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EVpedia: A Community Web Portal for Extracellular Vesicles Research.
Dae-Kyum Kim, Jaewook Lee, Sae Rom Kim, Dong-Sic Choi, Yae Jin Yoon, Ji Hyun Kim, Gyeongyun Go, Dinh Nhung, Kahye Hong, Su Chul Jang, Si-Hyun Kim, Kyong-Su Park, Oh Youn Kim, Hyun Taek Park, Ji Hye Seo, Elena Aikawa, Monika Baj-Krzyworzeka, Bas W M van Balkom, Mattias Belting, Lionel Blanc, Vincent Bond, Antonella Bongiovanni, Francesc E Borràs, Luc Buée, Edit I Buzás, Lesley Cheng, Aled Clayton, Emanuele Cocucci, Charles S Dela Cruz, Dominic M Desiderio, Dolores Di Vizio, Karin Ekström, Juan M Falcon-Perez, Chris Gardiner, Bernd Giebel, David W Greening, Julia Christina Gross, Dwijendra Gupta, An Hendrix, Andrew F Hill, Michelle M Hill, Esther Nolte-'t Hoen, Do Won Hwang, Jameel Inal, Medicharla V Jagannadham, Muthuvel Jayachandran, Young-Koo Jee, Malene Jørgensen, Kwang Pyo Kim, Yoon-Keun Kim, Thomas Kislinger, Cecilia Lässer, Dong Soo Lee, Hakmo Lee, Johannes van Leeuwen, Thomas Lener, Ming-Lin Liu, Jan Lötvall, Antonio Marcilla, Suresh Mathivanan, Andreas Möller, Jess Morhayim, François Mullier, Irina Nazarenko, Rienk Nieuwland, Diana N Nunes, Ken Pang, Jaesung Park, Tushar Patel, Gabriella Pocsfalvi, Hernando Del Portillo, Ulrich Putz, Marcel I Ramirez, Marcio L Rodrigues, Tae-Young Roh, Felix Royo, Susmita Sahoo, Raymond Schiffelers, Shivani Sharma, Pia Siljander, Richard J Simpson, Carolina Soekmadji, Philip Stahl, Allan Stensballe, Ewa Stępień, Hidetoshi Tahara, Arne Trummer, Hadi Valadi, Laura J Vella, Sun Nyunt Wai, Kenneth Witwer, María Yáñez-Mó, Hyewon Youn, Reinhard Zeidler, Yong Song Gho.
Bioinformatics
PUBLISHED: 11-13-2014
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Extracellular vesicles are spherical bilayered proteolipids, harboring various bioactive molecules. Due to the complexity of the vesicular nomenclatures and components, online searches for extracellular vesicle-related publications and vesicular components are currently challenging.
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Appropriateness of prescribing dabigatran etexilate and rivaroxaban in patients with nonvalvular atrial fibrillation: a prospective study.
Ann Pharmacother
PUBLISHED: 06-30-2014
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Direct oral anticoagulants have been developed to address some of the drawbacks of vitamin-K antagonists. However, special attention should be given when using these drugs, especially in patients with renal insufficiency, questionable compliance, and those at high risk of bleeding.
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Management of non-vitamin K antagonist oral anticoagulants in the perioperative setting.
Biomed Res Int
PUBLISHED: 05-30-2014
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The field of oral anticoagulation has evolved with the arrival of non-vitamin K antagonist oral anticoagulants (NOACs) including an anti-IIa agent (dabigatran etexilate) and anti-Xa agents (rivaroxaban and apixaban). The main specificities of these drugs are predictable pharmacokinetics and pharmacodynamics but special attention should be paid in the elderly, in case of renal dysfunction and in case of emergency. In addition, their perioperative management is challenging, especially with the absence of specific antidotes. Effectively, periods of interruption before surgery or invasive procedures depend on half-life and keeping a permanent balance between bleeding and thromboembolic risks. In addition, few data regarding the link between plasma concentrations and their effects are provided. Routine laboratory tests are altered by NOACs and quantitative measurements are not widely performed. This paper provides a review on the management of NOACs in the perioperative setting, including the estimation of the bleeding and thrombotic risk, the periods of interruption, the indication of heparin bridging, the usefulness of laboratory tests before surgery or invasive procedure, and the time of resuming. Most data are based on expert's opinions.
