Publications by authors named "Laurent Macchi"

20 Publications

  • Page 1 of 1

Bleeding complications during pregnancy and delivery in haemophilia carriers and their neonates in Western France: An observational study.

Haemophilia 2020 Nov 25;26(6):1046-1055. Epub 2020 Aug 25.

EA3878, Université de Bretagne Occidentale, Brest, France.

Background: Pregnancy, delivery and the postpartum period expose haemophilia carriers, as well as their potentially affected neonates to a high risk of haemorrhagic complications.

Objectives: To describe bleeding complications in haemophilia carriers and their newborns throughout pregnancy and postpartum and to identify potential factors increasing the risk of bleeding in this population.

Patients/methods: The ECHANGE multicentre observational cohort study was conducted between January 2014 and February 2019 using the BERHLINGO database comprised of patients from seven French haemophilia centres.

Results: During the 5 years study period, a total of 104 haemophilia carriers and 119 neonates were included, representing 124 pregnancies and 117 deliveries. Thirty-five (30%) bleeding events were observed, most of them (83%) occurred during the postpartum period, and 37% were reported during the secondary postpartum. Neuraxial anaesthesia was not complicated by spinal haematoma. Three (2.5%) neonates experienced cerebral bleeding. Caesarean section was associated with an increased risk of maternal bleeding in primary and secondary postpartum periods. Basal factor level <0.4 IU/mL was also found to be associated with an increased risk of bleeding during secondary postpartum.

Conclusion: In our cohort, bleeding events occurred in more than a third of haemophilia carriers mainly in the postpartum period, and a significant portion of this bleeding occurred during the secondary postpartum. Haemophilia carriers warrant specific attention during primary and secondary postpartum, in particular in case of caesarean section and low basal factor level. The ECHANGE study is registered at clinicaltrials.gov identifier: NCT03360149.
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http://dx.doi.org/10.1111/hae.14117DOI Listing
November 2020

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

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

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

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

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

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

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

Direct Rivaroxaban-Induced Factor XA Inhibition Proves to be Cardioprotective in Rats.

Shock 2020 06;53(6):730-736

INSERM U1082 IRTOMIT, Poitiers, France.

Background: Acute myocardial infarction is a leading cause of death worldwide. Though highly beneficial, reperfusion of myocardium is associated with reperfusion injury. While indirect inhibition of Factor Xa has been shown to attenuate myocardial ischemia-reperfusion (I/R) injury, the underlying mechanism remains unclear. Our study sought to evaluate the effect of rivaroxaban (RIV), a direct inhibitor of Factor Xa, on myocardial I/R injury and determine its cellular targets.

Experimental Approach: We used a rat model of 40-min coronary ligation followed by reperfusion. RIV (3 mg/kg) was given per os 1 h before reperfusion. Infarct size and myocardial proteic expression of survival pathways were assessed at 120 and 30 min of reperfusion, respectively. Plasmatic levels of P-selectin and von Willebrand factor were measured at 60 min of reperfusion. Cellular RIV effects were assessed using hypoxia-reoxygenation (H/R) models on human umbilical vein endothelial cells and on rat cardiomyoblasts (H9c2 cell line).

Key Results: RIV decreased infarct size by 21% (42.9% vs. 54.2% in RIV-treated rats and controls respectively, P < 0.05) at blood concentrations similar to human therapeutic (387.7 ± 152.3 ng/mL) levels. RIV had no effect on H/R-induced modulation of endothelial phenotype, nor did it alter myocardial activation of reperfusion injury salvage kinase and survivor activating factor enhancement pathways at 30 min after reperfusion. However, RIV exerted a cytoprotective effect on H9c2 cells submitted to H/R.

Conclusions: RIV decreased myocardial I/R injury in rats at concentrations similar to human therapeutic ones. This protection was not associated with endothelial phenotype modulation but rather with potential direct cytoprotection on cardiomyocytes.
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http://dx.doi.org/10.1097/SHK.0000000000001412DOI Listing
June 2020

Remote Ischemic Conditioning in a Model of Severe Renal Ischemia-Reperfusion Injury.

