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Background The range of normal values for coagulation factors in the healthy newborn was described 30 years ago but since then the reagents, automated systems, and dosing techniques have changed considerably. For 30 years, several authors have tried to update the standards and references in children using updated reagents but the newborn and infant population in these studies has been quite small, limiting the findings. The aim of this study was to establish the normal coagulation standards in healthy newborns. Methods We included all consecutive healthy newborns with pyloric stenosis presenting to our reference center over a period of 5 years. We calculated the reference ranges defined as mean ± 2 SD. Normality of distribution was checked graphically and by using the Shapiro–Wilk test. Correlations between two continuous variables were assessed using Spearman's rank coefficient correlation. Statistical testing was done at the two-tailed α-level of 0.05. Data were analyzed using the SAS software package, release 9.4 (SAS Institute, Cary, NC). Results We included 112 healthy newborns and infants. The median age was 35.5 days (15.0–88.0), median weight was 4062 g (2855–6040), and 90.2% were boys. Activated partial thromboplastin time (aPTT) and prothrombin time (PT) were not correlated with age (P = 0.92 and P = 0.21, respectively) or with weight (P = 0.16 and P = 0.90, respectively). The reference range was 28.6–46.2 s for aPTT, 0.91–1.49 for aPTT ratio, and 71.3–110.6 s for PT. Regarding fibrinogen (n = 24), the median was 2.2 g/L (1.2–3.2); the median for factor II was 67.0 U/dL (51.0–130.0; n = 20), and 101.5 U/dL for factor V (68.0–233.0; n = 20). Regarding factor VIII, the median was 75.0 U/dL (45.0–152.0; n = 25), 49.0 U/dL for factor IX (32.0–96.0; n = 25) and 53.0 U/dL (29.0–112.0) for factor XI (n = 23). Conclusion This study can help to establish standards for coagulation testing in this very specific population. Indeed, our study represents the largest newborn population in a recent investigation of PT and aPTT using updated reagents.

In April 2020, in response to the high thrombotic risk associated with COVID-19, the GIHP and GFHT published proposals for the prevention of venous thromboembolism (VTE) and haemostasis monitoring in patients with COVID-19 [1]. In February 2021, six authors from the proposals (CT, AM, AlG, AnG, SS, YG, PA) decided to update them. This update was justified by several points: - The epidemiology of thrombotic complications has been described. - Different anticoagulation regimens have been reported, and retrospective studies have suggested that higher-than-standard prophylactic anticoagulation may be beneficial. - Initially underestimated, bleeding complications have emerged as a limitation of increased-dose anticoagulation and occur later than thrombotic events. - The first results of large-scale randomised controlled studies on increased doses of anticoagulation have been published. - Immunomodulatory therapies (corticosteroids, interleukin-6 receptor antagonists) are now widely used, but their effect on the thrombotic risk is unknown. - Despite improved survival, thrombotic complications remain a concern [2].

International audience; BACKGROUND: Because of the high risk of thrombotic complications (TCs) during SARS-CoV-2 infection, several scientific societies have proposed to increase the dose of preventive anticoagulation, although arguments in favor of this strategy are inconsistent. RESEARCH QUESTION: What is the incidence of TC in critically ill patients with COVID-19 and what is the relationship between the dose of anticoagulant therapy and the incidence of TC? STUDY DESIGN AND METHODS: All consecutive patients referred to eight French ICUs for COVID-19 were included in this observational study. Clinical and laboratory data were collected from ICU admission to day 14, including anticoagulation status and thrombotic and hemorrhagic events. The effect of high-dose prophylactic anticoagulation (either at intermediate or equivalent to therapeutic dose), defined using a standardized protocol of classification, was assessed using a time-varying exposure model using inverse probability of treatment weight. RESULTS: Of 538 patients included, 104 patients experienced a total of 122 TCs with an incidence of 22.7% (95% CI, 19.2%-26.3%). Pulmonary embolism accounted for 52% of the recorded TCs. High-dose prophylactic anticoagulation was associated with a significant reduced risk of TC (hazard ratio, 0.81; 95% CI, 0.66-0.99) without increasing the risk of bleeding (HR, 1.11; 95% CI, 0.70-1.75). INTERPRETATION: High-dose prophylactic anticoagulation is associated with a reduction in thrombotic complications in critically ill patients with COVID-19 without an increased risk of hemorrhage. Randomized controlled trials comparing prophylaxis with higher doses of anticoagulants are needed to confirm these results.

Heparin-induced thrombocytopenia (HIT) is a rare, iatrogenic disease characterised by its potential severity, mainly related to thrombosis, and by difficulties regarding its diagnosis and management of affected patients. In 2002, a conference of experts mobilised by the French Society of Anaesthesia and Intensive Care Medicine (Société française d’anesthésie et de réanimation [SFAR]) drafted recommendations for the management of HIT [...]