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[Why, when and how to monitor new oral anticoagulants].
Rev Med Suisse
PUBLISHED: 03-15-2014
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Several direct oral anticoagulants (DOACs) are now widely used in the prevention and treatment of thromboembolic events. Unlike vitamin K antagonists, DOACs exhibit predictable pharmacokinetics and pharmacodynamics. DOACs are to be administered at fixed doses without routine coagulation monitoring. However, in some patient populations or specific clinical circumstances, measurement of drug exposure may be useful, such as in suspected overdose, in patients with a haemorrhagic or thromboembolic event during treatment with an anticoagulant, in those with acute renal failure, or in patients who require urgent surgery. This article provides practical guidance on laboratory testing of DOACs in routine practice and summarizes the influence of DOACs on commonly used coagulation assays.
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Preventive strategies against bleeding due to nonvitamin K antagonist oral anticoagulants.
Biomed Res Int
PUBLISHED: 02-28-2014
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Dabigatran etexilate (DE), rivaroxaban, and apixaban are nonvitamin K antagonist oral anticoagulants (NOACs) that have been compared in clinical trials with existing anticoagulants (warfarin and enoxaparin) in several indications for the prevention and treatment of thrombotic events. All NOACs presented bleeding events despite a careful selection and control of patients. Compared with warfarin, NOACs had a decreased risk of intracranial hemorrhage, and apixaban and DE (110 mg BID) had a decreased risk of major bleeding from any site. Rivaroxaban and DE showed an increased risk of major gastrointestinal bleeding compared with warfarin. Developing strategies to minimize the risk of bleeding is essential, as major bleedings are reported in clinical practice and specific antidotes are currently not available. In this paper, the following preventive approaches are reviewed: improvement of appropriate prescription, identification of modifiable bleeding risk factors, tailoring NOAC's dose, dealing with a missed dose as well as adhesion to switching, bridging and anesthetic procedures.
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Contributing role of extracellular vesicles on vascular endothelium haemostatic balance in cancer.
J Extracell Vesicles
PUBLISHED: 01-01-2014
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Extracellular vesicles (EVs) generated during tumourigenesis are thought to play a major role in the hypercoagulant state observed in cancer patients. They exhibit negatively charged phospholipids and tissue factor (TF) that promote coagulation cascade activation. In addition, they contain surface proteins and cytoplasmic molecules, both originating from the producing cell that can impact target cells' expression. By targeting endothelial cells of blood vessels, these EVs could disturb the physiological anticoagulant properties of these cells and be partly responsible for the vascular endothelium activation observed in cancer patients. Indeed, vascular endothelium naturally exhibits heparin-like proteoglycan, TF pathway inhibitor and protein C anticoagulant pathway that prevent thrombosis in physiological condition. An overexpression of TF and a decreased expression of coagulation cascade inhibitors have been reported after EVs' treatment of endothelial cells. The induction of apoptosis and an increased expression of platelet adhesion molecules have also been highlighted. These events may promote thrombus formation in cancer. The aim of this paper is to provide a targeted review on the current evidence and knowledge of roles and impact of EVs on endothelial surface anticoagulant and procoagulant factors and cellular adhesion molecules expression.
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The central role of extracellular vesicles in the mechanisms of thrombosis in paroxysmal nocturnal haemoglobinuria: a review.
J Extracell Vesicles
PUBLISHED: 01-01-2014
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Paroxysmal nocturnal haemoglobinuria (PNH) is an acquired disorder of the haematopoietic stem cell that makes blood cells more sensitive to the action of complement. PNH patients experience an increased risk of arterial and venous thrombosis - major causes of death due to this disease. Though many potential interlaced mechanisms are suspected, extracellular vesicles (EVs) of various origins may play a central role. The processes possibly involved are haemolysis, platelet activation, injured endothelial cells and monocyte activation. The impact of transfusion should be evaluated. A better understanding of the mechanisms involved may help to propose guidelines for the prophylaxis and treatment of thrombosis in PNH. In this paper, we propose an updated review of the pathophysiology of the underlying mechanisms of thrombosis associated with PNH, with specific focus on the prominent role of EVs.
