Publications by authors named "Jean-Christophe Gris"

100 Publications

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

NETosis Markers in Pregnancy: Effects Differ According to Histone Subtypes.

Thromb Haemost 2021 Jan 10. Epub 2021 Jan 10.

Department of Haematology, University Hospital, Nîmes, France.

NETosis is an innate immune response occurring after infection or inflammation: activated neutrophils expel decondensed DNA in complex with histones into the extracellular environment in a controlled manner. It activates coagulation and fuels the risk of thrombosis. Human pregnancy is associated with a mild proinflammatory state characterized by circulatory neutrophil activation which is further increased in complicated pregnancies, placenta-mediated complications being associated with an increased thrombotic risk. This aberrant activation leads to an increased release of nucleosomes in the blood flow. The aim of our study was to initially quantify nucleosome-bound histones in normal pregnancy and in placenta-mediated complication counterpart. We analyzed the role of histones on extravillous trophoblast function. Circulating nucleosome-bound histones H3 (Nu.QH3.1, Nu.QH3PanCit, Nu.QH3K27me3) and H4 (Nu.QH4K16Ac) were increased in complicated pregnancies. In vitro using the extravillous cell line HTR-8/SVNeo, we observed that free recombinant H2B, H3, and H4 inhibited migration in wound healing assay, but only H3 also blocked invasion in Matrigel-coated Transwell experiments. H3 and H4 also induced apoptosis, whereas H2B did not. Finally, the negative effects of H3 on invasion and apoptosis could be restored with enoxaparin, a low-molecular-weight heparin (LMWH), but not with aspirin. Different circulating nucleosome-bound histones are increased in complicated pregnancy and this would affect migration, invasion, and induce apoptosis of extravillous trophoblasts. Histones might be part of the link between the risk of thrombosis and pregnancy complications, with an effect of LMWH on both.
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http://dx.doi.org/10.1055/s-0040-1722225DOI Listing
January 2021

Editorial: Primary Antiphospholipid Syndrome.

Front Immunol 2020 28;11:1993. Epub 2020 Aug 28.

Department of Haematology, Centre Hospitalier Universitaire de Nîmes et Université de Montpellier, Nimes, France.

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http://dx.doi.org/10.3389/fimmu.2020.01993DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7484724PMC
April 2021

Placenta-mediated complications: Nucleosomes and free DNA concentrations differ depending on subtypes.

J Thromb Haemost 2020 12 18;18(12):3371-3380. Epub 2020 Oct 18.

Department of Haematology, CHU Nimes, Univ Montpellier, Nîmes, France.

Background: Placenta-mediated pregnancy complications generate short- and long-term adverse medical outcomes for both the mother and the fetus. Nucleosomes and free DNA (fDNA) have been described in patients suffering from a wide range of inflammatory conditions.

Objective: The objective of our study was to compare nucleosomes and fDNA circulating levels during pregnancy and particularly in women developing a placenta-mediated complication according to the subtype (preeclampsia or intrauterine growth restriction) (NCT01736826).

Patients/methods: A total of 115 women were prospectively included in the study across three groups: 30 healthy non-pregnant women, 50 with normal pregnancy, and 35 with a complicated pregnancy. Blood samples were taken up to every 4 weeks for several women with normal pregnancy and nucleosomes and fDNA were quantified using enzyme-linked immunosorbent assay and quantitative polymerase chain reaction, respectively.

Results: We show that nucleosomes and fDNA concentrations significantly increase during normal pregnancy, with concentrations at delivery differing between the two groups. Interestingly, we show that concentrations differ according to the type of placenta-mediated complications, with higher levels in preeclampsia compared to intrauterine growth restriction.

Conclusions: These data suggest that nucleosomes and fDNA may be additional actors participating in placenta-mediated pregnancy complications.
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http://dx.doi.org/10.1111/jth.15105DOI Listing
December 2020

Is There an Additional Value in Detecting Anticardiolipin and Anti-β2 glycoprotein I IgA Antibodies in the Antiphospholipid Syndrome?

