Publications by authors named "Brigitte Pan-Petesch"

29 Publications

  • Page 1 of 1

Efficacy and safety of a recombinant Von Willebrand Factor treatment in patients with inherited Von Willebrand Disease requiring surgical procedures.

Haemophilia 2021 Mar 6;27(2):270-276. Epub 2021 Feb 6.

Department of Haemostasis, Versailles Hospital, Versailles, France.

Introduction: Von Willebrand Disease is a common inherited haemorrhagic disorder due to a deficiency of Von Willebrand Factor (VWF). In case of surgical procedures in patients who are not responsive or have contraindications to desmopressin, replacement therapy with VWF concentrates is indicated. Until recently, only plasma-derived VWF concentrates were available. A new recombinant VWF (rVWF) concentrate that contains no Factor VIII (FVIII) but a high amount of high molecular weight VWF multimers has been available in France since 2018.

Aim: Describe real-world experience of using rVWF in surgical procedures.

Methods: Sixty-three surgeries for 55 patients were retrospectively analysed in 7 French haemostasis centres.

Results: During minor surgeries, the median (range) number of infusions was 1 (1-8) with a preoperative loading dose of 35 (19-56) rVWF IU/kg and a total median dose of 37.5 IU (12-288). During major surgeries, the median (range) number of infusions was only 3 (1-14) with a median preoperative loading dose of 36 IU (12-51) rVWF IU/kg, and a total median dose of 108 IU (22-340) rVWF IU/kg. The overall clinical efficacy was qualified as excellent/good in 61 of the procedures (97%), moderate in 1 (1.5%) and poor in 1 (1.5%). There was no accumulation of VWF or FVIII during postoperative monitoring. No thromboembolic events, anti-VWF antibodies or adverse events were reported.

Conclusion: This French 'real-world' experience shows that a few infusions and low doses of rVWF provided effective prevention of bleeding in major and minor surgeries in inherited VWD, with no clinically significant safety concerns.
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http://dx.doi.org/10.1111/hae.14242DOI Listing
March 2021

Factors associated with poor fetal outcome in placental abruption.

Pregnancy Hypertens 2021 Mar 25;23:59-65. Epub 2020 Nov 25.

Service d'Anatomopathologie, CHU de Brest, Hôpital Morvan, 29200 Brest, France; EA 4685 LIEN, Université Bretagne Loire, 29200 Brest, France.

Objectives: We aimed at describing placental abruption in our county and at evaluating factors associated with poor fetal outcome.

Study Design: In this case-control study, women with placental abruption were identified from two databases of Brest University Hospital between January 2013 and December 2018.

Main Outcome Measures: Placental histological findings, course of pregnancies, maternal and fetal characteristics were described and compared between cases (placental abruption with stillbirth or neonatal death) and controls.

Results: We identified 135 placental abruption, of whom 24.4% were complicated with stillbirth and 6.5% with neonatal death. Forty percent of women were smokers and 14.1% had a history of vasculoplacental disorder. Pregnancies were complicated with 42.2% of pre-eclampsia and 43% of intrauterine growth restriction. Cases were associated with more autoimmune diseases in mother (20.0% versus 3.2%, P = 0.003), more aspirin or heparin use during pregnancy (20.0% versus 6.3%, P = 0.03), less pre-eclampsia (25.0% versus 49.5%, P = 0.01) and more deliveries ≤ 34 weeks of gestation (80.0% versus 43.2%, P = 0.0001) than controls. Placentas from cases showed more placental indentation ≥ 30% (42.5% versus 5.3%, P < 0.0001) and less histological chronic inflammation, especially less chronic chorioamniotitis (2.5% versus 24.2%, P = 0.002) than controls. In multivariate analysis, factors negatively associated with poor fetal outcome were placental histological chronic inflammation (P = 0.01) and macroscopic infarcts (P = 0.01).

Conclusions: Poor fetal outcome is negatively associated with certain placental histological chronic lesions, but not with pre-eclampsia, what suggests various pathophysiological processes among placental abruption.
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http://dx.doi.org/10.1016/j.preghy.2020.11.004DOI Listing
March 2021

Effectiveness and safety of hFVIII/VWF concentrate (Voncento) in patients with inherited von Willebrand disease requiring surgical procedures: the OPALE multicentre observational study.

Blood Transfus 2021 Mar 27;19(2):152-157. Epub 2020 Nov 27.

Centre de Traitement de l'Hémophilie, CHU Hôtel-Dieu Nantes, Nantes, France.

Background: In patients with moderate to severe qualitative and quantitative von Willebrand disease (VWD), even minor surgical procedures can be associated with a risk of life-threatening bleeding. Treatment strategies vary according to the levels of von Willebrand factor (VWF) and Factor VIII (FVIII). The aim of this study was to evaluate the effectiveness and the safety of Voncento (CSL Behring, Marburg, Germany), a plasma-derived FVIII/VWF concentrate (ratio 1:2.4), during surgeries performed in patients with inherited VWD.

Materials And Methods: The OPALE study, a French multicentre observational study, was carried out from May 2016 to May 2019. It evaluated and analysed patients with inherited VWD (any type) requiring treatment with Voncento who underwent surgery.

Results: In total, 92 patients were enrolled, and 66 patients underwent 100 surgical procedures: 69 minor and 31 major surgeries conducted in 30 patients with type 1, 50 patients with type 2, and 20 patients with type 3 VWD. During minor surgeries, the median number of infusions was one (range: 1-9), the pre-operative loading dose was 41 IU VWF:RCo kg (range: 18-147), and the total dose was 63 (range: 18-594). During major surgeries, the number of infusions was 4 (range: 1-23), the pre-operative loading dose was 43 (range: 25-66) IU VWF: RCo kg, and the total dose was 155 (range: 40-575). The median FVIII:C levels ranged from 78 to 165 IU dL during 5 days after minor surgeries and from 86 and 167 IU dL during 11 days after major surgeries. VW:RCo levels ranged between 35 and 65 IU dL and between 34 and 76 IU dL after minor and major surgeries, respectively. The overall clinical effectiveness was qualified as "excellent" or "good" in 99% of patients. No thrombotic events related to Voncento were recorded.

