Publications by authors named "Éva Cochery-Nouvellon"

21 Publications

  • Page 1 of 1

Early ADAMTS13 testing associates with pre-eclampsia occurrence in antiphospholipid syndrome.

Thromb Res 2021 Apr 27;203:101-109. Epub 2021 Apr 27.

Department of Gynaecology and Obstetrics, First Moscow State Medical University (Sechenov University), Russian Federation; Department of Haematology, CHU Nîmes, Univ Montpellier, Nîmes, France; Faculty of Pharmaceutical and Biological Sciences, Montpellier University, Montpellier, France; UA 011 INSERM- Université de Montpellier, Institut Desbrest d'Epidémiologie et de Santé Publique, Montpellier, France. Electronic address:

Introduction: Women with obstetric antiphospholipid syndrome (oAPS) still develop placental diseases, mainly pre-eclampsia (PEcl), which diagnosis is associated with reduced ADAMTS13 levels. Testing ADAMTS13 in newly pregnant oAPS may provide evidence for risk stratification.

Materials And Methods: We retrospectively investigated the prognostic value of ADAMTS13 activity, antigen and antibodies on stored plasma samples obtained prior to beginning low-molecular weight heparin-low dose aspirin treatment in 513 oAPS women.

Results: Some women had evidences of early positive ADAMTS13 antibodies and low ADAMTS13 activity:antigen ratio, suggestive of ADAMTS13 dysfunction. Women with a subsequent PEcl had higher ADAMTS13 antibodies (p < 0.0001), and lower ADAMTS13 activity and activity:antigen ratios (p < 0.0001). In multivariate analysis, these markers were significant risk factors for PEcl and for the most devastating PEcl subgroups (early-onset PEcl, severe PEcl, PEcl with no living child after 28 days). ADAMTS13-related markers showed acceptable discrimination power to predict clinical events, particularly for ADAMTS13 activity:antigen ratio in predicting PEcl cases with no living child after 28 days (AUC: 0.844 (0.712-0.974), p < 0.0001), with excellent negative predictive value (0.990).

Conclusions: The characterization of ADAMTS13 in newly pregnant women with oAPS depicts the risk of PEcl occurrence. ADAMTS13 might help identify pregnant women with oAPS not requiring escalating treatment strategies to prevent PEcl.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.thromres.2021.04.021DOI Listing
April 2021

Urinary Placental Growth Factor for Prediction of Placental Adverse Outcomes in High-Risk Pregnancies.

Obstet Gynecol 2019 12;134(6):1326-1332

University Paris Est Créteil and CHI Créteil, the Department of Obstetrics-Gynecology and Reproductive Medicine, University Paris Est Créteil, Centre Hospitalier Inter-Communal de Créteil, Créteil, the Department of Hematology, University Hospital Caremeau, Nîmes, Faculty of Pharmaceutical and Biological Sciences, University of Montpellier, Montpellier, and the Center of Biological Resources, Centre Hospitalier Inter-Communal de Créteil, France; and the Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, California.

Objective: To evaluate whether urinary levels of placental growth factor (PlGF) during pregnancy are associated with the subsequent development of composite adverse outcomes (preeclampsia, fetal growth restriction, placental abruption, perinatal death, maternal death) occurring at less than 34 weeks of gestation.

Methods: This is a preplanned ancillary study of the Heparin-Preeclampsia trial, a randomized trial in pregnant women with a history of severe early-onset preeclampsia (less than 34 weeks of gestation). In the parent study, all women were treated with aspirin and then randomized to receive either low-molecular-weight (LMW) heparin or aspirin alone. For this substudy we measured urinary levels of PlGF and urinary creatinine at the following gestational windows: 10-13 6/7, 14-17 6/7, 18-21 6/7, 22-25 6/7, 26-29 6/7, 30-33 6/7, and 34-37 6/7 weeks of gestation.

