Publications by authors named "Emmanuel De Maistre"

51 Publications

Functional Flow Cytometric Assay for Reliable and Convenient Heparin-Induced Thrombocytopenia Diagnosis in Daily Practice.

Biomedicines 2021 Mar 25;9(4). Epub 2021 Mar 25.

Inserm U1059 Sainbiose, Université de Lyon, 42055 Saint-Etienne, France.

Reliable laboratory diagnosis of heparin-induced thrombocytopenia (HIT) remains a major clinical concern. Immunoassays are highly sensitive, while confirmatory functional tests (based on heparin-dependent platelet activation) lack standardization. We evaluated the diagnostic performance of a functional flow cytometric assay (FCA) based on the detection of heparin-dependent platelet activation with an anti-p-selectin. A total of 288 patients were included (131 HIT-positive and 157 HIT-negative) with a HIT diagnosis established by expert opinion adjudication (EOA) considering clinical data and local laboratory results. The FCA was centrally performed in a single laboratory on platelet-rich plasma, using a very simple four-color fluorometer. The results were standardized according to the Heparin Platelet Activation (HEPLA) index. The serotonin release assay (SRA) was performed in the four French reference laboratories. Based on the final HIT diagnosis established by EOA, the sensitivity and specificity of the FCA were 88 and 95%, respectively, values very similar to those of the SRA (88 and 97%, respectively). This study showed that the FCA, based on easily implementable technology, may be routinely used as a reliable confirmatory test for HIT diagnosis.
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http://dx.doi.org/10.3390/biomedicines9040332DOI Listing
March 2021

Assessment of shear-dependent kinetics of primary haemostasis with a microfluidic acoustic biosensor.

IEEE Trans Biomed Eng 2020 Oct 15;PP. Epub 2020 Oct 15.

Primary haemostasis is a complex dynamic process, which involves in-flow interactions between platelets and sub-endothelial matrix at the area of the damaged vessel wall. It results in a first haemostatic plug, which stops bleeding, before coagulation ensues and consolidates it. The diagnosis of primary haemostasis defect would benefit from evaluation of the whole sequence of mechanisms involved in platelet plug formation. This work proposes a new approach that is based on characterization of the shear-dependent kinetics that enables the evaluation of the early stages of primary haemostasis. We used a label-free method with a quartz crystal microbalance (QCM) biosensor to measure the platelet deposits over time onto covalently immobilized type I fibrillar collagen. We defined three metrics: total frequency shift, lag time, and growth rate. The measurement was completed at four predefined shear rates prevailing in small vessels (500, 770, 1000 and 1500s-1) during five minutes of perfusion with anticoagulated normal whole blood. The rate of the frequency shift over the first five minutes was strongly influenced by shear rate conditions, presenting a maximum around 770s-1, and varying by a factor larger than three in the studied shear rate range. To validate the biosensor signal, the total frequency shift was compared to results obtained by atomic force microscopy (AFM) on final platelet deposits. The results show that shear-dependent kinetics assays is promising as an advanced method for screening of primary haemostasis.
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http://dx.doi.org/10.1109/TBME.2020.3031542DOI Listing
October 2020

Comparative Analysis of a French Prospective Series of 144 Patients with Heparin-Induced Thrombocytopenia (FRIGTIH) and the Literature.

Thromb Haemost 2020 Jul 22;120(7):1096-1107. Epub 2020 Jun 22.

EA 7501, GICC, Université de Tours, Tours, France.

Background:  Heparin-induced thrombocytopenia (HIT) is a rare complication of heparin treatments, and only a few large patient cohorts have been reported. In this study, biological and clinical data from 144 French patients with HIT were analyzed in comparison with the literature.

Methods:  The diagnosis of HIT was confirmed in all patients by an immunoassay combined with serotonin release assay. In the literature, only cohorts of at least 20 HIT patients published from 1992 were selected for a comparative analysis.

Results:  Two-thirds of patients were hospitalized in surgery and most were treated with unfractionated heparin (83.2% vs. 16.8% with low molecular weight heparin only). Thrombotic events in 54 patients (39.7%) were mainly venous (41/54). However, arterial thrombosis was more frequent after cardiac surgery (13.2% vs. 2.4% in other surgeries,  = 0.042) with a shorter recovery time (median = 3 vs. 5 days,  < 0.001). The mortality rate was lower in our series than in the 22 selected published studies (median = 6.3% vs. 15.9%). Three genetic polymorphisms were also studied and homozygous subjects FcγRIIA RR were more frequent in patients with thrombosis (37.8 vs. 18.2% in those without thrombosis,  = 0.03).

Conclusion:  This study shows that the mortality rate due to HIT has recently decreased in France, possibly due to earlier diagnosis and improved medical care. It also confirms the strong association between polymorphism FcγRIIA H131R and thrombosis in HIT.
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http://dx.doi.org/10.1055/s-0040-1712957DOI Listing
July 2020

Anti-Domain I β2-Glycoprotein I Antibodies and Activated Protein C Resistance Predict Thrombosis in Antiphospholipid Syndrome: TAC(I)T Study.

J Appl Lab Med 2020 11;5(6):1242-1252

Nancy University Hospital, Vascular Medicine Division and Regional Competence Center for Rare Vascular and Systemic Autoimmune Diseases, Nancy, France.

Background: Antibodies binding to domain I of β2-glycoprotein I (aDI) and activated protein C (APC) resistance are associated with an increased risk of thrombosis in cross-sectional studies. The objective of this study was to assess their predictive value for future thromboembolic events in patients with antiphospholipid antibodies (aPL) or antiphospholipid syndrome.

Methods: This prospective multicenter cohort study included consecutive patients with aPL or systemic lupus erythematosus. We followed 137 patients (43.5 ± 15.4 year old; 107 women) for a mean duration of 43.1 ± 20.7 months.

Results: We detected aDI IgG antibodies by ELISA in 21 patients. An APC sensitivity ratio (APCsr) was determined using a thrombin generation-based test. The APCsr was higher in patients with anti-domain I antibodies demonstrating APC resistance (0.75 ± 0.13 vs 0.48 ± 0.20, P < 0.0001). In univariate analysis, the hazard ratio (HR) for thrombosis over time was higher in patients with aDI IgG (3.31 [95% CI, 1.15-9.52]; P = 0.03) and patients with higher APC resistance (APCsr >95th percentile; HR, 6.07 [95% CI, 1.69-21.87]; P = 0.006). A sensitivity analysis showed an increased risk of higher aDI IgG levels up to HR 5.61 (95% CI, 1.93-16.31; P = 0.01). In multivariate analysis, aDI IgG (HR, 3.90 [95% CI, 1.33-11.46]; P = 0.01) and APC resistance (HR, 4.98 [95% CI, 1.36-18.28]; P = 0.02) remained significant predictors of thrombosis over time.