Discussion: The present study suggests that Voncento is an effective and well-tolerated therapy for the peri-operative management of patients with all VWD types.
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http://dx.doi.org/10.2450/2020.0246-20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7925218PMC
March 2021

Long-term recurrence risk after a first venous thromboembolism in men and women under 50 years old: A French prospective cohort.

Eur J Intern Med 2021 Feb 16;84:24-31. Epub 2020 Nov 16.

Département de médecine vasculaire, médecine interne et pneumologie, CHU Brest, Univ Brest, Brest, France; EA3878, GETBO, Univ Brest, Brest, France; CIC INSERM1412, CHU Brest, Univ Brest, Brest, France.

Background: Data on long-term venous thromboembolism (VTE) recurrence risk according to gender are conflicting.

Objective: To evaluate long-term VTE recurrence risk after a first VTE in men and women under 50 years old.

Methods: Since May 2000, 875 consecutive patients (315 men, 560 women) with a first symptomatic VTE under 50 years old were enrolled in a French prospective multicentre cohort study and were followed up as long as possible. The primary outcome was symptomatic recurrent VTE during follow-up.

Results: At baseline, men were older and had more comorbidities than women. First VTE was mainly unprovoked in men (80.6%) and hormone-related in women (84.3%). During a median follow-up of 7.0 years (inter-quartile range, 5.0-11.0), recurrent VTE occurred in 97 men (30.8%) and in 72 women (12.9%) (annual incidence rates of recurrent VTE of 4.8% versus 1.8%-person-years, P<0.001). However, there was no difference according to gender in subgroups of patients with a first unprovoked VTE (5.8% versus 3.8%-person-years, P = 0.09). In women, duration of hormonal treatment before first VTE did not influence recurrence risk. In multivariable analysis, unprovoked VTE and family history of VTE were independently associated with recurrence (hazard ratio of 2.50 (95% confidence interval, 1.61 to 3.85) and 1.52 (1.11 to 2.09) respectively).

Limitations: Number of women with unprovoked VTE was low.

Conclusions: In patients with a first VTE under 50 years old, a first unprovoked episode and a family history of VTE, but not gender, were associated with a high risk of long-term recurrence.
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http://dx.doi.org/10.1016/j.ejim.2020.10.014DOI Listing
February 2021

Hemorrhage in Essential Thrombocythemia or Polycythemia Vera: Epidemiology, Location, Risk Factors, and Lessons Learned from the Literature.

Thromb Haemost 2021 May 13;121(5):553-564. Epub 2020 Nov 13.

Service d'Hématologie Clinique, Institut de Cancéro-Hématologie, CHRU de Brest, Bretagne, France.

Hemorrhage is a well-known complication of essential thrombocythemia (ET) and polycythemia vera (PV), but evidence-based data on its management and prevention are lacking to help inform clinicians. In this review, appropriate published data from the past 15 years regarding bleeding epidemiology, classification, location, and risk factors are presented and discussed. Research was conducted using the Medline database. The bleeding classifications were heterogeneous among the collected studies. The median incidences of bleeding and major bleeding were 4.6 and 0.79% patients/year, in ET patients and 6.5 and 1.05% patients/year in PV patients, respectively. The most frequent location was the gastrointestinal tract. Bleeding accounted for up to 13.7% of deaths, and cerebral bleeding was the main cause of lethal hemorrhage. Thirty-nine potential risk factors were analyzed at least once, but the results were discrepant. Among them, age >60 years, bleeding history, splenomegaly, myeloproliferative neoplasm subtype, and platelet count should deserve more attention in future studies. Among the treatments, aspirin seemed to be problematic for young patients with ET (especially -mutated ET patients) and anagrelide was also identified as a bleeding inducer, especially when associated with aspirin. Future studies should analyze bleeding risk factors in more homogeneous populations and with common bleeding classifications. More tools are needed to help clinicians manage the increased risk of potentially lethal bleeding events in these diseases.
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http://dx.doi.org/10.1055/s-0040-1720979DOI Listing
May 2021

Gastrointestinal bleeding from angiodysplasia in von Willebrand disease: Improved diagnosis and outcome prediction using videocapsule on top of conventional endoscopy.

J Thromb Haemost 2021 02 29;19(2):380-386. Epub 2020 Nov 29.

Department of Hematology and Transfusion, CHU Lille, Institut d'Hématologie Transfusion, Lille, France.

Background: Despite a high prevalence of angiodysplasia, no specific guidelines are available for the modalities of endoscopic exploration of gastrointestinal (GI) bleeding in von Willebrand disease (VWD). Whether VWD patients could benefit from video capsule endoscopy (VCE) looking for angiodysplasia eligible to endoscopic treatment or at high risk of bleeding is unknown.

Objectives: To assess the diagnostic efficacy for angiodysplasia and the prognostic value of VCE on top of conventional endoscopy in VWD patients with GI bleeding.

Patients/methods: A survey was sent to the 30 centers of the French-network on inherited bleeding disorders to identify VWD patients referred for endoscopic exploration of GI bleeding from January 2015 to December 2017. Data obtained included patient characteristics, VWD phenotype/genotype, GI bleeding pattern, results of endoscopic investigations, and medical management applied including endoscopic therapy. We assessed by Kaplan-Meier analysis the recurrence-free survival after the first GI bleeding event according to endoscopic categorization and, in patients with angiodysplasia, to the presence of small-bowel localizations on VCE exploration.

