Publications by authors named "Claire Flaujac"

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

Role of oculocerebrorenal syndrome of Lowe (OCRL) protein in megakaryocyte maturation, platelet production and functions: a study in patients with Lowe syndrome.

Br J Haematol 2021 Mar 2;192(5):909-921. Epub 2021 Feb 2.

Université de Paris, Innovations Thérapeutiques en Hémostase, Paris, INSERM U1140, France.

Lowe syndrome (LS) is an oculocerebrorenal syndrome of Lowe (OCRL1) genetic disorder resulting in a defect of the OCRL protein, a phosphatidylinositol-4,5-bisphosphate 5-phosphatase containing various domains including a Rho GTPase-activating protein (RhoGAP) homology domain catalytically inactive. We previously reported surgery-associated bleeding in patients with LS, suggestive of platelet dysfunction, accompanied with a mild thrombocytopenia in several patients. To decipher the role of OCRL in platelet functions and in megakaryocyte (MK) maturation, we conducted a case-control study on 15 patients with LS (NCT01314560). While all had a drastically reduced expression of OCRL, this deficiency did not affect platelet aggregability, but resulted in delayed thrombus formation on collagen under flow conditions, defective platelet spreading on fibrinogen and impaired clot retraction. We evidenced alterations of the myosin light chain phosphorylation (P-MLC), with defective Rac1 activity and, inversely, elevated active RhoA. Altered cytoskeleton dynamics was also observed in cultured patient MKs showing deficient proplatelet extension with increased P-MLC that was confirmed using control MKs transfected with OCRL-specific small interfering(si)RNA (siOCRL). Patients with LS also had an increased proportion of circulating barbell-shaped proplatelets. Our present study establishes that a deficiency of the OCRL protein results in a defective actomyosin cytoskeleton reorganisation in both MKs and platelets, altering both thrombopoiesis and some platelet responses to activation necessary to ensure haemostasis.
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http://dx.doi.org/10.1111/bjh.17346DOI Listing
March 2021

Rapid screening of COVID-19 patients using white blood cell scattergrams, a study on 381 patients.

Br J Haematol 2020 09 5;190(5):718-722. Epub 2020 Jul 5.

Department of Pharmacology, CH Versailles, Le Chesnay, France.

Complementary tools are warranted to increase the sensitivity of the initial testing for COVID-19. We identified a specific 'sandglass' aspect on the white blood cell scattergram of COVID-19 patients reflecting the presence of circulating plasmacytoid lymphocytes. Patients were dichotomized as COVID-19-positive or -negative based on reverse transcriptase polymerase chain reaction (RT-PCR) and chest computed tomography (CT) scan results. Sensitivity and specificity of the 'sandglass' aspect were 85·9% and 83·5% respectively. The positive predictive value was 94·3%. Our findings provide a non-invasive and simple tool to quickly categorize symptomatic patients as either COVID-19-probable or -improbable especially when RT-PCR and/or chest CT are not rapidly available.
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http://dx.doi.org/10.1111/bjh.16943DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7323204PMC
September 2020

Real Life Population Pharmacokinetics Modelling of Eight Factors VIII in Patients with Severe Haemophilia A: Is It Always Relevant to Switch to an Extended Half-Life?

Pharmaceutics 2020 Apr 21;12(4). Epub 2020 Apr 21.

Department of Medical Pharmacology, University Hospital of Reims, EA3801, SFR Cap-Santé, University of Reims, 51100 Reims, France.