Results: Urine samples were available from 187 patients: LMW heparin plus aspirin (n=93) and aspirin alone (n=94). The two groups had comparable baseline characteristics and had similar adverse composite outcomes at less than 34 weeks of gestation (14/93 [15.1%] vs 11/94 [11.7%]; P=.50). There were no significant differences in urine PlGF levels in the patients who received LMW heparin plus aspirin compared with those who received aspirin alone. However, median [interquartile range] urinary PlGF/creatinine concentrations (pg/mg) measured at mid-pregnancy (22-26 weeks of gestation) were significantly lower among women who developed composite adverse outcome at less than 34 weeks of gestation (42.7 [32.4-80.8] vs 255.6 [118.7-391.8] P<.001) and significantly lower among women who developed preeclampsia at less than 34 weeks of gestation (42.7 [27.5-80.7] vs 244.6 [112.9-390.6] P<.001). For a fixed false-positive rate of 10% the sensitivity of urinary PlGF concentrations at mid-pregnancy was 75.2% (area under the curve 0.93) for the subsequent development of composite adverse outcomes.

Conclusion: Decreased urinary PlGF at mid-gestation (22-26 weeks of gestation) is associated with the subsequent development of preeclampsia-related adverse outcomes at less than 34 weeks of gestation.

Clinical Trial Registration: ClinicalTrials.gov, NCT00986765.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/AOG.0000000000003547DOI Listing
December 2019

The role of haemostasis in placenta-mediated complications.

Thromb Res 2019 Sep;181 Suppl 1:S10-S14

University of Montpellier, France; Department of Vascular Imaging and Vascular Medicine, Nîmes University Hospital, France.

Normal pregnancy is associated with an increasing state of activation of the haemostatic system. This activation state is excessive in women with placenta-mediated pregnancy complications (PMPCs), including preeclampsia (PE). Platelet activation plays a crucial pathophysiological role in PE. The very early activation of coagulation in the intervillous space is mandatory for placental growth and morphogenesis but its excesses and/or inadequate control may participate to the emergence of the trophoblastic phenotype of PE. Extracellular vesicles, of endothelial but also of trophoblastic origin, can favour key cellular reactions of preeclampsia, acting as proactive cofactors. The understanding of this intricate relationship between haemostasis activation and PMPCs may provide interesting keys for new pathophysiological therapeutic developments.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/S0049-3848(19)30359-7DOI Listing
September 2019

Increased incidence of cancer in the follow-up of obstetric antiphospholipid syndrome within the NOH-APS cohort.

Haematologica 2020 31;105(2):490-497. Epub 2020 Jan 31.

UPRES EA2992 "Caractéristiques Féminines des Dysfonctions des Interfaces Vasculaires", University of Montpellier, Montpellier, France.

Malignancies can be associated with positive antiphospholipid antibodies but the incidence of cancer among women with the purely obstetric form of antiphospholipid syndrome (APS) is currently unknown. Our aim was to investigate the comparative incidence of cancers in women with a history of obstetric APS within a referral university hospital-based cohort (NOH-APS cohort). We performed a 17-year observational study of 1,592 non-thrombotic women with three consecutive spontaneous abortions before the 10 week of gestation or one fetal death at or beyond the 10 week of gestation. We compared the incidence of cancer diagnosis during follow-up among the cohort of women positive for antiphospholipid antibodies (n=517), the cohort of women carrying the rs6025 or rs1799963 polymorphism (n=279) and a cohort of women with negative thrombophilia screening results (n=796). The annualized rate of cancer was 0.300% (0.20%-0.44%) for women with obstetric APS and their cancer risk was substantially higher than that of women with negative thrombophilia screening [adjusted hazard ratio (aHR) 2.483; 95% confidence interval (CI) 1.27-4.85]. The computed standardized incidence ratio for women with obstetric APS was 2.89; 95% CI: 1.89-4.23. Among antiphospholipid antibodies, lupus anticoagulant was associated with incident cancers (aHR 2.608; 95% CI: 1.091-6.236). Our cohort study shows that the risk of cancer is substantially higher in women with a history of obstetric APS than in the general population, and in women with a similar initial clinical history but negative for antiphospholipid antibodies.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3324/haematol.2018.213991DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7012495PMC
April 2021

Clinical value of automated fibrin generation markers in patients with septic shock: a SepsiCoag ancillary study.