Conclusions: Our study shows that novel tests for antibodies recognizing domain I of β2-glycoprotein I and functional tests identifying APC resistance are significant predictors of thrombosis over time and may be useful for risk stratification.
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http://dx.doi.org/10.1093/jalm/jfaa072DOI Listing
November 2020

Autoimmune factor XIII deficiency with unusual laboratory and clinical phenotype.

J Thromb Haemost 2020 06 27;18(6):1330-1334. Epub 2020 Apr 27.

Division of Clinical Laboratory Science, Department of Laboratory Medicine, Faculty of Medicine, University of Debrecen, Debrecen, Hungary.

Hemorrhagic diathesis due to anti-factor XIII (FXIII) autoantibody is a rare but severe disorder. Challenges of the diagnosis and treatment is demonstrated by the case of a 67-year-old female without previous bleeding history, who suffered a huge muscular hematoma. Without blank subtraction 18% plasma FXIII activity was measured; however, after correction for blank the activity was below the limit of detection and the lack of fibrin cross-linking in the patient's plasma confirmed the latter result. FXIII-A antigen was not detectable by enzyme-linked immunosorbent assay (ELISA); however, it was well detected by western blotting. The autoantibody showed high affinity toward FXIII-A . Its considerable inhibitory activity was demonstrated by high titer in Bethesda units and the low immunoglobulin G concentration required for inhibition. The main biochemical effect was the inhibition of Ca -induced activation. Eradication therapy was only partially successful. Four months after the last hemorrhagic event the patient suffered deep vein thrombosis complicated by pulmonary embolism.
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http://dx.doi.org/10.1111/jth.14811DOI Listing
June 2020

Diagnosis and management of heparin-induced thrombocytopenia.

Anaesth Crit Care Pain Med 2020 04 13;39(2):291-310. Epub 2020 Apr 13.

Service d'anesthésie-réanimation, hôpital européen Georges-Pompidou, INSERM UMRS-1140, université Paris Descartes, 25, rue Leblanc, 75015 Paris, France. Electronic address:

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http://dx.doi.org/10.1016/j.accpm.2020.03.012DOI Listing
April 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

Correction of Severe Myelofibrosis, Impaired Platelet Functions and Abnormalities in a Patient with Gray Platelet Syndrome Successfully Treated by Stem Cell Transplantation.

Platelets 2020 May 10;31(4):536-540. Epub 2019 Sep 10.

Department of Hematology, Besançon Hospital, Franche-Comté University , Besançon, France.

Gray platelet syndrome (GPS) is an inherited disorder. Patients harboring GPS have thrombocytopenia with large platelets lacking α-granules. A long-term complication is myelofibrosis with pancytopenia. Hematopoietic stem cell transplant (HSCT) could be a curative treatment. We report a male GPS patient with severe pancytopenia, splenomegaly and a secondary myelofibrosis needing red blood cells transfusion. He received an HSCT from a 10/10 matched HLA-unrelated donor after a myeloablative conditioning regimen. Transfusion independence occurred at day+21, with a documented neutrophil engraftment. At day+ 180, we added ruxolitinib to cyclosporine and steroids for a moderate chronic graft versus host disease (GVHD) and persistent splenomegaly. At day+240 GVHD was controlled and splenomegaly reduced. Complete donor chimesrism was documented in blood and marrow and platelets functions and morphology normalized. At day+ 720, the spleen size normalized and there was no evidence of marrow fibrosis on the biopsy. In GPS, HSCT may be a curative treatment in selected patients with pancytopenia and myelofibrosis.
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http://dx.doi.org/10.1080/09537104.2019.1663809DOI Listing
May 2020

Management of bleeding and invasive procedures in haemophilia A patients with inhibitor treated with emicizumab (Hemlibra ): Proposals from the French network on inherited bleeding disorders (MHEMO), the French Reference Centre on Haemophilia, in collaboration with the French Working Group on Perioperative Haemostasis (GIHP).

Haemophilia 2019 Sep 11;25(5):731-737. Epub 2019 Jul 11.

Unité d'Hémostase Clinique, Louis Pradel Hospital, University Claude Bernard, Lyon, France.

Introduction: Emicizumab (Hemlibra ) recently became available and requires an adaptation for managing bleeding, suspected bleeding and emergency or scheduled invasive procedures in haemophilia A patients with inhibitor. This implicates a multidisciplinary approach and redaction of recommendations for care that must be regularly adapted to the available data.

Aim: The following text aims to provide a guide for the management of people with haemophilia A with inhibitor treated with emicizumab in case of bleeding or invasives procedures.

Methods: The French network on inherited bleeding disorders (MHEMO), the French Reference Centre on Haemophilia (CRH), in collaboration with the French Working Group on Perioperative Haemostasis (GIHP) have been working together to make proposals for the management of these situations.

Results: Haemostatic treatment and other medications should be given stepwise, according to the severity and location of the bleeding or the risk of bleeding of the procedure as well as the haemostatic response obtained at each step in order to ensure an optimal benefit/risk ratio.

Conclusion: The lack of data means that it is only possible to issue proposals rather than recommendations.
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http://dx.doi.org/10.1111/hae.13817DOI Listing
September 2019

Management of antiplatelet therapy for non-elective invasive procedures or bleeding complications: Proposals from the French Working Group on Perioperative Haemostasis (GIHP) and the French Study Group on Thrombosis and Haemostasis (GFHT), in collaboration with the French Society for Anaesthesia and Intensive Care (SFAR).

Arch Cardiovasc Dis 2019 Mar 6;112(3):199-216. Epub 2019 Jan 6.

Service d'angiologie et d'hémostase, département de spécialités de médecine, hôpitaux universitaires de Genève, 1205 Genève, Switzerland; Geneva Platelet Group, faculté de médecine, université de Genève, 1205 Genève, Switzerland.

The French Working Group on Perioperative Haemostasis (GIHP) and the French Study Group on Haemostasis and Thrombosis (GFHT), in collaboration with the French Society for Anaesthesia and Intensive Care (SFAR), drafted up-to-date proposals on the management of antiplatelet therapy for non-elective invasive procedures or bleeding complications. The proposals were discussed and validated by a vote; all proposals could be assigned with a high strength. Management of oral antiplatelet agents in emergency settings requires knowledge of their pharmacokinetic and pharmacodynamic parameters, evaluation of the degree of alteration of haemostatic competence and the associated bleeding risk. Platelet function testing may be considered. When antiplatelet agent-induced bleeding risk may worsen the prognosis, measures should be taken to neutralize antiplatelet therapy, by considering not only the efficacy of available means (which can be limited for prasugrel and even more for ticagrelor), but also the risks that these means expose the patient to. The measures include platelet transfusion at the appropriate dose and haemostatic agents (tranexamic acid; recombinant activated factor VII for ticagrelor). When possible, postponing non-elective invasive procedures at least for a few hours until the elimination of the active compound (which could compromise the effect of transfused platelets) or, if possible, for a few days (reduction of the effect of antiplatelet agents) should be considered.
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http://dx.doi.org/10.1016/j.acvd.2018.10.004DOI Listing
March 2019

Validation of the STA-Liatest DDi assay for exclusion of proximal deep vein thrombosis according to the latest Clinical and Laboratory Standards Institute/Food and Drug Administration guideline: results of a multicenter management study.

