Unite dHemostase Clinique

Sainte-Foy-lès-Lyon, France

Unite dHemostase Clinique

Sainte-Foy-lès-Lyon, France
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Sorensen B.,St Thomas Hospital | Dargaud Y.,Unite dHemostase Clinique | Kenet G.,National Hemophilia Center | Lusher J.,Childrens Hospital of Michigan | And 3 more authors.
Haemophilia | Year: 2012

On-demand therapy with recombinant activated factor VII (rFVIIa) can provide effective haemostasis for spontaneous bleeds in haemophilia patients with inhibitors. However, treatment approaches vary amongst physicians, positively or negatively affecting outcomes. A panel of physicians proposed recommendations for securing and maintaining predictable efficacy with rFVIIa, comparing these with 'real-life' patient management, using a questionnaire circulated to other expert physicians from haemophilia care centres in Europe and the United States. For rFVIIa treatment of spontaneous bleeds in inhibitor patients, early intervention with the highest appropriate dose is recommended. Home-based therapy can facilitate early intervention. If additional rFVIIa therapy is required after the initial dose, rFVIIa 90μgkg -1 may be administered at 2-3h intervals. Treatment should be tailored to bleed site/severity, recognizing the advantages of appropriate adjunct therapy. Questionnaire results suggested that many respondents adopted strategies in line with the recommendations. Most (36/46) recommended initial therapy within 1h of bleed onset. rFVIIa 270μgkg -1 was the most frequently prescribed/recommended initial dose for paediatric (aged ≤15years; 22/44 respondents) and adult (aged >15years; 23/44 respondents) patients. However, there may be opportunity for improved bleed management on occasion, with regard, for instance, to dosing and dose interval. To secure and maintain predictable efficacy with rFVIIa, judicious dose selection and treatment timing are important, together with adjunct therapy where necessary. As inhibitor patients present with different bleeding scenarios, a tailored treatment approach should be adopted. © 2011 Blackwell Publishing Ltd.

Aya A.G.,University of Nimes | Ducloy-Bouthors A.-S.,Lille University Hospital Center | Rugeri L.,Unite Dhemostase Clinique | Gris J.-C.,University of Nimes
Journal de Gynecologie Obstetrique et Biologie de la Reproduction | Year: 2014

Introduction. -Risk factors of maternal morbidity and mortality during postpartum hemorrhage(PPH) include non-optimal anesthetic management. As the anesthetic management of the initialphase is addressed elsewhere, the current chapter is dedicated to the management of severePPH.Methods -A literature search was performed using PubMed and Medline databases, and theCochrane Library, for articles published from 2003 up to and including 2013. Several keywordsrelated to anesthetic and critical care practice, and obstetrical management were used, invarious combinations. Guidelines from several societies and organisations were also read.Results -When PPH worsens, one should ask for additional team personnel (professionalconsensus). Patients should be monitored for heart rate, blood pressure, skin and mucosal pallor,bleeding at skin puncture sites, diuresis and the volume of genital bleeding (grade B). Becauseof the possible rapid worsening of coagulapathy, patients should undergo regular evaluation ofcoagulation status (professional consensus). Prevention and management of hypothermia shouldbe considered (professional consensus), by warming intravenous fluids and blood products, andby active body warming (grade C). Antibiotics should be given, if not already administered atthe initial phase (professional consensus). Vascular fluids must be given (grade B), the choicebeing left at the physician discretion. Blood products transfusion should be decided based onthe clinical severity of PPH (professional consensus). Priority is given to red blood cells (RBC)transfusion, with the aim to maintain Hb concentration > 8 g/dL. The first round of productscould include 3 units of RBC (professional consensus), and the following round 3 units of RBC,and 3 units of fresh frozen plasma (FFP). The FFP:RBC ratio should be kept between 1:2 and1:1 (professional consensus). Depending on the etiology of PPH, the early administration ofFFP is left at the discretion of the physician (professional consensus). Platelet count should bemaintained at > 50 G/L (professional consensus). During massive PPH, fibrinogen concentrationshould be maintained at > 2 g/L (professional consensus). Fibrinogen can be given without priorfibrinogen measurement in case of massive bleeding (professional consensus). General anesthe-sia should be considered in case of hemodynamic instability, even when an epidural catheter isin place (professional consensus).Conclusion-The anesthetic management aims to restore and maintain optimal respiratorystate and circulation, to treat coagulation disorders, and to allow invasive obstetrical andradiologic procedures. Clinical and instrumental monitoring are needed to evaluate the severityof PPH, to guide the choice of therapeutic options, and to assess treatments efficacy. © 2014 Published by Elsevier Masson SAS.