Thromb Haemost 2020 Nov 21;120(11):1557-1568. Epub 2020 Jul 21.

Coagulation Laboratory, Department of Diagnostic Sciences, Ghent University Hospital, Gent, Belgium.

Background:  Anticardiolipin (aCL) and anti-β2 glycoprotein I (aβ2GPI) immunoglobulin A (IgA) antiphospholipid antibodies (aPL) have shown to associate with thrombosis and pregnancy morbidity. However, inclusion of IgA aPL in the classification criteria of the antiphospholipid syndrome (APS) has been debated. We investigated the value of aCL and aβ2GPI IgA aPL in the detection of thrombosis and pregnancy morbidity in addition to the current aPL panel for APS.

Methods:  We included 1,068 patients from eight European medical centers: 259 thrombotic APS patients, 122 obstetric APS patients, 204 non-APS thrombosis patients, 33 non-APS obstetric patients, 60 APS patients with unspecified clinical manifestations, 196 patients with autoimmune diseases, and 194 controls. aCL and aβ2GPI IgG/M/A were detected with four commercial assays and lupus anticoagulant was determined by the local center.

Results:  Positivity for IgA aPL was found in 17 to 26% of the patients with clinical manifestations of APS and in 6 to 13% of the control population. Both aCL and aβ2GPI IgA were significantly associated with thrombosis and pregnancy morbidity. Isolated IgA positivity was rare in patients with clinical manifestations of APS (0.3-5%) and not associated with thrombosis and/or pregnancy morbidity. Addition of IgA to the current criterion panel did not increase odds ratios for thrombosis nor pregnancy morbidity.

Conclusion:  aCL and aβ2GPI IgA are associated with clinical manifestations of APS. However, isolated IgA positivity was rare and not associated with thrombosis or pregnancy morbidity. These data do not support testing for aCL and aβ2GPI IgA subsequent to conventional aPL assays in identifying patients with thrombosis or pregnancy morbidity.
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http://dx.doi.org/10.1055/s-0040-1714653DOI Listing
November 2020

COVID-19 associated coagulopathy: The crowning glory of thrombo-inflammation concept.

Anaesth Crit Care Pain Med 2020 06 4;39(3):381-382. Epub 2020 May 4.

Department of infectious and tropical diseases, university Montpellier, CHU Nîmes, Nîmes, France.

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http://dx.doi.org/10.1016/j.accpm.2020.04.013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7196534PMC
June 2020

Atypical transient perivascular inflammation of the carotid artery (TIPIC) in a previously diagnosed VWD type 2 M.

Haemophilia 2020 Jul 29;26(4):e221-e222. Epub 2020 Apr 29.

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

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http://dx.doi.org/10.1111/hae.14021DOI Listing
July 2020

Uncertainties on the prognostic value of D-dimers in COVID-19 patients.

J Thromb Haemost 2020 08 28;18(8):2066-2067. Epub 2020 May 28.

Department of Infectious and Tropical Diseases, Nîmes University Hospital, Nîmes, France.

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http://dx.doi.org/10.1111/jth.14876DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7267237PMC
August 2020

The risk of cesarean delivery after labor induction among women with prior pregnancy complications: a subgroup analysis of the AFFIRM study.

BMC Pregnancy Childbirth 2019 Nov 29;19(1):455. Epub 2019 Nov 29.

Clinical Epidemiology Program, Ottawa Hospital Research Institute, Ottawa, ON, Canada.

Background: To determine the risk of cesarean delivery after labor induction among patients with prior placenta-mediated pregnancy complications (pre-eclampsia, late pregnancy loss, placental abruption or intrauterine growth restriction).

Methods: The AFFIRM database includes patient level data from 9 randomized controlled trials that evaluated the role of LMWH versus no LMWH during pregnancy to prevent recurrent placenta-mediated pregnancy complications. The primary outcome of this sub-study was the proportion of women who had an unplanned cesarean delivery after induction of labor compared to after spontaneous labor.

