Publications by authors named "Lelia Grunebaum"

43 Publications

Follow-up of COVID-19 patients: LA is transient but other aPLs are persistent.

Autoimmun Rev 2021 Jun 16;20(6):102822. Epub 2021 Apr 16.

Service d'Immunologie Clinique-Médecine Interne, Centre National de Référence des Maladies Auto-immunes et Systémiques Rares Est/Sud-Ouest RESO, Hôpitaux Universitaires de Strasbourg, France. Electronic address:

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http://dx.doi.org/10.1016/j.autrev.2021.102822DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8050395PMC
June 2021

Heparin-induced thrombocytopenia: construction of a pre-test diagnostic score derived from the analysis of a prospective multinational database, with internal validation.

J Thromb Haemost 2021 Apr 19. Epub 2021 Apr 19.

F-Crin INNOVTE, Université de Lyon, CIC 1408, Inserm U1059 SAINBIOSE, Saint-Etienne, France.

Background: Diagnosis of heparin-induced thrombocytopenia (HIT) requires pre-test probability assessment and dedicated laboratory assays.

Objective: To develop a pre-test score for HIT.

Design: Observational; analysis of prospectively collected data of hospitalized patients suspected with HIT (ClinicalTrials.gov NCT00748839).

Setting: Thirty-one tertiary hospitals in France, Switzerland, and Belgium.

Patients: Patients tested for HIT antibodies (2,280 evaluable), randomly allocated to derivation and validation cohorts.

Measurements: Independent adjudicators diagnosed HIT based on the prospectively collected data and Serotonin Release Assay results.

Results: HIT was diagnosed in 234 (14.7%) and 99 (14.5%) patients in the two cohorts. Eight features were associated with HIT (in brackets, points assigned for score calculation of the score): unfractionated heparin (1); therapeutic-dose heparin (1); cardiopulmonary bypass (cardiac surgery) (2); major trauma (3); 5- to 21-day interval from anticoagulation initiation to suspicion of HIT (4); ≥ 40% decrease in platelet count over ≤ six days (3); thrombotic event, arterial (3) or venous (3). The C-statistic was 0.79 [95% CI, 0.76-0.82]. In the validation cohort, the area under the receiver operating characteristic curve was 0.77 [95% CI, 0.74-0.80]. Three groups of scores were defined; HIT prevalence reached almost 30% in the high-probability group.

Limitation: The performance of the score may depend on settings and practices.

Conclusion: The objective, easy-to-collect, clinical features of HIT we evidenced were incorporated into a pre-test score, which may guide clinical decisions regarding diagnostic testing and anticoagulation.
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http://dx.doi.org/10.1111/jth.15344DOI Listing
April 2021

Discrepancy in Von Willebrand Abnormalities Between Degenerative and Functional Mitral Regurgitation.

Am J Cardiol 2021 Mar 14. Epub 2021 Mar 14.

Université de Strasbourg, Pôle d'Activité Médico-Chirurgicale Cardio-Vasculaire, Nouvel Hôpital Civil, Centre Hospitalier Universitaire, Strasbourg, France.; UMR1260 INSERM, Nanomédecine Régénérative, Faculté de Pharmacie, Université de Strasbourg, Illkirch, France.

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http://dx.doi.org/10.1016/j.amjcard.2021.03.007DOI Listing
March 2021

Use of recombinant Von Willebrand factor during transcatheter aortic valve replacement in a patient with acquired von Willebrand syndrome.

Transfus Med 2021 Apr 24;31(2):142-144. Epub 2021 Feb 24.

Centre de Ressource et Compétence des Maladies Hémorragiques Constitutionnelles, Hôpitaux Universitaires de Strasbourg, Strasbourg, France.

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http://dx.doi.org/10.1111/tme.12765DOI Listing
April 2021

Higher anticoagulation targets and risk of thrombotic events in severe COVID-19 patients: bi-center cohort study.

Ann Intensive Care 2021 Jan 25;11(1):14. Epub 2021 Jan 25.

Service de Médecine Intensive Réanimation, Nouvel Hôpital Civil, Hôpitaux Universitaires de Strasbourg, 1, Place de l'Hôpital, 67091, Strasbourg Cedex, France.

Background: Thromboprophylaxis of COVID-19 patients is a highly debated issue. We aimed to compare the occurrence of thrombotic/ischemic events in COVID-19 patients with acute respiratory distress syndrome (ARDS) treated with either prophylactic or therapeutic dosage of heparin. All patients referred for COVID-19 ARDS in two intensive care units (ICUs) from two centers of a French tertiary hospital were included in our cohort study. Patients were compared according to their anticoagulant treatment to evaluate the risk/benefit of prophylactic anticoagulation versus therapeutic anticoagulation. Medical history, symptoms, biological data and imaging were prospectively collected.

Results: One hundred and seventy-nine patients (73% men) were analyzed: 108 in prophylactic group and 71 in therapeutic group. Median age and SAPS II were 62 [IQR 51; 70] years and 47 [IQR 37; 63] points. ICU mortality rate was 17.3%. Fifty-seven patients developed clinically relevant thrombotic complications during their ICU stay, less frequently in therapeutic group (adjusted OR 0.38 [0.14-0.94], p = 0.04). The occurrences of pulmonary embolism (PE), deep vein thrombosis (DVT) and ischemic stroke were significantly lower in the therapeutic group (respective adjusted OR for PE: 0.19 [0.03-0.81]; DVT: 0.13 [0.01-0.89], stroke: 0.06 [0-0.68], all p < 0.05). The occurrence of bleeding complications was not significantly different between groups, neither were ICU length of stay or mortality rate. D-dimer levels were significantly lower during ICU stay, and aPTT ratio was more prolonged in the therapeutic group (p < 0.05).

