Publications by authors named "Véronique Le Cam-Duchez"

33 Publications

Acquired factor XIII deficiency in a child with pure erythroid leukemia.

Pediatr Blood Cancer 2021 Jan 23:e28890. Epub 2021 Jan 23.

Vascular Hemostasis Unit, Normandie Université, UNIROUEN, Inserm U1096, Rouen University Hospital, Rouen, France.

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http://dx.doi.org/10.1002/pbc.28890DOI Listing
January 2021

Dabigatran Level Before Reversal Can Predict Hemostatic Effectiveness of Idarucizumab in a Real-World Setting.

Front Med (Lausanne) 2020 16;7:599626. Epub 2020 Dec 16.

Université de Paris, Innovative Therapies in Haemostasis, INSERM, Paris, France.

Idarucizumab has been included in guidelines for the management of bleeding or surgical procedure in dabigatran-treated patients without need for biological monitoring. The aim of the study was to assess the prognostic value of dabigatran plasma level before reversal to test the hemostatic efficacy of idarucizumab. The secondary objectives were (i) to analyze plasma dabigatran level according to the risk of rebound and (ii) to evaluate the incidence of post-reversal non-favorable clinical outcomes (including thromboembolism, bleeding, antithrombotic, and death) and antithrombotic resumption. This was an observational multicentric cohort study, which included all French patients who required idarucizumab for dabigatran reversal. Between May 2016 and April 2019, 87 patients from 21 French centers were enrolled. Patients received idarucizumab for overt bleeding ( = 61), urgent procedures ( = 24), or overdose without bleeding ( = 2). Among patients with major bleeding ( = 57), treatment with idarucizumab was considered effective in 44 (77.2%) of them. Patients who did not achieve effective hemostasis after reversal had a significantly higher mean level of plasma dabigatran at baseline (524.5 ± 386 vs. 252.8 ng/mL ± 235, = 0.033). Furthermore, patients who did not achieve effective hemostasis after reversal had less favorable outcomes during follow-up (46.2 vs. 81.8%, = 0.027). ROC curve identified a cutoff of 264 ng/mL for dabigatran level at admission to be predictive of ineffective hemostasis. No plasma dabigatran rebound was observed after reversal in patients with dabigatran plasma level < 264 ng/mL at baseline. This retrospective study shows that dabigatran level before reversal could predict hemostatic effectiveness and dabigatran plasma rebound after idarucizumab injection.
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http://dx.doi.org/10.3389/fmed.2020.599626DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7772865PMC
December 2020

Evidence for wall shear stress-dependent t-PA release in human conduit arteries: role of endothelial factors and impact of high blood pressure.

Hypertens Res 2021 Mar 18;44(3):310-317. Epub 2020 Sep 18.

Department of Pharmacology, Rouen University Hospital, 76000, Rouen, France.

Tissue plasminogen activator (t-PA) converts plasminogen into the serine protease plasmin, which in turn degrades fibrin clots. This study assessed whether an increase in shear stress is associated in humans in vivo with the release of t-PA in peripheral conduit arteries, the impact of high blood pressure and the role of NO and CYP450-derived epoxyeicosatrienoic acids (EETs). Local t-PA levels were quantified at baseline and during a sustained increase in radial artery wall shear stress induced by hand skin heating (from 34 to 44 °C) in a total of 25 subjects, among whom 8 were newly diagnosed essential hypertensive patients. The impact of the brachial infusion of NO synthase (L-NMMA) and CYP450 inhibitors (fluconazole) on t-PA release was assessed. The increase in shear stress induced by heating was associated with an increase in local t-PA release (from 3.0 ± 0.5 to 19.2 ± 5.5 ng/min, n = 25, P < 0.01). The magnitude of t-PA release was positively correlated with the increase in shear stress (r = 0.64, P < 0.001) and negatively correlated with mean blood pressure (r = -0.443, P = 0.027). These associations persisted after multiple adjustments for confounding factors. Finally, t-PA release was reduced by L-NMMA and to a larger extent by the combination of L-NMMA and fluconazole without a change in shear stress. The increase in wall shear stress in the peripheral conduit arteries induces a release of t-PA by a mechanism involving NO and EETs. The alteration of this response by high blood pressure may contribute to reducing the fibrinolytic potential and enhancing the risk of arterial thrombosis during exercise.
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http://dx.doi.org/10.1038/s41440-020-00554-5DOI Listing
March 2021

Factor VIII and IX assays for post-infusion monitoring in hemophilia patients: Guidelines from the French BIMHO group (GFHT).

Eur J Haematol 2020 Aug 27;105(2):103-115. Epub 2020 May 27.

Service d'Hématologie Hémostase, Hospices Civils de Lyon, Bron, France.

Replacement therapy with plasma-derived or recombinant FVIII and FIX (pdFVIII/pdFIX or rFVIII/rFIX) concentrates is the standard of treatment in patients with haemophilia A and B, respectively. Measurement of factor VIII (FVIII:C) or factor IX (FIX:C) levels can be done by one-stage clotting assay (OSA) or chromogenic substrate assay (CSA). The French study group on the Biology of Hemorrhagic Diseases (a collaborative group of the GFHT and MHEMO network) presents a literature review and proposals for the monitoring of FVIII:C and FIX:C levels in treated haemophilia A and B patients, respectively. The use of CSA is recommended for the monitoring of patients treated with pdFVIII or rFVIII including extended half-life (EHL) rFVIII. Except for rFVIII-Fc, great caution is required when measuring FVIII:C levels by OSA in patients substituted by EHL-rFVIII. The OSA is recommended for the monitoring of patients treated with pdFIX or rFIX. Large discordances in the FIX:C levels measured for extended half-life rFIX (EHL-rFIX), depending on the method and reagents used, must lead to great attention when OSA is used for measuring FIX:C levels in patients substituted by EHL-rFIX. Data of most of recent studies, obtained with spiked plasmas, deserve to be confirmed in plasma samples of treated patients.
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http://dx.doi.org/10.1111/ejh.13423DOI Listing
August 2020

Thrombin generation assay is a useful pre-operative tool to predict non-bleeding risk in a patient with mild factor V deficiency.