Results: There were 512 patients from 7 randomized trials included in our sub-study. There was no difference in the risk of cesarean delivery between women with labor induction (21/148, 14.2%) and spontaneous labor (79/364, 21.7%) (odds ratio (OR) 0.60, 95% CI, 0.35-1.01; p = 0.052). Among 274 women who used LMWH prophylaxis during pregnancy, the risk of cesarean delivery was lower among those that underwent labor induction (9.8%) compared to spontaneous labor (22.4%) (OR 0.38, 95% CI, 0.17-0.84; p = 0.01).

Conclusions: The risk of cesarean delivery is not increased after labor induction among a higher risk patient population with prior pregnancy complications. Our results suggest that women who receive LMWH during pregnancy might benefit from labor induction.
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http://dx.doi.org/10.1186/s12884-019-2615-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6884748PMC
November 2019

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

Detection of anti-domain I antibodies by chemiluminescence enables the identification of high-risk antiphospholipid syndrome patients: A multicenter multiplatform study.

J Thromb Haemost 2020 02;18(2):463-478

Coagulation Laboratory, Department of Laboratory Medicine, Ghent University Hospital, Department of Diagnostic Sciences, Ghent University, Ghent, Belgium.

Background: Classification of the antiphospholipid syndrome (APS) relies predominantly on detecting antiphospholipid antibodies (aPLs). Antibodies against a domain I (DI) epitope of anti-β2glycoprotein I (β2GPI) proved to be pathogenic, but are not included in the current classification criteria.

Objectives: Investigate the clinical value of detecting anti-DI IgG in APS.

Patients/methods: From eight European centers 1005 patients were enrolled. Anti-cardiolipin (CL) and anti-β2GPI were detected by four commercially available solid phase assays; anti-DI IgG by the QUANTA Flash β2GPI domain I assay.

Results: Odds ratios (ORs) of anti-DI IgG for thrombosis and pregnancy morbidity proved to be higher than those of the conventional assays. Upon restriction to patients positive for anti-β2GPI IgG, anti-DI IgG positivity still resulted in significant ORs. When anti-DI IgG was added to the criteria aPLs or used as a substitute for anti-β2GPI IgG/anti-CL IgG, ORs for clinical symptoms hardly improved. Upon removing anti-DI positive patients, lupus anticoagulant remained significantly correlated with clinical complications. Anti-DI IgG are mainly present in high-risk triple positive patients, showing higher levels. Combined anti-DI and triple positivity confers a higher risk for clinical symptoms compared to only triple positivity.

Conclusions: Detection of anti-DI IgG resulted in higher ORs for clinical manifestations than the current APS classification criteria. Regardless of the platform used to detect anti-β2GPI/anti-CL, addition of anti-DI IgG measured by QUANTA Flash did not improve the clinical associations, possibly due to reduced exposure of the pathogenic epitope of DI. Our results demonstrate that anti-DI IgG potentially helps in identifying high-risk patients.
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http://dx.doi.org/10.1111/jth.14682DOI Listing
February 2020

The (non-)sense of detecting anti-cardiolipin and anti-β2glycoprotein I IgM antibodies in the antiphospholipid syndrome.

J Thromb Haemost 2020 01 27;18(1):169-179. Epub 2019 Sep 27.

Department of Diagnostic Sciences, Coagulation Laboratory, Ghent University Hospital, Ghent, Belgium.

Background: The antiphospholipid syndrome (APS) is characterized by thrombosis and/or pregnancy morbidity with the persistent presence of lupus anticoagulant (LAC), anti-cardiolipin (aCL) and/or anti-β2glycoprotein I (aβ2GPI) antibodies of the immunoglobulin G/immunoglobulin M (IgG/IgM) isotype. However, the role of aCL and aβ2GPI IgM as a serologic marker in APS is debated.

Objectives: We aimed to assess the diagnostic and clinical value of IgM antiphospholipid antibodies (aPL) in APS within the classification criteria.

Patients/methods: Our multicenter study comprised 1008 patients, including APS patients and controls. Anti-CL and aβ2GPI IgG and IgM antibodies were detected with four commercially available solid phase assays.

