy parity with age-matched controls [NOHA studies: 4-9]. In this program, they were all basically investigated for classical prothrombotic factors as described (essential thrombocythemia, dysfibrinogenemia, deficiency in antithrombin, protein C or protein S, factor V Leiden and prothrombin G20210A mutations, high PAI-1 plasma levels, hyperhomocysteinemia, antiphospholipid/anticofactor antibodies such as lupus anticoagulant plasma activity (LA), anticardiolipin (aCL) and antiβ2-glycoprotein I (aβ2Gp1) IgG and IgM). In this work we included the 202 consecutive women seen between 1 January 2003 and 1 June 2003, with an unexplained first fetal loss from the 10th week of amenorrhea during their last pregnancy, but with negative thrombotic antecedents, and who agreed to participate in this study. Their median age was 24 years (range 18–31 years) and their median number of pregnancies was one (125: one pregnancy, 54: two pregnancies, 23: three pregnancies). A control group of 202 healthy mothers, matched for age, number of pregnancies and time elapsed since the end of the last pregnancy, with negative thrombotic antecedents and prothrombotic factors, was concomitantly recruited. Soluble EPCR plasma concentrations were measured using a commercially available enzyme-linked immunosorbent assay (AsserachromR sEPCR, Diagnostica Stago and Serbio, Asnières, France) and patients' plasma dilutions allowing measurement of all the samples containing high levels of sEPCR in the linear part of the standard curve. Anti-EPCR antibodies were tested by an assay derived from the original assay described by Hurtado et al. [10], using a commercially available recombinant extracellular portion of the human EPCR (Diagnostica Stago). The plasma concentrations of sEPCR were not statistically different in patients [median 100 ng mL−1, lower–upper quartiles 28–170 ng mL−1, range (41–736 ng mL−1)] and controls [106 ng mL−1, 48–167 ng mL−1, (62–374 ng mL−1), P =0.095]. No significant correlations were shown between sEPCR concentrations and anti-EPCR IgG (Spearman's correlation coefficient r2 = 0.081) or anti-EPCR IgM (r2 = 0.094). Patients having positive anti-EPCR antibodies, defined as values higher than the 99th percentile found in the control group, did not have higher sEPCR plasma concentrations than negative ones (Mann–Whitney rank-sum test; IgG: P = 0.48, IgM: P = 0.23). Plasma levels of sEPCR were not significantly correlated with values of anticardiolipin IgG (r2 = − 0.023), anticardiolipin IgM (r2 = − 0.034), antiβ2-glycoprotein 1 IgG (r2 = 0.08) or antiβ2-glycoprotein 1 IgM antibodies (r2 =− 0.062). The plasma sEPCR concentrations were not different in the case of positive or negative lupus anticoagulant (P =0.18) and in the case of positivity or negativity of each of the solid-phase antiphospholipid/anticofactor antibodies (aCL G: P = 020, aCL M: P = 0.25, aβ2Gp1 G: P = 0.29, aβ2Gp1 M: P = 0.33). We analyzed the distribution of the plasma concentrations of sEPCR in the patients and controls groups: through the representation of the values of the centiles (Fig. 1), we observed a shift towards higher values in patients beginning from the 80th percentile and women having sEPCR plasma concentration higher than 290 ng mL−1 (the value of percentile 95 in the control group) were more frequently patients than controls (29 vs. 8, P = 0.003). This fact was evidenced for the 202 case–control pairs, but also after exclusion of pairs with any positive antiphospholipid antibodies. This was controlled over time by performing an evaluation each 2 months for 6 months without significant variations. Figure 1Open in figure viewerPowerPoint Comparison of the values of the percentiles of sEPCR plasma concentrations in patients (P) and controls (C). The following percentiles are shown: 1st, 2nd, 3rd, 4th, 5th, 10th, 20th, 30th, 40th, 50th, 60th, 70th, 80th, 90th, 95th, 96th, 97th, 98th, 99th. The squares for the 95th, 96th, 97th, 98th and 99th percentiles are shown in white. The factor V Leiden mutation was more frequent in patients than in controls [12 vs. 2: P = 0.014; crude odds ratio (cOR) 6.4, 95% CI (1.4–29)] whereas the prothrombin G20210A mutation was not [6 vs. 2: P = 0.28; cOR 3.1, 95% CI (0.6–15)]. Positive antiphospholipid antibodies (aPL) were also more frequent in patients [26 vs. 7: P = 0.001; cOR 4.2, 95% CI (1.8–9.9)], as were women with sEPCR plasma concentrations higher than 290 ng mL−1[29 vs. 8: P = 0.003; cOR 3.6, 95% CI (1.6–6.9)]. Four patients had a high sEPCR concentration associated with a factor V Leiden mutation, whereas none of the controls had this association. We finally performed a multiparametric conditional regression analysis. High sEPCR concentrations (> 290 ng mL−1) were independent risk factors for fetal death [conditional OR 3.9, 95% CI (1.6–8.8), P = 0.005], together with a positivity for any of the classical aPL antibodies [2.8 (1.3–6.2), P = 0.015], with a positive anti-EPCR IgM [3.1 (1.5–7.1), P = 0.0025] and with the factor V Leiden mutation [4.8 (1.2–22), P = 0.023]. This analysis was also performed after exclusion of pairs with a positivity for classical aPL antibodies: high sEPCR concentrations [conditional OR 4.0, 95% CI (1.8–9.0), P = 0.004], positive anti-EPCR IgM [conditional OR 2.9, 95% CI (1.4–6.8), P = 0.003), and the factor V Leiden mutation [conditional OR 4.5, 95% CI (1.2–24), P = 0.02] were still independent risk factors for fetal death. In conclusion, our data indicate that plasma concentrations of the soluble endothelial protein C receptor can help to define the clinical risk of first pregnancy loss from the 10th week, independently from anti-EPCR IgM antibodies and from the factor V Leiden mutation in consecutive women with negative classical antiphospholipid antibodies. Also independently from classical antiphospholipid antibodies, antiphospholipid positive women are included in the group of consecutive women under investigation. One question is, however, to understand how high sEPCR concentrations may act. Acknowledgements We thank the numerous current and past obstetricians and gynecologist colleagues who agreed to participate in our Mediterranean Abnormal Pregnancy Study Program all patients and controls who agreed to join us in this long-distance running adventure. We thank Mrs Karine Martinez-Carrière, from Diagnostica Stago, Asnières, France, for logistic support. We thank Mrs Margaret Manson for editorial assistance. References 1 Isermann B, Sood R, Pawlinski R, Zogg M, Kalloway S, Degen JL, Mackman N, Weiler H. The thrombomodulin-protein C system is essential for the maintenance of pregnancy. Nat Med 2003; 9: 331– 7.DOI: 10.1038/nm825CrossrefCASPubMedWeb of Science®Google Scholar 2 Gu JM, Crawley JTB, Ferrell G, Zhang F, Li W, Esmon NL, Esmon CT. Disruption of the endothelial cell protein C receptor gene in mice causes placental thrombosis and early embryonic lethality. J Biol Chem 2002; 227: 43335– 43. 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