Results: GI bleeding source localization was significantly improved when including VCE exploration (P < .01), even in patients without history of angiodysplasia (P < .05). Patients with angiodysplasia had more GI bleeding recurrences (P < .01). A lower recurrence-free survival was observed in patients with angiodysplasia (log-rank test, P = .02), and especially when lesions were located in the small bowel (log-rank test, P < .01), even after endoscopic treatment with argon plasma coagulation (log-rank test, P < .01).

Conclusion: VCE should be more systematically used in VWD patients with unexplained or recurrent GI bleeding looking for angiodysplasia eligible to endoscopic treatment or at high risk of relapse.
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http://dx.doi.org/10.1111/jth.15155DOI Listing
February 2021

Bleeding complications during pregnancy and delivery in haemophilia carriers and their neonates in Western France: An observational study.

Haemophilia 2020 Nov 25;26(6):1046-1055. Epub 2020 Aug 25.

EA3878, Université de Bretagne Occidentale, Brest, France.

Background: Pregnancy, delivery and the postpartum period expose haemophilia carriers, as well as their potentially affected neonates to a high risk of haemorrhagic complications.

Objectives: To describe bleeding complications in haemophilia carriers and their newborns throughout pregnancy and postpartum and to identify potential factors increasing the risk of bleeding in this population.

Patients/methods: The ECHANGE multicentre observational cohort study was conducted between January 2014 and February 2019 using the BERHLINGO database comprised of patients from seven French haemophilia centres.

Results: During the 5 years study period, a total of 104 haemophilia carriers and 119 neonates were included, representing 124 pregnancies and 117 deliveries. Thirty-five (30%) bleeding events were observed, most of them (83%) occurred during the postpartum period, and 37% were reported during the secondary postpartum. Neuraxial anaesthesia was not complicated by spinal haematoma. Three (2.5%) neonates experienced cerebral bleeding. Caesarean section was associated with an increased risk of maternal bleeding in primary and secondary postpartum periods. Basal factor level <0.4 IU/mL was also found to be associated with an increased risk of bleeding during secondary postpartum.

Conclusion: In our cohort, bleeding events occurred in more than a third of haemophilia carriers mainly in the postpartum period, and a significant portion of this bleeding occurred during the secondary postpartum. Haemophilia carriers warrant specific attention during primary and secondary postpartum, in particular in case of caesarean section and low basal factor level. The ECHANGE study is registered at clinicaltrials.gov identifier: NCT03360149.
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http://dx.doi.org/10.1111/hae.14117DOI Listing
November 2020

Outcomes of pregnancy after bariatric surgery: results of a French matched-cohort study.

Surg Obes Relat Dis 2020 Sep 11;16(9):1275-1282. Epub 2020 May 11.

Groupe d'Etude de la Thrombose de Bretagne Occidentale (GETBO), University of Bretagne Occidentale, Brest, France; Department of Metabolic Surgery, La Cavale Blanche University Hospital, Boulevard Tanguy Prigent, Brest, France. Electronic address:

Background: While the benefits of bariatric surgery (BS) on pregnancy outcomes have been demonstrated for women compared with matched controls on presurgery body mass index (pB-BMI), data are lacking and those benefits are uncertain compared with matched controls on prepregnancy BMI (pP-BMI).

Objectives: Our study aimed to evaluate outcomes (obstetrical and neonatal) of single pregnancy in women previously exposed to BS compared with women unexposed to BS matched on pB-BMI and pP-BMI.

Settings: Retrospective matched cohort study from 2 observational studies of pregnant women conducted in a French administrative county (Finistère).

Methods: From April 1, 2015 to January 31, 2019, pregnant women with previous BS (n = 52) were included and compared with 2 different control groups as follows: group A (n = 104), matched for pB-BMI, age, and parity; and group B (n = 104), matched for pP-BMI, age, and parity.

Results: In women exposed to BS, mean age was 27.1 (±4.9) years and pB-BMI was 46.0 (±4.6) kg/m. Operated women differed significantly from group A but not from group B for pP-BMI (29.4 ± 6.1 versus 45.3 ± 4.5 group A versus 28.6 ± 6.6 group B) and gestational diabetes (12.0% versus 44.0% group A versus 17.0% group B), respectively. In the group of women exposed to BS, birth weight (g) was significantly lower (2960 ± 545 versus 3381 ± 735 group A versus 3310 ± 645 group B) and large-for-gestational-age infants less frequent (0% versus 13% group A versus 8% group B).

Conclusion: Bariatric surgery reduced risks of excessive fetal growth and gestational diabetes with a trend for a higher risk of small-for-gestational-age, despite matching on pP-BMI suggesting a risk associated to BS and solely to previous surgery-induced weight loss.
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http://dx.doi.org/10.1016/j.soard.2020.04.047DOI Listing
September 2020

Efficacy and safety of rIX-FP in surgery: An update from a phase 3b extension study.

Thromb Res 2020 09 28;193:139-141. Epub 2020 May 28.

Hôpital Louis Pradel, University Claude Bernard Lyon 1, Lyon, France. Electronic address:

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http://dx.doi.org/10.1016/j.thromres.2020.05.046DOI Listing
September 2020

Acquired von Willebrand syndrome and lymphoproliferative disorders: A case report.

Clin Case Rep 2020 May 9;8(5):900-904. Epub 2020 Mar 9.

Service d'Hématologie Institut de Cancéro-Hématologie EA3878 (GETBO) CHU Brest Univ Brest Brest France.