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Microparticle bearing tissue factor: A link between promyelocytic cells and hypercoagulable state.
Thromb. Res.
PUBLISHED: 07-22-2013
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Patients with hematological malignancies have a 28-fold increased risk of venous thromboembolism (VTE). Among patients with acute myelogenous leukemia (AML), the 2-year cumulative incidence of VTE is 5.2%. Several studies suggest that microvesicles (MVs) harboring TF may play a role in VTE and disseminated intravascular coagulation (DIC) in acute promyelocytic leukemia (APL). The aim of this study was to assess the capacity of untreated (APL) cells to shed procoagulant MVs. APL cells (NB4 and HL-60 cell lines) and MVs were separated by filtration (0.1-0.22-0.45-0.65?m). The procoagulant activity (PCA) was assessed by thrombin generation assay (TGA). Alternatively, MVs were incubated with anti-Tissue Factor (TF) antibodies, with annexin V to assess the contribution of TF and phospholipids (PL) to the PCA, respectively. NB4 cells had a high PCA mainly triggered by MVs of size under 0.45?m. The PCA of MVs was related to the expression of active TF and PL. HL-60 cells had a weaker PCA since TF is mostly present in its inactive form. Moreover, HL-60 do not produce MVs<0.65?m associated with PCA. MVs could have a predicting value for VTE and DIC in patients with acute promyelocytic leukemia and could inform physicians about the optimal use of a thromboprophylaxis.
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Inhibition of tissue factor pathway inhibitor increases the sensitivity of thrombin generation assay to procoagulant microvesicles.
Blood Coagul. Fibrinolysis
PUBLISHED: 06-29-2013
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Patients with cancer have a seven-fold to 10-fold increased risk of developing venous thromboembolism (VTE). Circulating microvesicles could be a predictive biomarker for VTE in cancer. Thrombin generation assay (TGA) is a useful technique to detect procoagulant activity of microvesicles. However, TGA suffers from a lack of sensitivity due to the presence of tissue factor pathway inhibitor (TFPI) in plasma. The aim of the study was to improve the sensitivity of TGA to tissue factor by limiting the interference of TFPI. Serial dilutions of MDA-MB231 cells were incubated for 45 min at 37°C to generate microvesicles. Samples were then centrifuged and supernatants that contain microvesicles were used for TGA. Normal pooled plasma was incubated with inhibitor of TFPI or was diluted twice to decrease plasma level of TFPI. Lagtime was used as a surrogate marker of TGA to detect procoagulant activity of microvesicles. Inhibition of TFPI decreased twice the cell concentration needed for a significant reduction of lagtime and decreased 2.4-fold the intraassay variability. Plasma dilution had no impact on the TGA sensitivity when TGA was triggered by microvesicles derived from MDA-MB-231. Thrombin generation is a very sensitive method to study the procoagulant activity of tissue factor bearing microvesicles. The sensitivity can be increased by inhibition of TFPI with specific monoclonal antibody against its Kunitz domain I. A two times plasma dilution is an interesting cheaper alternative to study the procoagulant activity of microvesicles by TGA with a good sensitivity, especially when low plasma quantities are available.
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Impact of apixaban on routine and specific coagulation assays: a practical laboratory guide.
Thromb. Haemost.
PUBLISHED: 05-07-2013
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Apixaban does not require monitoring nor frequent dose adjustment. However, searching for the optimal dose for the individual patient may be useful in some situations. Moreover, there is a need for clinicians to know whether coagulation assays are influenced by apixaban use. The aim of this study was to determine which coagulation assay could be used to assess the impact of apixaban on haemostasis and provide good laboratory recommendations for the accurate interpretation of haemostasis assays. Apixaban is spiked at concentrations ranging from 5 to 500 ng/mlin platelet-poor plasma. Routinely used or more specific coagulation assays are tested. Results show a concentration dependent prolongation of aPTT, PT and dilute PT. The sensitivity mainly depends on the reagent, but none of these tests is sensitive enough to ensure an accurate estimation of the pharmacodynamic effect of apixaban. FXa chromogenic assays show high sensitivity and a linear correlation depending on the reagent and/or the methodology. Immunological assays and assays acting below the FXa are not influenced by apixaban. In conclusion, PT and/or dilute PT cannot be used to assess apixaban pharmacodynamic properties. More specific and sensitive assays such as chromogenic FXa assays using specific calibrators are required. In case of thrombophilia or in the exploration of a haemorrhagic event, immunological assays should be recommended, when applicable. Standardisation of the time between the last intake of apixaban and the sampling is mandatory.