Blood Coagul Fibrinolysis 2018 Sep;29(6):562-566

Department of Vascular Medicine, Grenoble-Alpes University Hospital, Universite Grenoble Alpes CNRS/TIMC-IMAG UMR 5525/Themas, Grenoble, F-CRIN, INNOVTE (Investigation Network On Venous Thrombo-Embolism), France.

: Recommended strategy for venous thromboembolism (VTE) diagnosis includes the use of sensitive D-dimer (DDi) assays along with pretest probability (PTP) assessment. The Clinical and Laboratory Standards Institute (CLSI) recently issued a guideline (US FDA endorsed) on DDi in VTE exclusion. Such guideline specifies the ideal D-dimer assay characteristics and target population. Demonstrate STA-LiatestD-Di performance combined with a PTP score for proximal deep vein thrombosis (pDVT) exclusion in a CLSI compliant study. International, multicenter, prospective nonrandomized, noninterventional clinical outcome management study conducted in a standard-of-care setting. DDi was measured in DVT-suspected consecutive low/moderate PTP outpatients, without conditions possibly impacting DDi values independently of thrombosis presence (age >80, pregnancy, postoperative, cancer) using a 0.5 μg/ml (FEU) threshold for DVT exclusion. Results were used to determine test performance. One thousand two hundred and thirty-four patients (17 centers) signed informed consent. Nine hundred and eighty (mean age: 55) with valid results (494 negative DDi) completed the study (DVT prevalence: 8.7%). STA-LiatestD-Di performance exceeded CLSI/FDA requirements: sensitivity: 100% (95% CI 95.8-100%), NPV: 100% (95% CI 99.3-100%). STA-LiatestD-Di associated with PTP score showed excellent performance for pDVT exclusion, as recently demonstrated for pulmonary embolism. The assay allows safe VTE exclusion, avoiding unnecessary imaging tests.
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http://dx.doi.org/10.1097/MBC.0000000000000750DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6200385PMC
September 2018

Management of bleeding and emergency invasive procedures in patients on dabigatran: Updated guidelines from the French Working Group on Perioperative Haemostasis (GIHP) - September 2016.

Anaesth Crit Care Pain Med 2018 Aug 2;37(4):391-399. Epub 2018 May 2.

Department of Haematology, Toulouse University Hospital, 31300 Toulouse, France. Electronic address:

In 2013, the GIHP published guidelines for the management of severe haemorrhages and emergency surgery. This update applies to patients treated with dabigatran, with a bleeding complication or undergoing an urgent invasive procedure. It includes how to handle the available specific antidote (idarucizumab), when to measure dabigatran plasmatic concentration and when to use non-specific measures in these situations. It also includes guidelines on how to perform regional anaesthesia and analgesia procedures.
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http://dx.doi.org/10.1016/j.accpm.2018.04.009DOI Listing
August 2018

Rivaroxaban plasma levels in acute ischemic stroke and intracerebral hemorrhage.

Ann Neurol 2018 03 3;83(3):451-459. Epub 2018 Mar 3.

Stroke Center and Department of Neurology, Department of Clinical Research, University Hospital and University of Basel, Basel, Switzerland.

Objective: Information about rivaroxaban plasma level (RivLev) may guide treatment decisions in patients with acute ischemic stroke (AIS) and intracerebral hemorrhage (ICH) taking rivaroxaban.

Methods: In a multicenter registry-based study (Novel Oral Anticoagulants in Stroke Patients collaboration; ClinicalTrials.gov: NCT02353585) of patients with stroke while taking rivaroxaban, we compared RivLev in patients with AIS and ICH. We determined how many AIS patients had RivLev ≤ 100ng/ml, indicating possible eligibility for thrombolysis, and how many ICH patients had RivLev ≥ 75ng/ml, making them possibly eligible for the use of specific reversal agents. We explored factors associated with RivLev (Spearman correlation, regression models) and studied the sensitivity and specificity of international normalized ratio (INR) thresholds to substitute RivLev using cross tables and receiver operating characteristic curves.

Results: Among 241 patients (median age = 80 years, interquartile range [IQR] = 73-84; median time from onset to admission = 2 hours, IQR = 1-4.5 hours; median RivLev = 89ng/ml, IQR = 31-194), 190 had AIS and 51 had ICH. RivLev was similar in AIS patients (82ng/ml, IQR = 30-202) and ICH patients (102ng/ml, IQR = 51-165; p = 0.24). Trough RivLev occurred in 126/190 (66.3%) AIS and 34/51 (66.7%) ICH patients. Among AIS patients, 108/190 (56.8%) had RivLev ≤ 100ng/ml. In ICH patients, 33/51 (64.7%) had RivLev ≥ 75ng/ml. RivLev was associated with rivaroxaban dosage, and inversely with renal function and time since last intake (each p < 0.05). INR ≤ 1.0 had a specificity of 98.9% and a sensitivity of 25.7% to predict RivLev ≤ 100ng/ml. INR ≥ 1.4 had a sensitivity of 59.3% and specificity of 90.1% to predict RivLev ≥ 75ng/ml.

Interpretation: RivLev did not differ between patients with AIS and ICH. Half of the patients with AIS under rivaroxaban had a RivLev low enough to consider thrombolysis. In ICH patients, two-thirds had a RivLev high enough to meet the eligibility for the use of a specific reversal agent. INR thresholds perform poorly to inform treatment decisions in individual patients. Ann Neurol 2018;83:451-459.
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http://dx.doi.org/10.1002/ana.25165DOI Listing
March 2018

Position of the French Working Group on Perioperative Haemostasis (GIHP) on viscoelastic tests: What role for which indication in bleeding situations?

Anaesth Crit Care Pain Med 2019 10 3;38(5):539-548. Epub 2018 Feb 3.

Laboratoire d'hématologie, hôpital Necker, 75015 Paris, France.

Purpose: Viscoelastic tests (VETs), thromboelastography (TEG) and thromboelastometry (ROTEM) are global tests of coagulation performed on whole blood. They evaluate the mechanical strength of a clot as it builds and develops after coagulation itself. The time required to obtain haemostasis results remains a major problem for clinicians dealing with bleeding, although some teams have developed a rapid laboratory response strategy. Indeed, the value of rapid point-of-care diagnostic devices such as VETs has increased over the years. However, VETs are not standardised and there are few recommendations from the learned societies regarding their use. In 2014, the recommendations of the International Society of Thrombosis and Haemostasis (ISTH) only concerned haemophilia. The French Working Group on Perioperative haemostasis (GIHP) therefore proposes to summarise knowledge on the clinical use of these techniques in the setting of emergency and perioperative medicine.