Nair S.C.,Christian Medical College | Dargaud Y.,Unite dHemostase Clinique | Dargaud Y.,University of Lyon | Chitlur M.,Wayne State University | Srivastava A.,Christian Medical College
Haemophilia | Year: 2010

There is a potential for significant paradigm shift in the assessment of haemostasis from the conventional plasma recalcification times, such as prothrombin time (PT) and activated partial thromboplastin time (APTT), which correspond to artificially created compartments of haemostasis to tests that assess the entire process in a more physiological and holistic manner. These include the thrombin generation test, thromboelastogram and the clot wave form analysis. While these tests have been described many years ago, there is renewed interest in their use with modified technology for assessing normal haemostasis and its disorders. Although early data suggest that they can provide much greater information regarding the overall haemostasis process and its disorders, many challenges remain. Some of them are possible only on instruments that are proprietary technology, expensive and are not widely available. Furthermore, these tests need to be standardized with regard to their reagents, methodology and interpretation, and finally, much more data need to be collected regarding clinical correlations with the parameters measured. © 2010 The Authors. Journal compilation © 2010 Blackwell Publishing Ltd.

Dargaud Y.,Unite dHemostase Clinique | Wolberg A.S.,University of North Carolina at Chapel Hill | Luddington R.,Addenbrookes NHS Trust | Regnault V.,University of Lorraine | And 5 more authors.
Thrombosis Research | Year: 2012

The thrombin generation test (TGT) has demonstrated utility in evaluating overall hemostatic capacity both in bleeding and thrombotic disorders. Although the test is currently well accepted as a research tool, its role in clinical practice has not yet been defined through large prospective multicenter clinical studies. Such prospective studies have been limited by the lack of official standardization of the assay and its large inter-laboratory variability. This international study assessed the intra- and inter-assay imprecision of TGT as well as the inter-centre variability of results in one US and four European centres. Contact-inhibited plasmas from six healthy volunteers, one mild haemophilia A patient, and five patients with heterozygous prothrombin G20210 mutation were assayed. We demonstrated that, using identical equipement, standardized reagents, a carefully selected reference plasma for normalization of results and the same test procedure as described in our DVD, the assay variability was highly reduced compared to previously published data. Our results emphasize the importance of preheating on TGT results and the variability of the assay. In conclusion, our data demonstrated that the standardized TGT methodology evaluated in this study effectively reduces the variability of the assay to acceptable limits and may be used in clinical trials. © 2012 Elsevier Ltd. All rights reserved.

Ninivaggi M.,Synapse BV | Apitz-Castro R.,Synapse BV | Dargaud Y.,Unite dHemostase Clinique | De Laat B.,Synapse BV | And 2 more authors.
Clinical Chemistry | Year: 2012

BACKGROUND: The calibrated automated thrombogram (CAT) assay in plasma is a versatile tool to investigate patients with hypo- or hypercoagulable phenotypes. The objective was to make this method applicable for whole blood measurements. METHODS: Thin-layer technology and the use of a rhodamine 110-based thrombin substrate appear to be essential for a reliable thrombin generation (TG) assay in whole blood. Using this knowledge we developed a whole blood CAT-based assay. RESULTS: We demonstrated that the whole blood CAT-based assay is a sensitive and rapid screening test to assess function of the hemostatic system under more nearly physiological conditions than the TG assay in plasma. Under conditions of low tissue factor concentration (0.5 pmol/L) and 50% diluted blood, the intraassay CV of the thrombogram parameters, endogenous thrombin potential and thrombin peak height, were 6.7% and 6.5%, respectively. The respective interassay CVs were 12% and 11%. The mean interindividual variation (SD) of 40 healthy volunteers was 633 (146) nmol · min/L for the endogenous thrombin potential and 128 (23) nmol/L for the thrombin peak. Surprisingly, erythrocytes contributed more than platelets to the procoagulant blood cell membranes necessary for optimal TG. Statistically significant (P <0.001) and potentially clinically significant correlations were observed between circulating factor-VIII concentrations in blood of hemophilia A patients and endogenous thrombin potential (r = 0.62) and thrombin peak height (r = 0.58). CONCLUSIONS: We have developed a reliable method to measure TG in whole blood. The assay can be performed with a drop of blood and may provide a useful measurement of TG under more physiological conditions than plasma. © 2012 American Association for Clinical Chemistry.

Dargaud Y.,Unite dHemostase Clinique | Dargaud Y.,University of Lyon | Prevost C.,Unite dHemostase Clinique | Lienhart A.,Unite dHemostase Clinique | And 3 more authors.
Haemophilia | Year: 2011

It has been reported that thrombin generation test (TGT) may be a useful tool to monitor recombinant factor VIIa (rFVIIa). However, TGT does not reflect the stability of fibrin clot and its resistance to fibrinolysis which are crucial. Using whole-blood thromboelastography (TEG) and tissue plasminogen activator (tPA), we developed an in-vitro model to assess fibrin clot stability. Fibrin fibres were thicker in haemophiliacs compared with controls (P<0.0001). After addition of rFVIIa 90μgkg -1, the diameter of fibrin fibres was dramatically decreased (P=0.006). TEG-tPA assay showed a dose-dependent improvement of clot stability in the presence of rFVIIa. These data demonstrate a significant correlation between fibrin clot structure and its stability (P=0.001). We also showed a correlation between thrombin generating capacity and clot resistance to fibrinolysis. Despite this overall correlation, a relatively large spreading around a general trend was observed, suggesting that the two assays bring complementary information on the haemostatic effect of rFVIIa. © 2011 Blackwell Publishing Ltd.