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A comparison of six major platelet functional tests to assess the impact of carbon nanomaterials on platelet function: A practical guide.
Nanotoxicology
PUBLISHED: 04-15-2013
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Abstract The study of the haemocompatibility of nanomaterials that could be in contact with blood (e.g. nanoparticle (NP)-based drug-delivery system) is of major importance. The primary objective of this study was to compare the ability of six platelet functional tests to assess the impact of NPs on platelet function. The secondary objective was to determine an accurate and reliable screening test to measure the potential impact of NPs on primary haemostasis whatever their physicochemical properties. Four types of carbon NPs (carbon black, fullerenes, single-walled carbon nanotubes and multi-walled carbon nanotubes) were investigated on six platelet function tests: light transmission aggregometry, whole-blood impedance aggregometry, platelet function analyser-100 (PFA-100®) and Cone-and-Plate(let) analyser (Impact-R®), transmission- and field emission gun scanning electron microscopy (FEG-SEM). We considered that Impact-R® supported by FEG-SEM is the reference method to investigate the potential impact of NPs on platelet function.
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Comparison of calibrated chromogenic anti-Xa assay and PT tests with LC-MS/MS for the therapeutic monitoring of patients treated with rivaroxaban.
Thromb. Haemost.
PUBLISHED: 04-03-2013
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Possibilities to monitor rivaroxaban therapy could be useful in certain circumstances. Prothrombin time (PT) or chromogenic anti-Xa assays such as the Biophen Direct Factor Xa Inhibitor® (DiXaI) have been proposed to estimate rivaroxaban concentrations but are mainly based on in vitro studies. The study aim was to compare PT and Biophen DiXaI® measurements with liquid chromatography-tandem mass spectrometry (LC-MS/MS) measurements in plasma samples from patients treated with Xarelto®. Fifty-two plasma samples were included. PT was performed using Innovin® and Triniclot PT Excel S®. Biophen DiXaI® was performed according to instructions from the manufacturer. The rivaroxaban plasma concentration ranged between 0 and 485 ng/ml as measured by LC-MS/MS. The limits of quantification were 30 ng/ml and 5 ng/ml for Biophen DiXaI® and LC-MS/MS, respectively. The linear correlation between Biophen DiXaI® and LC-MS/MS analyses was high for all rivaroxaban concentrations (r² = 0.95). For concentrations ?100 ng/ml, r²-value was 0.83. The Bland-Altman analysis showed a mean difference of -16 ng/ml (SD: 25 ng/ml). The PT methods did not correlate well with plasma concentrations measured by LC-MS/MS (r² ? 0.60). In conclusion, the important inter-individual variability and the poor correlation with LC-MS/MS preclude the use of PT to estimate rivaroxaban concentrations. Thanks to its small inter-individual variability and good agreement with LC-MS/MS measurements, we recommend the use of Biophen DiXaI® assays to estimate concentrations of rivaroxaban >30 ng/ml. Quantification of low rivaroxaban levels (<30 ng/ml) requires the LC-MS/MS method.
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Characterisation of tissue factor-bearing extracellular vesicles with AFM: comparison of air-tapping-mode AFM and liquid Peak Force AFM.
J Extracell Vesicles
PUBLISHED: 01-01-2013
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Extracellular vesicles (EVs) are shed from cells and carry markers of the parent cells. Vesicles derived from cancer cells reach the bloodstream and locally influence important physiological processes. It has been previously shown that procoagulant vesicles are circulating in patients fluids. These EVs are therefore considered as promising biomarkers for the thrombotic risk. Because of their small size, classical methods such as flow cytometry suffer from limitation for their characterisation. Atomic force microscopy (AFM) has been proposed as a promising complementary method for the characterisation of EVs.
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Thrombin generation assay and transmission electron microscopy: a useful combination to study tissue factor-bearing microvesicles.