Conclusion: Increasing the anticoagulation of severe COVID-19 patients to a therapeutic level might decrease thrombotic complications without increasing their bleeding risk.
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http://dx.doi.org/10.1186/s13613-021-00809-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7829649PMC
January 2021

Delayed pulmonary embolism after COVID-19 pneumonia: a case report.

Eur Heart J Case Rep 2020 Dec 24;4(6):1-4. Epub 2020 Nov 24.

Pôle d'Activité Médico-Chirurgicale Cardiovasculaire, Hôpitaux Universitaires de Strasbourg, 1 Place de l'Hôpital 67091, Strasbourg Cedex, France.

Background : Since the onset of the COVID-19 pandemic, several cardiovascular manifestations have been described. Among them, venous thromboembolism (VTE) seems to be one of the most frequent, particularly in intensive care unit patients. We report two cases of COVID-19 patients developing acute pulmonary embolism (PE) after discharge from a first hospitalization for pneumonia of moderate severity.

Case Summary : Two patients with positive RT-PCR test were initially hospitalized for non-severe COVID-19. Both received standard thromboprophylaxis during the index hospitalization and had no strong predisposing risk factors for VTE. Few days after discharge, they were both readmitted for worsening dyspnoea due to PE. One patient was positive for lupus anticoagulant.

Discussion : Worsening respiratory status in COVID-19 patients must encourage physicians to search for PE since SARS-CoV-2 infection may act as a precipitant risk factor for VTE. Patients may thus require more aggressive and longer thromboprophylaxis after COVID-19 related hospitalization.
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http://dx.doi.org/10.1093/ehjcr/ytaa449DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7793223PMC
December 2020

D-Dimers Level as a Possible Marker of Extravascular Fibrinolysis in COVID-19 Patients.

J Clin Med 2020 Dec 24;10(1). Epub 2020 Dec 24.

Division of Cardiovascular Medicine, Nouvel Hôpital Civil, Strasbourg University Hospital, 67000 Strasbourg, France.

Background And Objective: Host defence mechanisms to counter virus infection include the activation of the broncho-alveolar haemostasis. Fibrin degradation products secondary to extravascular fibrin breakdown could contribute to the marked increase in D-Dimers during COVID-19. We sought to examine the prognostic value on lung injury of D-Dimers in non-critically ill COVID-19 patients without thrombotic events.

Methods: This study retrospectively analysed hospitalized COVID-19 patients classified according to a D-Dimers threshold following the COVID-19 associated haemostatic abnormalities (CAHA) classification at baseline and at peak (Stage 1: D-Dimers less than three-fold above normal; Stage 2: D-Dimers three- to six-fold above normal; Stage 3: D-Dimers six-fold above normal). The primary endpoint was the occurrence of critical lung injuries on chest computed tomography. The secondary outcome was the composite of in-hospital death or transfer to the intensive care unit (ICU).

Results: Among the 123 patients included, critical lung injuries were evidenced in 8 (11.9%) patients in Stage 1, 6 (20%) in Stage 2 and 15 (57.7%) in Stage 3 ( = 0.001). D-Dimers staging at peak was an independent predictor of critical lung injuries regardless of the inflammatory burden assessed by CRP levels (OR 2.70, 95% CI (1.50-4.86); < 0.001) and was significantly associated with increased in-hospital death or ICU transfer (14.9 % in Stage 1, 50.0% in Stage 2 and 57.7% in Stage 3 ( < 0.001)). D-Dimers staging at peak was an independent predictor of in-hospital death or ICU transfer (OR 2.50, CI 95% (1.27-4.93); = 0.008).

Conclusions: In the absence of overt thrombotic events, D-Dimers quantification is a relevant marker of critical lung injuries and dismal patient outcome.
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http://dx.doi.org/10.3390/jcm10010039DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7795726PMC
December 2020

Periprocedural Predictors of New-Onset Conduction Abnormalities After Transcatheter Aortic Valve Replacement.

Circ J 2020 09 1;84(10):1875-1883. Epub 2020 Sep 1.

Université de Strasbourg, Pôle d'Activité Médico-Chirurgicale Cardio-Vasculaire, Nouvel Hôpital Civil, Centre Hospitalier Universitaire.

Background: New-onset conduction abnormalities (CAs) following transcatheter aortic valve replacement (TAVR) are associated with hospital rehospitalization and long-term mortality, but available predictors are sparse. This study sought to determine clinical predictors of new-onset left bundle branch block (LBBB) and new permanent pacemaker (PPM) implantation in patients undergoing TAVR.Methods and Results:We enrolled 290 patients who received SAPIEN 3 (Edwards Lifesciences, Irvine, CA, USA; n=217) or Evolut R (Medtronic, Minneapolis, MN, USA; n=73) from a prospective registry at Nouvel Hôpital Civil, Strasbourg, France between September 2014 and February 2018. Of 242 patients without pre-existing LBBB, 114 (47%) experienced new-onset LBBB and/or new PPM implantation. A difference between membranous septal length and implantation depth (∆MSID) was the only predictor of CAs for both types of valves. In the multivariate analysis, PR interval and ∆MSID remained as sole predictors of CAs. The risk for adverse clinical events, including all-cause death, myocardial infarction, stroke, and heart failure hospitalization, was higher for patients with CAs as compared with patients without CAs (hazard ratio: 2.10; 95% confidence interval: 1.26 to 3.57; P=0.004).

Conclusions: Computed tomography assessment of membranous septal anatomy and implantation depth predicted CAs after TAVR with new-generation valves. Future studies are required to identify whether adjustment of the implantation depth can reduce the risk of CAs and adverse clinical outcomes.
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http://dx.doi.org/10.1253/circj.CJ-20-0257DOI Listing
September 2020

Staging Severity of COVID-19 according to Hemostatic Abnormalities (CAHA Score).

Thromb Haemost 2020 Dec 30;120(12):1716-1719. Epub 2020 Aug 30.