Shock 2019 06;51(6):795-799

MitoVasc Institute, INSERM-CNRS, University of Angers, Angers, France.

Ischemia-reperfusion (I/R) injury is a leading cause of acute renal dysfunction. Remote ischemic conditioning (rIC) is known to protect organs exposed to I/R. We sought to investigate whether rIC would influence renal function recovery in a severe renal I/R injury rat model. Rats were randomly assigned to four experimental groups following median laparotomy and right nephrectomy: Sham (n = 6); 30-min left renal ischemia (RI) only (n = 20); RI + rIC (n = 20) (four 5-min cycles of limb ischemia interspersed with 5-min limb reperfusion during RI); and RI + erythropoietin pretreatment (EPO) (n = 20). Renal function was evaluated by assessing blood urea nitrogen (BUN) and serum creatinine (Cr) levels before surgery and after 1 day of reperfusion. All animals were monitored for 7 days for survival analysis. BUN and Cr baseline levels did not significantly differ between groups. At day 1, BUN and Cr were significantly higher than baseline values in all groups. BUN and Cr levels did not significantly differ at day 1 between RI and RI + rIC (P = 0.68). Conversely, EPO pretreatment injected 60 min before RI was associated with lower BUN and Cr levels compared with RI (P < 0.001 and P = 0.003, respectively) and RI + rIC (P < 0.001 and P = 0.001, respectively). In addition, 7-day survival rates were significantly higher in the Sham group (100%) compared with RI (50%; P = 0.039 vs. Sham) and RI + rIC (45%; P = 0.026 vs. Sham). Conversely, survival rate did not significantly differ between the Sham and RI + EPO groups (70%, P = 0.15). In conclusion, rIC affected neither acute renal dysfunction nor early mortality in a severe I/R renal injury rat model, contrary to EPO pretreatment.
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http://dx.doi.org/10.1097/SHK.0000000000001187DOI Listing
June 2019

Remote ischaemic preconditioning in intermittent claudication.

Arch Cardiovasc Dis 2015 Oct 10;108(10):472-9. Epub 2015 Jun 10.

L'UNAM université, Nantes, France; EA 3860 cardioprotection, remodelage et thrombose, université Angers, rue Haute-de-Reculée, 49045 Angers, France; Service de cardiologie, CHU d'Angers, Angers, France. Electronic address:

Background: Remote ischaemic preconditioning (RIPC) protects tissues against ischaemia-reperfusion (I/R) injury, a common occurrence in several clinical settings.

Aims: To evaluate whether RIPC has a beneficial impact on walking disability in arterial intermittent claudication.

Methods: A total of 20 patients with proven intermittent claudication underwent two treadmill walking tests with a 7-day interval in between; they were randomized according to the order in which they received either RIPC or a control procedure before the first treadmill test, with a crossover at the second test. Patients received three cycles of alternating 5-minute inflation and 5-minute deflation of blood-pressure cuffs on both arms, with inflation to a pressure of 200 mmHg in the RIPC procedure or 10mmHg in the control procedure. Walking distances and limb oxygenation data, assessed with transcutaneous oximetry and near infrared spectroscopy measurements, were obtained during both RIPC and control procedures in all patients.

Results: Similar exercise intensities were achieved after the control and RIPC procedures. Walking distances did not significantly differ after the control and RIPC procedures (204 [141-259]m vs 215 [162-442]m, respectively; P=0.22). Similarly, no difference was observed in terms of transcutaneous oxygen pressure change and near infrared spectroscopy measurements during exercise between the two procedures.

Conclusion: RIPC did not improve walking distance or limb ischaemia variables in patients with peripheral artery disease and intermittent claudication.
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http://dx.doi.org/10.1016/j.acvd.2015.03.004DOI Listing
October 2015

Ex vivo thrombin generation patterns in septic patients with and without disseminated intravascular coagulation.

Thromb Res 2015 Jan 14;135(1):192-7. Epub 2014 Nov 14.

Angers University, UPRES EA 3860 "Cardioprotection, remodelage et thrombose" 49933 Angers, France.