Results: Positivity for aCL and/or aβ2GPI antibodies was significantly correlated with thrombosis and pregnancy morbidity, independent of the isotype and solid phase assay. Higher odds ratios were obtained for IgG compared to IgM positivity. Isolated IgM was rare in thrombotic APS, but more frequent in obstetric APS, ranging from 3.5% to 5.4% and 5.7% to 12.3%, respectively, dependent on the solid phase assay. In a multivariate logistic regression analysis of aPL, IgM positivity was found to be associated with pregnancy morbidity. However, detection of IgM was not independently associated with thrombosis. Combined positivity for LAC, IgG, and IgM was highly associated with thrombosis and pregnancy morbidity.

Conclusions: Our data support testing for aCL and aβ2GPI IgM in women suspected of obstetric APS. However, no added value was found for testing IgM in patients suspected of thrombotic APS. Still, IgM aPL might be useful as a second-line test to improve thrombotic risk stratification.
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http://dx.doi.org/10.1111/jth.14633DOI Listing
January 2020

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

Dendrigraft of Poly-l-lysine as a Promising Candidate To Reverse Heparin-based Anticoagulants in Clinical Settings.

ACS Med Chem Lett 2019 Jun 8;10(6):917-922. Epub 2019 May 8.

Univ. Lyon, Univ. Claude Bernard Lyon 1, ICBMS UMR CNRS 5246, 43 Boulevard du 11 Novembre 1918, 69622 Villeurbanne Cedex, France.

By using a combination of experimental and computational experiments, we demonstrated that a second-generation dendrigraft of poly-l-lysine neutralizes the anticoagulant activity of unfractionated heparin, low-molecular-weight heparin, and fondaparinux more efficiently than protamine does in human plasma, making this synthetic polymer a promising surrogate of this problematic protein in clinical settings.
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http://dx.doi.org/10.1021/acsmedchemlett.9b00090DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6580796PMC
June 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.
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http://dx.doi.org/10.3324/haematol.2018.213991DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7012495PMC
April 2021

Detection of Anti-Cardiolipin and Anti-β2glycoprotein I Antibodies Differs between Platforms without Influence on Association with Clinical Symptoms.

Thromb Haemost 2019 May 1;119(5):797-806. Epub 2019 Mar 1.

Coagulation Laboratory, Department of Diagnostic Sciences, Ghent University Hospital, Ghent University, Ghent, Belgium.

Background:  The anti-phospholipid syndrome (APS) is characterized by thrombosis and/or pregnancy morbidity with persistent presence of anti-phospholipid antibodies (aPL). Laboratory criteria include aPL detection by coagulation tests for lupus anticoagulant (LAC) or solid phase assays measuring anti-β2 glycoprotein I (aβ2GPI) or anti-cardiolipin (aCL) immunoglobulin (Ig) G/IgM antibodies. External quality control programs illustrate that commercially available aPL assays produce variable results.

Objective:  We aimed to investigate the agreement and diagnostic accuracy of solid phase assays.

Materials And Methods:  In this multi-centre study, 1,168 patient samples were tested on one site for aCL and aβ2GPI IgG/IgM antibodies by four solid phase test systems. Samples included APS patients, controls and monoclonal antibodies (MoAB) against different epitopes of β2GPI. LAC was determined by the local centre.

Results:  aCL IgM assays resulted in the most discrepancies (60%), while aCL IgG and aβ2GPI IgM assays resulted in lower discrepancies (36%), suggesting better agreement. Discrepant samples displayed lower median aPL titers. Dependent on the solid phase test system, odds ratios (ORs) for thrombosis and pregnancy morbidity ranged from 1.98 to 2.56 and 3.42 to 4.78, respectively. Three platforms showed lower sensitivity for MoAB directed against the glycine (Gly) 40-arginine (Arg) 43 epitope of domain I of β2GPI.

Conclusion:  Poor agreement was observed between different commercially available aCL and aβ2GPI IgG/IgM assays, hampering uniformity in the identification of aPL-positive patients. Clinical association was globally concordant between solid phase test systems considering results of the four aPL together. An assay sensitive in detecting the MoAB against Gly40-Arg43 of domain I of β2GPI reached the highest OR for thrombosis.
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http://dx.doi.org/10.1055/s-0039-1679901DOI Listing
May 2019

Disappearance of a strong triple positivity for antiphospholipid antibodies after treatment with anakinra.