Division of Cardiovascular Medicine, Nouvel Hôpital Civil, Strasbourg University Hospital, Strasbourg, France.

This is the first study to show a stepwise increase in venous thrombotic events according to COVID-19 coagulopathy (COVID-19-associated hemostatic abnormalities [CAHA]) staging and lung injuries assessed by chest computed tomography. Excess mortality and/or transfer to intensive care unit according to CAHA staging.
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http://dx.doi.org/10.1055/s-0040-1715836DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7869051PMC
December 2020

Predictive Impact of Paravalvular Leak Assessments on Clinical Outcomes Following Transcatheter Aortic Valve Replacement.

Am J Cardiol 2020 11 25;135:181-182. Epub 2020 Aug 25.

Université de Strasbourg, Pôle d'Activité Médico-Chirurgicale Cardio-Vasculaire, Nouvel Hôpital Civil, Centre Hospitalier Universitaire, Strasbourg, France; UMR1260 INSERM, Nanomédecine Régénérative, Faculté de Pharmacie, Université de Strasbourg, Illkirch, France. Electronic address:

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http://dx.doi.org/10.1016/j.amjcard.2020.08.006DOI Listing
November 2020

COVID-19 in a pediatric patient with Glanzmann thrombasthenia.

Pediatr Blood Cancer 2020 10 15;67(10):e28662. Epub 2020 Aug 15.

Centre de Ressource et Compétence des Maladies Hémorragiques Constitutionnelles, Hôpitaux Universitaires de Strasbourg, Strasbourg, France.

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http://dx.doi.org/10.1002/pbc.28662DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7460953PMC
October 2020

Paradoxical Increase of Stroke in Patients with Defect of High Molecular Weight Multimers of the von Willebrand Factors following Transcatheter Aortic Valve Replacement.

Thromb Haemost 2020 Sep 29;120(9):1330-1338. Epub 2020 Jul 29.

Pôle d'Activité Médico-Chirurgicale Cardio-Vasculaire, Nouvel Hôpital Civil, Centre Hospitalier Universitaire, Université de Strasbourg, Strasbourg, France.

Background:  Stroke is a major cause of disability after transcatheter aortic valve replacement (TAVR) and stroke prediction models and data are crucially needed. Following TAVR, high molecular weight (HMW) multimers defect of von Willebrand factor (VWF) as assessed by closure time of adenosine diphosphate (CT-ADP) value > 180 seconds is an independent predictor of bleeding events. This study sought to identify predictors of ischemic neurological events in patients who underwent TAVR and the specific impact of HMW multimers defect of VWF.

Methods:  Patients were prospectively enrolled between November 2012 and May 2018 at our institution. The CT-ADP, a point-of-care measure of hemostasis, was assessed the day before and 24 hours after the procedures. The rate of ischemic stroke and transient ischemic attack (TIA) was recorded up to 30 days after the procedures.

Results:  Of 565 TAVR patients, ischemic stroke/TIA was observed in 21 (3.7%) patients within 30 days. Ischemic stroke/TIA was associated with major/life-threatening bleeding complications (MLBCs) (9 [43%] vs. 88 [16%],  = 0.002) and postprocedure CT-ADP > 180 seconds (10 [48%] vs. 116 [21%],  = 0.01). By multivariate analysis, MLBCs (odds ratio [OR]: 3.58; 95% confidence interval [CI]: 1.45-8.84;  = 0.006) and postprocedure CT-ADP > 180 seconds (OR: 3.38; 95% CI: 1.38-8.25;  = 0.008) were evidenced as independent predictors of ischemic stroke/TIA.

Conclusion:  MLBCs and CT-ADP > 180 seconds were identified as predictors for ischemic stroke or TIA. The present study suggests that the defects of HMW multimers of the VWFs may contribute not only to bleeding events but also to thrombotic events.
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http://dx.doi.org/10.1055/s-0040-1713424DOI Listing
September 2020

Venous thromboembolism in non-critically ill patients with COVID-19 infection.

Thromb Res 2020 09 17;193:166-169. Epub 2020 Jul 17.

Division of Cardiovascular Medicine, Nouvel Hôpital Civil, Strasbourg University Hospital, Strasbourg, France; INSERM (French National Institute of Health and Medical Research), UMR 1260, Regenerative Nanomedicine, FMTS, Strasbourg, France. Electronic address:

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http://dx.doi.org/10.1016/j.thromres.2020.07.033DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7367026PMC
September 2020

COVID-19 Related Coagulopathy: A Distinct Entity?

J Clin Med 2020 May 31;9(6). Epub 2020 May 31.

Université de Strasbourg, Pôle d'Activité Médico-Chirurgicale Cardio-Vasculaire, Nouvel Hôpital Civil, Centre Hospitalier Universitaire, 67000 Strasbourg, France.

The coronavirus disease 2019 (COVID-19) pandemic has impacted healthcare communities across the globe on an unprecedented scale. Patients have had diverse clinical outcomes, but those developing COVID-19-related coagulopathy have shown a disproportionately worse outcome. This narrative review summarizes current evidence regarding the epidemiology, clinical features, known and presumed pathophysiology-based models, and treatment guidance regarding COVID-19 coagulopathy.
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http://dx.doi.org/10.3390/jcm9061651DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7356260PMC
May 2020

Refractory non-variceal upper gastrointestinal bleeding in a liver-transplant patient: Everolimus withdrawal should be considered.

Therapie 2020 May 8. Epub 2020 May 8.

Service de médecine intensive réanimation & Inserm U1121 & FMTS, faculté de médecine de strasbourg, avenue Molière, hôpitaux universitaires de Strasbourg, 67098 Strasbourg, France; Centre régional de pharmacovigilance, hôpitaux universitaires de Strasbourg, 67091, Strasbourg, France. Electronic address:

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http://dx.doi.org/10.1016/j.therap.2020.04.006DOI Listing
May 2020

High risk of thrombosis in patients with severe SARS-CoV-2 infection: a multicenter prospective cohort study.