Transfus Med 2020 10 6;30(5):408-409. Epub 2020 Apr 6.

Vascular Hemostasis Unit, Normandie Univ, UNIROUEN, INSERM U1096, Rouen University Hospital, Rouen, France.

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http://dx.doi.org/10.1111/tme.12680DOI Listing
October 2020

[Theophylline adenosine dipyridamole (CTAD) and citrate evaluation to survey unfractionated heparin treatment: a delayed centrifugation validation for anti-Xa measurement?].

Ann Biol Clin (Paris) 2020 02;78(1):27-34

Service d'hématologie biologique, CHU Charles Nicolle, Rouen, France, Inserm U1096, CHU Charles Nicolle, Rouen, France.

Unfractionated heparin (UFH) is the main anticoagulante used in intensive care unit. The anticoagulant effect is monitored by activated partial thrombin time (aPTT) and anti-Xa activity (anti-Xa) measurement. However, delayed centrifugation induces platelet factor 4 (PF4) release and anti-Xa decrease. Several studies have concluded that aPTT and anti-Xa measurement should be performed within 2 hours in citrated anticoagulant but may be delayed longer in citrate theophylline adenosine and dypiridamol (CTAD) anticoagulant. The objective of this study was to compare the stability of both aPTT and anti-Xa in citrate and CTAD samples, and to determine the effect of delayed centrifugation on both aPTT, anti-Xa results, and PF4 release in citrate samples only.

Methods: aPTT and anti-Xa were measured in citrate and CTAD anticoagulant samples from 93 patients. Delayed centrifugation was performed in citrate samples from 31 additional patients, with hourly aPTT and anti-Xa measurement from 1 to 6 hours. In 14 of these last patients, PF4 release was also evaluated with Human CXCL4/PF4 Quantikine ELISA Kit.

Results: We observed a significant correlation between citrate and CTAD anticoagulant for aPTT (r=0.94) and anti-Xa (r=0.95). With Bland-Altman correlation, a minor bias was observed for anti-Xa (-0.025±0.041). Delayed centrifugation in citrated anticoagulant showed an excellent concordance from 1 to 4 hours for aPTT (-4.0±5.3 s) and anti-Xa (1.10±0.058 UI/mL) measurements. Moreover, PF4 release was not different between 1 hour (31.5±14.7 ng/mL) and 4 hours (33.8±11.8 ng/mL).

Conclusion: We have demonstrated that anti-Xa measurement for unfractionated heparin should be done 4 hours in citrated plasma and that CTAD was not better than citrate. However, these initial findings require confirmation using other aPTT and calibrated anti-Xa assays.
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http://dx.doi.org/10.1684/abc.2020.1525DOI Listing
February 2020

Is citrate theophylline adenosine dipyridamole (CTAD) better than citrate to survey unfractionated heparin treatment? Has delayed centrifugation a real impact on this survey?

J Thromb Thrombolysis 2019 Aug;48(2):277-283

Rouen University Hospital, Vascular Hemostasis Unit, 76031, Rouen, France.

Unfractionated heparin (UFH) is the main anticoagulant used in intensive care unit. The anticoagulant effect is monitored by activated partial thrombin time (aPTT) and anti-Xa activity (anti-Xa) measurement. However, delayed centrifugation induces platelet factor 4 (PF4) release and anti-Xa decrease. Several studies have concluded that aPTT and anti-Xa measurement should be performed within 2 h in citrated anticoagulant but may be delayed longer in Citrate Theophylline Adenosine and Dypiridamol (CTAD) anticoagulant. The objective of this study was to compare the stability of both aPTT and anti-Xa in citrate and CTAD samples, and to determine the effect of delayed centrifugation on both aPTT, anti-Xa results, and PF4 release in citrate samples only. aPTT and anti-Xa were measured in citrate and CTAD anticoagulant samples from 93 patients. Delayed centrifugation was performed in citrate samples from 31 additional patients, with hourly aPTT and anti-Xa measurement from 1 to 6 h. In 14 of these last patients, PF4 release was also evaluated with Human CXCL4/PF4 Quantikine ELISA Kit. We observed a significant correlation between citrate and CTAD anticoagulant for aPTT (r = 0.94) and anti-Xa (r = 0.95). With Bland-Altman correlation, a minor bias was observed for anti-Xa (- 0.025 ± 0.041). Delayed centrifugation in citrated anticoagulant showed an excellent concordance from 1 to 4 h for aPTT (- 4.0 ± 5.3 s) and anti-Xa (1.10 ± 0.058 UI/ml) measurements. Moreover, PF4 release was not different between 1 h (31.5 ± 14.7 ng/ml) and 4 h (33.8 ± 11.8 ng/ml). We have demonstrated that anti-Xa measurement for unfractionated heparin should be done 4 h in citrated plasma and that CTAD was not better than citrate. However, these initial findings require confirmation using other aPTT and calibrated anti-Xa assays.
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http://dx.doi.org/10.1007/s11239-019-01882-1DOI Listing
August 2019

Hydroxychloroquine reverses the prothrombotic state in a mouse model of antiphospholipid syndrome: Role of reduced inflammation and endothelial dysfunction.

PLoS One 2019 14;14(3):e0212614. Epub 2019 Mar 14.