Br J Haematol 2018 11 11;183(4):636-647. Epub 2018 Sep 11.

Intensive Care Unit, CHU Nîmes, Univ Montpellier, France.

An ancillary analysis to the SepsiCoag multicentric prospective observational study on patients entering an intensive care unit with septic shock evaluated the prognostic potential of fibrin generation markers (FGMs) tested at inclusion in the study, on survival at day 30. After centralization of samples, three automated FGMs were compared: D-dimers (DDi), fibrin/fibrinogen degradation products (FDP) and fibrin monomers (FM). FM was the single FGM that was significantly higher in non-surviving patients, area under the receiver-operator characteristic curve (AUC ): 0·617, P < 0·0001. Significantly higher International Society on Thrombosis and Haemostasis Disseminated Intravascular Coagulation (ISTH DIC) scores were calculated in non-survivors using each of the three FGMs. A dose-effect relationship was observed between ISTH DIC scores and non-survival, with highest significance obtained using FM as the FGM. An overt DIC diagnosis using the ISTH DIC score calculated using FM was a predictor of non-survival at day 30, independently from overt DIC diagnosis based on scores calculated using FDP or DDi. The AUC values testing the ability of the ISTH DIC score to predict non-survival were 0·650, 0·624 and 0·602 using FM, DDi and FDP, respectively, as the FGM. In patients with septic shock, among the commercially-available automated assays, automated FM is the FGM best related with late prognosis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/bjh.15576DOI Listing
November 2018

Angiogenic Factor Profiles in Pregnant Women With a History of Early-Onset Severe Preeclampsia Receiving Low-Molecular-Weight Heparin Prophylaxis.

Obstet Gynecol 2018 01;131(1):63-69

University Paris Est Créteil and CHI Créteil, Créteil, France; the Center for Vascular Biology Research, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts; the Department of Hematology, University Hospital Caremeau, Nîmes UPRES EA2992, and faculty of pharmaceutical and biological sciences, University of Montpellier, Montpellier, France; and the Division of Nephrology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts.

Objective: To evaluate whether daily low-molecular-weight (LMW) heparin prophylaxis during pregnancy alters profile of circulating angiogenic factors that have been linked with the pathogenesis of preeclampsia and fetal growth restriction.

Methods: This is a planned ancillary study of the Heparin-Preeclampsia trial, a randomized trial in pregnant women with a history of severe early-onset preeclampsia (less than 34 weeks of gestation). In the parent study, all women were treated with aspirin and then randomized to receive LMW heparin or aspirin alone. In this study, we measured serum levels of circulating angiogenic factors (soluble fms-like tyrosine kinase-1, placental growth factor, and soluble endoglin by immunoassay) at the following gestational windows: 10-13 6/7 weeks, 14-17 6/7 weeks, 18-21 6/7 weeks, 22-25 6/7 weeks, 26-29 6/7 weeks, 30-33 6/7 weeks, and 34-37 6/7 weeks.

Results: Samples were available from 185 patients: LMW heparin+aspirin (n=92) and aspirin alone (n=93). The two groups had comparable baseline characteristics and had similar adverse composite outcomes (35/92 [38.0%] compared with 36/93 [38.7%]; P=.92). There were no significant differences in serum levels of soluble fms-like tyrosine kinase-1, placental growth factor, and soluble endoglin in the participants who received LMW heparin and aspirin compared with those who received aspirin alone regardless of gestational age period. Finally, women who developed an adverse composite outcome at less than 34 weeks of gestation demonstrated significant alterations in serum angiogenic profile as early as 10-13 6/7 weeks that was most dramatic 6-8 weeks preceding delivery.

Conclusion: Prophylactic LMW heparin therapy when beginning from before 14 weeks of gestation with aspirin during pregnancy is not associated with an improved angiogenic profile. This may provide a molecular explanation for the lack of clinical benefit noted in recent trials.

Clinical Trial Registration: ClinicalTrials.gov, NCT00986765.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/AOG.0000000000002380DOI Listing
January 2018

Antiphospholipid antibodies are associated with positive screening for common mental disorders in women with previous pregnancy loss. The NOHA-PSY observational study.