Acquired von Willebrand syndrome is a rare bleeding disorder often secondary to an underlying lymphoproliferative disorder. We report a case in whom response of both the acquired von Willebrand syndrome and smoldering multiple myeloma persist 14 months after daratumumab treatment discontinuation.
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http://dx.doi.org/10.1002/ccr3.2770DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7250994PMC
May 2020

Gynecological and obstetric outcome in the French cohort of women with factor XIII deficiency.

Thromb Res 2020 07 21;191:22-25. Epub 2020 Apr 21.

Hospices Civils de Lyon, Unité Hémostase Clinique, Hôpital Louis Pradel, Hospices Civils de Lyon, Bron, France.

Introduction: Congenital factor XIII deficiency is a very rare bleeding disorder affecting 33 patients in France. Besides its role in fibrin clot stabilization, factor XIII is involved in placental attachment. Fetal miscarriages represent a frequent and concerning issue for these patients. The aim of the present study was to describe clinical characteristics of women presenting severe congenital FXIII deficiency in France, to focus on gynecological and obstetrical events, and to report the management of these rare situations.

Methods: We conducted a retrospective study in the French Hemophilia Comprehensive Care and Clinical Hemostasis Centers. Women between 15 and 65 years with factor XIII activity <10 IU dL were included. Biological, clinical and therapeutic events that occurred to these patients during their gynecological and obstetrical period were recorded.

Results: Among 31 centers, eleven patients were included. The median age at diagnosis was 1.5 years (range: 0-35), and at inclusion it was 30 years (range: 15-63). Fetal miscarriage was the primary manifestations in 2 (18%) patients, the remaining were diagnosed during hemorrhage. Menorrhagias were reported by 2 women (27%), 13 pregnancies were reported by 9 women including one abortion. Every pregnancy was conducted under factor XIII substitution, no hemorrhagic episode was reported. Four patients (36%) experienced at least one fetal miscarriage with a total amount of 30 miscarriages with 6 occurring during substitution.

Conclusion: Altogether, our data confirmed the high incidence of miscarriage in women with factor XIII deficiency. Good outcome of pregnancies required prophylaxis in accordance with international guidelines.
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http://dx.doi.org/10.1016/j.thromres.2020.04.010DOI Listing
July 2020

Long-term safety and efficacy of rIX-FP prophylaxis with extended dosing intervals up to 21 days in adults/adolescents with hemophilia B.

J Thromb Haemost 2020 05 30;18(5):1065-1074. Epub 2020 Mar 30.

Angelo Bianchi Bonomi Hemophilia and Thrombosis Center, Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico, Milan, Italy.

Background: An international, multicenter extension study evaluated recombinant fusion protein linking recombinant coagulation factor IX (FIX) with recombinant human albumin (rIX-FP) in hemophilia B (FIX ≤ 2%) patients previously enrolled in a phase III study or who initiated rIX-FP prophylaxis following surgery.

Objectives: To investigate the long-term safety and efficacy of rIX-FP prophylaxis in adult previously treated patients (PTPs) with hemophilia B.

Methods: Male PTPs were treated with a 7- (35-50 IU/kg), 10- or 14-day regimen (50-75 IU/kg). Patients ≥18 years who were well-controlled on a 14-day regimen for ≥6 months could switch to a 21-day regimen (100 IU/kg).

Results: A total of 59 patients (aged 13-63 years) participated in the study. Following a single dose of 100 IU/kg rIX-FP, in patients eligible for the 21-day regimen, the mean terminal half-life was 143.2 hours. Mean steady-state FIX trough activity levels ranged from 22% with the 7-day regimen to 7.6% with the 21-day regimen. Median (Q1, Q3) annualized spontaneous bleeding rates were 0.00 (0.00, 1.67), 0.28 (0.00, 1.10), 0.37 (0.00, 1.68), and 0.00 (0.00, 0.45) for the 7-, 10-, 14-, and 21-day regimens, respectively. Comparable efficacy was demonstrated for both the 14- and 21-day regimens compared to the 7-day regimen. Overall, 96.5% of bleeding episodes were treated successfully with 1 to 2 rIX-FP infusions. No patients developed an inhibitor and treatment was well tolerated.

Conclusions: rIX-FP extended interval prophylaxis provides dosing flexibility and, in selected patients, a 21-day regimen may provide an alternative option to minimize treatment burden and individualize treatment.
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http://dx.doi.org/10.1111/jth.14778DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7318213PMC
May 2020

Correlation of biological parameters with placental parameters and pregnancy outcomes in pre-eclamptic women.

Pregnancy Hypertens 2020 Jan 26;19:61-66. Epub 2019 Dec 26.

Service d'anatomopathologie, CHU de Brest, Hôpital Morvan, Brest Cedex, France; EA 4685 LIEN, Université de Bretagne Occidentale, Brest Cedex, France.

Introduction: Pre-eclampsia is characterized by maternal vascular malperfusion and chronic inflammation in placenta. Our purpose was to investigate the potential correlation of biological parameters with placental parameters and pregnancy outcomes in pre-eclamptic women.

Methods: Pre-eclamptic women were identified by interrogation of the Medical Registry Department in six French maternities between April 2013 and June 2018. Histological parameters in placentas (weight, macroscopic and microscopic lesions), baseline maternal characteristics and pregnancy outcomes (course of pregnancy, newborns' characteristics) were collected. Biological parameters were blood cell ratios (Platelet-to-Lymphocyte Ratio (PLR), Neutrophil-to-Lymphocyte Ratio (NLR)) collected at delivery and Placental growth factor (PlGF) measured in women with an available first trimester serum sample. Correlations of blood cell ratios and PlGF levels with placental parameters and pregnancy outcomes were assessed by Pearson's correlation test for quantitative parameters and by logistic regression analysis for qualitative parameters.