Intensive Care Med 2020 06 4;46(6):1089-1098. Epub 2020 May 4.

Service de Médecine Intensive Réanimation, Nouvel Hôpital Civil, Hôpitaux universitaires de Strasbourg, 1, Place de l'Hôpital, 67091, Strasbourg Cedex, France.

Purpose: Little evidence of increased thrombotic risk is available in COVID-19 patients. Our purpose was to assess thrombotic risk in severe forms of SARS-CoV-2 infection.

Methods: All patients referred to 4 intensive care units (ICUs) from two centers of a French tertiary hospital for acute respiratory distress syndrome (ARDS) due to COVID-19 between March 3rd and 31st 2020 were included. Medical history, symptoms, biological data and imaging were prospectively collected. Propensity score matching was performed to analyze the occurrence of thromboembolic events between non-COVID-19 ARDS and COVID-19 ARDS patients.

Results: 150 COVID-19 patients were included (122 men, median age 63 [53; 71] years, SAPSII 49 [37; 64] points). Sixty-four clinically relevant thrombotic complications were diagnosed in 150 patients, mainly pulmonary embolisms (16.7%). 28/29 patients (96.6%) receiving continuous renal replacement therapy experienced circuit clotting. Three thrombotic occlusions (in 2 patients) of centrifugal pump occurred in 12 patients (8%) supported by ECMO. Most patients (> 95%) had elevated D-dimer and fibrinogen. No patient developed disseminated intravascular coagulation. Von Willebrand (vWF) activity, vWF antigen and FVIII were considerably increased, and 50/57 tested patients (87.7%) had positive lupus anticoagulant. Comparison with non-COVID-19 ARDS patients (n = 145) confirmed that COVID-19 ARDS patients (n = 77) developed significantly more thrombotic complications, mainly pulmonary embolisms (11.7 vs. 2.1%, p < 0.008). Coagulation parameters significantly differed between the two groups.

Conclusion: Despite anticoagulation, a high number of patients with ARDS secondary to COVID-19 developed life-threatening thrombotic complications. Higher anticoagulation targets than in usual critically ill patients should therefore probably be suggested.
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http://dx.doi.org/10.1007/s00134-020-06062-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7197634PMC
June 2020

[Switching toward the use of recombinant factor VIII Fc fusion protein Study among 30 patients with severe hemophilia A].

Ann Biol Clin (Paris) 2020 02;78(1):35-46

Centre de ressource et de compétence, maladie hémorragique constitutionnelle, CHU Hautepierre, Strasbourg, France.

Only a few studies on real-world clinical use of recombinant factor VIII -fusionned with Fc (rFVIIIFc, efmoroctocog alpha) have been performed to date, with data on the annual bleeding rate (ABR), the prophylaxis regimen, and FVIII consumption. The aim of our study was to report the real-world clinical application of rFVIIIFc with additional elements, both biological and clinical. A prospective monocentric study has been conducted in the Haemophilia treatment center (HTC) of the Strasbourg university hospital among the severe haemophilia A patients. Thirty male patients were enrolled in the study. After injection of rFVIIIFc, the average time spent above 5%, 2% and 1% of FVIII was respectively almost 3, 4 and 5 days. The average half-life was 15.8 hours. A strong linear correlation between incremental recovery of rFVIIIFc and weight and between rFVIIIFc half-life and basal VWF:Ag level was observed. FVIII activity measurement for rFVIIIFc showed similar results than those previously published. In the follow-up, residual FVIII activity was on average the one of a mild haemophilia patient, corroborated by the results of endogenous thrombin potential of the thrombin generation assay. In clinical practice, rFVIIIFc was well tolerated and patients were mostly satisfied or indifferent of the switch. A single failure was however noticed. No FVIII inhibitor has been detected. Decrease in FVIII consumption was observed, with reduced or unchanged ABR. The switch was an actual success for almost all of the 30 patients, corroborated by satisfactory clinical and biological results.
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http://dx.doi.org/10.1684/abc.2020.1520DOI Listing
February 2020

Thromboprophylaxis in the obese surgical patient.

Eur J Anaesthesiol 2019 02;36(2):162-163

From the Department of Anaesthesiology and Intensive Care, Nouvel Hôpital Civil (AS, CAT), Laboratory of Haemostasis, University Hospital Strasbourg (LG) and EA 7293, Faculty of Pharmacy, FMTS, University of Strasbourg , France (FT).

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http://dx.doi.org/10.1097/EJA.0000000000000936DOI Listing
February 2019

Primary Hemostatic Disorders and Late Major Bleeding After Transcatheter Aortic Valve Replacement.

J Am Coll Cardiol 2018 10;72(18):2139-2148

Université de Strasbourg, Pôle d'Activité Médico-Chirurgicale Cardio-Vasculaire, Nouvel Hôpital Civil, Centre Hospitalier Universitaire, Strasbourg, France; UMR 1260 INSERM Nanomédecine Régénérative, Université de Strasbourg, Strasbourg, France. Electronic address:

Background: Periprocedural and late (>30 days) bleedings represent major complications after transcatheter aortic valve replacement and have been identified as potential areas for improved patient care.

Objectives: The authors sought to evaluate the impact of ongoing primary hemostasis disorders on late major/life-threatening bleeding complications (MLBCs).

Methods: Bleedings were assessed according to the VARC-2 (Valve Academic Research Consortium-2) criteria. Closure time of adenosine diphosphate (CT-ADP), a surrogate marker of high molecular weight von Willebrand multimers proteolysis was assessed 24 h after the procedure. Ongoing primary hemostasis disorder was defined by a CT-ADP >180 s.