World J Biol Psychiatry 2019 01 19;20(1):51-63. Epub 2017 Jun 19.

f Department of Internal Medicine , University Hospital , Nîmes , France.

Objectives: Case reports describe neuropsychiatric manifestations associated with antiphospholipid antibodies (aPlAbs). In patients sharing the same symptoms fulfilling the antiphospholipid syndrome (APS) clinical criteria, the prevalence of common mental disorders has, however, never been studied.

Methods: We observed women with three consecutive abortions before the 10th week of gestation or one foetal loss at or beyond the 10th week. We compared the prevalence of common psychiatric disorders detected through screening using the Mini International Neuropsychiatric Interview, 10 years after inclusion, in women with APS (n = 506), women negative for aPlAbs but carrying the F5rs6025 or F2rs1799963 thrombogenic polymorphism (n = 269), and women with negative thrombophilia screening results as controls (n = 764).

Results: Similar prevalence values were obtained for controls and women bearing one of the two thrombogenic polymorphisms. Women with APS more frequently had mood disorders (relative risk (RR) 1.57 (1.262-1.953), P = .0001) and anxiety (RR 1.645 (1.366-1.979), P < .0001). Within the APS group, lupus anticoagulant (LA) and anti-β2GP1 IgG, or triple positivity, were strong risk factors for mood disorders.

Conclusions: Women with obstetric APS have a higher risk of positive screening for common mental disorders than women without APS.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1080/15622975.2017.1333146DOI Listing
January 2019

Obstetric antiphospholipid syndrome: early variations of angiogenic factors are associated with adverse outcomes.

Haematologica 2017 05 25;102(5):835-842. Epub 2017 Jan 25.

Department of Hematology, University Hospital, Nîmes, France

The prognostic value of angiogenic factors in newly pregnant women with obstetric antiphospholipid syndrome (oAPS) has not been documented. We observed 513 oAPS who experienced three consecutive spontaneous abortions before the 10 week of gestation or one fetal loss at or beyond the 10 week. We assessed the plasma concentrations of the proangiogenic factor placenta growth factor (PIGF) and of the antiangiogenic factor soluble fms-like tyrosine kinase-1 on the eve and on the 4 day of the low-molecular weight heparin-low-dose aspirin treatment. Placenta growth factor and fms-like tyrosine kinase-1 plasma concentrations showed marked increases. Treatment-associated variations of PIGF and of soluble fms-like tyrosine kinase-1 were antagonist risk factors for placenta-mediated complications (PMC) and for severe PMC, for fetal death, stillbirth and neonatal death. The ratio between PIGF increase and soluble fms-like tyrosine kinase-1 was a summary variable whose best cut-off values (1.944.10) had high negative predictive values for PMC (0.918) and may be used to help rule out the development of PMC in evolutive pregnancies after 19 completed weeks. The early variations of PIGF and soluble fms-like tyrosine kinase-1 concentrations in newly pregnant oAPS may help to detect patients at low risk of PMC. ().
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3324/haematol.2016.155184DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5477602PMC
May 2017

Comparative incidence of pregnancy outcomes in treated obstetric antiphospholipid syndrome: the NOH-APS observational study.

Blood 2014 Jan 7;123(3):404-13. Epub 2013 Nov 7.

Department of Hematology, University Hospital, Nîmes, France;

The incidence of pregnancy outcomes for women with the purely obstetric form of antiphospholipid syndrome (APS) treated with prophylactic low-molecular-weight heparin (LMWH) plus low-dose aspirin (LDA) has not been documented. We observed women without a history of thrombosis who had experienced 3 consecutive spontaneous abortions before the 10th week of gestation or 1 fetal loss at or beyond the 10th week. We compared the frequencies of complications during new pregnancies between treated women with APS (n = 513; LMWH + LDA) and women negative for antiphospholipid antibodies as controls (n = 791; no treatment). Among APS women, prior fetal loss was a risk factor for fetal loss, preeclampsia (PE), premature birth, and the occurrence of any placenta-mediated complication. Being positive for anticardiolipin immunoglobulin M antibodies was a risk factor for any placenta-mediated complication. Among women with a history of recurrent abortion, APS women were at a higher risk than other women of PE, placenta-mediated complications, and neonatal mortality. Among women with prior fetal loss, LMWH + LDA-treated APS women had lower pregnancy loss rates but higher PE rates than other women. Improved therapies, in particular better prophylaxis of late pregnancy complications, are urgently needed for obstetric APS and should be evaluated according to the type of pregnancy loss.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1182/blood-2013-08-522623DOI Listing
January 2014

Comparative incidence of pregnancy outcomes in thrombophilia-positive women from the NOH-APS observational study.