We retrospectively analysed the data files of 171 adults and 87 children/adolescents with severe haemophilia, except for 14 patients (moderate; minor) (1), to develop a global population pharmacokinetic (PK) model for eight factors VIII (FVIII) that could estimate individual PK parameters for targeting the desired level of FVIII activity (FVIII:C); and (2) to compare half-life (HL) in patients switching from a standard half-life (SHL) to an extended half-life (EHL) and evaluate the relevance of the switch. One-stage clotting assay for the measurement of FVIII activity (FVIII:C, IU/mL) was used for population PK modelling. The software, Monolix version 2019R1, was used for non-linear mixed-effects modelling. A linear two-compartment model best described FVIII:C. The estimated PK parameters (between-subject variability) were: 2640 mL (23.2%) for volume of central compartment (V1), 339 mL (46.8%) for volume of peripheral compartment (V2), 135 mL/h for Q (fixed random effect), and 204 mL/h (34.9%) for clearance (Cl). Weight, age, and categorical covariate EHL were found to influence Cl and only weight for V1. This model can be used for all of the FVIII cited in the study. Moreover, we demonstrated, in accordance with previous studies, that Elocta had longer half-life (EHL) than SHL (mean ratio: 1.48) as compared to Advate, Factane, Kogenate, Novoeight, and Refacto.
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http://dx.doi.org/10.3390/pharmaceutics12040380DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7238177PMC
April 2020

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

Multicentre pharmacokinetic evaluation of rFVIII-Fc (efmoroctocog alfa) in a real life and comparison with non-extended half-life FVIII concentrates.

Haemophilia 2020 Mar 27;26(2):282-289. Epub 2020 Feb 27.

Laboratoire d'Hémostase Hémobiologie, CHU de Lille, Lille, France.

The use of enhanced half-life (EHL) FVIII has improved the quality of prophylaxis in haemophilia A, but with a benefit that may vary from one patient to another. We analysed the pharmacokinetic data obtained with efmoroctocog alfa (rFVIII-Fc) in 114 patients and, in 47 cases, compared them to those previously measured with non-EHL FVIII. The in vivo recovery (IVR) of rFVIII-Fc measured with one stage clotting assay (OSA) and chromogenic assay (CSA) was 2.2 and 2.8 IU/mL per IU/kg, respectively. The median half-life (T ) of rFVIII-Fc was 14.5 hours whatever the FVIII:C assay used, but variable and correlated with preinfusion VWF:Ag levels (r = .76). Both IVR and T were lower in patients under 12 years old (2.4 IU/mL per IU/kg and 11.1 hours, respectively; CSA). PK study of rFVIII-Fc vs non-EHL FVIII showed a T ratio of 1.4 in favour of rFVIII-Fc, regardless of the patient's age. However the relative increase in T with rFVIII-Fc was lower than 30% in one-third of patients evaluated, particularly when the previous FVIII administered was a BHK-derived product. This study therefore suggests that analysis of individual PK profile in response to a specific FVIII concentrate is potentially useful before a switch in haemophilia A patients.
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http://dx.doi.org/10.1111/hae.13946DOI Listing
March 2020

[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

Guidelines for certification of International Normalized Ratio (INR) for vitamin K antagonists monitoring according to the EN ISO 22870 standards.

Ann Biol Clin (Paris) 2018 Jun;76(3):271-299

Laboratoire central d'hématologie, Hôpital Necker, AP-HP, Paris, France.

Point of care testing (POCT) must comply with regulatory requirements according to standard EN ISO 22870, which identify biologists as responsible for POCT. INR for vitamin K antagonists (VKAs) monitoring is a test frequently performed in haemostasis laboratories. Bedside INR is useful in emergency room, in particular in case of VKAs overdosage but also for specific populations of patients like paediatrics or geriatrics. INR POCT devices are widely used at home by the patients for self-testing, but their use in the hospital by the clinical staff for bedside measurement is growing, with devices which now comply with standard for POCT accreditation for hospital use. The majority of point of care devices for INR monitoring has shown a good precision and accuracy with results similar to those obtained in laboratory. With the aim to help the multidisciplinary groups for POCT supervision, the medical departments and the biologists to be in accordance with the standard, we present the guidelines of the GFHT (Groupe français d'étude sur l'hémostase et la thrombose, subcommittee "CEC et biologie délocalisée") for the certification of POCT INR. These guidelines are based on the SFBC guidelines for the certification of POCT and on the analysis of the literature to ascertain the justification of clinical need and assess the analytical performance of main analysers used in France, as well as on a survey conducted with biologists.
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http://dx.doi.org/10.1684/abc.2018.1332DOI Listing
June 2018

Are Screening Tests Reliable to Rule Out Direct Oral Anticoagulant Plasma Levels at Various Thresholds (30, 50, or 100 ng/mL) in Emergency Situations?