Results: Among 372 patients who survived at 30 days, MLBCs occurred in 42 patients (11.3%) at a median follow-up of 383 days (interquartile range: 188 to 574 days). MLBCs were mainly of gastrointestinal origin (42.8%) and were associated with increased overall mortality (hazard ratio [HR]: 5.66; 95% confidence interval [CI]: 3.10 to 10.31; p < 0.001) and cardiac mortality (HR: 11.62; 95% CI: 4.59 to 29.37; p < 0.001). A 2.5-fold elevation of MLBCs could be evidenced in patients with a CT-ADP > 180 s (27.4% vs. 11.5%; p < 0.001). Multivariate regression analysis identified paravalvular leak (PVL) (HR: 6.31; 95% CI: 3.43 to 11.60; p < 0.0001) and CT-ADP > 180 s (HR: 3.08; 95% CI: 1.62 to 5.81; p = 0.0005) as predictor of MLBCs.

Conclusions: MLBCs after transcatheter aortic valve replacement are frequent and associated with an increased morbidity and mortality. PVL and CT-ADP >180 s were identified as strong predictors for MLBCs. These findings strongly suggest that persistent HMW defects contribute to enhanced bleeding risk in patients with residual PVL.
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http://dx.doi.org/10.1016/j.jacc.2018.08.2143DOI Listing
October 2018

CT-ADP Point-of-Care Assay Predicts 30-Day Paravalvular Aortic Regurgitation and Bleeding Events following Transcatheter Aortic Valve Replacement.

Thromb Haemost 2018 05 28;118(5):893-905. Epub 2018 Mar 28.

Pôle d'Activité Médico-Chirurgicale Cardio-Vasculaire, Nouvel Hôpital Civil, Centre Hospitalier Universitaire, Université de Strasbourg, Strasbourg, France.

Background: Paravalvular aortic regurgitation (PVAR) remains a frequent postprocedural concern following transcatheter aortic valve replacement (TAVR). Persistence of flow turbulence results in the cleavage of high-molecular-weight von Willebrand multimers, primary haemostasis dysfunction and may favour bleedings. Recent data have emphasized the value of a point-of-care measure of von Willebrand factor-dependent platelet function (closure time [CT] adenosine diphosphate [ADP]) in the monitoring of immediate PVAR. This study examined whether CT-ADP could detect PVAR at 30 days and bleeding complications following TAVR.

Methods: CT-ADP was assessed at baseline and the day after the procedure. At 30 days, significant PVAR was defined as a circumferential extent of regurgitation more than 10% by transthoracic echocardiography. Events at follow-up were assessed according to the Valve Academic Research Consortium-2 consensus classification.

Results: Significant PVAR was diagnosed in 44 out of 219 patients (20.1%). Important reduction of CT-ADP could be found in patients without PVAR, contrasting with the lack of CT-ADP improvement in significant PVAR patients. By multivariate analysis, CT-ADP > 180 seconds (hazard ratio [HR]: 5.1, 95% confidence interval [CI]: 2.5-10.6;  < 0.001) and a self-expandable valve were the sole independent predictors of 30-day PVAR. At follow-up, postprocedural CT-ADP >180 seconds was identified as an independent predictor of major/life-threatening bleeding (HR: 1.7, 95% CI [1.0-3.1];  = 0.049). Major/life-threatening bleedings were at their highest levels in patients with postprocedural CT-ADP > 180 seconds (35.2 vs. 18.8%;  = 0.013).

Conclusion: Postprocedural CT-ADP > 180 seconds is an independent predictor of significant PVAR 30 days after TAVR and may independently contribute to major/life-threatening bleedings.
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http://dx.doi.org/10.1055/s-0038-1639352DOI Listing
May 2018

Adjusted calculation model of heparin management during cardiopulmonary bypass in obese patients: A randomised controlled trial.

Eur J Anaesthesiol 2018 08;35(8):613-620

From the Department of Anesthesiology and Intensive Care (MV, EH, TW, FL, CT, OC, P-MM, AS), Laboratory of Haemostasis (LG, LS), Department of Cardiac Surgery, NHC (THM) and Department of BioStatistics (FS), Federation de Medecine Translationelle, University Hospital, Strasbourg, France.

Background: Anticoagulation during cardiopulmonary bypass (CPB) is usually adapted to total body weight (TBW). This may be inaccurate in obese patients and lead to heparin overdose with a risk of bleeding.

Objectives: To validate the efficacy and safety of an adjusted calculation model of heparin dosing based on ideal body weight (IBW) rather than TBW in obese CPB patients, with an expected target mean plasma heparin concentration of 4.5 IU ml after onset of CPB in the experimental group.

Design: Randomised controlled study.

Setting: University hospital.

Patients: Sixty obese patients (BMI ≥ 30 kg m) scheduled for CPB were included from January to June 2016.

Interventions: Patients received a bolus dose of unfractionated heparin of either 300 IU kg of TBW or 340 IU kg of IBW before onset of CPB. Additional adjusted boluses were injected to maintain an activated clotting time (ACT) of at least 400 s.

Main Outcome Measures: Plasma heparin concentration and ACT were measured at different time points. Total heparin doses and transfusion requirements were recorded.

Results: The target heparin concentration of 4.5 IU ml was reached in the IBW group at the onset of CPB and maintained at all time points during CPB. Heparin concentrations were significantly higher in the TBW group after the bolus (6.52 ± 0.97 vs. 4.54 ± 1.13 IU ml, P < 0.001) and after cardioplegia (5.10 ± 1.03 vs. 4.31 ± 1.00 IU ml, P = 0.02). Total heparin doses were significantly higher in the TBW group. Mean ACT was significantly lower in the IBW group but remained over 400 s during CPB. The correlation between heparin and ACT was poor. Peri-operative bleeding and transfusion requirements were comparable. No thrombotic event occurred in the CPB circuit.

Conclusion: The current IBW-adjusted regimen of heparin administration may be used efficiently in obese CPB patients, thereby avoiding overdose which cannot be accurately assessed by ACT monitoring alone.