Objectif Evaluer le cout de la prise en charge medicale de certaines pathologies rares a partir des bases du systeme national des donnees de sante (SNDS) et estimer le surcout specifique lie a la maladie. Methode L’etude etait fondee sur l’exploitation des donnees du SNDS en ciblant cinq pathologies rares identifiables a partir de codes diagnostics dans le SNDS et selectionnees de maniere a illustrer des situations et manifestations morbides contrastees (Syndrome de Rett, Drepanocytose, Maladie de Willebrand, Amyotrophie spinale infantile (SMA), Syndrome de Marfan). Les patients ont ete identifies a partir des codes diagnostics des hospitalisations et/ou des motifs d’ALD (Affection de longue duree) entre 2012 et 2016. Les analyses ont permis d’identifier, sur l’annee 2017, la consommation totale de soins (soins de ville et hospitaliers) des patients presentant les maladies identifiees, par postes de consommation et la consommation attribuable a la pathologie (fardeau) a travers une comparaison cas-temoins apparies sur l’annee de naissance, le genre et le departement de residence. Resultats Les bases du SNDS ont permis d’identifier 694 patients atteints du syndrome de Rett (95,1 % de femmes ; 19,3 ans en moyenne), 19 016 patients drepanocytaires (60,3 % d’hommes ; 29 ans en moyenne), 5243 patients atteints du syndrome de Marfan (53,2 % d’hommes ; 37,7 ans en moyenne), 1085 patients atteints de SMA (hors type 1) (51,8 % d’hommes ; 33,9 ans en moyenne) et 8762 de patients atteints de la maladie de Willebrand (34,7 % d’hommes ; 41,1 ans en moyenne) toujours vivants au 31/12/2017. Le cout total de la consommation de soins en 2017 variait de 5003 en moyenne pour le syndrome de Marfan (mediane : 1682) a 18 762 pour les patients atteints SMA (hors type 1 et hors patients traites par Spinraza®) (mediane : 10 389), avec un surcout attribuable a la maladie (differentiel avec les temoins) de respectivement 3375 et 17 317 en moyenne. Ce surcout s’elevait a 3685 pour la maladie de Willebrand, 7456 pour la drepanocytose et 12 364 pour le syndrome de Rett. Discussion Malgre une methodologie exploratoire, des difficultes d’identification des pathologies dans les bases du SNDS et une forte variabilite des resultats, l’etude a permis de mettre en evidence pour chaque pathologie un surcout significatif lie a la maladie et a ses complications. Les depenses non presentees au remboursement, et donc certains restes a charge, ne sont pas prises en compte mais seront estimees dans un volet complementaire de l’etude, via un recueil aupres des patients/familles.

Background Major vascular (VAC) and life-threatening or major bleeding (LT/MB) complications still represent one of the most frequent adverse outcomes of percutaneous transfemoral TAVR (TF-TAVR) and are associated with an increased risk of mortality. Ultrasound guidance technique allows to puncture in the non-calcified central and horizontal segment of common femoral artery. However the clinical impact of ultrasound (US)-guidance has never been studied in TF-TAVR in comparison of standard fluoroscopic guidance and could explain the lack of adoption of US guidance. We sought first to evaluate in our study the impact of US-guidance on the vascular and bleeding complications. Methods US-guidance for vascular access was implemented as the default approach in our institution in June 2013 for all TF-TAVR and was applied by all operators after a short training course. Thus, we defined three period and groups of consecutive patients according to the method of percutaneous puncture (fluoroscopic or US-guidance) and the generation of THV (2nd or 3rd gen.). US-guided-2nd gen. group: TF-TAVR with 2nd generation THV and performed via US-guidance. This group refers to the period patients from June 2013 to November 2014 (n=119). Fluo-guided-2nd gen. group: The last TF-TAVR with 2nd gen. THV and performed via fluoroscopic guidance (n=119). US-guided-3rd gen. group: Patients implanted with 3rd gen. THV (SAPIEN 3, Evolut R) from November 2014 to December 2018 while US-guidance was systematic for all TF-TAVR (n=308). Patients performed with US-guidance were 1:1 successfully matched with 95 patients performed with fluoroscopic guidance (fluo-guided group) with propensity-score (10 variables). We separately analyzed the consecutive patients of the US-guided-3rd gen. group. Results After propensity-matching, resulting in similar baseline characteristics, all the vascular and bleeding complications were reduced in the US-guided-2nd gen. group compared to Fluo-guided-2nd gen. group with respectively: VAC (6.3% vs 16.8%; OR=0.31; 95% CI: 0.12–0.85; p=0.023); LT/MB (22.1% vs 6.3%; OR=0.24, CI: 0.09–0.63; p=0.004); and VAC related to vascular access (12.6 vs 4.2%; OR=0.31; CI: 0.10–1.01; p=0.052). We also observed a reduction of the mean fluoroscopic time (1753±620 min vs 1228±405 min; p In the US-guided-3rd gen. group (n=308), the US-guided puncture achieved a rate of VAC of 3.2% (CI: 1.6–5.9) and of LT/MB of 3.6% (CI: 1.8–6.3). In the overall population (n=546), we observed that LT/MB (p=0.02) was associated with a 1.7-fold increase of mortality risk. Conclusion The present study is the first and the largest to evaluate the impact of US-guidance in TF-TAVR. We demonstrated that US-guided cannulation is able to reduce the risk of vascular and bleeding complications. These data endorses US-guidance as the standard method of puncture for TAVR.