Chest 2018 01;153(1):288-290

Service d'Hématologie biologique, Hôpital Lariboisière (Assistance Publique-Hôpitaux de Paris), Paris, France; INSERM UMR-S 1140, Université Paris Descartes, Sorbonne Paris Cité, Paris, France. Electronic address:

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http://dx.doi.org/10.1016/j.chest.2017.09.047DOI Listing
January 2018

First venous thromboembolism and hormonal contraceptives in young French women.

Medicine (Baltimore) 2017 Aug;96(34):e7734

University Paris-Saclay and Paris-Sud, UVSQ, CESP, U1018, INSERM, Villejuif Gynecology Endocrinology Unit, Port-Royal Hospital, Paris University Paris Descartes Hematology Biology Unit, Hôpital Universitaire Paris centre, Paris, France.

Information on the clinical and biological characteristics of combined hormonal contraceptives (CHC) users experiencing a venous thromboembolism (VTE) event is scarce. Better knowledge of factors determining the VTE risk in CHC users could help identify women at high risk.Data were obtained from a large cohort of consecutive women with the first documented VTE event. Cross-sectional analysis of clinical and biological characteristics of the women was performed.Of the 3009 women with the first VTE included, 31% were nonusers and 69% CHC users at time of VTE. CHC users were significantly younger (29.0 ± 7.2) than nonusers (31.6 ± 7.1) (P < .001). No difference in VTE familial history was observed between the 2 groups. Compared with nonusers, the CHC users experienced more frequently pulmonary embolism: odds ratio (OR) = 1.28 (1.06-1.55; 95% confidence interval [CI]), factor V Leiden mutations were more frequent in this group (OR = 1.41 [1.11-1.80; 95% CI]). Venous sclerotherapy and travel were associated with VTE in CHC users, whereas surgery and bed rest were significantly associated with VTE in nonusers. Finally, 2/3 of CHC users with VTE had additional VTE risk factors.CHC users experiencing the first VTE differ from nonusers with respect to clinical and genetic background. Better understanding of the characteristics of VTE and associated risk factors could allow more appropriate management of these women and contribute to more accurate benefit-risk assessment before prescribing a CHC.
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http://dx.doi.org/10.1097/MD.0000000000007734DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5571999PMC
August 2017

Bleeding risk of surgery and its prevention in patients with inherited platelet disorders.

Haematologica 2017 07 6;102(7):1192-1203. Epub 2017 Apr 6.

Department of Medicine, Section of Internal and Cardiovascular Medicine, University of Perugia, Italy

Excessive bleeding at surgery is a feared complication in patients with inherited platelet disorders. However, very few studies have evaluated the frequency of surgical bleeding in these hemorrhagic disorders. We performed a worldwide, multicentric, retrospective study to assess the bleeding complications of surgery, the preventive and therapeutic approaches adopted, and their efficacy in patients with inherited platelet disorders: the Surgery in Platelet disorders And Therapeutic Approach (SPATA) study. We rated the outcome of 829 surgical procedures carried out in 423 patients with well-defined forms of inherited platelet disorders: 238 inherited platelet function disorders and 185 inherited platelet number disorders. Frequency of surgical bleeding was high in patients with inherited platelet disorders (19.7%), with a significantly higher bleeding incidence in inherited platelet function disorders (24.8%) than in inherited platelet number disorders (13.4%). The frequency of bleeding varied according to the type of inherited platelet disorder, with biallelic Bernard Soulier syndrome having the highest occurrence (44.4%). Frequency of bleeding was predicted by a pre-operative World Health Organization bleeding score of 2 or higher. Some types of surgery were associated with a higher bleeding incidence, like cardiovascular and urological surgery. The use of pre-operative pro-hemostatic treatments was associated with a lower bleeding frequency in patients with inherited platelet function disorders but not in inherited platelet number disorders. Desmopressin, alone or with antifibrinolytic agents, was the preventive treatment associated with the lowest bleedings. Platelet transfusions were used more frequently in patients at higher bleeding risk. Surgical bleeding risk in inherited platelet disorders is substantial, especially in inherited platelet function disorders, and bleeding history, type of disorder, type of surgery and female sex are associated with higher bleeding frequency. Prophylactic pre-operative pro-hemostatic treatments appear to be required and are associated with a lower bleeding incidence.
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http://dx.doi.org/10.3324/haematol.2016.160754DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5566025PMC
July 2017