J Extracell Vesicles
PUBLISHED: 01-01-2013
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Patients with cancer have a 7- to 10-fold increased risk of developing venous thromboembolism. Circulating microvesicles could be a useful predictive biomarker for venous thromboembolism in cancer. Validated and standardised techniques that could be used to determine the complete microvesicle phenotype are required.
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No effect of lysis solutions on absolute CD19+ lymphocytes count and CD45 index in chronic lymphocytic leukemia.
Cytometry B Clin Cytom
PUBLISHED: 04-19-2011
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The absolute CD19+ lymphocytes count is essential for chronic lymphocytic leukemia (CLL) management. At the present time, no standardized flow cytometry (FCM) protocol to measure B-lymphocytes counts is established. The aims of the present study were first to evaluate the effect of different lysis solutions and of red blood cell lysis per se on CLL lymphocytes count and B-lymphocytes CD45 expression and second to compare absolute B-lymphocytes counts obtained by single (SP) and dual platforms (DP). Absolute CD19+ B-lymphocytes counts and CD45 expression in 35 whole-blood CLL samples were determined by FCM using either different lysis solutions or using a no wash no lyse (NWNL) protocol. Single platform using microbeads was also evaluated for absolute quantification. The absolute CD19+ B-lymphocytes counts using different red blood cell lysis solutions correlated with NWNL method without any effect on CD45 expression. Bland and Altman plot showed homogenous distribution of bias; mean bias was less than 1% for all lysing solutions. Moreover, no statistically significant difference between SP and DP was observed. The type of lysis solution influences neither the CD19+ B-lymphocytes count nor the CD45 expression. The two systems, SP and DP, yield comparable values with excellent agreement. However, the tendency of slightly lower results with SP showed the requirement of larger studies before standardization of B-lymphocytes count in CLL patients.
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Morphology, cytogenetics, and survival in myelodysplasia with del(20q) or ider(20q): a multicenter study.
Ann. Hematol.
PUBLISHED: 04-18-2011
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Isochromosome of the long arm of chromosome 20 with interstitial loss of material [ider(20q)] is a rare cytogenetic abnormality reported in myelodysplastic syndrome (MDS), with neither specific morphological pattern nor clear prognostic significance. The aim of this retrospective multicentric study is to compare the peripheral blood and bone marrow morphology of MDS patients with ider(20q) (n?=?13) and del(20q) (n?=?21) and controls (n?=?47) in order to investigate whether the ider(20q) harbors specific morphological features. The secondary objective is to compare the outcome of patients from both groups. This study performed on the largest cohort of MDS patients with ider(20q) is the first that identifies specific morphological features (hypogranulated and vacuolized neutrophils and neutrophil erythrophagocytosis) allowing the identification of this cytogenetic abnormality with high sensitivity (70%) and specificity (85.7%). Suspected ider(20q) by morphology should therefore support targeted FISH tests in case of non informative karyotype. This combined approach will allow a better estimation of the prevalence of this underdiagnozed entity. The overall survival and progression-free survival did not statistically differ in both groups. However, hypogranulated and vacuolized neutrophils were significantly associated with survival.
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Validation of the calibrated thrombin generation test (cTGT) as the reference assay to evaluate the procoagulant activity of nanomaterials.
Nanotoxicology
PUBLISHED: 04-13-2011
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We validated a preclinical toxicological screening assay and provided guidelines to evaluate the potential impact of nanoparticles (NPs) on blood coagulation. Five NPs with various physicochemical properties were studied using several existing methods of clotting times and thrombin generation assays in human normal pool plasma. In both recalcification clotting time (RCT) and calibrated thrombin generation test (cTGT), the NPs exhibited procoagulant activity (SiO? ? SiC ? TiC > CuO > CB) but cTGT was more sensitive and relevant than RCT. Thus, the cTGT appears as a reference assay to investigate the nanoparticle (NP) procoagulant activity in human plasma. It should be used as the reference toxicity test for evaluating the effects of nanomaterials on coagulation cascade. In addition, we also showed that the use of the Pluronic F-108 dispersant and/or the sonication for the NP suspension preparation may mask their procoagulant activity and thus should be avoided.