Background Several mechanisms are suspected to thrombocytopenia under Extracorporeal Membrane Oxygenation (ECMO) such as platelet-consumption or sepsis. Shedding of glycoprotein-(GP)Ibα is a recently identified mechanism of platelet clearance. ECMO generates high shear stress forces that could impact GPIbα-shedding. We hypothesized that ECMO continuous-flow devices could directly induce thrombocytopenia through shear-induced GPIbα-shedding. Aims Determine if ECMO induce GpIb-shedding in vitro and in vivo and determinates the kinetic evolution of platelet-count and GpIb-shedding after patient's implantation. Methods Platelet GPIbα-shedding was first investigated in vitro using a high-shear pump loop model. Plasma with normal platelet count (plasma-NPC) was obtained by dilution of platelet-rich plasma obtained from healthy donors in fresh-frozen-plasma. Samples were collected before and after (5, 30, 60 and 180 min) perfusion at 37°C of plasma-NPC at intermediate and high speed (2.6 and 3.6 L min–1 respectively, n=4 each). Platelet count and GPIbα-shedding were next investigated in 20 ECMO patients before/after implantation (WITECMO trial) and in 20 healthy volunteers. The geometric mean-fluorescence-intensity (gMFI) of platelet GPIbα (PE-staining) and GPIX (FITC-staining) was measured with a Navios flow cytometer (Beckman Coulter, Miami, FL). Results are expressed as GPIbα/GPIX gMFI-ratio. Results A significant time-dependent loss of GPIbα/GPIX gMFI-ratio was already apparent after 30 min in vitro and was significantly more pronounced at high-speed compared to intermediate-speed (pANOVA Figure 1. A. Significant time-dependent loss of platelet GPIbα/GPIX gMFI-ratio (pANOVA

Serum concentrations of lathosterol, the plant sterols campesterol and sitosterol and the cholesterol metabolite 5α-cholestanol are widely used as surrogate markers of cholesterol synthesis and absorption, respectively. Increasing numbers of laboratories utilize a broad spectrum of well-established and recently developed methods for the determination of cholesterol and non-cholesterol sterols (NCS). In order to evaluate the quality of these measurements and to identify possible sources of analytical errors our group initiated the first international survey for cholesterol and NCS. The cholesterol and NCS survey was structured as a two-part survey which took place in the years 2013 and 2014. The first survey part was designed as descriptive, providing information about the variation of reported results from different laboratories. A set of two lyophilized pooled sera (A and B) was sent to twenty laboratories specialized in chromatographic lipid analysis. The different sterols were quantified either by gas chromatography-flame ionization detection, gas chromatography- or liquid chromatography-mass selective detection. The participants were requested to determine cholesterol and NCS concentrations in the provided samples as part of their normal laboratory routine. The second part was designed as interventional survey. Twenty-two laboratories agreed to participate and received again two different lyophilized pooled sera (C and D). In contrast to the first international survey, each participant received standard stock solutions with defined concentrations of cholesterol and NCS. The participants were requested to use diluted calibration solutions from the provided standard stock solutions for quantification of cholesterol and NCS. In both surveys, each laboratory used its own internal standard (5α-cholestane, epicoprostanol or deuterium labelled sterols). Main outcome of the survey was, that unacceptably high interlaboratory variations for cholesterol and NCS concentrations are reported, even when the individual laboratories used the same calibration material. We discuss different sources of errors and recommend all laboratories analysing cholesterol and NCS to participate in regular quality control programs.

Purpose The CorWave LVAD employs a unique “wave membrane” technology, inspired from the motion of aquatic animals, to generate blood flow. This low shear method of blood propulsion can be rapidly modulated to produce a physiologic pulse. The present study evaluated the hydraulic, hemodynamic and hemocompatibility performance of the device in vitro and in animal implants. Methods The pump membrane, oscillation frequency and magnitude, and blood flow path were simulated by CFD analysis in COMSOL and refined to improve hydraulic efficiency and eliminate areas of flow stagnation. Hydraulic testing in a mock circulatory loop and hemolysis measurements in static and pulsatile conditions were then performed in vitro. Acute and chronic implants of the improved pumps were carried out in sheep. Results The device was successfully operated in 4 different modes: continuous or fixed (similar to rotary VADs with a constant operating point), synchronous co-pulsation and counter-pulsation, and asynchronous pulsation modes. Sensorless detection of native ventricle systole was developed using a mock circulatory loop, with performance confirmed in acute implants in sheep with induced heart failure. The pump could generate average flow rates of 6+ lpm against physiologic pressure, and instantaneous flow rates exceeding 12 LPM during pulsatile operation. Acute and chronic animal implants (up to 60+ days) demonstrated low hemolysis and an absence of significant thrombus or thromboembolic events. Conclusion The first long-term chronic animal studies of the CorWave LVAD validated the hemocompatibility and hemodynamic performance of the pump. The ability to restore physiologic pulsatility by sensorless synchronization with the native heart was demonstrated in pre-clinical implants. Extensive computational simulation and bench top testing were used to optimize this unique LVAD, displaying the full flow capacity and adding physiologically relevant pulsatility without excessive shear rates.