Impact of a pneumatic tube system transport on hemostasis parameters measurement: the experiment of Cochin universitary hospital (AP-HP, Paris, France).

Ann Biol Clin (Paris) 2017 Feb;75(1):93-100

Service d'hématologie biologique, Hôpital Cochin, APHP, Paris, France.

Samples transported by pneumatic tube system are submitted to forces of acceleration and deceleration which can affect laboratory parameters. At Cochin hospital, majority of samples of hemostasis, except for platelets tests, are transported by pneumatic tube system. The objective of this study was to evaluate the impact of a pneumatic tube system (PTS) transport compared to hand-delivered transport on samples and to qualify Cochin hospital PTS according to requirements of standard ISO 15189. A bibliographical study was made and showed that pneumatic tube system particularly influences platelets tests. Four citrate tubes were collected in 5 healthy volunteers in the maternity: 2 tubes were transported by PTS and 2 others were hand-delivered to the laboratory. Five coagulation tests were analyzed: prothrombine time (PT), activated partial thromboplastin time (aPTT), factor (F) V, FVIII and platelet closure time with PFA-100TM collagen/epinephrine. For each volunteer, the results obtained by PTS and by hand-delivered transport were compared with formula usually used for biological analysis retake: 2.8 x standard deviation of reproductibility variation coefficient (SH GTA 01, COFRAC). This study did not show an impact of PTS on PT, aPTT, FV and FVIII. For PFA-100TM collagen/epinephrine, we noted an impact on 2/5 volunteers. These results, in agreement with the literature, led to the conclusion that Cochin hospital PTS is in compliance to transport samples for usual coagulation tests except platelet tests. This study allowed to issue French recommendations for PTS transport of hemostasis tubes qualification available on "Groupe français d'hémostase et thrombose" Web site.
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http://dx.doi.org/10.1684/abc.2016.1215DOI Listing
February 2017

Reply to: assessment of haemostasis in patients with liver cirrhosis.

Eur J Anaesthesiol 2017 01;34(1):35-36

From the Department of Anaesthesia and Intensive Care (CL, CMS), and Department of Biological Haematology (CF, IGT), Paris Descartes University, Faculty of Medicine, Assistance Publique - Hôpitaux de Paris, Cochin University Hospital, EA 3623, 27 rue du Faubourg Saint Jacques, 75679 Paris Cedex 14, France.

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http://dx.doi.org/10.1097/EJA.0000000000000496DOI Listing
January 2017

Reply to: thrombin generation tests and viscoelastic testing in cirrhosis: comparing apples and oranges?

Eur J Anaesthesiol 2017 01;34(1):38-39

From the Department of Anaesthesia and Intensive Care (CL, CMS) and the Department of Biological Haematology (CF, IGT), Faculty of Medicine, Assistance Publique - Hôpitaux de Paris, Cochin University Hospital, Paris Descartes University, Paris, France.

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http://dx.doi.org/10.1097/EJA.0000000000000513DOI Listing
January 2017

PT, aPTT, TT and the hemostatic safety threshold of dabigatran and rivaroxaban.