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Additional erythrocytic and reticulocytic parameters helpful for diagnosis of hereditary spherocytosis: results of a multicentre study.
Ann. Hematol.
PUBLISHED: 08-22-2010
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Hereditary spherocytosis (HS) is characterised by weakened vertical linkages between the membrane skeleton and the red blood cells lipid bilayer, leading to the release of microparticles. All the reference tests suffer from specific limitations. The aim of this study was to develop easy to use diagnostic tool for screening of hereditary spherocytosis based on routinely acquired haematological parameters like percentage of microcytes, percentage of hypochromic cells, reticulocyte counts, and percentage of immature reticulocytes. The levels of haemoglobin, mean cell volume, mean corpuscular haemoglobin concentration, reticulocytes (Ret), immature reticulocytes fraction (IRF), hypochromic erythrocytes (Hypo-He) and microcytic erythrocytes (MicroR) were determined on EDTA samples on Sysmex instruments from a cohort of 45 confirmed SH. The HS group was then compared with haemolytical disorders, microcytic anaemia, healthy individuals and routine samples (n = 1,488). HS is characterised by a high Ret count without an equally elevated IRF. All 45 HS have Ret >80,000/?l and Ret(10(9)/L)/IRF (%) greater than 7.7 (rule 1). Trait and mild HS had a Ret/IRF ratio greater than 19. Moderate and severe HS had increased MicroR and MicroR/Hypo-He (rule 2). Combination of both rules gave predictive positive value and negative predictive value of respectively 75% and 100% (n=1,488), which is much greater than single parameters or existing rules. This simple and fast diagnostic method could be used as an excellent screening tool for HS. It is also valid for mild HS, neonates and ABO incompatibilities and overcomes the lack of sensitivity of electrophoresis in ankyrin deficiencies.
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A GEIL flow cytometry consensus proposal for quantification of plasma cells: application to differential diagnosis between MGUS and myeloma.
Cytometry B Clin Cytom
PUBLISHED: 01-10-2010
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Flow cytometry is the sole available technique for quantification of tumor plasma-cells in plasma-cell disorders, but so far, no consensus technique has been proposed. Here, we report on a standardized, simple, robust five color flow cytometry protocol developed to characterize and quantify bone marrow tumor plasma-cells, validated in a multicenter manner.
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Assessment of the impact of rivaroxaban on coagulation assays: laboratory recommendations for the monitoring of rivaroxaban and review of the literature.
Thromb. Res.
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Rivaroxaban does not require monitoring nor frequent dose adjustment. However, searching for the optimal dose in the individual patient may be useful in some situations.
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The effect of clonidine, an alpha-2 adrenergic receptor agonist, on inflammatory response and postischemic endothelium function during early reperfusion in healthy volunteers.
J. Cardiovasc. Pharmacol.
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Ischemia-reperfusion disturbs endothelial physiology and generates a proinflammatory state. Animal studies showed that clonidine administered prior hypoxia improves posthypoxic endothelial function. To investigate this effect in human, we have assessed the postischemic endothelium function and the proinflammatory state in healthy volunteers with and without clonidine. Seven volunteers were included. Each subject underwent the experimental protocol (15 minutes nondominant forearm ischemia) with and without clonidine. Endothelial function was assessed by flow-mediated dilatation (FMD) in the brachial artery before ischemia (FMDPI), immediately after ischemia (FMDIAI), and 15 minutes after ischemia (FMD15AI). Neutrophil (CD11b/CD18) and platelet (CD42b) activations were measured by flow cytometry during reperfusion in blood samples from ischemic (local) and nonischemic (systemic) forearms. Proinflammatory state was assessed by serum concentration of interleukin (IL)-1? and -6. Clonidine does not influence baseline FMD (P = 0.118) but improves FMDIAI (P = 0.018) and FMD15AI (P = 0.018). It increases platelet activation in systemic circulation (P = 0.003) during reperfusion but not in local circulation (P = 0.086). Clonidine increases neutrophil activation in local circulation (P = 0.001) but not in systemic circulation (P = 0.642). In local circulation, clonidine decreases IL-6 (P = 0.044) but does not influence IL-1? (P = 0.113). By contrast, it decreases both IL-6 (P = 0.026) and IL-1? (P = 0.027) concentrations in systemic circulation. In conclusion, clonidine improves endothelial function and modulates inflammation during reperfusion.