International audience

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 Medicine (SFAR) drafted up-to-date proposals for the management of antiplatelet therapy in patients undergoing elective invasive procedures. The proposals were discussed and validated by a vote; all proposals but one could be assigned with a high strength. The management of antiplatelet therapy is based on their indication and the procedure. The risk of bleeding related to the procedure can be divided into high, moderate and low categories depending on the possibility of performing the procedure in patients receiving antiplatelet agents (none, monotherapy and dual antiplatelet therapy respectively). If discontinuation of antiplatelet therapy is indicated before the procedure, a last intake of aspirin, clopidogrel, ticagrelor and prasugrel 3, 5, 5 and 7 days before surgery respectively is proposed. The thrombotic risk associated with discontinuation should be assessed according to each specific indication of antiplatelet therapy and is higher for patients receiving dual therapy for coronary artery disease (with further refinements based on a few well-accepted items) than for those receiving monotherapy for cardiovascular prevention, for secondary stroke prevention or for lower extremity arterial disease. These proposals also address the issue of the potential role of platelet functional tests and consider management of antiplatelet therapy for regional anaesthesia, including central neuraxial anaesthesia and peripheral nerve blocks, and for coronary artery surgery., SCOPUS: ar.j, info:eu-repo/semantics/published

BACKGROUND AND PURPOSE Whereas intravenous thrombolysis (IVT) is allowed for acute ischaemic stroke in patients on vitamin K antagonists with international normalized ratio ≤1.7, there are no similar recommendations for patients on direct oral anticoagulants (DOACs), notably due to the lack of coagulation tests to assess the therapeutic effects. Although the literature is scarce, consisting of small case series and retrospective studies, considering the frequency of this situation the French Vascular Neurology Society and the French Study Group on Haemostasis and Thrombosis have worked on a joint position paper to provide a practical position regarding the emergency management of ischaemic stroke in patients on DOACs. METHOD Based on a review of the literature, the authors wrote a first text that was submitted to a broad panel of members from the two societies. The text was then amended by the authors to address experts' comments and to reach a consensus. RESULTS In patients with normal renal function and who stopped the DOAC for at least 48 h, the management should not differ from that in patients without oral anticoagulant. In patients who are still on DOACs, mechanical thrombectomy is encouraged preferentially when applicable in first line. Otherwise, when specific tests are available, values

New direct oral anticoagulants (NOAC), inhibitors of factor IIa or Xa, are expected to be widely used for the treatment of venous thromboembolic disease, or in case of atrial fibrillation. Such anticoagulant treatments are known to be associated with haemorrhagic complications. Moreover, it is likely that such patients on long-term treatment with NOAC will be exposed to emergency surgery or invasive procedures. Due to the present lack of experience in such conditions, we cannot make recommendations, but only propose management for optimal safety as regards the risk of bleeding in such emergency conditions. In this article, only dabigatran and rivaroxaban were discussed. For emergency surgery at risk of bleeding, we propose to dose the plasmatic concentration of drug. Levels inferior or equal to 30ng/mL for both dabigatran and rivaroxaban, should enable the realization of a high bleeding risk surgery. For higher concentration, it was proposed to postpone surgery by monitoring the evolution of the drug concentration. Action is then defined by the kind of NOAC and its concentration. If the dosage of the drug is not immediately available, proposals only based on the usual tests, PT and aPTT, also are presented. However, these tests do not really assess drug concentration or bleeding risk. In case of severe haemorrhage in a critical organ, it is proposed to reduce the effect of anticoagulant therapy using a nonspecific procoagulant drug (activated prothrombin concentrate, FEIBA, 30-50U/kg, or non-activated 4-factors prothrombin concentrates 50U/kg). For any other type of severe haemorrhage, the administration of such a procoagulant drug, potentially thrombogenic in these patients, will be discussed regarding concentration of NACO and possibilities for mechanical haemostasis.

Le TRALI (transfusion-related acute lung injury) est defini cliniquement comme un oedeme pulmonaire lesionnel survenant dans les six heures suivant la transfusion d’un produit sanguin. C’est une cause majeure de morbimortalite liee a la transfusion. Sa physiopathologie est complexe et n’est pas totalement comprise. Le TRALI est le resultat d’une lesion de l’endothelium vasculaire induite par les polynucleaires. On distingue des formes liees a la presence d’anticorps antileucocytaires et des formes non immunologiques liees a des substances biologiquement actives qui pourraient apparaitre lors de la conservation des produits sanguins. L’existence d’une leucostase pulmonaire liee a une agression inflammatoire chez le receveur constitue une etape de priming qui precede l’activation des polynucleaires et la lesion. Les patients de reanimation, compte tenu de ces mecanismes, semblent particulierement exposes. Cette revue fait le point sur ces mecanismes physiopathologiques en s’appuyant sur les donnees epidemiologiques et experimentales publiees.