Ann Biol Clin (Paris) 2016 Aug;74(4):457-64

Laboratoire d'hématologie, Hôpitaux universitaires Paris Centre Cochin-Broca-Hôtel Dieu (AP-HP), Paris, France.

The proposals of the Working group on perioperative hemostasis (Groupe d'intérêt en hémostase péri-opératoire (GIHP)) concerning the perioperative management of patients receiving the direct oral anticoagulants (DOACs) are based on the measure of their anticoagulant activities (anti-Xa for rivaroxaban and anti-IIa for dabigatran) with a safety threshold ≤ 30 ng/mL. If the dosage of the drug is not available, proposals are based on the combination of a PT ≥80% and an aPTT ≤1.20. The aim of our study was to evaluate the performance of PT, aPTT and thrombin time to predict values above or below the safety threshold. The measurement of DOACs concentration was carried out in 64 samples from patients treated with rivaroxaban and 48 samples from patients treated with dabigatran. The PT and aPTT were measured for all samples, while the TT was measured only for patients receiving dabigatran. The absence of agreement between the global hemostasis tests and the DOACs concentrations was observed for 10% of patients receiving dabigatran and 27% of patients with rivaroxaban treatment. Apart from dabigatran for which the predictive negative value of PT and aPTT or TT allows to exclude a concentration >30 ng/mL in 100% of cases, our results highlight the risk of misinterpretation when using global coagulation tests (PT and aPPT) for determination of the safety threshold for patients receiving the DOACs.
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http://dx.doi.org/10.1684/abc.2016.1173DOI Listing
August 2016

Peri-procedural management of dabigatran and rivaroxaban: Duration of anticoagulant discontinuation and drug concentrations.

Thromb Res 2015 Oct 14;136(4):763-8. Epub 2015 Aug 14.

Inserm UMR-S1140, Faculté de Pharmacie, Paris, France; AP-HP, Hôpital Cochin, Laboratoire d'hématologie, Paris, France; Université Paris Descartes, Sorbonne Paris Cité, Paris, France.

Background: Peri-procedural management of direct oral anticoagulants (DOAC) is challenging. The optimal duration of pre-procedural discontinuation that guarantees a minimal DOAC concentration ([DOAC]) at surgery is unknown. The usual 48-hour discontinuation might not be sufficient for all patients.

Objectives: To test the hypothesis that a 48-hour DOAC discontinuation is not sufficient to ensure a minimal per-procedural [DOAC], defined as [DOAC]<30ng/mL. To investigate the factors associated with per-procedural [DOAC]. To evaluate the ability of normal PT and aPTT to predict [DOAC]<30ng/mL.

Methods: Patients treated with dabigatran or rivaroxaban, and requiring any invasive procedure were included in this multicentre, prospective, observational study. [DOAC], PT and aPTT were measured during invasive procedure.

Results: Sixty-five patients were enrolled. Duration of DOAC discontinuation ranged from 1-168h. Per-procedural [DOAC] ranged from <30 to 466ng/mL. [DOAC]<30ng/mL occurred more frequently after 48-hour discontinuation than after a shorter delay. [DOAC] remained ≥30ng/mL in 36% and 14% of measurements performed 24-48h and 48h-120h after discontinuation, respectively. According to ROC curve, a cut-off value of 120hours for DOAC discontinuation had a better specificity than a cut-off value of 48hours to predict [DOAC]<30ng/mL. Normal PT and aPTT ratios had good specificity and positive predictive value, but limited sensitivity (74%) and negative predictive value (73%) to predict [DOAC]<30ng/mL.

Conclusions: A 48-hour discontinuation does not guarantee a [DOAC]<30ng/mL in all patients. Normal PT and aPTT are flawed to predict this threshold and could not replace specific assays. Further studies are needed to define the relationship between per-procedural [DOAC] and clinical outcomes.
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http://dx.doi.org/10.1016/j.thromres.2015.08.006DOI Listing
October 2015

Assessment of haemostasis in patients with cirrhosis: Relevance of the ROTEM tests?: A prospective, cross-sectional study.