Results: 202 pregnancies were included, among which 68 had a first trimester PlGF quantification. No correlation was found between biological parameters and placental lesions. Low PLR was correlated with low placental weight (r = 0.156, p = 0.036) and with low birth weight (r = 0.179, p = 0.015). Low PlGF was correlated with long time from pre-eclampsia diagnosis to delivery (r = -0.250, p = 0.048).

Conclusions: There is no correlation between biological parameters and placental lesions in pre-eclamptic women. Yet, low PLR at delivery is correlated with low placental and birth weights. Moreover, low first trimester PlGF is correlated with long time from pre-eclampsia diagnosis to delivery.
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http://dx.doi.org/10.1016/j.preghy.2019.12.008DOI Listing
January 2020

First trimester serum biomarkers in pregnancies complicated with placental chronic inflammation.

Eur J Obstet Gynecol Reprod Biol 2019 Oct 23;241:119-125. Epub 2019 Aug 23.

Service d'anatomopathologie, CHU de Brest, Hôpital Morvan, Brest Cedex, France; EA 4685 LIEN, Université Bretagne Loire, Brest Cedex, France.

Objective: This study aimed at determining if first trimester serum biomarkers could predict adverse pregnancy outcomes associated with villitis (VUE) and chronic intervillositis of unknown etiology (CIUE).

Study Design: Between January 2013 and June 2018, we selected from pathology department files placentas with VUE or CIUE associated with VUE and control placentas with available first trimester Down syndrome screening results. First trimester PAPP-A and βhCG levels were recorded. Placental growth factor (PlGF) levels were measured in patients with an available first trimester serum sample. Histological findings in placentas, course of pregnancies and newborns' characteristics were compared between cases and controls.

Results: 78 cases and 75 controls were included. In cases, there were 21,8% intrauterine growth restriction (IUGR), 30,8% small for gestational age (SGA). Compared to controls, placentas from cases were smaller (425 g [IQR 370-480] vs 460 g [IQR 390-523], p = 0,03), showed more maternal vascular malperfusion features (79,5% vs 22,7%, p < 0,0001) and more fetal vascular malperfusion features (33,3% vs 12%, p = 0,002). Cases had lower PlGF (29,74 pg/ml [IQR 19,74-36,17] vs 36,37 pg/ml [IQR 27,36-49,13], p = 0,007) and βhCG levels (0,74 MoM [IQR 0,53-1,12] vs 1,00 MoM [IQR 0,72-1,53], p = 0,002) than controls. These differences resulted from lower PlGF levels in VUE patients compared to CIUE associated with VUE patients and controls (28,35 vs 34,05 and 36,37 pg/ml, p = 0,01) and from lower βhCG levels in CIUE associated with VUE patients compared to VUE patients and controls (0,65 vs 0,86 and 1, p = 0,005).

Conclusion: Low first trimester PlGF levels in cases, especially in VUE patients, suggest that reduced angiogenesis is involved in adverse pregnancy outcomes related to VUE.
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http://dx.doi.org/10.1016/j.ejogrb.2019.08.014DOI Listing
October 2019

A very potent factor V inhibitor interferes with the levels of all coagulation factors and causes a fatal hemorrhagic syndrome.

Eur J Haematol 2019 Aug 28;103(2):137-139. Epub 2019 May 28.

CHRU Brest - Laboratoire d'Hématologie, Brest, France.

We report a very high factor V inhibitor affecting the measurement of all coagulation factors besides fibrinogen, all these factors being dramatically decreased. This inhibitor could be linked to antibiotic use. The patient died of massive hemorrhage before a plasma exchange could be initiated.
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http://dx.doi.org/10.1111/ejh.13249DOI Listing
August 2019

Six months two years of oral anticoagulation after a first episode of unprovoked deep-vein thrombosis. The PADIS-DVT randomized clinical trial.

Haematologica 2019 07 3;104(7):1493-1501. Epub 2019 Jan 3.

Départementde Médecine Interne et Pneumologie, CHU de Brest, Université de Bretagne Occidentale, EA 3878, CIC INSERM 1412, F-CRIN INNOVTE, Brest.

The optimal duration of anticoagulation after a first episode of unprovoked deep-vein thrombosis is uncertain. We aimed to assess the benefits and risks of an additional 18 months of treatment with warfarin placebo, after an initial 6 months of anticoagulation for a first unprovoked proximal deep-vein thrombosis. We conducted a multicenter, randomized, double-blind, controlled trial comparing an additional 18 months of warfarin with placebo in patients with a unprovoked proximal deep-vein thrombosis initially treated for 6 months (treatment period: 18 months; follow up after treatment period: 24 months). The primary outcome was the composite of recurrent venous thromboembolism or major bleeding at 18 months. Secondary outcomes were the composite at 42 months, as well as each component of the composite, and death unrelated to pulmonary embolism or major bleeding, at 18 and 42 months. All outcomes were centrally adjudicated. A total of 104 patients, enrolled between July 2007 and October 2013 were analyzed on an intention-to-treat basis; no patient was lost to follow-up. During the 18-month treatment period, the primary outcome occurred in none of the 50 patients in the warfarin group and in 16 out of 54 patients (cumulative risk, 29.6%) in the placebo group (hazard ratio, 0.03; 95% confidence interval: 0.01 to 0.09; <0.001). During the entire 42-month study period, the composite outcome occurred in 14 patients (cumulative risk, 36.8%) in the warfarin group and 17 patients (cumulative risk, 31.5%) in the placebo group (hazard ratio, 0.72; 95% confidence interval: 0.35-1.46). In conclusion, after a first unprovoked proximal deep-vein thrombosis initially treated for 6 months, an additional 18 months of warfarin therapy reduced the composite of recurrent venous thrombosis and major bleeding compared to placebo. However, this benefit was not maintained after stopping anticoagulation. .
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http://dx.doi.org/10.3324/haematol.2018.210971DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6601089PMC
July 2019

Generalized pustular psoriasis as an unusual cause of acquired haemophilia A.