Rouen University Hospital, Department of Internal Medicine, Rouen, France.

Antiphospholipid antibodies (aPL) promote endothelial dysfunction, inflammation and procoagulant state. We investigated the effect of hydroxychloroquine (HCQ) on prothrombotic state and endothelial function in mice and in human aortic endothelial cells (HAEC). Human aPL were injected to C57BL/6 mice treated or not with HCQ. Vascular endothelial function and eNOS were assessed in isolated mesenteric arteries. Thrombosis was assessed both in vitro by measuring thrombin generation time (TGT) and tissue factor (TF) expression and in vivo by the measurement of the time to occlusion in carotid and the total thrombosis area in mesenteric arteries. TGT, TF, and VCAM1 expression were evaluated in HAEC. aPL increased VCAM-1 expression and reduced endothelium dependent relaxation to acetylcholine. In parallel, aPL shortened the time to occlusion and extended thrombus area in mice. This was associated with an overexpression of TF and an increased TGT in mice and in HAEC. HCQ reduced clot formation as well as TGT, and improved endothelial-dependent relaxations. Finally, HCQ increased the p-eNOS/eNOS ratio. This study provides new evidence that HCQ improves procoagulant status and vascular function in APS by modulating eNOS, leading to an improvement in the production of NO.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0212614PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6417644PMC
November 2019

[Factor VIII assays in treated hemophilia A patients].

Ann Biol Clin (Paris) 2019 02;77(1):53-65

CHU Lille, Institut d'hématologie-transfusion, Inserm U1011, Lille, France.

Replacement therapy with plasma-derived or recombinant FVIII (pdFVIII or rFVIII) concentrates is the standard of treatment in patients with hemophilia A. The reference method used for measuring factor VIII (FVIII:C) levels in patients treated by FVIII concentrates is the chromogenic substrate assay (CSA). However, the one-stage clotting assay (OSA) is predominantly used in current clinical practice, but this method depends on the activated partial thromboplastin time (APTT) reagent and the coagulation analyzer used, and wide variations in the measurements of FVIII recovery have been reported with some factor concentrates. The French study group on the biology of hemorrhagic diseases (a collaborative group of the GFHT and MHEMO network) presents a review of the literature and proposals for the monitoring of FVIII:C levels in treated hemophilia A patients. The use of CSA calibrated with a plasma reference tested against the current FVIII WHO (World Health Organization) International Standard is recommended for the monitoring of patients treated with pdFVIII or rFVIII including extended half-life (EHL) rFVIII. OSA are adequate for the monitoring of patients treated with pdFVIII or with most of rFVIII concentrates. However, preliminary comparison with CSA is mandatory before measuring FVIII:C by OSA in patients treated by Refacto AF. For rFVIII-EHL, OSA are only acceptable for Elocta®. Great caution is therefore required when measuring FVIII:C levels by OSA in patients substituted by other EHL-rFVIII. Indeed, most of recent studies reported data obtained with spiked plasmas, which deserve to be confirmed on plasma samples collected in treated patients.
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http://dx.doi.org/10.1684/abc.2019.1413DOI Listing
February 2019

[Factor IX assays in treated hemophilia B patients].

Ann Biol Clin (Paris) 2019 02;77(1):41-52

Service d'hématologie hémostase, Hospices civils de Lyon, Bron, France.

Replacement therapy with plasma-derived or recombinant FIX (pdFIX or rFIX) concentrates is the standard of treatment in patients with hemophilia B. The method predominantly used for measuring factor IX (FIX:C) levels is the one-stage clotting assay (OSA) but this method depends on the activated partial thromboplastin time (APTT) reagent and the coagulation analyzer used, and wide variations in the measurements of FIX recovery have been reported with some factor concentrates. The French study group on the biology of hemorrhagic diseases (a collaborative group of the GFHT and MHEMO network), presents a review of the literature and proposals for the monitoring of FIX:C levels in treated hemophilia B patients. The use of OSA calibrated with a plasma reference tested against the current FIX WHO International Standard is recommended for the monitoring of patients treated with pdFIX or rFIX. Chromogenic substrate assays (CSA) are adequate for the monitoring of patients treated with Rixubis, but data available for Benefix are currently too limited. For extended half-life rFIX (EHL-rFIX), large discordances in the FIX:C levels measured were evidenced, depending on the method and reagents used. Great attention is therefore required for measuring FIX:C levels by OSA in patients substituted by EHL-rFIX. Commercial kits for CSA are not equivalent, and although potentially useful, they are not validated for all EHL-rFIX. Most of recent studies reported data obtained with spiked plasmas, which deserve to be confirmed on plasma samples collected in treated patients.
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http://dx.doi.org/10.1684/abc.2019.1414DOI Listing
February 2019

Thrombin generation profile in non-thrombotic factor V Leiden carriers.

J Thromb Thrombolysis 2019 Apr;47(3):473-477

Normandie Univ, UNIROUEN, INSERM U1096, Rouen University Hospital, Vascular Hemostasis Unit, F 76000, Rouen, France.