Blood 2014 Jan 7;123(3):414-21. Epub 2013 Nov 7.

Department of Hematology, University Hospital, Nîmes, France;

The incidence of pregnancy outcomes in women with constitutive thrombophilia is uncertain. We observed women with no history of thrombotic events (nonthrombotic), who had experienced 3 consecutive spontaneous abortions before the 10th week of gestation or 1 fetal death at or beyond the 10th week of gestation. We compared the frequencies of complications during a new pregnancy attempt among women carrying the F5 rs6025 or F2 rs1799963 polymorphism (n = 279; low-molecular-weight heparin [LMWH] treatment during pregnancy only in case of prior fetal death), and women with negative thrombophilia screening results as control women (n = 796; no treatment). Among women with prior recurrent abortions, thrombophilic women were at increased risk for fetal death. Among women with prior fetal death, thrombophilic women experienced less fetal death recurrences, less preterm births and preeclampsia, and more live births as they were treated with LMWH. In nonthrombotic F5 rs6025 or F2 rs1799963 heterozygous women with prior pregnancy loss, fetal loss may indicate a clinical subgroup in which future therapeutic randomized controlled trials testing the effect of LMWH prophylaxis are required in priority.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1182/blood-2013-09-525014DOI Listing
January 2014

Comparative incidence of a first thrombotic event in purely obstetric antiphospholipid syndrome with pregnancy loss: the NOH-APS observational study.

Blood 2012 Mar 6;119(11):2624-32. Epub 2011 Dec 6.

Department of Hematology, University Hospital, Nîmes, France.

The incidence of thrombosis in the purely obstetric form of antiphospholipid syndrome is uncertain. We performed a 10-year observational study of 1592 nonthrombotic women who had experienced 3 consecutive spontaneous abortions before the 10th week of gestation or 1 fetal death at or beyond the 10th week of gestation. We compared the frequencies of thrombotic events among women positive for antiphospholipid Abs (n = 517), women carrying the F5 6025 or F2 rs1799963 polymorphism (n = 279), and women with negative thrombophilia screening results (n = 796). The annual rates of deep vein thrombosis (1.46%; range, 1.15%-1.82%), pulmonary embolism (0.43%; range, 0.26%-0.66%), superficial vein thrombosis (0.44%; range, 0.28%-0.68%), and cerebrovascular events (0.32%; range, 0.18%-0.53%) were significantly higher in aPLAbs women than in the other groups despite low-dose aspirin primary prophylaxis. Women carrying 1 of the 2 polymorphisms did not experience more thrombotic events than women who screened negative for thrombophilia. Lupus anticoagulant was a risk factor for unprovoked proximal and distal deep and superficial vein thrombosis and women in the upper quartile of lupus anticoagulant activity had the highest risk. Despite data suggesting that aPLAbs may induce pregnancy loss through nonthrombotic mechanisms, women with purely obstetric antiphospholipid syndrome are at risk for thrombotic complications.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1182/blood-2011-09-381913DOI Listing
March 2012

[Is haemostasis assessment mandatory in case of pregnancy loss?].

Rev Med Suisse 2011 Feb;7(281):361-4

Laboratoire et Consultations d'Hématologie, Centre Hospitalier Universitaire, Groupe Hospitalo-Universitaire Caremeau, Nîmes, France.