Haematologica 2019 02 25;104(2):e83-e84. Epub 2018 Oct 25.

Consultations et laboratoire d'hématologie, CHU de Nîmes, France

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http://dx.doi.org/10.3324/haematol.2018.205484DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6355488PMC
February 2019

Successful Pregnancy under Fibrinogen Substitution with Heparin and Aspirin in a Woman with Dysfibrinogenemia Revealed by Placental Abruption.

Thromb Haemost 2018 Nov 8;118(11):2006-2008. Epub 2018 Oct 8.

Department of Haematology, Nîmes University Hospital, University of Montpellier, Nîmes, France.

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http://dx.doi.org/10.1055/s-0038-1673615DOI Listing
November 2018

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

Analysis of C3 Gene Variants in Patients With Idiopathic Recurrent Spontaneous Pregnancy Loss.

Front Immunol 2018 7;9:1813. Epub 2018 Aug 7.

Department of Translational Medicine, Lund University, Malmö, Sweden.

Miscarriage is the most common complication of pregnancy. Approximately 1% of couples trying to conceive will experience recurrent miscarriages, defined as three or more consecutive pregnancy losses and many of these cases remain idiopathic. Complement is implicated both in the physiology and pathology of pregnancy. Therefore, we hypothesized that alterations in the C3 gene could potentially predispose to this disorder. We performed full Sanger sequencing of all exons of C3, in 192 childless women, with at least two miscarriages and without any known risk factors. All exons carrying non-synonymous alterations found in the patients were then sequenced in a control group of 192 women. None of the identified alterations were significantly associated with the disorder. Thirteen identified non-synonymous alterations (R102G, K155Q, L302P, P314L, Y325H, V326A, S327P, V330I, K633R, R735W, R1591G, G1606D, and S1619R) were expressed recombinantly, upon which C3 expression and secretion were determined. The L302P and S327P were not secreted from the cells, likely due to misfolding and intracellular degradation. Y325H, V326A, V3301I, R1591G, and G1606D yielded approximately half C3 concentration in the cell media compared with wild type (WT). We analyzed the hemolytic activity of the secreted C3 variants by reconstituting C3-depleted serum. In this assay, R1591G had impaired hemolytic activity while majority of remaining mutants instead had increased activity. R1591G also yielded more factor B activation in solution compared with WT. R1591G and G1606D showed impaired degradation by factor I, irrespectively if factor H, CD46, or C4b-binding protein were used as cofactors. These two C3 mutants showed impaired binding of the cofactors and/or factor I. Taken together, several alterations in C3 were identified and some of these affected the secretion and/or the function of the protein, which might contribute to the disorder but the degree of association must be evaluated in larger cohorts.
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http://dx.doi.org/10.3389/fimmu.2018.01813DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6090058PMC
September 2019

Benefit of Risk Score-Guided Prophylaxis in Pregnant Women at Risk of Thrombotic Events: A Controlled Before-and-After Implementation Study.

Thromb Haemost 2018 Sep 13;118(9):1564-1571. Epub 2018 Aug 13.

INSERM U1059, Saint-Etienne, France.

Background:  Management of pregnant women at risk of venous thromboembolism (VTE) and placental vascular complications (PVCs) remains complex. Guidelines do not definitively specify optimal strategies.

Objective:  Our objective was to evaluate the impact of employing risk score-driven prophylaxis strategies on VTE and PVC rates in at-risk pregnant women.

Materials And Methods:  This study, conducted in 21 French maternity units, compared VTE and PVC rates before and after implementation of a risk scoring system to determine prophylactic strategies.