Methods: A review of the literature.

Principal Findings: The role of the VETs seems established in the management of severe trauma and in cardiac surgery, both adult and paediatric. In other situations, their role remains to be defined: hepatic transplantation, postpartum haemorrhage, and non-cardiac surgery. They must be part of the global management of haemostasis based on algorithms defined in each centre and for each population of patients. Their position at the bedside or in the laboratory is a matter of discussion between clinicians and biologists.

Conclusion: VETs must be included in algorithms. In consultation with the biology laboratory, these devices should be situated according to the way each centre functions.
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http://dx.doi.org/10.1016/j.accpm.2017.12.014DOI Listing
October 2019

Clinical, laboratory and molecular findings and long-term follow-up data in 96 French patients with PMM2-CDG (phosphomannomutase 2-congenital disorder of glycosylation) and review of the literature.

J Med Genet 2017 12 27;54(12):843-851. Epub 2017 Sep 27.

Reference Center for Inherited Metabolic Disease, AP-HP, Necker-Enfants Malades Hospital, IMAGINE Institute affiliate, University Paris Descartes-Sorbonne Paris Cité, Paris, France.

Background: Phosphomannomutase 2-congenital disorder of glycosylation (PMM2-CDG) is a multisystem inborn error of metabolism.

Objectives: To better characterise the natural history of PMM2-CDG.

Methods: Medical charts of 96 patients with PMM2-CDG (86 families, 41 males, 55 females) were retrospectively reviewed. Data on clinical, laboratory and molecular parameters at diagnosis were analysed. Follow-up data at last examination were reported for 25 patients.

Results: The patients were born between 1963 and 2011. Diagnosis of PMM2-CDG was made at a mean (SD) age of 6.8 (8.5) years. The presenting signs were mostly neurological (hypotonia, intellectual disability, cerebellar syndrome) and observed in almost all the patients. A total of 38 patients (14 males, 24 females) exhibited, in addition to neurological signs, visceral features including at least one of these: feeding difficulty requiring a nutritional support (n=23), cardiac features (n=20; pericarditis: 14, cardiac malformation: 9, cardiomyopathy: 2), hepato-gastrointestinal features (n=12; chronic diarrhoea: 7, protein-losing enteropathy: 1, ascites: 3, liver failure: 1, portal hypertension: 1), kidney features (n=4; nephrotic syndrome: 2, tubulopathy: 2) and (n=1). Twelve patients died at a mean age of 3.8 years (especially from pericarditis and other cardiac issues). Laboratory abnormalities mostly included elevated transaminases and abnormal coagulation parameters. High thyreostimulin levels, hypocholesterolemia, hypoalbuminemia and elevated transaminases were associated with the visceral phenotype. Besides the common Arg141His variant harboured by half of the patients, 45 different variants were observed.

Conclusions: PMM2-CDG clinical phenotype is heterogeneous in terms of clinical course, with no clear division between neurological and visceral presentations.
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http://dx.doi.org/10.1136/jmedgenet-2017-104903DOI Listing
December 2017

Evaluation of dabigatran, rivaroxaban and apixaban target-specific assays in a multicenter French study.

Thromb Res 2017 Oct 4;158:126-133. Epub 2017 Sep 4.

Hematology Laboratory, Toulouse University Hospital, Toulouse, France.

Dabigatran etexilate, rivaroxaban and apixaban (DOACs) are widely used and measurement of their concentration is desirable in certain clinical situations. Target-specific assays are available but limited information exists on their performance especially in their ability to accurately measure low and high concentrations.

Aims: To define, in a multicenter study, the precision and accuracy of DOAC measurements in daily practice.

Methods: 15 plasma samples (kindly provided by Hyphen-Biomed) spiked with 5 blinded concentrations of dabigatran, rivaroxaban or apixaban (targeted 0-40-100-250-500ng/mL, actual concentrations measured by HPLC-MS/MS), were sent to 30 haemostasis laboratories. DOAC concentration, PT and aPTT were measured once in each sample using local reagents. Interlaboratory precision was determined by its coefficient of variation (CV) and accuracy by its bias.

Results: 464 DOAC measurements were performed in the 30 laboratories using 4 dabigatran and 5 rivaroxaban/apixaban calibrated assays on 3 analysers. Inter-laboratory CVs were below 18% for concentrations ≥100ng/mL, and higher for concentrations ~40ng/mL; biases were below 8% for all drugs and concentrations. In DOAC-free samples, concentrations were all below the lower limit of quantification except for one value (dabigatran: 35ng/mL). Depending on the concentrations, significant differences were found between reagents in rivaroxaban and apixaban concentration values. PT and aPTT ratios displayed a low sensitivity to apixaban.

Conclusion: Our results suggest that calibrated DOAC assays allow the reliable measurement of a wide range of drug concentrations, even though improvement of their performances is necessary, especially for measuring low concentrations.
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http://dx.doi.org/10.1016/j.thromres.2017.09.001DOI Listing
October 2017

Management of Severe Bleeding in Patients Treated with Direct Oral Anticoagulants: An Observational Registry Analysis.