Introduction: The thrombin generation test (TGT) describes the ability of the plasma to generate thrombin. Its usefulness in septic patients has yet to be assessed.

Methods: Patients admitted for severe sepsis in a medical intensive care unit were sampled for TGT on day 0, 3, 6, and 10. TGT data were compared to "classical" hemostastic tests and to outcome parameters, notably disseminated intravascular coagulation (DIC) according to International Society for Thrombosis and Hemostasis criteria as well as survival.

Results: A total of 102 patients were recruited of whom 11 received therapeutic anticoagulation and showed profoundly-altered TGT parameters. In comparison to healthy subjects, the 67 septic patients without DIC exhibited longer Lag times, higher Rate Indices, no change in peak or amount of thrombin generated, although the return to baseline was prolonged. In the 24 DIC patients, Lag time and Rate Index did not differ from healthy subjects (Rate Index being significantly lower than in Sepsis patients). The decreases in peak and amount of thrombin generated were not significant. Return to baseline was prolonged comparatively to Sepsis patients. Due to a large overlap of TGT values between groups, the ability of TGT parameters to diagnose DIC or predict survival was respectively poor or absent.

Conclusion: The thrombin Generation Test displayed particular patterns in septic patients and in septic DIC patients. The wide overlap between patients in TGT values prevents the usefulness of this test in clinical practice.
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http://dx.doi.org/10.1016/j.thromres.2014.11.001DOI Listing
January 2015

RISK and SAFE signaling pathway involvement in apolipoprotein A-I-induced cardioprotection.

PLoS One 2014 19;9(9):e107950. Epub 2014 Sep 19.

L'UNAM Université, Angers, France; Université d'Angers, Laboratoire Cardioprotection, Remodelage et Thrombose, Angers, France; CHU Angers, Service de Cardiologie, Angers, France.

Unlabelled: Recent findings indicate that apolipoprotein A-I (ApoA-I) may be a protective humoral mediator involved in remote ischemic preconditioning (RIPC). This study sought to determine if ApoA-I mediates its protective effects via the RISK and SAFE signaling pathways implicated in RIPC. Wistar rats were allocated to one of the following groups.

Control: rats were subjected to myocardial ischemia/reperfusion (I/R) without any further intervention; RIPC: four cycles of limb I/R were applied prior to myocardial ischemia; ApoA-I: 10 mg/Kg of ApoA-I were intravenously injected prior to myocardial ischemia; ApoA-I + inhibitor: pharmacological inhibitors of RISK/SAFE pro-survival kinase (Akt, ERK1/2 and STAT-3) were administered prior to ApoA-I injection. Infarct size was significantly reduced in the RIPC group compared to CONTROL. Similarly, ApoA-I injection efficiently protected the heart, recapitulating RIPC-induced cardioprotection. The ApoA-I protective effect was associated with Akt and GSK-3β phosphorylation and substantially inhibited by pretreatment with Akt and ERK1/2 inhibitors. Pretreatment with ApoA-I in a rat model of I/R recapitulates RIPC-induced cardioprotection and shares some similar molecular mechanisms with those of RIPC-involved protection of the heart.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0107950PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4169577PMC
November 2015

An ex vivo evaluation of blood coagulation and thromboresistance of two extracorporeal circuit coatings with reduced and full heparin dose.

Interact Cardiovasc Thorac Surg 2014 Jun 14;18(6):763-9. Epub 2014 Mar 14.

Department of Cardiovascular and Thoracic Surgery, Cardiopulmonary Bypass Unit, University Hospital of Angers, Angers, France

Objectives: Bioactive Carmeda® heparin-coated extracorporeal circuits (ECCs) have been shown to reduce contact phase and coagulation activation during cardiopulmonary bypass (CPB). Heparin coating is therefore effective in safely reducing coagulation during routine CPB. Balance® Biosurface is a new, recently developed biopassive coating containing negatively charged sulphonated polymers. This study sought to compare the clotting activation and thromboresistance of the Balance® (B) circuit with that of the Carmeda® (C) with full-dose systemic heparin (FDH) and reduced-dose systemic heparin (RDH).