Results:  A total of 2,085 pregnant women at risk of VTE or PVC were enrolled. Vascular events occurred in 190 (19.2%) patients before and 140 (13.0%) after implementation of risk score-driven prophylaxis (relative risk [RR] = 0.68 [0.55; 0.83]). The incidence of deep vein thrombosis during pregnancy was reduced (RR = 0.30 [0.14; 0.67]). PVC comprised mainly pre-eclampsia, occurring in 79 patients before and 42 patients after risk score implementation (RR = 0.52 [0.36; 0.75]). Post-partum haemorrhage occurred in 32 patients (3.2%) before and 48 patients (4.5%) after risk score implementation (RR = 1.38 [0.89; 2.13],  = 0.15).

Conclusion:  Use of a simple risk scoring system, developed by experts in VTE and PVC research to guide prophylaxis, reduced the risk of thrombotic events during pregnancy without any significant increase in bleeding risk.
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http://dx.doi.org/10.1055/s-0038-1668524DOI Listing
September 2018

Updated French practical guidelines on the management of dabigatran-treated patients.

Anaesth Crit Care Pain Med 2018 08;37(4):311-312

Department of Haematology, University Hospital, Nîmes, France; UPRES EA 2992, Faculty of Pharmaceutical, Biological Sciences, Montpellier University, Montpellier, France.

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http://dx.doi.org/10.1016/j.accpm.2018.07.004DOI Listing
August 2018

Complete remission of agranulocytosis after splenectomy in a variant form of T-cell large granular lymphocyte leukemia.

Leuk Lymphoma 2019 01 2;60(1):254-257. Epub 2018 Jul 2.

b Department of Hematology , Nimes University Hospital , Nimes , France.

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http://dx.doi.org/10.1080/10428194.2018.1471601DOI Listing
January 2019

Risk Assessment and Management of Venous Thromboembolism in Women during Pregnancy and Puerperium (SAVE): An International, Cross-sectional Study.

TH Open 2018 Apr 4;2(2):e116-e130. Epub 2018 Apr 4.

Republican Specialized Scientific Practical Medical Center of Obstetrics and Gynecology, Tashkent, Uzbekistan.

The clinical burden of obstetric venous thromboembolism (VTE) risk is inadequately established. This study assessed the prevalence and management of VTE risk during pregnancy and postpartum outside the Western world. This international, noninterventional study enrolled adult women with objectively confirmed pregnancy attending prenatal care/obstetric centers across 18 countries in Africa, Eurasia, Middle-East, and South Asia. Evaluations included proportions of at-risk women, prophylaxis as per international guidelines, prophylaxis type, factors determining prophylaxis, and physicians' awareness about VTE risk management guidelines and its impact on treatment decision. Data were analyzed globally and regionally. Physicians (  = 181) screened 4,978 women, and 4,010 were eligible. Of these, 51.4% were at risk (Eurasia, 90%; South Asia, 19.9%), mostly mild in intensity; >90% received prophylaxis as per the guidelines (except South Asia, 77%). Women in Eurasia and South Asia received both pharmacological and mechanical prophylaxes (>55%), while pharmacological prophylaxis (>50%) predominated in Africa and the Middle-East. Low-molecular-weight heparin was the pharmacological agent of choice. Prophylaxis decision was influenced by ethnicity, assisted reproductive techniques, caesarean section, and persistent moderate/high titer of anticardiolipin antibodies, though variable across regions. Prophylaxis decision in at-risk women was similar, irrespective of physicians' awareness of guidelines (except South Asia). A majority (>80%) of the physicians claimed to follow the guidelines. More than 50% of women during pregnancy and postpartum were at risk of VTE, and >90% received prophylaxis as per the guidelines. Physicians are generally aware of VTE risk and comply with guidelines while prescribing prophylaxis, although regional variations necessitate efforts to improve implementation of the guidelines.
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http://dx.doi.org/10.1055/s-0038-1635573DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6524867PMC
April 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.
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http://dx.doi.org/10.1097/AOG.0000000000002380DOI Listing
January 2018

THBD sequence variants potentially related to recurrent pregnancy loss.

Reprod Biol Endocrinol 2017 Dec 1;15(1):92. Epub 2017 Dec 1.