Anesthesiology 2017 07;127(1):111-120

From the Department of Anesthesiology and Intensive Care Medicine, Grenoble-Alpes University Hospital, Grenoble, France (P.A.); Department of Anesthesiology and Intensive Care Medicine, Assistance Publique-Hôpitaux de Paris, Cochin University Hospital, Paris Descartes University, Paris, France (C.-M.S.); Department of Hematology, Toulouse University Hospital, Toulouse, France (P. Sié, V.M.); Department of Anesthesiology and Intensive Care Medicine, Clermont-Ferrand University Hospital, Clermont-Ferrand, France (S.K.); Laboratory of Hematology, La Timone Hospital; INSERM, UMR_S 1062, Nutrition Obesity and Risk of Thrombosis; Nutrition Obesity and Risk of Thrombosis, Aix-Marseille University, UMR_S 1062, Marseille, France (P. Suchon); Department of Emergency Medicine, Saint Etienne University Hospital, Saint Etienne, France (A.V.); Department of Anesthesiology and Intensive Care Medicine, Hospices Civils de Lyon, Lyon Sud University Hospital, Pierre Benite, France (J.S.D.); Department of Hematology, Tours University Hospital, Tours, France (Y.G.); Department of Anesthesiology and Intensive Care Medicine, Brest University Hospital, Brest, France (L.B.); Department of Hematology, Dijon University Hospital, Dijon, France (E.d.M.); and Center of Clinical Investigation (P.R., J.-L.B.), Biostatistic Unit (S.T.), and Department of Vascular Medicine (G.P.), Grenoble Alpes University Hospital, Techniques pour l'Evaluation et la Modélisation des Actions de Santé (ThEMAS), Techniques de l'Ingénierie Médicale et de la Complexité (TIMC), Unité Mixte de Recherche (UMR), CNRS 5525, Université Grenoble-Alpes, Grenoble, France. Clermont-Ferrand University Hospital, Clermont-Ferrand, France (n = 67) Clermont-Ferrand University Hospital, Clermont-Ferrand, France (n = 67) Clermont-Ferrand University Hospital, Clermont-Ferrand, France (n = 67) Clermont-Ferrand University Hospital, Clermont-Ferrand, France (n = 67) Clermont-Ferrand University Hospital, Clermont-Ferrand, France (n = 67) Toulouse University Hospital, Toulouse, France (n = 66) Assistance Publique- Hôpitaux de Marseille, Marseille, France (n = 64) Assistance Publique- Hôpitaux de Marseille, Marseille, France (n = 64) Assistance Publique- Hôpitaux de Marseille, Marseille, France (n = 64) Assistance Publique- Hôpitaux de Marseille, Marseille, France (n = 64) Grenoble University Hospital, Grenoble, France (n = 56) Grenoble University Hospital, Grenoble, France (n = 56) Grenoble University Hospital, Grenoble, France (n = 56) Saint Etienne University Hospital, Saint Etienne, France (n = 55) Saint Etienne University Hospital, Saint Etienne, France (n = 55) Saint Etienne University Hospital, Saint Etienne, France (n = 55) Hospices Civils de Lyon, Lyon-Sud University Hospital, Pierre Benite, France (n = 48) Hospices Civils de Lyon, Lyon-Sud University Hospital, Pierre Benite, France (n = 48) Hospices Civils de Lyon, Lyon-Sud University Hospital, Pierre Benite, France (n = 48) Hospices Civils de Lyon, Lyon-Sud University Hospital, Pierre Benite, France (n = 48) Tours University Hospital, Tours, France (n = 46) Brest University Hospital, Brest, France (n = 42) Dijon University Hospital, Dijon, France (n = 39) Strasbourg University Hospital, Strasbourg, France (n = 29) Strasbourg University Hospital, Strasbourg, France (n = 29) Strasbourg University Hospital, Strasbourg, France (n = 29) Bordeaux University Hospital, Bordeaux, France (n = 27) Assistance Publique-Hôpitaux de Paris, Georges Pompidou University Hospital, Paris, France (n = 23) Assistance Publique-Hôpitaux de Paris, Georges Pompidou University Hospital, Paris, France (n = 23) Assistance Publique-Hôpitaux de Paris, Georges Pompidou University Hospital, Paris, France (n = 23) Agen General Hospital, Agen, France (n = 21) Agen General Hospital, Agen, France (n = 21) Annecy Regional Hospital, Annecy, France (n = 19) Annecy Regional Hospital, Annecy, France (n = 19) Annecy Regional Hospital, Annecy, France (n = 19) Annecy Regional Hospital, Annecy, France (n = 19) Centre Médico-Chirurgical Foch, Suresnes, France (n = 18) Assistance Publique-Hôpitaux de Paris, Bicêtre University Hospital, Le Kremlin Bicêtre, France (n = 17) Assistance Publique-Hôpitaux de Paris, Bicêtre University Hospital, Le Kremlin Bicêtre, France (n = 17) Assistance Publique-Hôpitaux de Paris, Cochin University Hospital, Paris, France (n = 13) Assistance Publique-Hôpitaux de Paris, Cochin University Hospital, Paris, France (n = 13) Rennes University Hospital, Rennes, France (n = 11) Rennes University Hospital, Rennes, France (n = 11) Rennes University Hospital, Rennes, France (n = 11) Rennes University Hospital, Rennes, France (n = 11) Brugmann University Hospital, Brussels, Belgium, (n = 10) Montpellier University Hospital, Montpellier, France (n = 10) Montpellier University Hospital, Montpellier, France (n = 10) Montpellier University Hospital, Montpellier, France (n = 10) Hospices Civils de Lyon, Edouard Herriot University Hospital, Lyon, France (n = 8) Hospices Civils de Lyon, Edouard Herriot University Hospital, Lyon, France (n = 8) Nantes University Hospital, Nantes, France (n = 7) Nantes University Hospital, Nantes, France (n = 7) Nantes University Hospital, Nantes, France (n = 7) Assistance Publique-Hôpitaux de Paris, Bichat University Hospital, Paris, France (n = 6) Assistance Publique-Hôpitaux de Paris, Bichat University Hospital, Paris, France (n = 6) Assistance Publique-Hôpitaux de Paris, Beaujon University Hospital, Clichy, France (n = 5) Assistance Publique-Hôpitaux de Paris, Beaujon University Hospital, Clichy, France (n = 5) Alpes Léman Hospital, Contamine sur Arve, France (n = 5) Groupe Hospitalier Mutualiste, Grenoble, France (n = 4) Groupe Hospitalier Mutualiste, Grenoble, France (n = 4) Angers University Hospital, Angers, France (n = 4) Angers University Hospital, Angers, France (n = 4) Chambéry General Hospital, Chambéry, France (n = 3) Chambéry General Hospital, Chambéry, France (n = 3) Chambéry General Hospital, Chambéry, France (n = 3) Amiens University Hospital, Amiens, France (n = 3) Saint Anne Military Hospital, Toulon, France (n = 2) Saint Anne Military Hospital, Toulon, France (n = 2) Lille University Hospital, Lille, France (n = 1) Nimes University Hospital, Nimes, France (n = 1) Gap General Hospital, Gap, France (n = 1) Castres General Hospital, Castres, France (n = 1) Rotschild Foundation, Paris, France (n = 1).

Background: The use of prothrombin complex concentrates and the role of plasma concentration of anticoagulants in the management of bleeding in patients treated with direct oral anticoagulants are still debated. Our aim was to describe management strategies and outcomes of severe bleeding events in patients treated with direct oral anticoagulants.

Methods: We performed a prospective cohort study of 732 patients treated with dabigatran, rivaroxaban, or apixaban hospitalized for severe bleeding, included prospectively in the registry from June 2013 to November 2015.

Results: Bleeding was gastrointestinal or intracranial in 37% (212 of 732) and 24% (141 of 732) of the cases, respectively. Creatinine clearance was lower than 60 ml/min in 61% (449 of 732) of the cases. The plasma concentration of direct oral anticoagulants was determined in 62% (452 of 732) of the cases and was lower than 50 ng/ml or higher than 400 ng/ml in 9.2% (41 of 452) and in 6.6% (30 of 452) of the cases, respectively. Activated or nonactivated prothrombin complex concentrates were administered in 38% of the cases (281 of 732). Mortality by day 30 was 14% (95% CI, 11 to 16).