Few scientific evidences are available in the literature, and the methodologic quality of the studies is often under average. Nevertheless, the conclusions are the following. Nephrectomy, renal transplantation, open surgery of the lower urinary tract and lumbar or pelvic lymph nodes dissection are at high risk for thromboembolic events. Other open or endoscopic urological procedures are at low risk. The laparoscopic approach doesn't change the risk associated with the procedure itself. Thromboprophylaxis is recommended in high-risk procedures. There was no evidence to recommend starting the prophylaxis before more than after the procedure. The use of low molecular weight heparin is recommended for prophylaxis. It can be associated with compressive stockings. It is recommended to treat for around seven days after the procedure. In case of cancer surgery, prophylaxis could be needed for four to six weeks.

Venous thromboemboembolism is a multigenic and a multifactorial disease. Several genetic risk factors have been identified: antithrombin, protein C and protein S deficiencies, and molecular defects in factor V gene (factor V Leiden) or factor II gene (G 20210A transition). Retrospective and prospective studies have demonstrated that hormone replacement therapy (HRT) in women is associated with a 2-3-fold increase of venous thromboembolism events. To minimize this risk, it seems desirable to carefully evaluate the individual clinical risk factors. Prescribing HRT should clearly be avoided in women with previous thromboembolic events. In case of familial thrombophilia, HRT should probably be prescribed with caution. Recent data suggest that transdermal HRT would induce a lower increase in thrombotic risk, but additional studies are needed to determine whether they can be safely used in women at risk. In each case, the net balance of risk and benefit of HRT use must consider the potential beneficial health effects, the most evident being the relief of climacteric symptoms.

Resume Dans la plupart des CIVD, l’exposition de facteur tissulaire (FT) au sang circulant est la principale etiologie. Ce contact resulte de lesions tissulaires majeures, de l’expression anormale de FT par des cellules circulantes (monocytes) lors de sepsis a bacteries a Gram positif ou negatif, ou de l’expression de FT par des cellules malignes. Ce contact anormal entraine l’activation de la cascade de la coagulation, avec generation de thrombine. Par ailleurs, la liaison du FT avec son ligand naturel le facteur VII entraine une signalisation intracellulaire capable d’activer la synthese de cytokines pro-inflammatoires, ce qui contribue a perenniser et a amplifier le processus pathologique. Les deux possibilites d’inhibition specifique de la voie du FT sont : 1) le recours au TFPI, inhibiteur naturel du couple FT- facteur VIIa, actuellement produit par genie genetique ; 2) l’utilisation de substitut inactif du VIIa, le FFR-VIIa, egalement produit par genie genetique. Ces deux molecules sont en cours d’experimentation, la premiere dans le sepsis severe, la seconde dans le syndrome de detresse respiratoire aigu, qui est aussi lie a une activation de la voie du FT.

Background. Heparin is the most commonly used drug in patients requiring therapeutic anticoagulation. But the use of heparin has serious side effects such as heparin-induced thrombocytopenia (HIT). The diagnosis of HIT is often difficult. This study was designed to test the diagnosis value of 2 laboratory tests: the platelet aggregation test and the ELISA test (Enzym Linked Immuno-Sorbent Assay). Methods and Results. In order to evaluate the diagnostic value of these 2 tests, we prospectively performed both tests in all patients referred to our laboratory with suspected type II HIT, and compared their results with clinical outcome. Plasmas from 60 patients suspected of HIT, were tested for heparin-dependent platelet-reactive antibodies with a platelet agregation test (PAT) and with an ELISA which detects anti heparin platelet factor 4 antibodies (Anti PF4-H Ab). Among the 60 explored patients, the clinical diagnosis of HIT was confirmed in 27 patients by clinical criteria. In 16 of these 27 patients, PAT and anti PF4-H. Ab were both positive, and in the 11 other patients, one of the 2 tests was negative. In 29 of the 33 patients with no clinical HIT, PAT and anti PF4-H. Ab were both negative, in the 4 remaining patients, one of the 2 tests was positive. Conclusion. For 75% of patients, biological results were concordant with the final clinical diagnosis. The combination of both tests is more reliable than the use of a single test; in the present series, all patients with positive results on both tests had clinically confirmed HIT, and all patients with negative results on both tests had not clinically confirmed HIT.

The management of massive bleeding has improved, thanks to high-quality blood components and new transfusion strategies. However, it remains controversial and, despite a huge body of literature, randomised control trials are still lacking. However, the therapeutic approach has also evolved, requiring earlier and more active management. If a 'no delay' management is well recognized, its modes are still discussed. Immediate delivery of blood products with ratios close to 1:1:1 for RBC units/fresh frozen plasma/platelet concentrates, through massive transfusion protocol using blood packs, has been advocated, but yet this approach is not evidence-based. Secondly, a targeted strategy to provide fibrinogen concentrates is under evaluation. Tranexamic acid is effective in trauma patients. Recombinant factor VIIa should only be used on a compassionate basis.