Factor V Leiden (FVL) mutation is the most common genetic risk factor for venous thromboembolism. In families with a history of thrombosis, FVL can be present in 18%. Thrombin generation test is commonly used as an evaluation tool of thrombotic risk. The objective of this study was to evaluate the thrombogenic potential of FVL in asymptomatic carriers and in patients with personal or familial history of thrombosis. This was a retrospective single center study including 160 patients. Among them, 43 had personal history of thrombosis and 117 had familial history of thrombosis. Thrombin generation (TG) was realized in frozen platelet poor plasma with 1 pM of tissue factor and 4 µM of phospholipid. FVL mutation was associated with a global increase of TG. No difference was observed between patients with provoked thrombosis and patients with first-degree familial history of thrombosis (endogenous thrombin potential (ETP): 1501.0 ± 316.4 nM min and thrombin peak: 253.4 ± 71.5 nM vs. 1520.4 ± 283.8 nM min and 268.6 ± 68.0 nM). An increase of TG was observed in patients with unprovoked thrombosis (n = 23) and in patients with provoked thrombosis (n = 20) (ETP: 1819.5 ± 319.8 nM min and peak: 332.3 ± 55.8 nM). In the unprovoked thrombosis group, patients with a pulmonary embolism had a higher ETP than patients with deep vein thrombosis (DVT) (2036 ± 343 nM min vs. 1707 ± 261 nM min). With a predictive score formula (s = 0.1315 × Age + 0.0105 × ETP) with a threshold of 22.1 as risk to develop an unprovoked thrombosis among patients with second-degree familial history. The results of our analysis suggest that measurement of thrombin generation in patients with FVL mutation may identify subjects with an increased risk of unprovoked thrombosis. Further studies are needed to examine the usefulness of predicting thrombotic presentation in asymptomatic carriers.
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http://dx.doi.org/10.1007/s11239-019-01821-0DOI Listing
April 2019

Anti-Xa Oral Anticoagulant Plasma Concentration Assay in Real Life: Rivaroxaban and Apixaban Quantification in Emergency With LMWH Calibrator.

Ann Pharmacother 2019 04 31;53(4):341-347. Epub 2018 Oct 31.

1 Rouen University Hospital, France.

Background: Oral anti-Xa inhibitors have demonstrated noninferiority to vitamin K antagonists (VKAs) for the prevention of stroke in patients with atrial fibrillation and recurrent venous thromboembolism. They are associated with a decrease in major bleeding. In contrast with VKA, no coagulation monitoring is required. However, in clinical practice, determination of drug concentration is sometimes necessary.

Objective: The objective of this study was to evaluate a low-molecular-weight heparin (LMWH) calibrated anti-Xa assay for the quantification of rivaroxaban and apixaban plasma concentration in emergency.

Methods: The anti-Xa plasma concentration of rivaroxaban and apixaban were measured in emergency in 210 patients using STA anti-Xa liquid assay. For each plasma concentration <150 ng/mL of rivaroxaban or apixaban, an anti-Xa assay calibrated with LMWH was performed.

Results: We demonstrated a significant correlation between LMWH anti-Xa activity and rivaroxaban ( R = 0.947) or apixaban ( R = 0.959) concentration and a significant correlation between rivaroxaban and apixaban plasma concentration ( R = 0.972). A LMWH anti-Xa activity <0.50 IU/mL could exclude a plasma concentration of rivaroxaban and apixaban >30 ng/mL and indicate the feasibility of invasive procedure. Conclusion and Relevance: In the absence of a specific test, LMWH-calibrated anti-Xa assay could be used to determine the presence and evaluate the plasma concentration of oral anti-Xa inhibitors. However, these initial findings require confirmation using other chromogenic calibrated oral anti-Xa assays.
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http://dx.doi.org/10.1177/1060028018811657DOI Listing
April 2019

Management of dabigatran after overdosage: two case reports and suggestions for monitoring.

Blood Coagul Fibrinolysis 2018 Nov;29(7):653-655

Normandie Univ, UNIROUEN, INSERM U1096, Rouen University Hospital, Vascular Hemostasis Unit.

: Bleeding is the main complication of anticoagulant treatments as dabigatran etexilate. In patients with atrial fibrillation, dabigatran, at certain doses, has been associated with similar rates of stroke and embolism, and a lower rate of major hemorrhage compared to warfarin. Before the recent possibility of reversing the anticoagulant effect of dabigatran with idarucizumab, prothrombin complex concentrate (PCC) was the main available treatment in cases of severe bleeding or emergency surgery . We describe two different cases with very high overdosage in which PCC or idarucizumab was used to reverse the effect of dabigatran etexilate.
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http://dx.doi.org/10.1097/MBC.0000000000000763DOI Listing
November 2018

Development of a thrombin generation test in cultured endothelial cells: Evaluation of the prothrombotic effects of antiphospholipid antibodies.

Thromb Res 2018 09 17;169:87-92. Epub 2018 Jul 17.

Normandie Univ, UNIROUEN, INSERM U1096, Rouen University Hospital, Vascular Hemostasis Unit, F 76000 Rouen, France. Electronic address:

Introduction: Circulating antiphospholipid antibodies (APL) induce vascular injury and endothelial dysfunction, which are associated with thrombotic events and/or fetal loss. We developed a model in which calibrated automated thrombin generation (CAT) is carried out in wells lined with cultured endothelial cells. Then we investigated how far b2GP1 antibodies provoked thrombin generation (TG) enhancing effects in these cells and/or in blood platelets.

Materials And Methods: Thrombin generation induced by different concentrations of tissue factor and different levels of endothelial aortic cell confluence was investigated by calibrated automated thrombogram. Endothelial cells were incubated with the purified anti-β2glycoprotein I antibodies of patients with antiphospholipid syndrome (APS). Platelet free plasma and platelet rich plasma were used to study thrombin generation in endothelial cells and platelet reactivity, respectively.

Results: Endothelial cell confluence was negatively correlated with thrombin generation which was dependent on the concentration of APL incubated. Activation of endothelial cells with APL significantly increased thrombin generation triggered by PFP. Triggering by PRP increased thrombinogram parameters. Moreover, anti-β2glycoprotein I antibodies incubated with platelet significantly amplified thrombin formation in PRP and induced platelet activation without tissue factor.