Conclusions: Management of severe bleeding in patients treated with direct oral anticoagulants appears to be complex. The use of prothrombin complex concentrates differs depending on bleeding sites and direct oral anticoagulant plasma concentrations. Mortality differs according to bleeding sites and was similar to previous estimates.
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http://dx.doi.org/10.1097/ALN.0000000000001631DOI Listing
July 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

[Hemorrhage treatment: Evaluation of the proper use of fibrinogen concentrate].

Therapie 2017 Oct 22;72(5):517-524. Epub 2017 Feb 22.

Service pharmacie, hôpital François-Mitterrand, 14, rue Gaffarel, 21000 Dijon, France.

An increase in fibrinogen concentrate prescriptions was noticed in 2015 after several guidelines regarding their use were published. We tried to evaluate if they were used appropriately. To evaluate the conformity of the prescriptions to these guidelines, we searched for each prescription if a dosage of blood fibrinogen was made, if its result was below the limit recommended to prescribe fibrinogen concentrate, and if the posology was in line with the recommendations. Effect and security of the treatment was also evaluated. We analyzed 202 prescriptions for 117 patients. The indications are respected except for one prescription for which we could not find it. The blood fibrinogen is measured for 76% of the prescriptions, 59% of the results are below the limit recommended to prescribe. The posology is conforming to the guidelines for 73% of the prescriptions, it is below the dose recommended for 20%. Patients who were prescribed low doses seemed less at risk than the others which questions the necessity of the prescriptions. The guidelines respect depends on the emergency of the prescription situation. It would be interesting to conduct a prospective study to better explain why doses below those recommended are prescribed.
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http://dx.doi.org/10.1016/j.therap.2017.01.009DOI Listing
October 2017

Are Myeloproliferative neoplasms a risk factor for Heparin-Induced Thrombocytopenia?

Br J Haematol 2016 11 23;175(3):537-539. Epub 2015 Dec 23.

Haematological Laboratory, Dijon Hospital, Dijon, France.

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http://dx.doi.org/10.1111/bjh.13874DOI Listing
November 2016

Incremental predictive value of mean platelet volume/platelet count ratio in in-hospital stroke after acute myocardial infarction.

Platelets 2017 Jan 26;28(1):54-59. Epub 2016 Jul 26.

a Department of Cardiology , University Hospital , Dijon , France.

Stroke is a serious complication after acute myocardial infarction (AMI) and is associated with an increased risk of death. Though the pathophysiological mechanisms are not exactly known, increased inflammation and platelet reactivity could play an important role in the occurrence of stroke during AMI. We aimed to investigate the relationship between both mean platelet volume (MPV), a parameter of platelet function, and C-reactive protein (CRP) and the occurrence of in-hospital ischemic stroke (IHS) after AMI. Data were obtained from a French regional survey for AMI that included 5976 patients admitted to an intensive care unit (ICU) between 2001 and 2010. Patients were divided into two groups according to the occurrence of IHS. MPV, platelet count (PC), and CRP were routinely measured at admission to the ICU; 99 (1.6%) IHSs were recorded during hospitalization after admission for AMI. In multivariate analysis, IHS was independently associated with a history of stroke (OR: 1.99%, CI: 1.1-3.49, p = 0.01), impaired left ventricular ejection fraction <40% (OR: 1.88, 95% CI: 1.20-2.94, p = 0.006), impaired renal function (OR: 1.94, 95% CI: 1.27-2.95, p = 0.002), CRP > 10 mg/l (OR: 2.19, 95% CI: 1.44-3.33, p < 0.001), and MPV/PC ratio (OR: 1.04, 95% CI: 1.01-1.08, p = 0.023). Compared with the first to fourth quintiles, the last quintile of the MPV/PC ratio was associated with higher rates of IHS on survival curve analysis (p = 0.014). At hospital admission, a high MPV/PC ratio and a high level of CRP might help to identify patients at increased risk of IHS. Moreover, these results provide new insights into the potential role played by increased inflammation and platelet reactivity in the occurrence of stroke after AMI.
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http://dx.doi.org/10.1080/09537104.2016.1203397DOI Listing
January 2017

Validation of STA-Liatest D-Di assay for exclusion of pulmonary embolism according to the latest Clinical and Laboratory Standard Institute/Food and Drug Administration guideline. Results of a multicenter management study.

Blood Coagul Fibrinolysis 2017 Apr;28(3):254-260

aDepartment of Vascular Medicine, Grenoble University Hospital, Grenoble, France bPathology and Laboratory Medicine, Ohio State University, Columbus, Ohio, USA cHematology Laboratory, University Hospital, Dijon, France dPathology and Laboratory Medicine, Medical University South Carolina, Charleston, South Carolina, USA eDepartment of Haematology, Hôpital Maisonneuve-Rosemont, University of Montreal, Montreal, Canada fDepartment of Haematology, Santa Barbara General Hospital, Soria gLaboratio de Coagulación, Centro Sanitario Hospital General Universitario de Alicante, Alicante, Spain hDepartment of Angiology and Blood Coagulation 'Marino Golinelli', Bologna University Hospital Corporation, Policlinica S. Orsola Malpighi, Bologna iCoagulation Service and Thrombosis Research Unit, Scientific Institute San Raffaele, Milano, Italy.

: Combined clinical pretest probability (PTP) and D-dimer testing have great diagnostic value for pulmonary embolism exclusion. To harmonize performance levels of D-dimer assays available on the market, the Clinical and Laboratory Standard Institute (CLSI) has published a guideline, endorsed by the US Food and Drug Administration (FDA). Such guideline specifies the ideal D-dimer assay characteristic and target population. This study was conducted following the CLSI guideline to upgrade the assay-intended use and obtain FDA clearance of STA-Liatest D-Di assay for pulmonary embolism exclusion in patient with low/moderate PTP. This was an international, multicenter, prospective nonrandomized, noninterventional clinical outcome management study conducted in a standard of care setting. D-dimer assay was performed in consecutive, ambulatory outpatients suspected of pulmonary embolism, with low/moderate PTP, and without medical conditions or in clinical settings known to alter default D-dimer values regardless of the presence of thrombosis using a threshold of 0.5 μg/ml (fibrinogen equivalent units) for venous thromboembolism exclusion. Results were used to determine test performance. Of 1141 patients who underwent D-dimer testing, 1060 had valid results and completed study as planned. STA-Liatest D-Di assay performance has exceeded the CLSI/FDA guidance requirements, with a sensitivity of 97.6% (95% confidence interval: 91.7-99.7%) and a negative predictive value of 99.7% (95% confidence interval: 99.0-100%). STA-Liatest D-Di assay has an excellent performance when used in combination with a PTP score in relevant patients and has the potential to minimize the economic healthcare burden avoiding unnecessary and expensive imaging tests.
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http://dx.doi.org/10.1097/MBC.0000000000000591DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5407630PMC
April 2017

Lupus anticoagulant-hypoprothrombinemia syndrome and catastrophic antiphospholipid syndrome in a patient with antidomain I antibodies.