Eur J Anaesthesiol 2016 Feb;33(2):126-33

From the Department of Anaesthesia and Intensive Care (CL, MB, C-MS), Department of Biological Haematology (CF, FI, IG-T), and Hepatology Unit (PS), Paris Descartes University, Faculty of Medicine, Assistance Publique Hôpitaux de Paris, Cochin University Hospital, Paris Cedex, France.

Background: In patients with cirrhosis, decreased rotational thromboelastometry (ROTEM) parameters suggest hypocoagulability secondary to liver dysfunction. However, observed normal or increased thrombin generation suggests preserved haemostasis and/or a procoagulant state. The correlated levels of both coagulation factors and inhibitors also support preserved haemostasis.

Objective: The objective of this study is to investigate the correlation between three specific approaches of haemostasis (ROTEM, thrombin generation and coagulation factors/inhibitors) on the same plasma sample from patients with cirrhosis.

Design: A prospective, observational study.

Setting: Single university hospital.

Participants: Forty patients with cirrhosis.

Intervention: Measurement of the following factors: model for end-stage liver disease (MELD) scores; ROTEM maximum clot firmness (ROTEM-MCF) in EXTEM, INTEM, FIBTEM assays; fibrinogen; factors V and VIII; von Willebrand factor; protein C; protein S; antithrombin; and the thrombin generation test (TGT) enabling the calculation of endogenous thrombin potential without and with thrombomodulin, and the ratio of endogenous thrombin potential with-to-without thrombomodulin (regarded as an index of hypercoagulability).

Results: ROTEM-MCF values were distributed within the normal and hypocoagulation ranges; were correlated to variations in factor V, fibrinogen, protein C and S and antithrombin; and were inversely correlated to MELD scores (ρ > 0.5; P < 0.05). Levels of von Willebrand factor were above normal and were not correlated with any other factor levels. After addition of thrombomodulin, endogenous thrombin potential values were distributed within or above normal values. Factor V variation was correlated to the ratio of endogenous thrombin potential with-to-without thrombomodulin.

Conclusion: ROTEM indicated hypocoagulability correlated to liver dysfunction. In contrast, the TGT indicated a preserved or even increased coagulation profile (which was supported by the correlation between coagulant factors and inhibitors) and a potential for hypercoagulability inversely correlated to the degree of liver dysfunction. ROTEM may not be appropriate for haemostasis assessment in patients with liver cirrhosis and could lead to the unnecessary transfusion of fresh frozen plasma.

Trial Registration: S.C. 3024 - ID RCB: 2012-A01728-35.
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http://dx.doi.org/10.1097/EJA.0000000000000322DOI Listing
February 2016

[Non-VKA oral anticoagulants: an update for the clinical biologists].

Ann Biol Clin (Paris) 2015 May-Jun;73(3):333-44

Groupe hospitalier Cochin-Broca-Hôtel-Dieu, Paris, France.

Non-VKA oral anticoagulants (NOACs), thanks to their ease of use and their similar or superior safety/efficacy profiles versus warfarin, have now widely reached the lucrative market of anticoagulation. However, while the marketing authorization holders always claim, in a quite unclear way that no monitoring is required, accumulative evidence and cases of major bleeding have been described in the literature and reported by spontaneous reporting systems at the regulator's level. These compounds are usually given at fixed doses without routine coagulation monitoring. However, new data suggests that an assessment of the response at the individual level could improve the benefit-risk ratio of, at least dabigatran. Therefore, in certain patient populations, i.e. acute or chronic renal impairment or multiple drug interactions, measurement of drug exposure may be useful to ensure an optimal treatment response. More specific circumstances such as patients experiencing a haemorrhagic or thromboembolic event during the treatment duration, patients who require urgent surgery or an invasive procedure, or patient with a suspected overdose could benefit from such a measurement. This article aims at providing guidance on how to best estimate the intensity of anticoagulation using laboratory assays in daily practice.
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http://dx.doi.org/10.1684/abc.2015.1025DOI Listing
May 2016

Assessment of apixaban plasma levels by laboratory tests: suitability of three anti-Xa assays. A multicentre French GEHT study.