Conclusion: In this in vitro study, we demonstrate the feasibility of using thrombin generation test in cultured endothelial cells and suggest the need to realize adjustments to standardize results. The mechanism of prothrombotic states in APS requires endothelial dysfunction and platelet activation. The quantification of thrombin formation shows that APL incubation induces endothelial injury in cultured cells amplified by platelets.
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http://dx.doi.org/10.1016/j.thromres.2018.07.021DOI Listing
September 2018

Thrombin generation test as a marker for high risk venous thrombosis pregnancies.

J Thromb Thrombolysis 2018 Jan;45(1):114-121

Normandie Univ, UNIROUEN, Inserm 1096, Department of Biological Hematology, Rouen University Hospital, F 76000, Rouen, France.

Pregnancy is a well-established risk factor for venous thromboembolism and is associated with a state of hypercoagulability. The use of sensitive and specific biological markers to predict risk factors for thrombosis is essential during pregnancy. Our objective was to investigate the usefulness of thrombin generation test (TGT) as a marker to predict the risk of thrombosis in high risk venous thrombosis (HRVT) pregnancies compared to normal pregnancies. This retrospective study enrolled 134 women with HRVT pregnancies, 78 of whom had monozygotic, spontaneous and untreated pregnancies and formed the study group. The control group comprised 106 women with normal pregnancies. Routine assessment of coagulation activation markers: fibrinogen, D-dimer, prothrombin fragments 1 + 2 (F1 + 2), thrombin-antithrombin complexes (TAT) and fibrin monomer complexes (FMC) was performed every 5 weeks in the study group to detect a possible pathological state of hypercoagulability. TGT was performed using platelet-free plasma, 1 and 5 pM tissue factor (TF), supplemented by phospholipids (PL) ± thrombomodulin. Fibrinogen, D-dimer, F1 + 2, and TAT, but not FMC, increased significantly throughout pregnancy in both groups but no difference was shown between the groups. TGT showed an early increase in thrombin generation in both groups, which stabilized during the second month of pregnancy. No correlation was demonstrated between thrombin generation parameters and coagulation activation markers. Based on our results, TGT did not prove conclusive as a marker to predict the risk of thrombosis in HRVT pregnancies. Finding a sensitive and specific biological marker to predict thrombosis risk requires further investigation.
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http://dx.doi.org/10.1007/s11239-017-1572-3DOI Listing
January 2018

Adjusted value of thromboprophylaxis in hospitalized obese patients: A comparative study of two regimens of enoxaparin: The ITOHENOX study.

Thromb Res 2017 Jul 12;155:1-5. Epub 2017 Apr 12.

Department of internal medicine, vascular and thrombosis unit, Rouen University Hospital, Rouen, France. Electronic address:

Thromboprophylaxis is a mainstay of hospital care in patients at high risk of thrombosis. Fixed doses of low-molecular-weight heparin (LMWH) are recommended for thromboprophylaxis in patients admitted to hospital for an acute medical condition. However, the distribution of LMWH is weight-based, and the efficacy of standard doses in obese patients may be decreased. Data for obese patients are mainly available in bariatric surgery with extremely obese patients who are at greater risk of venous thromboembolism than those hospitalized for a medical condition. We conducted a randomized control trial in medically obese inpatients (BMI≥30kg/m) assessing two regimens of enoxaparin (40mg and 60mg SQ daily) in order to determine whether a stronger dosage would achieve higher anti-Xa level suitable for thromboprophylaxis. Between September 2013 and April 2015, 91 patients were included in the study (mean (±standard deviation) age was 70.4±10.7years, average BMI 37.8±6.4kg/m). Main indications of thromboprophylaxis were mainly acute infection (50%), acute respiratory failure (10%), acute congestive heart failure (9%) and acute rheumatic disorders (18%). Average anti-Xa activity, measured 4h after the third administration of enoxaparin was 0.25±0.09IU/mL in group 1 (enoxaparin 40mg) and 0.35±0.13IU/mL in group 2 (enoxaparin 60mg) (P<10). The proportions of patients with normal anti-Xa activity (between 0.32 and 0.54IU/mL) were 31% (n=11) and 69% (n=24) in group 1 and 2 respectively (P=0.007). The proportions of anti-Xa activity measurement below the normal range were 64% and 36% in group 1 and 2 (P<10) respectively. Subgroup analysis focusing on high weight patients (above 100kg, n=45) showed a marked difference in the proportion of patients with normal anti-Xa activity between group 1 (9%) and 2 (44%) (P=0.009). No venous thromboembolism occurred during the study and one patient in group 1 died because of hemorrhagic shock due to a gastric ulcer. Incidence of adverse events was not different between the two groups (P=0.52). In conclusion, the ITOHENOX study shows in medically obese inpatients that thromboprophylaxis with enoxaparin 60mg provides higher control of anti-Xa activity, without more bleeding complications than the standard enoxaparin regimen. This trial is registered with ClinicalTrials.gov, number NCT01707732.
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http://dx.doi.org/10.1016/j.thromres.2017.04.011DOI Listing
July 2017

Acquired hemophilia possibly induced by etanercept in a patient with rheumatoid arthritis.

Joint Bone Spine 2015 May 20;82(3):200-2. Epub 2015 Jan 20.

Service de rhumatologie, CHU-Hôpitaux de Rouen, Inserm U905, CRB CIC 1404, IRIB, Université de Rouen, 76031 Rouen Cedex, France.