Trial Registration: ClinicalTrials.gov identifier: NCT02675647.
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http://dx.doi.org/10.1097/EJA.0000000000000784DOI Listing
August 2018

Thrombomodulin favors leukocyte microvesicle fibrinolytic activity, reduces NETosis and prevents septic shock-induced coagulopathy in rats.

Ann Intensive Care 2017 Dec 8;7(1):118. Epub 2017 Dec 8.

UMR INSERM 1176-Universite Paris Sud, Hôpital Bicêtre, 78 rue du Général Leclerc, 94270, Le Kremlin-Bicêtre, France.

Background: Septic shock-induced disseminated intravascular coagulation is responsible for increased occurrence of multiple organ dysfunction and mortality. Immunothrombosis-induced coagulopathy may contribute to hypercoagulability. We aimed at determining whether recombinant human thrombomodulin (rhTM) could control exaggerated immunothrombosis by studying procoagulant responses, fibrinolysis activity borne by microvesicles (MVs) and NETosis in septic shock.

Methods: In a septic shock model after a cecal ligation and puncture-induced peritonitis (H0), rats were treated with rhTM or a placebo at H18, resuscitated and monitored during 4 h. At H22, blood was sampled to perform coagulation tests, to characterize MVs and to detect neutrophils extracellular traps (NETs). Lungs were stained with hematoxylin-eosin for inflammatory injury assessment.

Results: Coagulopathy was attenuated in rhTM-treated septic rats compared to placebo-treated rats, as attested by a significant decrease in procoagulant annexin A5-MVs and plasma procoagulant activity of phospholipids and by a significant increase in antithrombin levels (84 ± 8 vs. 64 ± 6%, p < 0.05), platelet count (582 ± 157 vs. 319 ± 91 × 10/L, p < 0.05) and fibrinolysis activity borne by MVs (2.9 ± 0.26 vs. 0.48 ± 0.29 U/mL urokinase, p < 0.05). Lung histological injury score showed significantly less leukocyte infiltration. Decreased procoagulant activity and lung injury were concomitant with decreased leukocyte activation as attested by plasma leukocyte-derived MVs and NETosis reduction after rhTM treatment (neutrophil elastase/DNA: 93 ± 33 vs. 227 ± 48 and citrullinated histones H3/DNA: 96 ± 16 vs. 242 ± 180, mOD for 10 neutrophils/L, p < 0.05).

Conclusion: Thrombomodulin limits procoagulant responses and NETosis and at least partly restores hemostasis control during immunothrombosis. Neutrophils might thus stand as a promising therapeutic target in septic shock-induced coagulopathy.
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http://dx.doi.org/10.1186/s13613-017-0340-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5722785PMC
December 2017

Early Detection of Disseminated Intravascular Coagulation During Septic Shock: A Multicenter Prospective Study.

Crit Care Med 2016 Oct;44(10):e930-9

1Service de Réanimation Médicale, Nouvel Hôpital Civil, Hôpitaux Universitaires de Strasbourg, Strasbourg, France.2EA 7293, Fédération de Médecine Translationnelle de Strasbourg (FMTS), Faculté de médecine, Université de Strasbourg, Strasbourg, France.3Department of Intensive Care, François Mitterrand University Hospital, Dijon, France.4Lipness Team, INSERM Research Center UMR 866 and LabExLipSTIC, University of Burgundy, Dijon, France.5INSERM CIC 1432, Clinical Epidemiology, University of Burgundy, Dijon, France.6EA 7290, Faculté de Médecine, Université de Strasbourg, Strasbourg, France.7Service de Réanimation Médicale, Centre Hospitalier Universitaire de Tours, Tours, France.8Inserm CIC 1435, Réanimation Polyvalente, CHU Dupuytren, Limoges, France.9Laboratoire de biostatistique et d'informatique médicale, Faculté de médecine, Université de Strasbourg, Strasbourg, France.10Groupe méthode en recherche clinique, service de santé publique, Hôpitaux Universitaires de Strasbourg, Strasbourg, France.11Laboratoire d'hématologie et hémostase, Hôpital de Hautepierre, Hôpitaux Universitaires de Strasbourg, Strasbourg, France.12UMR 7213 CNRS, Faculté de Pharmacie, Université de Strasbourg, Illkirch, France.

Objectives: Inadequate stratification of septic shock patients may result in inappropriate treatment allocation in randomized clinical trials, especially regarding anticoagulant. We previously reported that endothelial-derived microparticles are relevant biomarkers of sepsis-induced disseminated intravascular coagulation. In this validation cohort, we assess microparticles as surrogates of cell activation to improve early disseminated intravascular coagulation diagnosis and patient stratification.

Design: Prospective observational study in septic shock patients.

Settings: Four medical ICUs in university hospitals.

Patients And Methods: Two hundred sixty-five patients with septic shock from four ICUs were consecutively enrolled. Disseminated intravascular coagulation was diagnosed according to Japanese Association for Acute Medicine 2006 score. Endothelial- and leukocyte-derived circulating procoagulant microparticles were isolated and quantified by prothrombinase assay at admission, day 3, and day 7.

Intervention: None.

Measurements And Main Results: Two hundred fifty-nine patients were analyzed. Sixty-one had disseminated intravascular coagulation at admission, and 32 developed disseminated intravascular coagulation during the first 24 hours after admission. Multiple logistic regression model confirmed that endothelial cell-derived microparticles were associated with disseminated intravascular coagulation: CD105-microparticles (odds ratio, 2.13) and CD31-microparticles (odds ratio, 0.65) (p < 0.05). Furthermore, CD11a-microparticles to leukocyte ratio evidenced leukocyte activation (odds ratio, 1.59; p < 0.05). Prediction of disseminated intravascular coagulation was also analyzed after exclusion of patients with disseminated intravascular coagulation at admission. A new multiple logistic regression analysis demonstrated the association of CD105-microparticles (> 0.60 nM eq. PhtdSer; odds ratio, 1.67; p < 0.01), platelets count (≤ 127 g/L; odds ratio, 0.99; p < 0.01), and prothrombin time (≤ 58%; odds ratio, 0.98; p < 0.05) with disseminated intravascular coagulation. A combining score at admission is predictive of the absence of disseminated intravascular coagulation (area under the curve, 72.9%; specificity, 71.2%; sensitivity, 71.0%, with a negative predictive value of 93.1% and a positive predictive value of 31.0%).