New direct oral anticoagulants (NOAC), inhibitors of factor IIa or Xa, are expected to be widely used for the treatment of venous thromboembolic disease, or in case of atrial fibrillation. Such anticoagulant treatments are known to be associated with haemorrhagic complications. Moreover, it is likely that such patients on long-term treatment with NOAC will be exposed to emergency surgery or invasive procedures. Due to the present lack of experience in such conditions, we cannot make recommendations, but only propose management for optimal safety as regards the risk of bleeding in such emergency conditions. In this article, only dabigatran and rivaroxaban were discussed. For emergency surgery at risk of bleeding, we propose to dose the plasmatic concentration of drug. Levels inferior or equal to 30ng/mL for both dabigatran and rivaroxaban, should enable the realization of a high bleeding risk surgery. For higher concentration, it was proposed to postpone surgery by monitoring the evolution of the drug concentration. Action is then defined by the kind of NOAC and its concentration. If the dosage of the drug is not immediately available, proposals only based on the usual tests, PT and aPTT, also are presented. However, these tests do not really assess drug concentration or bleeding risk. In case of severe haemorrhage in a critical organ, it is proposed to reduce the effect of anticoagulant therapy using a nonspecific procoagulant drug (activated prothrombin concentrate, FEIBA, 30-50U/kg, or non-activated 4-factors prothrombin concentrates 50U/kg). For any other type of severe haemorrhage, the administration of such a procoagulant drug, potentially thrombogenic in these patients, will be discussed regarding concentration of NACO and possibilities for mechanical haemostasis.

Introduction Les complications vasculaires de l’insuffisance renale chronique (IRC) et/ou du diabete sont multifactorielles notamment secondaires a l’exposition aux produits de la glycation avancee ou AGEs. Ces derniers (endogenes) peuvent etre egalement apportes par l’alimentation (exogenes). Si les effets deleteres des AGEs endogenes sont bien connus, principalement via leur interaction avec le RAGE (recepteur aux AGEs), peu d’etudes ont ete realisees concernant la toxicite des AGEs alimentaires (cuisson brutale ou a haute temperature). L’objectif de notre travail etait d’evaluer l’effet de la carboxymethyllysine (CML) alimentaire sur le vieillissement arteriel et d’etudier l’implication du RAGE (modele murin, RAGE-KO). Materiels et methodes Des souris C57BL/6 sauvages et RAGE-KO ont ete exposees pendant 3–6 ou 9 mois a un regime enrichi en CML (50, 100 ou 200 μg CML/g d’aliment). La relaxation aortique endothelium-dependante et la mesure de la vitesse de l’onde de pouls (VOP) en IRM ont ete evaluees. L’expression des marqueurs de dysfonction endotheliale (RAGE et VCAM-1) et de vieillissement arteriel (expression de sirtuine-1 (SIRT1) et integrite de l’elastine) a ete etudiee. Resultats Apres 9 mois d’exposition a la CML alimentaire (200 μg/g), nous avons observe chez les souris sauvages : (1) une diminution de la relaxation endothelium-dependante ( p p p p p p Discussion et conclusion L’exposition alimentaire chronique a la CML induit une dysfonction endotheliale et provoque un vieillissement vasculaire premature RAGE-dependant. Le controle de la glycation alimentaire constitue une nouvelle piste de protection vasculaire et renale au cours de l’IRC et du diabete.

Unite de medecine vasculaire, CHU de Grenoble, BP 217, 38043 Grenoble cedex 09, France UJF-Grenoble 1/CNRS TIMC-IMAG UMR 5525/Themas, 38041 Grenoble, France c Pole anesthesie-reanimation, CHU de Grenoble, BP 217, 38043 Grenoble cedex 09, France d Service d’anesthesie-reanimation, Hotel-Dieu, AP–HP, 1, place du Parvis-Notre-Dame, 75181 Paris cedex 04, France e Pole d’hematologie transfusion, centre de biologie pathologie, boulevard du Professeur-Jules-Leclercq, 59037 Lille cedex, France f Laboratoire d’hemostase, 2 bis, boulevard Tonnelle, 37032 Tours cedex, France g Laboratoire d’hemostase-thrombose, CHUM hopital Notre-Dame, 1560 Sherbrooke Est, H2L 4M1, Montreal, Canada h Laboratoire d’hemostase speciale, hopital cantonal universitaire, 4, rue Gabrielle-Perret-Gentil, 1211 Geneve 14, Suisse i Service de cardiologie, hopital St-Antoine, 184, rue du Faubourg-Saint-Antoine, 75571 Paris cedex 12, France Department of anesthesiology and critical care, hopital universitaire, Valencia, Espagne Departement d’anesthesie-reanimation, hopital Cochin, AP–HP, 27, rue du Faubourg-Saint-Jacques, 75014 Paris, France l Laboratoire central d’hematologie, hopital Saint-Eloi, CHU de Montpellier, 80, avenue Augustin-Fliche, 34295 Montpellier cedex 5, France CRTH et centre des coagulopathies, hopital du Bocage, BP 77 908, 21079 Dijon cedex, France n Laboratoire d’hematologie, groupe hospitalier Hotel-Dieu Cochin, 1, place du Parvis-Notre-Dame, 75181 Paris cedex 04, France Groupe de recherche sur la thrombose, unite de recherche clinique, innovation et pharmacologie, hopital Nord, 120, avenue Albert-Raimond, 42055 Saint-Etienne cedex 2, France p Laboratoire d’hematologie, hopital Rangueil, CHU de Toulouse, 1, avenue du Pr-Jean-Poulhess, TSA 50032, 31059 Toulouse cedex, France

Postpartum haemorrhage is the leading cause of maternal death in France and worldwide. Guidelines help to conduct a timed management and to reduce maternal morbidity and mortality. Rescue and surgical care, transfusion and monitoring have to be previously organized.