A 47-year-old woman with rheumatoid arthritis (RA) treated successively with infliximab, abatacept, and etanercept spontaneously developed subcutaneous bruises and a noncompressive hematoma 11 months after starting etanercept therapy (50mg/week). Her prothrombin time was normal but her activated partial thromboplastin time was increased to 2.48 (normal range, 0.85-1.17). She had a circulating anticoagulant (Rosner index, 45; normal,<13) due to an anti-factor VIII antibody in a titer of 45 Bethesda units. Her factor VIII level was less than 1% (normal range, 55-150). The etanercept and leflunomide were stopped and prednisone was given in a daily dosage of 1mg/kg, in combination with rituximab, two 1-g doses at an interval of 2 weeks. After 5 months, persistence of the anti-factor VIII antibody prompted the initiation of azathioprine therapy, 2mg/kg/d. A remission was achieved 9 months after the diagnosis of acquired hemophilia and was sustained at last follow-up after 3 years. This new case of acquired hemophilia in a patient with RA may reflect a simple association or an inducing role of etanercept.
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http://dx.doi.org/10.1016/j.jbspin.2014.12.003DOI Listing
May 2015

Comparative study of the effect of rivaroxaban and fondaparinux on monocyte's coagulant activity and cytokine release.

Exp Hematol Oncol 2014 17;3(1):30. Epub 2014 Dec 17.

Laboratory MERCI (EA 3829), Faculty of Medicine and Pharmacy, CHU Rouen, Rouen, France.

Objectives: Tissue factor (TF) exposed on activated monocytes and macrophages is involved in thrombosis through activation of factor X and cytokine release, responsible for inflammation and thrombosis. We investigated the effect of two anti-factor Xa drugs: rivaroxaban, a direct anti-Xa inhibitor, and fondaparinux, an antithrombin dependent anti-Xa inhibitor, on monocyte/macrophage procoagulant activity and cytokine release.

Methods: Rivaroxaban and fondaparinux were tested at pharmacological concentrations on LPS-activated monocytes and on THP-1 cells, a human monocytic cell line, to assess 1) TF expression by flow cytometry 2) prothrombinase activity by its coagulant activity and 3) cytokine release in cell supernatants by antibody based cytokine array and ELISA for IL-8 and TNFα.

Results And Conclusion: Rivaroxaban and fondaparinux did not modify TF expression level on activated cells. In contrast procoagulant activity associated to monocytes and macrophages was dose dependently inhibited by rivaroxaban, but not significantly by fondaparinux. These results could explain why patients undergoing major orthopedic surgery with rivaroxaban prophylaxis were able to achieve significant reductions in venous thromboembolism, compared with drugs commonly used, i.e. fondaparinux and low molecular weight heparin. In addition, rivaroxaban and fondaparinux suppressed some chemokine secretion produced by activated macrophages. This may also contribute to their antithrombotic effect in clinic.
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http://dx.doi.org/10.1186/2162-3619-3-30DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4298120PMC
January 2015

Involvement of Arg306 mutation in factor V gene in two young men with ischemic stroke.

Blood Coagul Fibrinolysis 2014 Dec;25(8):916-7

aUnit of Haemostasis, Rouen University Hospital, bDepartment of Neurology, Rouen University Hospital cINSERM, U1096 Institute for Research and Innovation in Biomedicine, Rouen University Hospital, Rouen, France.

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http://dx.doi.org/10.1097/MBC.0000000000000165DOI Listing
December 2014

Role of Toll-like receptors 2 and 4 in mediating endothelial dysfunction and arterial remodeling in primary arterial antiphospholipid syndrome.

Arthritis Rheumatol 2014 Nov;66(11):3210-20

Rouen University Hospital, INSERM U1096, University of Rouen, and Centre d'Investigation Clinique, INSERM 1404, Rouen, France.

Objective: To assess the role of Toll-like receptors (TLRs) in antiphospholipid antibody (aPL)-mediated vascular abnormalities in patients with primary arterial antiphospholipid syndrome (APS).

Methods: Forty-eight subjects participated in the study. Arterial function and structure and TLR pathway activation were determined in patients with primary arterial APS and matched controls. The pathogenic effects of aPL isolated from patients were assessed in wild-type (WT) and TLR-knockout mice.

Results: APS patients had endothelial dysfunction, arterial stiffening, and hypertrophy, as evidenced by decreased brachial artery endothelium-dependent flow-mediated dilation (FMD) and increased aortic pulse wave velocity and carotid intima-media thickness (IMT), as compared with controls. Plasma samples from APS patients revealed decreased nitric oxide (NO) availability and a pro-oxidative, proinflammatory, and prothrombotic state illustrated by a decrease in nitrite and an increase in lipid peroxidation, tumor necrosis factor α levels, and tissue factor (TF) levels. Furthermore, TLR pathway activation was found in APS patients with increased TLR-2 and TLR-4 messenger RNA expression and increased protein levels of the activated TLR transduction protein interleukin-1 receptor-associated kinase 1 in peripheral blood mononuclear cells. Moreover, agonist-stimulated cell-surface expression of TLR-2 and TLR-4 in circulating monocytes was higher in APS patients than in controls. These changes were positively associated with IMT and negatively associated with FMD. Finally, aPL injection decreased mesenteric endothelium-dependent relaxation and increased TF expression in WT mice but not in TLR-2- or TLR-4-knockout mice.

Conclusion: This translational study supports the notion that TLR-2 and TLR-4 play a role in mediating vascular abnormalities in patients with primary arterial APS. TLRs thus constitute a promising pharmacologic target for preventing cardiovascular complications in APS.
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http://dx.doi.org/10.1002/art.38785DOI Listing
November 2014

Analysis of 339 pregnancies in 181 women with 13 different forms of inherited thrombocytopenia.

Haematologica 2014 Aug 24;99(8):1387-94. Epub 2014 Apr 24.

Department of Medicine and Haematology, University Hospital of Verona, Verona, Italy.