Eur J Dermatol 2018 Jun;28(3):417-418

Department of Dermatology, University Hospital, Brest, France.

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http://dx.doi.org/10.1684/ejd.2018.3271DOI Listing
June 2018

Determinants of adherence and consequences of the transition from adolescence to adulthood among young people with severe haemophilia (TRANSHEMO): study protocol for a multicentric French national observational cross-sectional study.

BMJ Open 2018 07 25;8(7):e022409. Epub 2018 Jul 25.

Haemophilia Treatment Centre, Hospital Edouard Herriot, University Hospital of Lyon, Lyon, France.

Introduction: Severe haemophilia is a rare disease characterised by spontaneous bleeding from early childhood, which may lead to various complications, especially in joints. It is nowadays possible to avoid these complications thanks to substitutive therapies for which the issue of adherence is major. The transition from adolescence to adulthood in young people with severe haemophilia is a critical period as it is associated with a high risk of lack of adherence to healthcare, which might have serious consequences on daily activities and on quality of life.

Methods And Analysis: We present the protocol for a cross-sectional, observational, multicentric study to assess the differences between adolescents and young adults with severe haemophilia in France through the transition process, especially on adherence to healthcare. This study is based on a mixed methods design, with two complementary and consecutive phases, comparing data from a group of adolescents (aged 14-17 years) with those from a group of young adults (aged 20-29 years). The quantitative phase focuses on the determinants (medical, organisational, sociodemographic and social and psychosocial and behavioural factors) of adherence to healthcare (considered as a marker of the success of transition). The qualitative phase explores participants' views in more depth to explain and refine the results from the quantitative phase. Eligible patients are contacted by the various Haemophilia Treatment Centres participating in the French national registry FranceCoag.

Ethics And Dissemination: The study was approved by the French Ethics Committee and by the French National Agency for Medicines and Health Products Safety (number: 2016-A01034-47). Study findings will be disseminated to the scientific and medical community in peer-reviewed journals and presented at scientific meetings. Results will be popularised to be communicated via the French association for people with haemophilia to participants and to the general public.

Trial Registration Number: NCT02866526; Pre-results.
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http://dx.doi.org/10.1136/bmjopen-2018-022409DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6067371PMC
July 2018

Statin exposure and thrombosis risk in patients with myeloproliferative neoplasms.

Thromb Res 2018 07 16;167:57-59. Epub 2018 May 16.

EA 3878 (GETBO), Brest University, 29200 Brest, France; Oncology and Hematology Institute, Hôpital Morvan, 29609 Brest Cedex, France.

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http://dx.doi.org/10.1016/j.thromres.2018.05.014DOI Listing
July 2018

Risk factors for recurrent venous thromboembolism after unprovoked pulmonary embolism: the PADIS-PE randomised trial.

Eur Respir J 2018 01 4;51(1). Epub 2018 Jan 4.

Dépt de Médecine Interne et Pneumologie, EA 3878, CIC INSERM 1412, Centre Hospitalo-Universitaire de Brest, Université de Bretagne Occidentale, Brest, France

We aimed to identify risk factors for recurrent venous thromboembolism (VTE) after unprovoked pulmonary embolism.Analyses were based on the double-blind randomised PADIS-PE trial, which included 371 patients with a first unprovoked pulmonary embolism initially treated during 6 months who were randomised to receive an additional 18 months of warfarin or placebo and followed up for 2 years after study treatment discontinuation. All patients had ventilation/perfusion lung scan at inclusion ( at 6 months of anticoagulation).During a median follow-up of 41 months, recurrent VTE occurred in 67 out of 371 patients (6.8 events per 100 person-years). In main multivariate analysis, the hazard ratio for recurrence was 3.65 (95% CI 1.33-9.99) for age 50-65 years, 4.70 (95% CI 1.78-12.40) for age >65 years, 2.06 (95% CI 1.14-3.72) for patients with pulmonary vascular obstruction index (PVOI) ≥5% at 6 months and 2.38 (95% CI 1.15-4.89) for patients with antiphospholipid antibodies. When considering that PVOI at 6 months would not be available in practice, PVOI ≥40% at pulmonary embolism diagnosis (present in 40% of patients) was also associated with a 2-fold increased risk of recurrence.After a first unprovoked pulmonary embolism, age, PVOI at pulmonary embolism diagnosis or after 6 months of anticoagulation and antiphospholipid antibodies were found to be independent predictors for recurrence.
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http://dx.doi.org/10.1183/13993003.01202-2017DOI Listing
January 2018

Immune thrombocytopenia in adults: a prospective cohort study of clinical features and predictors of outcome.

Haematologica 2016 09 26;101(9):1039-45. Epub 2016 May 26.

Centre de Référence des Cytopénies Auto-Immunes de l'Adulte, Service de Médecine Interne, CHU Henri Mondor, Créteil, France.