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A case of therapy-related myeloid neoplasm in a patient with Crohns disease treated with azathioprine.
Acta Haematol.
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Acute leukaemia (AL) has been observed in association with Crohns disease (CD) notably in patients treated with azathioprine (AZA), which is an immunosuppressant known for its carcinogenicity and in particular known to induce therapy-related acute myeloid leukaemia according to the 2008 WHO classification. Whereas the link between inflammatory bowel disease and AL has been well established, the exact role of AZA remains controversial. In this paper, we report the case of a 71-year-old white Caucasian male with CD treated for 7 years with AZA who developed an acute leukaemia. Chemotherapy was administered unsuccessfully and the patient died from this haematological disorder 9 months after diagnosis. We reviewed the current evidence on the interactions between CD, AL and AZA as well as the potential underlying mechanisms of leukaemia in AZA-treated patients. From this review, we concluded that AL should be questioned when facing cytopenia in a patient with CD. The nature of the association between AZA and AL in CD patients warrants further investigation.
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Impact of dabigatran on a large panel of routine or specific coagulation assays. Laboratory recommendations for monitoring of dabigatran etexilate.
Thromb. Haemost.
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Due to low bioavailability and high inter-individual variability, monitoring of dabigatran may be required in specific situations to prevent the risk of bleedings or thrombosis. The aim of the study was to determine which coagulation assay(s) could be used to assess the impact of dabigatran on secondary haemostasis. Dabigatran was spiked at concentrations ranging from 4.7 ng/ml to 943.0 ng/ml in pooled citrated human platelet-poor plasma. The following clotting assays were performed: prothrombin time (PT); activated partial thromboplastin time (aPTT); thrombin time (TT); ecarin clotting time (ECT); ecarin chromogenic assay (ECA); prothrombinase-induced clotting time (PiCT); activated clotting time (ACT); Hemoclot Thrombin Inhibitor (HTI) and thrombin generation assay (TGA). A concentration-dependent prolongation of PT, dPT, and aPTT was observed with aPTT being the more sensitive test. The results varied mostly due to the clotting reagent. HTI, ECT and TGA were the most sensitive tests but are not available 24 hours a day. In addition, HTI showed a linear correlation with a good reproducibility. Dabigatran induced a concentration-dependent delay and inhibition of tissue factor-induced TGA. Cut-offs related with higher risk of bleedings or thrombosis were defined for each reagent of aPTT and HTI. In conclusion, aPTT could be used for the monitoring of dabigatran and as screening test for the risk of overdose. However, because of its higher sensitivity, good reproducibility, excellent linear correlation at all doses, its simplicity of use, and possibilities of automation, HTI should be considered as the gold-standard.
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Comparison of five D-dimer reagents and application of an age-adjusted cut-off for the diagnosis of venous thromboembolism in emergency department.
Blood Coagul. Fibrinolysis
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There is still a considerable uncertainty concerning D-dimer cut-off values used in exclusion of venous thromboembolic (venous thromboembolism, VTE) disease, especially among the elderly patients. The objectives were to compare five different D-dimer reagents in the daily practice of an emergency department and to test retrospectively the performances of an age-adjusted cut-off. A total of 473 consecutive ambulatory outpatients suspected of VTE (confirmed VTE?=?21) were included in this study. Five commercially available tests were assessed: STA-Liatest D-Di (LI), AxSYMD-Dimer (AX), VIDAS D-Dimer (VI), INNOVANCE D-Dimer (IN), and HemosIL D-Dimer HS (HS). When using a cut-off value of 500?ng/ml fibrinogen equivalent units (FEUs), D-dimer reagents differ in their abilities to avoid further testing. Indeed, LI allowed exclusion of VTE diagnosis in statistically more patients than VI, AX, and IN but not HS. The use of an age-adjusted cut-off is cost-effective without increasing significantly the number of false negative results. The interest of such strategy is more or less pronounced, depending on the type of D-dimer reagent. The application of an age-adjusted cut-off may be useful to reduce differences among D-dimer reagents to lower costly imaging studies. Prospective validation studies on large cohorts of patients are required to determine the safety of such strategy.
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