Pregnancy in women with inherited thrombocytopenias is a major matter of concern as both the mothers and the newborns are potentially at risk of bleeding. However, medical management of this condition cannot be based on evidence because of the lack of consistent information in the literature. To advance knowledge on this matter, we performed a multicentric, retrospective study evaluating 339 pregnancies in 181 women with 13 different forms of inherited thrombocytopenia. Neither the degree of thrombocytopenia nor the severity of bleeding tendency worsened during pregnancy and the course of pregnancy did not differ from that of healthy subjects in terms of miscarriages, fetal bleeding and pre-term births. The degree of thrombocytopenia in the babies was similar to that in the mother. Only 7 of 156 affected newborns had delivery-related bleeding, but 2 of them died of cerebral hemorrhage. The frequency of delivery-related maternal bleeding ranged from 6.8% to 14.2% depending on the definition of abnormal blood loss, suggesting that the risk of abnormal blood loss was increased with respect to the general population. However, no mother died or had to undergo hysterectomy to arrest bleeding. The search for parameters predicting delivery-related bleeding in the mother suggested that hemorrhages requiring blood transfusion were more frequent in women with history of severe bleedings before pregnancy and with platelet count at delivery below 50 × 10(9)/L.
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http://dx.doi.org/10.3324/haematol.2014.105924DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4116839PMC
August 2014

[Comparison between the centrifugation on MPA C10 (Roche Diagnostics) and the centrifugation according recommendations of GEHT (Groupe d'étude de l'hémostase et de la thrombose) for the daily hemostasis assays].

Ann Biol Clin (Paris) 2014 Mar-Apr;72(2):231-5

Unité fonctionnelle d'hémostase, hématologie biologique, Institut de biologie clinique, CHU de Rouen, France.

Actually, many laboratories tend to acquire pre analytic automates to prepare specimens for analysis. For haemostasis, these pre analytical modules are not always in agreement with the recommendations from the Groupe d'étude de l'hémostase et de la thrombose (GEHT). For example in the MPA C10 module (Roche Diagnostics) the speed of centrifugation was not rather fast compared with the GEHT recommandations. Then, to be able to use this automate for routine coagulation assays, we compared results of Quick time, activated partial prothombin time, fibrinogen, factor II, factor V, factor VII, factor X and antithrombin levels and unfractioned heparin anti-Xa activity measurement after MPA (1,885 g - 999 sec) or GEHT (2,500 g - 900 sec) protocol of centrifugation. First, we verified platelet counts: in 82% of specimens, the platelet counts were under 10.10(9)/L after centrifugation on MPA module. Moreover, a good correlation was observed in all comparisons. Then we concluded the MPA C10 module was usable for routine coagulation tests.
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http://dx.doi.org/10.1684/abc.2014.0941DOI Listing
January 2015

Comparison of markers of coagulation activation and thrombin generation test in uncomplicated pregnancies.

Thromb Res 2013 Sep 2;132(3):386-91. Epub 2013 Aug 2.

Unit of Haemostasis, Rouen University Hospital, Rouen, France.

Introduction: Pregnancy is a well-established risk factor for venous thromboembolism, and is associated with a state of hypercoagulability or parameters of thrombin generation. Currently, there is a lack of consensual data on thrombin generation during pregnancy. This study aimed to find a sensitive and specific biological marker of coagulation activation and to identify parameters of thrombin generation.

Patients And Methods: The population included 101 women with uncomplicated pregnancies. The objective of this study was to correlate thrombin generation test (measured at 5pM tissue factor, 4μM lipids and without thrombomodulin), with fibrinogen and markers of blood coagulation activation: D-dimer, prothrombin fragments 1+2 (F1+2), thrombin-antithrombin complexes (TAT) and fibrin monomer complexes (FMC) in these women. Internal quality control was performed in each set of experiments.

Results: Fibrinogen, D-dimer, F1+2, and TAT concentrations increased significantly throughout pregnancy, and were correlated with term of pregnancy. In our study, thrombin generation seemed to increase early on, and then remained stable throughout normal pregnancy, in contrast with other markers of blood coagulation activation, excepting FMC. The latter are subject to large inter-individual variations, especially during second trimester. No correlation was demonstrated between thrombin generation parameters and other activation markers.

Conclusion: While markers of coagulation activation significantly increased during pregnancy, thrombin generation increased only early on and remains stable during pregnancy. Finding a sensitive and specific biological marker for vascular pregnancy complications, such as FMC and thrombin generation levels, requires further investigation.
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http://dx.doi.org/10.1016/j.thromres.2013.07.022DOI Listing
September 2013

Risk of venous thromboembolism associated with single and combined effects of Factor V Leiden, Prothrombin 20210A and Methylenetethraydrofolate reductase C677T: a meta-analysis involving over 11,000 cases and 21,000 controls.

Eur J Epidemiol 2013 Aug 31;28(8):621-47. Epub 2013 Jul 31.

Institute of Public Health - Section of Hygiene, Department of Public Health, Università Cattolica del Sacro Cuore, L.go F.Vito 1, 00168, Rome, Italy.