This prospective observational cohort study aimed to explore the clinical features of incident immune thrombocytopenia in adults and predictors of outcome, while determining if a family history of autoimmune disorder is a risk factor for immune thrombocytopenia. All adults, 18 years of age or older, recently diagnosed with immune thrombocytopenia were consecutively recruited across 21 hospital centers in France. Data were collected at diagnosis and after 12 months. Predictors of chronicity at 12 months were explored using logistic regression models. The association between family history of autoimmune disorder and the risk of developing immune thrombocytopenia was explored using a conditional logistic regression model after matching each case to 10 controls. One hundred and forty-three patients were included: 63% female, mean age 48 years old (Standard Deviation=19), and 84% presented with bleeding symptoms. Median platelet count was 10×10(9)/L. Initial treatment was required in 82% of patients. After 12 months, only 37% of patients not subject to disease-modifying interventions achieved cure. The sole possible predictor of chronicity at 12 months was a higher platelet count at baseline [Odds Ratio 1.03; 95%CI: 1.00, 1.06]. No association was found between outcome and any of the following features: age, sex, presence of either bleeding symptoms or antinuclear antibodies at diagnosis. Likewise, family history of autoimmune disorder was not associated with incident immune thrombocytopenia. Immune thrombocytopenia in adults has been shown to progress to a chronic form in the majority of patients. A lower platelet count could be indicative of a more favorable outcome.
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http://dx.doi.org/10.3324/haematol.2016.146373DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5060020PMC
September 2016

Long-acting recombinant coagulation factor IX albumin fusion protein (rIX-FP) in hemophilia B: results of a phase 3 trial.

Blood 2016 04 11;127(14):1761-9. Epub 2016 Jan 11.

Clinical Research and Development, CSL Behring, King of Prussia, PA.

A global phase 3 study evaluated the pharmacokinetics, efficacy, and safety of recombinant fusion protein linking coagulation factor IX with albumin (rIX-FP) in 63 previously treated male patients (12-61 years) with severe hemophilia B (factor IX [FIX] activity ≤2%). The study included 2 groups: group 1 patients received routine prophylaxis once every 7 days for 26 weeks, followed by either 7-, 10-, or 14-day prophylaxis regimen for a mean of 50, 38, or 51 weeks, respectively; group 2 patients received on-demand treatment of bleeding episodes for 26 weeks and then switched to a 7-day prophylaxis regimen for a mean of 45 weeks. The mean terminal half-life of rIX-FP was 102 hours, 4.3-fold longer than previous FIX treatment. Patients maintained a mean trough of 20 and 12 IU/dL FIX activity on prophylaxis with rIX-FP 40 IU/kg weekly and 75 IU/kg every 2 weeks, respectively. There was 100% reduction in median annualized spontaneous bleeding rate (AsBR) and 100% resolution of target joints when subjects switched from on-demand to prophylaxis treatment with rIX-FP (P< .0001). The median AsBR was 0.00 for all prophylaxis regimens. Overall, 98.6% of bleeding episodes were treated successfully, including 93.6% that were treated with a single injection. No patient developed an inhibitor, and no safety concerns were identified. These results indicate rIX-FP is safe and effective for preventing and treating bleeding episodes in patients with hemophilia B at dosing regimens of 40 IU/kg weekly and 75 IU/kg every 2 weeks. This trial was registered at www.clinicaltrials.gov as #NCT0101496274.
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http://dx.doi.org/10.1182/blood-2015-09-669234DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4825413PMC
April 2016

A missense mutation in the alpha-actinin 1 gene (ACTN1) is the cause of autosomal dominant macrothrombocytopenia in a large French family.

PLoS One 2013 17;8(9):e74728. Epub 2013 Sep 17.

Institut National de la Santé et de la Recherche Médicale (INSERM), U1078, Brest, France ; Faculté de Médecine et des Sciences de la Santé, Université de Bretagne Occidentale (UBO), Brest, France ; Laboratoire de Génétique Moléculaire et d'Histocompatibilité, Centre Hospitalier Universitaire (CHU) Brest, Hôpital Morvan, Brest, France.

Inherited thrombocytopenia is a heterogeneous group of disorders characterized by a reduced number of blood platelets. Despite the identification of nearly 20 causative genes in the past decade, approximately half of all subjects with inherited thrombocytopenia still remain unexplained in terms of the underlying pathogenic mechanisms. Here we report a six-generation French pedigree with an autosomal dominant mode of inheritance and the identification of its genetic basis. Of the 55 subjects available for analysis, 26 were diagnosed with isolated macrothrombocytopenia. Genome-wide linkage analysis mapped a 10.9 Mb locus to chromosome 14 (14q22) with a LOD score of 7.6. Candidate gene analysis complemented by targeted next-generation sequencing identified a missense mutation (c.137GA; p.Arg46Gln) in the alpha-actinin 1 gene (ACTN1) that segregated with macrothrombocytopenia in this large pedigree. The missense mutation occurred within actin-binding domain of alpha-actinin 1, a functionally critical domain that crosslinks actin filaments into bundles. The evaluation of cultured mutation-harboring megakaryocytes by electron microscopy and the immunofluorescence examination of transfected COS-7 cells suggested that the mutation causes disorganization of the cellular cytoplasm. Our study concurred with a recently published whole-exome sequence analysis of six small Japanese families with congenital macrothrombocytopenia, adding ACTN1 to the growing list of thrombocytopenia genes.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0074728PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3775762PMC
June 2014

A case-control study to assess the risk of immune thrombocytopenia associated with vaccines.

Blood 2012 Dec 24;120(25):4938-44. Epub 2012 Oct 24.

LA-SER, 10 Place de Catalogne, Paris, France.