Blood Coagul Fibrinolysis 2016 Jul;27(5):580-2

aNancy University Hospital, Vascular Medicine Division and Regional Competence, Center for Rare Vascular And Systemic Autoimmune DiseasesbDijon University Hospital, Haematology laboratory, Nancy, FrancecBiochemistry, Cardiovascular Research Institute Maastricht (CARIM), Maastricht, University, Maastricht, the NetherlandsdNancy University Hospital, Nuclear Medecine & Nancyclotep Experimental Imaging, PlatformeUniversité de LorrainefInserm, UMR_S 1116gNancy University Hospital, Department of Critical Care Medicine, Nancy, France.

Lupus anticoagulant-hypoprothrombinemia syndrome is a rare condition characterized by the association of acquired factor II deficiency and lupus anticoagulant. Contrary to classical antiphospholipid syndrome, it may cause severe life-threatening bleeding (89% of published cases). We report a patient, positive for antidomain I antibodies, with initially primary lupus anticoagulant-hypoprothrombinemia syndrome without previous clinical manifestation or underlying systemic disease. Five years later, he experienced the first systemic lupus erythematous flare. Within a few days, catastrophic antiphospholipid syndrome was diagnosed with heart, liver and kidney involvement. The patient recovered under pulse steroids, intravenous heparin and intravenous immunoglobulins.
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http://dx.doi.org/10.1097/MBC.0000000000000545DOI Listing
July 2016

Epidemiology and pathophysiology of adulthood-onset thrombotic microangiopathy with severe ADAMTS13 deficiency (thrombotic thrombocytopenic purpura): a cross-sectional analysis of the French national registry for thrombotic microangiopathy.

Lancet Haematol 2016 May 16;3(5):e237-45. Epub 2016 Apr 16.

Service d'Hématologie biologique, Hôpital Lariboisière, Assistance Publique-Hôpitaux de Paris and EA3518, Institut Universitaire d'Hématologie-Hôpital Saint Louis, Université Paris Diderot, Paris, France. Electronic address:

Background: Thrombotic thrombocytopenic purpura is a thrombotic microangiopathy related to a severe deficiency of ADAMTS13 (a disintegrin and metalloprotease with thrombospondin type 1 repeats, member 13; activity <10%). We aimed to investigate the association between mechanisms for ADAMTS13 deficiency and the epidemiology and pathophysiology of thrombotic thrombocytopenic purpura at initial presentation.

Methods: Between Jan 1, 1999, and Dec 31, 2013, we did a cross-sectional analysis of the French national registry for thrombotic microangiopathy to identify all patients with adult-onset thrombotic microangiopathy (first episode after age 18 years) who had severe ADAMTS13 deficiency at presentation. ADAMTS13 activity, anti-ADAMTS13 IgG, and ADAMTS13 gene mutations were investigated by a central laboratory. We collected patients' clinical data for correlation with their ADAMTS13 phenotype and genotype. We used logistic regression analysis to identify variables significantly associated with idiopathic thrombotic thrombocytopenic purpura, as measured by estimated odds ratios (ORs) and 95% CIs. This study is registered with ClinicalTrials.gov, number NCT00426686.

Findings: We enrolled 939 patients with adult-onset thrombotic thrombocytopenic purpura, of whom 772 (82%) patients had available data and samples at presentation and comprised the cohort of interest. The prevalence of thrombotic thrombocytopenic purpura in France was 13 cases per million people. At presentation, 378 (49%) patients had idiopathic thrombotic thrombocytopenic purpura, whereas 394 (51%) patients had disease associated with miscellaneous clinical situations (infections, autoimmunity, pregnancy, cancer, organ transplantation, and drugs). Pathophysiologically, three distinct forms of thrombotic thrombocytopenic purpura were observed: 585 (75%) patients had autoimmune disease with anti-ADAMTS13 IgG, 166 (22%) patients had acquired disease of unknown cause and 21 (3%) patients had inherited disease (Upshaw-Schulman syndrome) with mutations of the ADAMTS13 gene. Idiopathic thrombotic thrombocytopenic purpura were mainly autoimmune (345 [91%] cases), whereas non-idiopathic diseases were heterogeneous, including a high rate of unexplained mechanisms for ADAMTS13 deficiency (133 [34%] cases). Obstetrical thrombotic thrombocytopenic purpura cases (n=62) were specifically remarkable because of the high rate of patients with Upshaw-Schulman syndrome (21 [34%] patients).

Interpretation: Our study shows that thrombotic thrombocytopenic purpura is a heterogeneous syndrome, and that features of the disease at presentation are strongly associated with the mechanisms of ADAMTS13 deficiency. In addition to mechanistic insight, our findings could have implications for the initial therapeutic management of patients with this disorder.

Funding: Assistance Publique-Hôpitaux de Paris.
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http://dx.doi.org/10.1016/S2352-3026(16)30018-7DOI Listing
May 2016

Argatroban in the management of heparin-induced thrombocytopenia: a multicenter clinical trial.

Crit Care 2015 Nov 11;19:396. Epub 2015 Nov 11.

Laboratory of Hematology, University Hospital of Dijon, Dijon, France.

Introduction: The aim of this study was to collect data in France in patients with heparin-induced thrombocytopenia who required parenteral anticoagulation and for whom other non-heparin anticoagulant therapies were contraindicated including patients with renal failure, cross-reactivity to danaparoid or at high hemorrhagic risk.

Methods: A total of 20 patients, of mean age 72 ± 10 years, were enrolled in this open-label, multicenter clinical study. Exploratory statistical data analysis was performed with descriptive interpretation of intra-individual comparisons using simple univariate statistics.

Results: The diagnosis of HIT was confirmed in 16 subjects by an independent scientific committee. Fourteen patients (70 %) were in an intensive care unit during the course of the study. Patients were treated with argatroban for a mean duration of 8.5 ± 6.1 days. The mean starting dose of argatroban was 0.77 ± 0.45 μg/kg/min. Platelet recovery was rapid. aPTT and anti-IIa activity assays were used to monitor the dose of argatroban. The mean baseline aPTT value was 45.0 ± 9.8 sec and increased to 78.2 ± 35.8 sec two hours after initiating argatroban. At this time mean argatroban concentration was 0.34 ± 0.16 and 0.61 ± 0.28 μg/ml using ECT and TT measurements, respectively. New and/or extended thromboses were reported in 25 % of patients and major bleedings were documented in 15 %. Six patients died due to their underlying medical condition.