Conclusions: Procoagulant microparticles from endothelial cells and leukocytes reflect a vascular injury during sepsis-induced disseminated intravascular coagulation that precedes obvious activation of coagulation. A combination of prothrombin time, endothelium-derived CD105-microparticles, and platelet count at admission could predict the absence of disseminated intravascular coagulation and allow a better stratification in future randomized clinical trials.
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http://dx.doi.org/10.1097/CCM.0000000000001836DOI Listing
October 2016

Identifying optimal heparin management during cardiopulmonary bypass in obese patients: A prospective observational comparative study.

Eur J Anaesthesiol 2016 Jun;33(6):408-16

From the Department of Anaesthesiology (EH, FF, FL, SD, OC, PMM, AS); Department of Haematology (LG); and Department of Cardiovascular Surgery, Strasbourg University Hospital, France (MK).

Background: The heparin regimen providing anticoagulation during cardiopulmonary bypass (CPB) is usually adapted to total body weight (TBW), but may be inaccurate in obese patients in whom TBW exceeds their ideal body weight.

Objectives: The objective is to compare the effects of heparin injection based on TBW on haemostatic parameters between obese and nonobese patients during cardiac surgery and to calculate the optimal heparin regimen.

Design: Prospective comparative study.

Setting: University hospital.

Patients: Two groups of 50 patients (BMI≥ or <30 kg m) were included in the study over a 9-month period in 2013. The study started on 27 February 2013.

Interventions: An unfractionated heparin (UFH) bolus of 300 IU kg TBW was injected before initiation of CPB followed by additional doses (50 to 100 IU kg) to maintain a target activated coagulation time (ACT) of at least 400 s.

Main Outcome Measures: ACT and plasma heparin concentration were measured at different time points after initiation of, and weaning from CPB.

Results: Obese patients received higher initial and total doses of heparin (P < 0.0001). Plasma heparin concentrations were significantly higher in obese patients at each time point (P < 0.001) and reached very high values after the initial bolus (5.90 vs. 4.48 IU ml, P < 0.0001). The relationship between plasma heparin concentration and ACT after the initial bolus was not linear and followed an asymptotic regression curve. Haemoglobin concentration decreased intraoperatively to a greater extent in the obese group (P < 0.001). No significant differences in postoperative bleeding or global transfusion requirements were observed.

Conclusion: The standard heparin regimen based on TBW in obese patients during CPB results in excessive plasma heparin concentrations and a significant intraoperative decrease in haemoglobin concentration. ACT monitoring was not accurate in identifying this excess dosage. An initial bolus of 340 IU kg ideal body weight would achieve a heparin concentration of 4.5 IU ml, similar to that observed in nonobese patients. Further investigations are warranted to confirm this heparin regimen.
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http://dx.doi.org/10.1097/EJA.0000000000000431DOI Listing
June 2016

Once versus twice daily injection of enoxaparin for thromboprophylaxis in bariatric surgery: effects on antifactor Xa activity and procoagulant microparticles. A randomized controlled study.

Surg Obes Relat Dis 2016 Mar-Apr;12(3):613-621. Epub 2015 Sep 19.

Faculty of Pharmacy, UMR CNRS 7213, University of Strasbourg, Strasbourg, France.

Background: The optimal scheme of thromboprophylaxis in bariatric surgery remains uncertain, because clinical practice is different between countries and randomized trials are lacking.

Objectives: The primary objective of this randomized multicenter study was to determine the optimal regimen of enoxaparin providing an antifactor Xa peak activity between .3 and .5 IU/mL at equilibrium and to evaluate the course of procoagulant microparticles (MPs).

Setting: University hospital.

Methods: A total of 164 patients scheduled for gastric bypass were allocated to 3 groups (A, B, and C) of enoxaparin treatment (4000, 6000, or 2×4000 IU, respectively). Antifactor Xa activity was measured before and 4 hours after each injection from D0 to D2. Doppler screening of the lower limbs was performed at D1, D9, and D30. Bleeding (BE) and thrombotic events (TE) were recorded during the first postoperative month. Total MPs were measured at D0, D9, and D30. MPs of leucocyte, platelet, and granulocyte origin were assessed in one third of the patients from each group. The 3 groups were compared by ANOVA.

Results: A total of 135 patients were analyzed. The equilibrium of antifactor Xa peak levels was obtained 52 hours after the presurgery injection and 12.8%, 56.4%, and 27.3% of the patients reached the target in groups A, B, and C, respectively (P<.001). No TE was detected. BE occurred in 1, 2, and 6 patients in groups A, B, and C, respectively). Total MPs remained unchanged over time. While no significant variation was observed in the other groups, platelet GP1 b(+)-MPs increased (P = .01) at D9 in group C, suggesting an incomplete control of anticoagulation leading to cell activation and procoagulant MP release that was confirmed by the higher MP levels measured at D30 (P = .04). CD66(+)-MPs were also highly elevated at J9 and D30 in group C indicating a granulocyte contribution.

Conclusions: This study shows that a single dose of enoxaparin 6000 IU/d allowed most of the patients to reach the target range of antifactor Xa activity without increasing the bleeding risk, with the most likely efficient reduction of procoagulant MPs. (Surg Obes Relat Dis 2015;0:000-000.) © 2015 American Society for Metabolic and Bariatric Surgery. All rights reserved.
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http://dx.doi.org/10.1016/j.soard.2015.08.505DOI Listing
October 2017

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

Effects of transcutaneous aortic valve implantation on aortic valve disease-related hemostatic disorders involving von Willebrand factor.