Pregnancy losses must be categorised into biochemical loss, early embryonic loss, late foetal loss and stillbirth cases. No haemostasis-related investigations are necessary for biochemical losses. Antiphospholipid antibodies must be checked for three early losses or one late loss. A complete blood count will reveal the rare essential thrombocytemias, a functional fibrinogen assay the exceptional dysfibrinogenemia cases. Vitamin B12 and intracellular folates levels must be checked in case of clinical or biological suspicion. Constitutive thrombophilias must not be routinely assessed because a therapeutic option is not definitively demonstrated. Screening for constitutive thrombophilias should be only indicated for clinical research purposes, only for late foetal loss and stillbirth cases.
View Article and Find Full Text PDF

Download full-text PDF

Source
February 2011

The A6936G polymorphism of the endothelial protein C receptor gene is associated with the risk of unexplained foetal loss in Mediterranean European couples.

Thromb Haemost 2009 Oct;102(4):656-67

Haematology Laboratory, University Hospital, Nîmes, France.

The endothelial protein C receptor (EPCR) is expressed by trophoblast cells. Mid-gestation pregnancy loss is described in animals with a haemochorial placenta lacking EPCR. The A6936G allele of the EPCR gene (PROCR) may be associated with lower EPCR densities on trophoblasts, but data are lacking for its effect on the risk of pregnancy loss in humans. A 1:2 case-control study on unexplained pregnancy loss was nested in the NOHA First cohort: 3,218 case couples and 6,436 control couples were studied for PROCR A6936G, coagulation factor V gene (F5) G1691A and coagulation factor II gene (F2) G20210A polymorphisms. Ethnicity and time of pregnancy loss defined through biometry-based gestational ages (embryonic loss < 10(th) week > or = foetal loss) were analysed. The PROCR A6936G allele, in mothers and fathers, was associated only with foetal loss in both Europeans and non-Europeans. Increasing probability levels of carrying a homozygous child were increasingly associated with the risk of foetal demise. The F5 G1691A and F2 G20210A alleles, only in mothers, were only and independently associated with foetal loss in Europeans. In our population, the PROCR A6936G allele describes women, but also men and thus couples, at risk for first unexplained foetal loss. This risk is independent of the foetal loss risk conferred to our local Mediterranean European women by the F5 G1691A and F2 G20210A alleles. Data confirm that the relationship between thrombophilias and pregnancy loss varies according to ethnicity and loss type.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1160/TH-09-04-0224DOI Listing
October 2009

Interleukin 10 gene promoter polymorphisms in women with pregnancy loss: preferential association with embryonic wastage.

Biol Reprod 2009 Jun 4;80(6):1115-20. Epub 2009 Feb 4.

Laboratoire Central d'Hématologie, Centre Hospitalier Universitaire de Reims, Reims, France.

Interleukin 10 (IL10) is associated with maternal immunotolerance. IL10 also down-regulates decidual cell tissue factor expression, the main molecule triggering coagulation activation: this antithrombotic effect may protect the umbilicoplacental vasculature from the 10th wk of gestation onward. IL10 down-regulation may thus dispose to early pregnancy loss (PL) due to maternal immunotolerance defect or late pregnancy failure due to placental vascular insufficiency. IL10 gene promoter polymorphisms associated with cytokine down-regulation may help to identify the actual and probable mechanisms of IL10 modulation in pregnancy outcomes. We investigated the following four IL10 promoter polymorphisms associated with IL10 down-regulation: two single-nucleotide polymorphisms rs1800871 and rs1800872 and two polymorphic CA repeat microsatellites IL10 X78437.2:g8134CA(14_29) and IL10 X78437.2:g.5325CA(11_15). Each microsatellite was analyzed as a biallelic polymorphism. Based on a review of the literature, we define a short allele and a long allele for each microsatellite. We compared their frequencies in early PL occurring before 10 wk of amenorrhea (n = 342) and in PL occurring later on (n = 123). The mutated alleles rs1800871T (odds ratio, 3.083; 95% confidence interval, 1.984-4.792) and rs1800872A (odds ratio, 3.013; 95% confidence interval, 1.924-4.719) were associated with early PL. The haplotype rs1800872A/rs1800871T/X78437.2:g.8134CA[14_25]/X78437.2:g.5325CA[11_13], which includes the two mutated alleles, was significantly associated with the risk of early PL in a dose-dependent manner. Positivity for one haplotype was significantly associated with a 5.6-fold increase in the risk of early pregnancy failure, and positivity for two haplotypes was associated with an 8-fold increase in risk. In women with PL, some polymorphisms of the IL10 gene promoter seem to be constitutional risk factors for early (embryonic) pregnancy failure.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1095/biolreprod.108.072215DOI Listing
June 2009

Analysis of the venous thromboembolic risk associated with severe postpartum haemorrhage in the NOHA First cohort.