The cause of immune thrombocytopenia (ITP) remains unknown. Studies have suggested immunizations as possible triggering factors of ITP through molecular mimicry. This case-control study explored potential associations between adult ITP and various routinely administered vaccines. A network of internal medicine and hematology centers across France recruited 198 incident (ie, newly diagnosed) cases of ITP between April 2008 and June 2011. These cases were compared with 878 age- and sex-matched controls without ITP recruited in general practice. Information on vaccination was obtained from patients' standardized telephone interviews. Sixty-six of 198 cases (33.3%) and 303 of 878 controls (34.5%) received at least 1 vaccine within the 12 months before the index date. We found no evidence of an increase in ITP after vaccination in the previous 6 or 12 months (adjusted odds ratio [OR] for the previous 12 months = 1.0; 95% confidence interval, 0.7-1.4). When the 2-month time window was used, higher ORs were observed for all vaccines (OR = 1.3). This increase was mainly attributable to the vaccination against diphtheria-tetanus-pertussis-poliomyelitis (OR = 1.5) and was not statistically significant. The results of the present study show that in an adult population, the exposure to common vaccines is on average not associated with an observable risk of developing ITP.
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http://dx.doi.org/10.1182/blood-2012-05-431098DOI Listing
December 2012

Revisiting the molecular epidemiology of factor XI deficiency: nine new mutations and an original large 4qTer deletion in western Brittany (France).

Thromb Haemost 2012 Jan 8;107(1):44-50. Epub 2011 Dec 8.

Université de Brest, Faculté de Médecine et des Sciences de la Santé, UMR-S613, Brest, France.

Constitutional deficiency in factor XI (FXI) is a rare bleeding disorder in the general population, with the exception of Ashkenazi Jews. During the last decade, the detection of FXI-deficient patients has shifted from clinical screening identifying mostly severe bleeders to biological screening combining findings of prolonged activated partial thromboplastin time and FXI coagulation activity (FXI:C) below 50 U/dl. The goal of this study was to determine the molecular basis of FXI deficiency in western Brittany, France. Over the course of four years, we detected 98 FXI-deficient patients through biological screening, and 44 patients agreed to participate in this study corresponding to 25 index cases. We developed an efficient mutation detection strategy (combining direct sequencing and QFM-PCR to search for heterozygous rearrangements in a routine setting) that detected F11 mutations in 24 out of the 25 index cases. An unexpected allelic heterogeneity was found, with 14 different single point mutations being detected, among which nine are new. Moreover, a large heterozygous deletion of the entire F11 gene was detected, and was then further defined using a CGH array as a 4q34.2 telomeric deletion of 7 Mb containing 77 genes. We propose that the observed recurrent mutations may be considered as genetic tags of a population. This study highlights the importance of screening for large deletions in molecular studies of F11 .
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http://dx.doi.org/10.1160/TH11-06-0415DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3399784PMC
January 2012

Biological determinants of bleeding in patients with heterozygous factor XI deficiency.

Br J Haematol 2012 Jan 21;156(2):245-51. Epub 2011 Nov 21.

Centre Hospitalier Régional Universitaire de Brest, Haematology Laboratory, Brest , France.

Bleeding risk is not predictable in patients with factor XI (FXI; F11) deficiency. In this prospective study, our objectives were to determine the biological determinants for bleeding risk in patients with heterozygous FXI deficiency. Patients were classified as either bleeding patients or non-bleeding patients by calculating the bleeding score (BS) described for von Willebrand disease. Primary haemostasis, thrombin generation, thromboelastometry, procoagulant proteins, inhibitors, fibrinolysis, and F11 gene mutations were compared between bleeding and non-bleeding patients. Thirty-nine patients were included. BS significantly correlated with clinical assessment (P=0·001), and a score over 3 discriminated between bleeding (n=15) and non-bleeding (n=24) patients (P=0·034). Despite normal values, von Willebrand factor (VWF) and thrombomodulin (TM) plasma levels were significantly lower in bleeding patients than non-bleeding patients [ristocetin cofactor activity (VWF:RCo)=80·6±29·7 iu/dl and 101·8±29·5iu/dl respectively, P=0·043; and VWF antigen (VWF:Ag)=84·0±28·0 iu/dl and 106·3±36·1 iu/dl respectively, P=0·035; and TM=17·7±11·7ng/ml and 23·6±9·7ng/ml respectively, P=0·043]. When considering BS as a continuous variable, only VWF:RCo remained significant (P=0·042), which accounted for 11% of the variability in BS.
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http://dx.doi.org/10.1111/j.1365-2141.2011.08945.xDOI Listing
January 2012

Influence of coagulation factors and tissue factor concentration on the thrombin generation test in plasma.

Thromb Haemost 2008 Apr;99(4):767-73

Service d'Hématologie biologique, Hôpital La Cavale Blanche, Bd Tanguy Prigent, 29609 Brest Cedex, France.

The thrombin generation test is used to study coagulation in patients with haemorrhagic diseases or with high thrombotic risk. To our knowledge, this is the first study investigating the relative influence of coagulation factors on thrombin generation in plasma. The aim was to investigate the influence of coagulant factors, anticoagulant factors, and tissue factor (TF) on three parameters: endogenous thrombin potential (ETP), peak thrombin concentration, and lag time for the appearance of thrombin. At a low TF concentration, all factors except factor XI influenced thrombin generation. At a high TF concentration, only the factors of the extrinsic pathway exerted an influence. ETP and peak thrombin were linearly correlated to factor II concentration. Factor V and factor VII effects increased hyperbolically with factor concentration. The influence of factor X on thrombin generation depended on TF concentration. In the absence of factor VIII and factor IX, ETP fell to 60-70% of the normal when peak thrombin fell to 25-30% of the normal. Fibrinogen concentration influenced ETP and peak thrombin and decreasing fibrinogen levels shortened the lag time. As expected, decreasing antithrombin concentration caused dramatic increases in thrombin generation. Protein S prolonged the lag time, especially at a low TF concentration. No effect of protein C was observed, likely due to the absence of thrombomodulin. The thrombin generation test was more sensitive to factor deficiencies at low than at high TF concentration. ETP was not the most critical parameter for studying coagulation factor deficiencies. Instead, peak thrombin was the most sensitive parameter.
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http://dx.doi.org/10.1160/TH07-09-0581DOI Listing
April 2008