Thromb Haemost 2014 Feb 31;111(2):240-8. Epub 2013 Oct 31.

Isabelle Gouin Thibault, Laboratoire d'Hématologie, Groupe Hospitalier Cochin-Hôtel Dieu, 27, rue du Faubourg Saint-Jacques, 75 679 Paris Cedex 14, France, Tel.: +33 1 42 34 84 47, Fax: +33 1 58 41 19 97, E-mail:

While laboratory monitoring is not required in patients treated with apixaban, a direct factor-Xa inhibitor, assessment of its concentration is useful in some critical situations. However, few data are available on its effect on coagulation tests and on the suitability of anti-Xa assays for its quantification. It was the objective of this study to identify laboratory tests suitable for apixaban concentration assessment. Coagulation tests - PT and aPTT- and anti-Xa assays were performed in apixaban-spiked plasma samples. To evaluate the sensitivity of PT and aPTT to apixaban, we conducted a first monocenter part, with a wide range of concentrations (50-1,000 ng/ml), a large panel of reagents (20 reagents), and two coagulometers (STAR®, Stago and ACL TOP®, IL), and a second multicenter part involving 13 laboratories using either a common PT reagent (RecombiPlastin2G®) or the local PT and aPTT reagents. In the multicentre part, five blinded apixaban-spiked plasma samples (0/100/200/400/800 ng/ml - checked by HPLC-MS/MS) were used; apixaban concentrations were measured with three anti-Xa assays, apixaban calibrators and controls (Stago). PT and aPTT tests using a large panel of reagents displayed a low sensitivity to a wide range of apixaban concentrations. The concentrations to double PT ranged from 400 to >1,000 ng/ml with the 10 reagents. With the three anti-Xa assays, inter-laboratory precision and accuracy were below 11% and 12%, respectively. In conclusion, whereas PT and aPTT tests were not sensitive enough to detect apixaban, the three anti-Xa assays tested using lyophilised apixaban calibrators and controls allowed to reliably quantify a wide range of apixaban concentrations.
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http://dx.doi.org/10.1160/TH13-06-0470DOI Listing
February 2014

Duration of postoperative fibrinolysis after total hip or knee replacement: a laboratory follow-up study.

Thromb Res 2013 Jan 26;131(1):e6-e11. Epub 2012 Nov 26.

Cochin-Hôtel Dieu University Hospital, Assistance Publique - Hôpitaux de Paris, Université Paris Descartes, France.

Introduction: Hyperfibrinolysis is observed during and immediately after major orthopedic surgery. The kinetics and duration of this phase should be defined to adjust the duration of antifibrinolytic treatment with tranexamic acid (TXA).

Objective: We aimed to quantify the duration of postoperative fibrinolysis and to assess the biological impact of TXA administration.

Materials And Methods: Fourteen patients undergoing total hip replacement (THR) and 10 patients undergoing total knee replacement (TKR) with tourniquet were included in an observational, prospective, single-center study. Among these patients, 7 THR patients and 5 TKR patients received TXA (15mg/kg IV intraoperatively, followed by continuous infusion of 15mg/kg/h until end of surgery, then every 4hours until 16±2hours after surgery). D-dimers, euglobulin lysis time (ELT), and thrombin generation time (TGT) were measured prior to surgery as well as 6, 18 and 24hours (H) after.

Results: No significant difference in ELT was observed between the groups. In contrast, D-dimers significantly increased postoperatively in patients not treated with TXA (p<0.001), while such an increase was prevented in patients receiving TXA, as measured at H0, H6, H18 and H24 after THR, and at H6 and H18 after TKR (p<0.001). No significant between-group change in TGT, was observed (peak thrombin and endogenous thrombin potential) all along the study.