Dargaud Y.,Unite dHemostase Clinique | Dargaud Y.,University of Lyon | Lienhart A.,Unite dHemostase Clinique | Negrier C.,Unite dHemostase Clinique | Negrier C.,University of Lyon
Blood | Year: 2010

Clinical response to bypassing agents (BPAs) may vary between patients. Surgery is a particular situation, requiring effective hemostasis during the procedure and for several days postoperatively to obtain satisfactory wound healing. However, the optimal dose of BPA in different surgical situations has not been clearly established. We report here a prospective assessment of thrombin generation test (TGT) in monitoring the effectiveness of BPA during 10 elective invasive procedures performed in 6 patients with severe hemophilia and high-titer inhibitors. A standardized 3-step protocol was used in all cases to individually tailor BPA. Thrombin-generating capacity of patients increased after in vitro and ex vivo addition of BPA in a dose-dependent manner. Our results also showed a correlation between in vivo clinical response to BPA and thrombin-generating capacity. These data suggest that TGT may represent a surrogate marker for monitoring bypassing therapies in surgical situations. © 2010 by The American Society of Hematology.

Dargaud Y.,Unite dHemostase Clinique | Dargaud Y.,University of Lyon | Negrier C.,Unite dHemostase Clinique | Negrier C.,University of Lyon
Haemophilia | Year: 2010

Haemophilia comprehensive care centres (HCCC) were first created more than 50 years ago. Their first objective was educating the patient and healthcare professionals in the management of bleeding. Today HCCCs are centres of excellence with multidisciplinary specialists, which continue to provide essential services that are continually reassessed in light of new scientific information. In addition, HCCCs make significant research contributions by studying new methods to improve the well-being of patients with haemophilia. Laboratory expertise is one of the central pillars of HCCCs with a direct impact on diagnosis and management of the haemophilia disease. Vast efforts have been made for the standardization of factor VIII (FVIII) and FIX measurements and inhibitor detection. Molecular biology has improved diagnostics and made it possible to develop new, more secure FVIII and FIX concentrates for replacement therapy. However, phenotyping of each haemophilia patient with an accurate prediction of the individual bleeding risk and also the individual response of patients to antihaemophilic treatment still remains a challenge. In the last 5 years, an expanding interest of haematologists for thrombin generation testing (TGT) reflects the need for new laboratory tools able to evaluate the overall coagulating capacity of patients. This study will review unmet laboratory needs in haemophilia and the potential applications of TGT in the management of haemophiliacs. Furthermore, technical and standardization issues of the method will be discussed. © 2009 Blackwell Publishing Ltd.

Rugeri L.,Unite dHemostase Clinique | Quelin F.,University of Versailles | Chatard B.,Unite dHemostase Clinique | De Mazancourt P.,University of Versailles | And 2 more authors.
Haemophilia | Year: 2010

Factor XI (FXI) deficiency is a rare bleeding disorder. Most patients with FXI deficiency are mild bleeders but certain patients with similar FXI activity exhibit different bleeding phenotype. Routine laboratory assays do not help physicians to estimate the individual bleeding risk in these patients. Thrombin generation test (TGT) is a more comprehensive, global function test of the clotting system. We investigated whether or not the bleeding tendency of patients with FXI deficiency is correlated with features of the TGT. Twenty-four patients with FXI deficiency were divided in two groups: (i) severe bleeders (n = 9) and (ii) mild or non-bleeders (n = 15). All severe bleeders had a personal history of surgery-related severe bleeding. Thrombin generation (TG) was measured in platelet-rich plasma (PRP) using a low concentration of tissue factor 0.5 pm. In patients exhibiting severe bleeding tendency, independently of their FXI level, a dramatically impaired TG was observed. For example, despite a low plasma FXI = 1 IU dl-1, a clinically non-bleeding individual exhibited normal TG results whereas another patient with severe bleeding history and FXI = 40 IU dl-1 had a very low TG capacity. Low velocity and delayed TG were the main parameters suggesting a higher bleeding risk. DNA analysis of patients reported eight novel mutations of the FXI gene but neither mutation location nor secretion or not of the variant correlated with the bleeding tendency. The results of this study suggest that TG measurement in PRP may be a useful tool to predict bleeding risk in FXI deficiency and should be studied further in larger prospective clinical studies. © 2010 Blackwell Publishing Ltd.

The pathogenesis of the prothrombotic state of cancer patients ismostly due to the ability of cancer cells to activate the coagulation system. There are several complex and not fully understood interactions between the malignant cell and the clotting system. Tumour cells possess the capacity to interact with the haemostatic system in multiple ways. The principal mechanisms include the expression of haemostatic proteins by tumour cells, the production of inflammatory cytokines and the direct adhesion of tumour cells to platelets, endothelial cells and monocytes. This paper summarizes the prothrombotic mechanisms of tumour cells and their role in both coagulation and tumour growth and metastasis. © 2012 Springer-Verlag France.

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