Thromb Haemost 2008 Nov;100(5):773-9

Laboratoire d'hématologie, Centre Hospitalier Universitaire, Groupe hospitalo-universitaire Caremeau, Place du Pr. Robert Debré, F-30029 Nîmes cedex 9, France.

Severe postpartum haemorrhages (PPH) are responsible for maternal morbidity/mortality. Their complex management sometimes requires haemostatic supplementation, and therapeutic trials on fibrinogen or activated factor VII, which may add to the thrombotic risk, are currently being considered. Furthermore, there is a risk of venous thromboembolism (VTE) during the postpartum period, hence we studied the relationship between severe PPH and VTE in women during their first pregnancy. Among the 32,463 women enrolled between January 1, 1999 and February 1, 2004 in the NOHA First cohort, 317 developed severe PPH, 11 postpartum VTE and 60 had postpartum superficial vein thrombosis (SVT). In the women with severe PPH, whilst there were no episodes of VTE, there were three episodes of SVT, which occurred 6 weeks postpartum. All of the women with severe PPH received packed red blood cell (RBC) units, 29 (9.1%) platelets units, 51 (16.1%) fresh frozen plasma and 29 (9.1%) fibrinogen concentrates. Three patients with both severe PPH and SVT received only packed RBC. Severe PPH or packed RBC unit transfusion were associated with postpartum SVT (adjusted relative risk: 5.3 (1.6-17) and 4.7 (1.5-15) respectively), independent of caesarean section delivery and low-molecular-weight heparin (LMWH) use in the postpartum, but were not independent indicators of one another. This the VTE and SVT risks associated with severe PPH are low (<1% and <2%, respectively). Severe PPH increases the risk of postpartum SVT, but transfusion with platelet units and plasma supplementation using fresh frozen plasma or fibrinogen concentrates do not markedly modulate the risk of venous thrombosis.
View Article and Find Full Text PDF

Download full-text PDF

Source
November 2008

Monocyte IL-10 produced in response to lipopolysaccharide modulates thrombin generation by inhibiting tissue factor expression and release of active tissue factor-bound microparticles.

Thromb Haemost 2007 Apr;97(4):598-607

Laboratoire Central d'Hématologie, Hôpital Robert Debré, Avenue du Général Koenig, Reims Cedex, France.

Lipopolysaccharide (LPS)-stimulated monocytes are known to have a procoagulant effect. This property is currently explained by the fact that monocytes, in response to LPS, can express tissue factor (TF) and undergo a process of membrane microvesiculation. Interleukin-10 (IL-10) has been shown to downregulate TF expression and inhibit procoagulant activity (PCA). In order to further characterize the inhibitory effect of IL-10 on LPS-induced PCA, we used the integrated system of analysis of kinetics of thrombin generation in normal plasma (thrombinography). For this, we developed an original method of elutriation allowing to obtain a highly purified monocyte preparation, under endotoxin-free conditions. Thrombin generation was measured using a highly sensitive and specific fluorogenic method which we adapted to inhibit the contact factor pathway. Results show that recombinant human IL-10 decreased the kinetics of thrombin generation in a dose-dependent manner. Furthermore, the inhibition of endogenous IL-10 released by monocytes in response to LPS is associated with an increase in the kinetics of thrombin generation. We demonstrated that this effect was a consequence of the up-regulation of TF expression and TF-bound microparticle release. In conclusion, we report that IL-10 can regulate thrombin generation in conditions close to physiology as allowed by thrombinography, and that endogenous IL-10 regulates TF expression and release of active TF-bound microparticles by a negative feed back loop through IL-10 receptor alpha.
View Article and Find Full Text PDF

Download full-text PDF

Source
April 2007

Interleukin-10 promoter polymorphism and venous thrombosis: a case-control study.