Center For Research in Genetics and Genomics-CIGGUR, GENIUROS Research Group, School of Medicine and Health Sciences, Universidad del Rosario, Carrera 24 N° 63C, -69, Bogotá, Colombia.

Recurrent pregnancy loss (RPL) is a frequently occurring disease, which is classified as idiopathic in more than 50% of cases. THBD, the endothelial cell receptor for thrombin, has been associated with distinct biological processes and considered a coherent RPL-related candidate gene. In the present study, we have sequenced the complete coding region of THBD in 262 patients affected by RPL. Bioinformatics analysis and screening of controls strongly suggested that the THBD-p.Trp153Gly mutation might be related to RPL aetiology. It could be used, after its validation by functional assays, as a molecular marker for diagnostic/prognostic purposes.
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http://dx.doi.org/10.1186/s12958-017-0311-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5709961PMC
December 2017

Novel genes and mutations in patients affected by recurrent pregnancy loss.

PLoS One 2017 10;12(10):e0186149. Epub 2017 Oct 10.

Center For Research in Genetics and Genomics-CIGGUR. GENIUROS Research Group. School of Medicine and Health Sciences, Universidad del Rosario. Bogotá, Colombia.

Recurrent pregnancy loss is a frequently occurring human infertility-related disease affecting ~1% of women. It has been estimated that the cause remains unexplained in >50% cases which strongly suggests that genetic factors may contribute towards the phenotype. Concerning its molecular aetiology numerous studies have had limited success in identifying the disease's genetic causes. This might have been due to the fact that hundreds of genes are involved in each physiological step necessary for guaranteeing reproductive success in mammals. In such scenario, next generation sequencing provides a potentially interesting tool for research into recurrent pregnancy loss causative mutations. The present study involved whole-exome sequencing and an innovative bioinformatics analysis, for the first time, in 49 unrelated women affected by recurrent pregnancy loss. We identified 27 coding variants (22 genes) potentially related to the phenotype (41% of patients). The affected genes, which were enriched by potentially deleterious sequence variants, belonged to distinct molecular cascades playing key roles in implantation/pregnancy biology. Using a quantum chemical approach method we established that mutations in MMP-10 and FGA proteins led to substantial energetic modifications suggesting an impact on their functions and/or stability. The next generation sequencing and bioinformatics approaches presented here represent an efficient way to find mutations, having potentially moderate/strong functional effects, associated with recurrent pregnancy loss aetiology. We consider that some of these variants (and genes) represent probable future biomarkers for recurrent pregnancy loss.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0186149PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5634651PMC
October 2017

Angiogenic factors for prediction of preeclampsia and intrauterine growth restriction onset in high-risk women: AngioPred study.

J Matern Fetal Neonatal Med 2019 Jan 22;32(2):248-257. Epub 2017 Sep 22.

a Department of Gynaecology and Obstetrics , University Hospital , Saint Étienne , France.

Objective: The study aimed to compare the level of two angiogenic factors, soluble fms-like tyrosine kinase-1 (sFlt1) and soluble endoglin (sEng), for the prediction of preeclampsia and intrauterine growth restriction in high-risk pregnant women.

Methods: A prospective multicenter cohort study of 200 pregnant patients was conducted between June 2008 and October 2010. sFlt1 and sEng were measured by enzyme-linked immunosorbent assay.

Results: Forty-five patients developed a placenta-mediated adverse pregnancy outcome. Plasma levels of sFlt1 and sEng were higher in patients who will experience a preeclampsia at 28, 32, and 36 weeks compared with patients with no complication. The same results were observed for intrauterine growth restriction. Plasma levels of sFlt1 and sEng were not significantly different for patients with preeclampsia compare to patients with intrauterine growth restriction. Patients with early pre-eclampsia (PE) had very high rates of angiogenic factors at 20, 24, and 28 weeks. Patients with late PE and early and late intrauterine growth retardation (IUGR) had high rates at 32 and 36 weeks.

Conclusion: In high-risk women, angiogenic factors are disturbed before the onset of preeclampsia and this is true for intrauterine growth restriction.
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http://dx.doi.org/10.1080/14767058.2017.1378325DOI Listing
January 2019