Conclusion: Considering its hepatic elimination and its short half-life, argatroban can be considered as a safe therapeutic option in HIT patients at high hemorrhagic risk and with renal failure, particularly in an ICU setting.
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http://dx.doi.org/10.1186/s13054-015-1109-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4641392PMC
November 2015

Natural history of patients with congenital dysfibrinogenemia.

Blood 2015 Jan 15;125(3):553-61. Epub 2014 Oct 15.

Division of Angiology and Haemostasis, University Hospitals of Geneva and Faculty of Medicine, Geneva, Switzerland;

We conducted a multicenter study of 101 patients with congenital dysfibrinogenemia (CD) to characterize the incidence of hemorrhagic and thrombotic events as well as complications of pregnancy and surgery. At the time of diagnosis, 10.9% and 13.9% had experienced major bleeding and thrombotic events, respectively. During a mean follow-up of 8.8 years after CD diagnosis, the incidence of major bleeding and thrombotic events was 2.5 and 18.7 per 1000 patient-years, respectively, with estimated cumulative incidences at age 50 years of 19.2% and 30.1%. We identified 111 pregnancies with an overall incidence of spontaneous abortions and postpartum hemorrhage of 19.8% and 21.4%, respectively. The risk of postpartum hemorrhage was associated with a previously identified bleeding phenotype (odds ratio, 5.8; 95% CI, 1.2 to 28.0). Among 137 surgical procedures analyzed, 9 (6.5%) were complicated by abnormal bleeding. Propositi vs relatives, sex, mutation hotspots, fibrinogen levels, and activity:antigen ratios were not associated with the risk of thrombotic or bleeding outcomes. In conclusion, the results of our study, the largest in genotyped CD and the first including long-term history, indicate that propositi with CD and their relatives carry not only a high risk of major bleeding, including postpartum hemorrhage, but also of thrombotic event.
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http://dx.doi.org/10.1182/blood-2014-06-582866DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4296015PMC
January 2015

Performance of two new automated assays for measuring von Willebrand activity: HemosIL AcuStar and Innovance.

Thromb Haemost 2014 Oct 7;112(4):825-30. Epub 2014 Aug 7.

Dr. Marc Trossaërt, Centre Régional de Traitement de l'Hémophilie, 1 Place Alexis RICORDEAU, Centre Hospitalier Universitaire, 44093 Nantes Cedex 1, France, Tel.: +33 2 40 08 74 68, Fax: +33 2 40 08 42 59, E-mail:

The ristocetin cofactor activity assay (VWF:RCo) is the reference method for assessing von Willebrand factor (VWF) activity but remains difficult to perform, and the coefficient of variation of the method is high (about 20-30%). This study evaluated and compared the performance for measuring the VWF activity of two newly commercialised assays [VWF:Ac Innovance (VWF:Ac) and VWF:RCo Acustar (VWF:RCo Acu)] with the reference VWF:RCo aggregation in 123 pathological plasma samples. The correlation and concordance between both new tests (VWF:RCo-Acu and VWF:Ac) and the reference VWF:RCo were good. The results of the VWF activity to VWF antigen ratio were also comparable whatever the method for the classification of VWF deficiency in all patients. Our results showed that both new tests could replace the "gold standard" VWF:RCo in aggregometry with several benefits: they are fully automated, easier and faster to perform, better adapted to emergency situations if necessary.
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http://dx.doi.org/10.1160/TH14-02-0108DOI Listing
October 2014

Spectrum of the mutations in Bernard-Soulier syndrome.

Hum Mutat 2014 Sep 15;35(9):1033-45. Epub 2014 Jul 15.

Institute for Maternal and Child Health - IRCCS "Burlo Garofolo", Trieste, Italy; Department of Medical Sciences, University of Trieste, Trieste, Italy.

Bernard-Soulier syndrome (BSS) is a rare autosomal recessive bleeding disorder characterized by defects of the GPIb-IX-V complex, a platelet receptor for von Willebrand factor (VWF). Most of the mutations identified in the genes encoding for the GP1BA (GPIbα), GP1BB (GPIbβ), and GP9 (GPIX) subunits prevent expression of the complex at the platelet membrane or more rarely its interaction with VWF. As a consequence, platelets are unable to adhere to the vascular subendothelium and agglutinate in response to ristocetin. In order to collect information on BSS patients, we established an International Consortium for the study of BSS, allowing us to enrol and genotype 132 families (56 previously unreported). With 79 additional families for which molecular data were gleaned from the literature, the 211 families characterized so far have mutations in the GP1BA (28%), GP1BB (28%), or GP9 (44%) genes. There is a wide spectrum of mutations with 112 different variants, including 22 novel alterations. Consistent with the rarity of the disease, 85% of the probands carry homozygous mutations with evidence of founder effects in some geographical areas. This overview provides the first global picture of the molecular basis of BSS and will lead to improve patient diagnosis and management.
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http://dx.doi.org/10.1002/humu.22607DOI Listing
September 2014

Unusual Case of HIT With Cardiac Arrest During Hemodialysis.

Ann Pharmacother 2014 Aug 20;48(8):1086-1089. Epub 2014 May 20.

University Hospital, Dijon, France.

Objective: To report an unusual case of heparin-induced thrombocytopenia (HIT) with cardiac arrest during hemodialysis (HD).

Case Summary: An 88-year-old man previously treated with HD under enoxaparin for 3 years presented with dizziness and cyanosis at the beginning of HD on 3 consecutive sessions. Even though the dialyzer membrane was changed, he presented with cardiac arrest, from which he recovered quickly. At the same time, the platelet count fell, and HIT was suspected. No thrombosis was found. Anti-PF4/H, IL8, and NAP2 antibodies were negative, but platelet aggregation tests and serotonin-release assay were positive. After implementing HD with danaparoid, the platelet count returned to normal, and the patient remained asymptomatic.

Discussion: Given the clinical context (low-molecular-weight heparin), complications (cardiac arrest and no thrombosis), and timing (3 years), this was an unusual case of HIT. According to the Naranjo probability scale, the causality of enoxaparin was evaluated as probable. In most reported cases, time to onset was short, clotting occurred in the extracorporeal system, and biological tests, including ELISA (enzyme-linked immunosorbent assay) anti-PF4/heparin, were positive. We found no triggering factor in this case, and given the biological results, a new antigenic target may be involved.

Conclusions: HIT must be considered when acute systemic reactions occur at the beginning of HD sessions, even after several years of HD and with no change of anticoagulant, including low-molecular-weight heparin. The platelet count should be measured immediately after the reaction. The diagnosis is important because of possible cardiac arrest in this context.
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http://dx.doi.org/10.1177/1060028014535361DOI Listing
August 2014