Coagulopathy during massive haemorrhage increases morbidity and mortality rates. The modalities of treatment by transfusion of fresh frozen plasma (FFP) are a matter of debate. According to most clinical practice guidelines, FFP administration is driven by coagulation tests but, in cases of massive transfusion, patient management may be delayed whilst awaiting results and thawing FFP. Several retrospective cohort studies of military or civilian multiple trauma casualties requiring massive transfusion (10 red blood cells (RBC) within 24h) have suggested that early use of FFP and high FFP:RBC ratios (approaching 1) might improve survival and lessen morbidity. However, the methodology of these studies is suboptimal. They are subject, in particular, to survival bias. Massive FFP transfusions can also lead to an enhanced incidence of transfusion-related acute lung injury (TRALI), acute respiratory distress syndrome (ARDS), and multi-organ failure. At the present time, it is clear that FFP transfusion should be initiated early with a high FFP:RBC ratio in massive bleeding associated with haemostatic abnormalities such as multiple trauma. This does not imply that such a recommendation can be extended to the correction of high blood loss in other situations such as scheduled surgery. Actually, very few patients are likely to derive benefit from a 1/1 FFP:RBC transfusion strategy. They are chiefly multiple trauma victims with haemorrhagic shock and cases of ruptured abdominal aortic aneurysm. In other patients, in order to minimize risks and costs, a more parsimonious FFP use policy remains the best option until evidence for the benefit of 1/1 FFP:RBC is demonstrated.

Venous thromboemboembolism is a multigenic and a multifactorial disease. Several genetic risk factors have been identified: antithrombin, protein C and protein S deficiencies, and molecular defects in factor V gene (factor V Leiden) or factor II gene (G 20210A transition). Retrospective and prospective studies have demonstrated that hormone replacement therapy (HRT) in women is associated with a 2-3-fold increase of venous thromboembolism events. To minimize this risk, it seems desirable to carefully evaluate the individual clinical risk factors. Prescribing HRT should clearly be avoided in women with previous thromboembolic events. In case of familial thrombophilia, HRT should probably be prescribed with caution. Recent data suggest that transdermal HRT would induce a lower increase in thrombotic risk, but additional studies are needed to determine whether they can be safely used in women at risk. In each case, the net balance of risk and benefit of HRT use must consider the potential beneficial health effects, the most evident being the relief of climacteric symptoms.

Systolic heart failure is mainly due to a decreased left ventricular systolic function after myocardial infarction. Despite significant improvements in medical management of heart failure, the prognostic remains poor, with a 5-years survival only of 30%.Current treatments are only able to delay progression toward end-stage heart failure. Heart transplantation is accessible only for selected patients. Thus, in the context of post-myocardial infarction, cell therapy appears to be a new original technique, available for the majority of patients and potentially non-invasive.After promising results in experimental models, a phase I clinical trial has been conducted in France, showing the feasibility of intracardiac autologous skeletal myoblast implantation. Other studies in Europe and USA are currently testing a variety of cells and delivery systems. A phase II-trial will begin in France.

Background. Heparin is the most commonly used drug in patients requiring therapeutic anticoagulation. But the use of heparin has serious side effects such as heparin-induced thrombocytopenia (HIT). The diagnosis of HIT is often difficult. This study was designed to test the diagnosis value of 2 laboratory tests: the platelet aggregation test and the ELISA test (Enzym Linked Immuno-Sorbent Assay). Methods and Results. In order to evaluate the diagnostic value of these 2 tests, we prospectively performed both tests in all patients referred to our laboratory with suspected type II HIT, and compared their results with clinical outcome. Plasmas from 60 patients suspected of HIT, were tested for heparin-dependent platelet-reactive antibodies with a platelet agregation test (PAT) and with an ELISA which detects anti heparin platelet factor 4 antibodies (Anti PF4-H Ab). Among the 60 explored patients, the clinical diagnosis of HIT was confirmed in 27 patients by clinical criteria. In 16 of these 27 patients, PAT and anti PF4-H. Ab were both positive, and in the 11 other patients, one of the 2 tests was negative. In 29 of the 33 patients with no clinical HIT, PAT and anti PF4-H. Ab were both negative, in the 4 remaining patients, one of the 2 tests was positive. Conclusion. For 75% of patients, biological results were concordant with the final clinical diagnosis. The combination of both tests is more reliable than the use of a single test; in the present series, all patients with positive results on both tests had clinically confirmed HIT, and all patients with negative results on both tests had not clinically confirmed HIT.