Conclusion: This study shows that fibrinolysis peaked 6hours after end of surgery and maintained about 18hours after surgery, as evidenced by an increase in D-dimers. When administered for up to 16±2hours after surgery, TXA reduced postoperative fibrinolysis.
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http://dx.doi.org/10.1016/j.thromres.2012.11.006DOI Listing
January 2013

Platelets and viruses: an ambivalent relationship.

Cell Mol Life Sci 2010 Feb 12;67(4):545-56. Epub 2009 Dec 12.

Service d'Hématologie et d'Immunologie, Hôpital Ambroise Paré, Boulogne-Billancourt, 92100 Paris, France.

Thrombocytopenia is a frequent complication of viral infections providing evidence that interaction of platelets with viruses is an important pathophysiological phenomenon. Multiple mechanisms are involved depending on the nature of the viruses involved. These include immunological platelet destruction, inappropriate platelet activation and consumption, and impaired megakaryopoiesis. Viruses bind platelets through specific receptors and identified ligands, which lead to mutual alterations of both the platelet host and the viral aggressor. We have shown that HIV-1 viruses are internalized specifically in platelets and megakaryocytes, where they can be either sheltered, unaltered (with potential transfer of the viruses into target organs), or come in contact with platelet secretory products leading to virus destruction and facilitated platelet clearance. In this issue, we have reviewed the various pathways that platelets use in order to interact with viruses, HIV and others. This review also shows that more work is still needed to precisely identify platelet roles in viral infections, and to answer the challenge of viral safety in platelet transfusion.
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http://dx.doi.org/10.1007/s00018-009-0209-xDOI Listing
February 2010

Platelet dysfunction after normothermic cardiopulmonary bypass in children: effect of high-dose aprotinin.

Thromb Haemost 2007 Aug;98(2):385-91

Département d'hématologie Biologique, Hôpital Necker, 149 rue de Sèvres, 75743 Paris cedex 15, France.

Platelet dysfunction after cardiopulmonary bypass (CPB) can contribute to excessive post-operative bleeding. Most trials of the protective effect of aprotinin in this setting have involved hypothermic CPB, which is more deleterious for platelets than normothermic CPB. Here we investigated the effect of aprotinin on platelet function during normothermic CPB in pediatric patients. Twenty patients (9 newborns [<1 month old] and 11 infants [<36 month old]), weighting less than 15 kg and undergoing normothermic CPB (35-36 degrees C) were randomly assigned to two equal groups, one of which received high-dose aprotinin. Platelet function was assessed by flow cytometry just before CPB and 5 minutes after heparin neutralization. F1 + 2 fragments were measured by ELISA before and 5 minutes after CPB. Platelet activation marker expression (CD62P and activated alphaIIbbeta3) induced by ADP or TRAP was lower after CPB than before CPB, suggesting a deleterious effect of normothermic CPB on platelet function. Prothrombin fragment F1 + 2 levels increased after CPB. Aprotinin administration did not influence the level of prothrombin fragments or platelet marker expression measured in basal condition. However, after CPB, the capacity for platelet activation was higher in the aprotinin group, as shown by measuring CD62P expression after TRAP activation (p = 0.05). This study suggests that pediatric normothermic CPB causes platelet dysfunction, and that high-dose aprotinin has a protective effect.
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August 2007

Severe prekallikrein deficiencies due to homozygous C529Y mutations.

Blood Coagul Fibrinolysis 2007 Apr;18(3):283-6

Laboratoire de Biologie Clinique, Hôpital Foch, Suresnes, France.

Two consecutive severe prekallikrein deficiencies were investigated. The first was identified in a 63-year-old patient admitted for ischemic stroke. The second deficiency was identified in a 38-year-old patient admitted for a second-trimester pregnancy loss. A homozygous C529Y mutation was identified for both cases, whereas they are unrelated and no consanguineous marriage is known from the patients. These data point to a possible high frequency of this mutation as a cause of prekallikrein deficiency.
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http://dx.doi.org/10.1097/MBC.0b013e328010bcdeDOI Listing
April 2007