Can J Cardiol 2015 Jun 24;31(6):738-43. Epub 2015 Jan 24.

Department of Cardiology, University Hospital of Strasbourg, Nouvel Hôpital Civil, Strasbourg, France.

Background: Aortic valve stenosis (AVS) can be complicated by bleeding associated with acquired type 2A von Willebrand syndrome. The association of AVS and gastrointestinal bleeding from angiodysplasia is defined as Heyde syndrome. We sought to evaluate the effect of transcutaneous aortic valve implantation (TAVI) on hemostasis disorders and to assess its effectiveness to treat Heyde syndrome.

Methods: We prospectively enrolled 49 consecutive patients with severe AVS addressed for TAVI at our institution. Biological hemostasis parameters involving von Willebrand factor (vWF) were assessed at baseline and 1 week after the procedure.

Results: At baseline, a significant link between vWF abnormalities and the severity of AVS was evidenced: mean aortic transvalvular gradient was negatively correlated with the levels of vWF antigen (vWF:Ag) (r = -0.29; P < 0.05), vWF ristocetin cofactor activity (r = -0.402; P = 0.006), and vWF collagen-binding activity (vWF:CB; r = -0.441; P = 0.005). One week after the procedure, a significant increase of vWF:Ag, vWF ristocetin cofactor activity, and vWF:CB was evidenced in the whole cohort (respectively, 3.32 vs. 2.29 IU/mL, P < 0.001; 2.98 vs. 1.86 IU/mL, P < 0.001; and 3.16 vs. 2.16 IU/mL, P < 0.001). Patients with pre-TAVI vWF abnormalities consistent with a type 2A vWF syndrome (ratio vWF:CB/vWF:Ag < 0.7) preferentially improved their vWF function with respect to patients with a normal ratio (relative increase of vWF:CB of 63.8% vs. 3.5%).

Conclusions: Hemostasis parameters involving vWF are improved after TAVI, especially in patients with pre-existing abnormalities consistent with acquired type 2A von Willebrand syndrome.
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http://dx.doi.org/10.1016/j.cjca.2015.01.012DOI Listing
June 2015

Microparticles are new biomarkers of septic shock-induced disseminated intravascular coagulopathy.

Intensive Care Med 2013 Oct 21;39(10):1695-703. Epub 2013 Jun 21.

Service de Réanimation Médicale, Nouvel Hôpital Civil, Hôpitaux Universitaires de Strasbourg, 1, Place de l'Hôpital, 67091, Strasbourg Cedex, France.

Purpose: Septic shock-induced disseminated intravascular coagulopathy (DIC) contributes to multiple organ failure. Mechanisms governing vascular responses to open occurrence of DIC have not yet been established. Circulating plasma microparticles (MPs), released upon cell stress, constitute a catalytic procoagulant surface and are surrogates of vascular cell activation/injury. Herein, MPs were assessed as possible markers of haemostatic and vascular dysfunction in the DIC time course.

Methods: One hundred patients with septic shock from three ICUs were enrolled and their haemostatic status evaluated at admission (D1), D2, D3 and D7. Circulating procoagulant MPs were isolated, quantified by prothrombinase assay and their cellular origin determined. DIC diagnosis was made according to the JAAM 2006 score.

Results: Ninety-two patients were analysed and 40 had DIC during the first 24 h. Routine clotting times and factor/inhibitor activity did not allow assessing vascular cell involvement. At admission, thrombin generation and fibrinolysis were observed in both groups while impaired fibrin polymerisation was evidenced only in DIC patients. Sustained thrombin generation persisted over time in both groups at D7. While total microparticle concentrations were in the same range regardless of DIC diagnosis, specific phenotypes were already detected at admission in DIC patients. Endothelial- and leucocyte-derived MPs were higher in DIC while an increased soluble glycoprotein V/platelet ratio was delayed, underscoring the first involvement of endothelial cells and leucocytes whereas platelet activation was delayed. Endothelium-derived CD105-MPs (OR 6.55) and CD31-MPs (OR 0.49) were strongly associated with early DIC in multivariate analysis.

Conclusion: Endothelial-derived microparticles are relevant biomarkers of septic shock-induced DIC and could be used to evaluate early vascular injury.
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http://dx.doi.org/10.1007/s00134-013-2993-xDOI Listing
October 2013

[Post-varicella cerebral thrombophlebitis with anti-protein S: report of a pediatric case].

Ann Biol Clin (Paris) 2012 Jan-Feb;70(1):99-103

Pôle de pédiatrie, Hôpital de Hautepierre, Strasbourg.

Purpura fulminans and venous thrombosis are rare complications of chickenpox. We report the case of a 6 year old with no history individuals who experienced cerebral thrombophlebitis, 3 weeks after varicella. MRI, performed at admission, has objectified longitudinal sinus thrombosis and a frontal parenchymal hematoma law. Meanwhile, a recent varicella seroconversion was demonstrated. The assessment of thrombophilia, meanwhile, has objectified a significant decrease in free protein S and activity, without associated DIC. Origin acquired this deficit was confirmed by the detection of antibodies (IgG and IgM) against the total protein S by ELISA. After evaluation of the benefit/risk only anticoagulation was initiated. The clinical and biological evolution was favorable, with rapid normalization of the S protein and decrease of anti-protein S. Many studies report the presence of anti-protein S in young children at the waning of chickenpox, without their exact frequency is determined. The decrease in protein S they cause leads to a transient hypercoagulable state may result in different clinical pictures. Cases of purpura fulminans seem more frequent when venous thrombosis isolated post chickenpox, sometimes atypical, appear rare.
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http://dx.doi.org/10.1684/abc.2011.0657DOI Listing
March 2012