Pentoxifylline (PTX), a methylxanthine phosphodiesterase inhibitor, is poorly active as an immunosuppressant but prevents the synthesis of proinflammatory cytokines. In a randomized double-blind study comparing PTX versus placebo in 140 patients receiving cadaveric kidney grafts under cyclosporine and prednisone, we have shown that PTX weakened the consequences of rejection on graft survival. To assess the mechanism underlying the beneficial effect recorded during this trial, we analyzed the impact of PTX on tumor necrosis factor (TNF-alpha) production and expression of cell adhesion molecules.Plasma levels of TNF-alpha and its soluble receptors (sTNF-RI, sTNF-RII) and of soluble vascular cell adhesion molecule 1 (sVCAM-1) were monitored over the 6 months postgraft period when PTX or placebo were administered. Expression of VCAM-1 and intercellular cell adhesion molecule 1 was scored by immunohistochemical staining of biopsy specimens from patients who underwent rejection crisis. Lymphocyte subset composition was analyzed longitudinally during cytomegalovirus (CMV) infections.Plasma TNF-alpha levels were significantly reduced in the PTX-treated group over the 6 months of administration, and specifically during isolated rejection episodes and during CMV infections. Plasma levels of sTNFR-I, sTNFR-II, and sVCAM-1 did not differ between the two groups of patients, but a decrease in renal tubular VCAM-1 expression was observed in the PTX group. During CMV infections, CD8 lymphocytosis and expansion of CD57+ (CD28-) CD8+ T cells were similar in the two groups.The data collected during this double-blind study point to an immunomodulatory role of PTX, the beneficial effect on graft survival resulting from a restraining effect of the drug on the inflammatory conditions involved in acute graft rejection.

Methods: Blood was sampled from 31 women undergoing IVF treatment at maximal down-regulation (DR) of estradiol synthesis using gonadothropinreleasing hormone analogues and during high level stimulation (HLS) of estradiol synthesis by using follicle-stimulating hormone. ETP was determined at DR and HLS by the Thrombogram-ThrombinoscopeTM assay (Synapse, Maastricht, The Netherlands) using the protocol and reagents as provided and described by the manufacturer. Results: S-estradiol increased from 154 to 5889 pg/mL (range 1620– 19500). Both ETP and Peak of thrombin generation levels increased from 1542±287 to 1739±288nM*min (p < 0.001) and from 290±42 to 343±38nM (p < 0.0001), respectively. Time to Peak levels and lagtime decreased from 5.3±0.7 to 4.8±0.6 s (p < 0.0001) and 2.7±0.6 to 2.5±0.5 s (p < 0.01), respectively, reflecting a quick thrombin formation. Twelve patients got pregnant and all except one were primigravidae. Three patients developed mild ovarian hyperstimulation syndrome (OHSS), and their ETP levels increased from 1735±335 at DR to 1903±444 at HLS. Conclusion: Increased ETP levels were found during IVF. This seems to be especially pronounced in the three patients who developed OHSS. The findings suggest an activation of coagulation during IVF and that ETP could be used as a sensitive marker.

Purpose The CorWave LVAD employs a unique “wave membrane” technology, inspired by the motion of aquatic animals, to generate blood flow. This low shear method of blood propulsion can be rapidly modulated to produce a physiologic pulse. CorWave LVADs have been implanted for up to 2 months in sheep with low hemolysis and good hemodynamic performance. We are finalizing the clinical system by confirming system durability, conducting final blood path optimization, and challenging the pump pulsatility control algorithms. Methods Computational simulations were used to optimize shear stress in the blood flow path to less than 9 dyn/cm2, the maximum that occurs in normal physiology. Test fixtures and prototype pumps were employed to confirm the hydraulic and hemocompatibility results with the optimized flow paths. Test pumps were placed in static and dynamic mock circulation loops for real-time testing, initially targeting 6 months, but then extending to indefinite test durations. The pulsatility control algorithms were tested for sensorless synchronization, arrhythmia detection, pulse pressure amplitude generation, in mock circulation loops (MCLs) and during acute implants in sheep with ischemia-induced heart failure. Results In vitro tests of the optimized flow paths confirmed significant improvements in hydraulic output and hemocompatibility measures. Hemolysis was reduced by 70%, while pump output increased by 30%. 7 pumps completed 6-month durability tests, with testing beyond 6 months ongoing in 6 additional pumps. The pulsatility algorithms successfully detected ventricular systole in heart failure models in MCLs and during acute implants, allowing the aortic valve to open with each beat prior to increasing the pump output. The algorithm identified arrhythmia conditions for safe transitions to non-synchronized operating modes. In vitro, CorWave pumps generated pulse pressures exceeding 30 mmHg, while in vivo pulse pressure increased to over 25 mmHg but was constrained due to limitations of the animal model. VWF multimers were preserved during the acute implants. Conclusion The CorWave LVAD has achieved milestones for durability, hemocompatibility, and pulsatile operation, demonstrating substantial progress towards clinical readiness.