Thromb Haemost 2006 Jul;96(1):24-8

Laboratoire Central d'hématologie, CHU Robert Debré, Université de Reims Champagne-Ardenne, France.

The human interleukin-10 promoter gene is highly polymorphic. IL-10 polymorphisms have been associated with various autoimmune and lymphoproliferative disorders. Although IL-10 has been shown to modulate thrombin generation in several experimental models, it is not known whether IL-10 polymorphisms could be a risk factor for venous thrombosis. We therefore conducted a case-control study comparing 74 consecutive patients who experienced at least one episode of documented venous thromboembolic event and 100 healthy controls. All subjects were Caucasians. Five polymorphisms of the IL-10 promoter gene were studied: two highly polymorphic dinucleotide repeats, IL-10 R and IL-10G, and three single nucleotide polymorphisms at position -1082, -819 and -592. Factor VG1691C Leiden mutation was systematically determined. Multivariate logistic regression analysis showed that IL-10 G13 and G10 alleles are independent risk factors for venous thrombosis (Odds ratio:OR = 3.33, p = 0.003 and OR = 2.83, p = 0.03, respectively). Furthermore, IL-10 G10 allele is more frequent in recurrent disease.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1160/TH06-01-0027DOI Listing
July 2006

The association between hereditary thrombophilias and pregnancy loss.

Haematologica 2005 Sep;90(9):1223-30

Laboratory of Hematology, University Hospital Nîmes, France.

The correlation between hereditary thrombophilia and fetal loss is supported by several observations. In murine models, the protein C system has been shown to be essential for the maintenance of pregnancy, as it indirectly acts as a growth factor for trophoblast cells and protects them from apoptosis. In humans, it has been shown that the placenta replaces the yolk sac as an essential source of blood supply to the embryo during the 8th and 9th weeks of gestation. Furthermore, meta-analysis of epidemiological data demonstrates a correlation between thrombophilic polymorphisms such as factor V Leiden and prothrombin 20210G-->A and isolated or recurrent fetal losses. Finally, therapeutic non-controlled trials indicate the benefits and safety of low-molecular weight heparins as secondary prophylaxis. However, it is still necessary to further clarify the association between thrombophilia and fetal loss, especially during a first pregnancy, with regard to the type of pregnancy loss and with respect to other related factors.
View Article and Find Full Text PDF

Download full-text PDF

Source
September 2005

Low-molecular-weight heparin versus low-dose aspirin in women with one fetal loss and a constitutional thrombophilic disorder.

Blood 2004 May 22;103(10):3695-9. Epub 2004 Jan 22.

Hematology Laboratory, University Hospital, Nîmes, France.

The prospective evaluation of the effect of thromboprophylaxis in women with one unexplained pregnancy loss from the 10th week of amenorrhea was performed. A total of 160 patients with heterozygous factor V Leiden mutation, prothrombin G20210A mutation, or protein S deficiency were given 5 mg folic acid daily before conception, to be continued during pregnancy, and low-dose aspirin 100 mg daily or low-molecular-weight heparin enoxaparin 40 mg was taken from the 8th week. Twenty-three of the 80 patients treated with low-dose aspirin and 69 of the 80 patients treated with enoxaparin had a healthy live birth (odds ratio [OR], 15.5; 95% confidence interval [CI], 7-34, P <.0001). Enoxaparin was superior to low-dose aspirin in each subgroup defined according to the underlying constitutional thrombophilic disorder. An associated protein Z deficiency and/or positive antiprotein Z antibodies were associated with poorer outcomes. The neonate weight was higher in the women successfully treated with enoxaparin, and neonates small for gestational age were more frequent in patients treated with low-dose aspirin. No significant side effects of the treatments could be evidenced in patients or newborns. As there is no argument to prove that low-dose aspirin may have been deleterious, these results support enoxaparin use during such at-risk pregnancies.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1182/blood-2003-12-4250DOI Listing
May 2004