Genetic and environmental factors interact in determining the risk of venous thromboembolism (VTE). The risk associated with the polymorphic variants G1691A of factor V (Factor V Leiden, FVL), G20210A of prothrombin (PT20210A) and C677T of methylentetrahydrofolate reductase (C677T MTHFR) genes has been investigated in many studies. We performed a pooled analysis of case-control and cohort studies investigating in adults the association between each variant and VTE, published on Pubmed, Embase or Google through January 2010. Authors of eligible papers, were invited to provide all available individual data for the pooling. The Odds Ratio (OR) for first VTE associated with each variant, individually and combined with the others, were calculated with a random effect model, in heterozygotes and homozygotes (dominant model for FVL and PT20210A; recessive for C677T MTHFR). We analysed 31 databases, including 11,239 cases and 21,521 controls. No significant association with VTE was found for homozygous C677T MTHFR (OR: 1.38; 95 % confidence intervals [CI]: 0.98-1.93), whereas the risk was increased in carriers of either heterozygous FVL or PT20210 (OR = 4.22; 95 % CI: 3.35-5.32; and OR = 2.79;95 % CI: 2.25-3.46, respectively), in double heterozygotes (OR = 3.42; 95 %CI 1.64-7.13), and in homozygous FVL or PT20210A (OR = 11.45; 95 %CI: 6.79-19.29; and OR: 6.74 (CI 95 % 2.19-20.72), respectively). The stratified analyses showed a stronger effect of FVL on individuals ≤ 45 years (p value for interaction = 0.036) and of PT20210A in women using oral contraceptives (p-value for interaction = 0.045). In this large pooled analysis, inclusive of large studies like MEGA, no effect was found for C677T MTHFR on VTE; FVL and PT20210A were confirmed to be moderate risk factors. Notably, double carriers of the two genetic variants produced an impact on VTE risk significantly increased but weaker than previously thought.
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http://dx.doi.org/10.1007/s10654-013-9825-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3935237PMC
August 2013

Factor v Leiden homozygous genotype and pregnancy outcomes.

Obstet Gynecol 2009 Dec;114(6):1249-1253

From the Laboratoire d'Hématologie, CHRU Saint-Eloi, Montpellier; Pôle d'Hématologie-Transfusion, Centre de Biologie Pathologie, CHRU bd du Pr. Leclerc, Lille; Hémostase Vasculaire - Hématologie Biologique, CHRU Ch. Nicolle, Rouen; Laboratoire d'Hématologie, CHRU Trousseau, Tours; Laboratoire d'hématologie, CHRU, Caen; Laboratoire d'hématologie, CHRU du bocage, Dijon; Laboratoire d'Hématologie et d'Oncologie Biologique, CHRU, Poitiers; Laboratoire d'hématologie, C.H. J. Monod, 29, Le Havre; Hématologie Biologique, CHRU, Grenoble; and Laboratoire d'Hématologie, CHRU bd J Moulin, Marseille, France.

Objective: To assess the rate of early (first trimester) and late (second and third trimester) fetal loss in women who are factor V Leiden homozygous.

Methods: Between December 1995 and February 2007, consecutive, unrelated white women who were factor V Leiden homozygous and who had been pregnant at least once were recruited from 10 French hemostasis units. For reasons of comparison, we included women who were factor V Leiden heterozygous and a group of noncarriers. The frequency of early and late fetal loss was assessed retrospectively and compared among the three groups. The effect of concomitant thrombophilic abnormalities was evaluated. The overall pregnancy outcome was reported.

Results: We analyzed 240 thromboprophylaxis-free pregnancies in 95 women who were factor V Leiden homozygous, 425 in 195 women who were factor V Leiden heterozygous, and 182 in 73 women who were noncarriers. The risk of late fetal loss was higher in women who were homozygous (13/95, 13.7%) compared with those who were noncarriers (1/73, 1.4%, odds ratio 11.41, 95% confidence interval 1.46-89.46, P=.002), whereas it was similar in women who were heterozygous and in noncarriers (6/195, 3.1% compared with 1/73, 1.4%, P=.68). The percentage of women with early fetal loss was similar in the three groups (P=.81). The live-birth rate was 80%, 84%, and 85%, respectively, for women who where homozygous, heterozygous, and noncarriers (P=.88).

Conclusion: The factor V Leiden homozygous genotype increases the risk of late fetal loss. However, the overall likelihood of a positive outcome is high in our series of women who were homozygous.

Level Of Evidence: III.
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http://dx.doi.org/10.1097/AOG.0b013e3181c2243dDOI Listing
December 2009

Rare genotypes of protein Z gene are a risk factor for premature myocardial infarction but not protein Z plasma level.

Thromb Haemost 2009 Jul;102(1):131-6

Unit of Vascular Haemostasis, Rouen University Hospital, Rouen, France.

Protein Z (PZ) is the cofactor of PZ dependent inhibitor (ZPI) that inhibits activated coagulation factor X. PZ was expected to play a role in coronary artery disease (CAD) but with inconsistent clinical findings. We therefore evaluated whether PZ plasma level and/or three genetic variants encoding for low PZ plasma level were associated with premature CAD in stable young post-myocardial infarction (MI) patients. PZ plasma level and three polymorphisms A-13G, G-103A and G79A were determined in 176 young stable post-MI patients and in 176 sex- and age-matched controls (FITE-NAT population). Moreover the genotypes, resulting from the combination of the three polymorphisms (A-13G/G-103A/G79A), were studied. PZ plasma level and the number of patients disclosing a PZ deficiency did not differ between post-MI patients and controls. The presence of the mutated allele for each polymorphism was associated with a significantly reduced level of PZ. The A-13G polymorphism was associated with premature CAD only in univariate analysis. Whereas, the presence of rare genotypes of PZ gene was an independent risk factor for premature CAD. In conclusion, PZ plasma level is not a key player in the pathophysiology of premature coronary artery disease. But, rare genotypes of PZ gene were found to be associated with premature CAD.
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http://dx.doi.org/10.1160/TH09-01-0007DOI Listing
July 2009

Factor V Cambridge mutation and activated protein C resistance assays.

Thromb Haemost 2006 Mar;95(3):581-3

Rouen University Hôpital, Faculty of Medicine, Rouen, France.

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http://dx.doi.org/10.1160/TH05-11-0740DOI Listing
March 2006