Methods: This ex vivo study set-up comprising 40 experiments consisted of simplified ECC and circulation of freshly donated human blood. RDH and FDH regimens were obtained with 0.5 IU/ml and 1 IU/ml heparin administered to reach target activated clotting times (ACTs) of 250 and 500 s, respectively. The study design comprised four groups: FDH-C, FDH-B, RDH-C and RDH-B (all n = 10). Blood was sampled prior to and during the 2-h CPB. Coagulation activation was assessed (FXIIa, F1.2) and electron microscope scan imaging of oxygenators enabled determination of adhesion scores.

Results: With a biopassive compared with bioactive surface, mean ACT was lower, regardless of the heparin regimen applied (P < 0.001), whereas the total heparin dose required to maintain ACT was above target level (P < 0.001). However, FXIIa and F1.2 values were similar in all groups throughout, as were pressure gradients among oxygenators. All groups demonstrated similar adhesion scores following ultrastructural oxygenator assessment.

Conclusions: In the absence of surgical-related haemostatic disturbances and based on target ACT levels under reduced- or full-dose heparin, the clotting process was similar to heparin-coated and new sulphonated polymer-coated ECC, both demonstrating similar thromboresistance.
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http://dx.doi.org/10.1093/icvts/ivu011DOI Listing
June 2014

The synthetic pentasaccharide fondaparinux attenuates myocardial ischemia-reperfusion injury in rats via STAT-3.

Shock 2014 Feb;41(2):166-71

*L'Université Nantes Angers Le Mans; †Université d'Angers, Laboratoire Cardioprotection, Remodelage et Thrombose; ‡CHU Angers, Laboratoire d'Hématologie; §Université d'Angers, INSERM U771, CNRS UMR 6214, CHU Angers, Département de Biochimie et Génétique; and ∥CHU Angers, Service de Cardiologie, Angers, France.

Acute myocardial infarction is a leading cause of mortality and morbidity worldwide. Although essential for successful recovery, myocardium reperfusion is associated with reperfusion injury. Two major cell survival signaling cascades are known to be protective against ischemia-reperfusion (I/R) injury: the reperfusion injury salvage kinase, including Akt, extracellular signal-regulated kinase 1/2, and the downstream target GSK-3β, and the survivor activating factor enhancement, which involves STAT-3. Pharmacologic inhibition of factor Xa has been shown to attenuate I/R injury, but the cellular mechanism is poorly understood. Our aim was to determine the role of whole blood in fondaparinux (FDX)-induced cardioprotection and the involvement of reperfusion injury salvage kinase and survivor activating factor enhancement pathways. We investigated FDX ability to prevent in vivo I/R injury using a transient coronary ligation rat model and ex vivo using a model of crystalloid-perfused isolated rat heart. In both models, infarct size was assessed after 120 min of reperfusion. Myocardial tissues were collected after 15 and 30 min of reperfusion for Western blot analysis. In vivo, FDX decreased infarct size by 29% and induced significant STAT-3 and GSK-3β phosphorylation in comparison to controls. Adding AG490, an inhibitor of JAK/STAT pathway, before I/R, prevented STAT-3 phosphorylation and abolished FDX-induced cardioprotection. On the contrary, FDX did not have an effect on infarct size or hemodynamic parameters in the isolated-heart model. Fondaparinux decreased I/R injury in vivo, but not in a crystalloid-perfused isolated heart. Under our experimental conditions, FDX required whole blood to be protective, and this beneficial effect was mediated through STAT-3 phosphorylation.
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http://dx.doi.org/10.1097/SHK.0000000000000072DOI Listing
February 2014

Compound heterozygous mutations of the TNXB gene cause primary myopathy.

Neuromuscul Disord 2013 Aug 12;23(8):664-9. Epub 2013 Jun 12.

Centre de référence des Maladies Neuromusculaires, Département de Neurologie, Centre Hospitalier Universitaire d'Angers, France.

Complete deficiency of the extracellular matrix glycoprotein tenascin-X (TNX) leads to recessive forms of Ehlers-Danlos syndrome, clinically characterized by hyperextensible skin, easy bruising and joint hypermobility. Clinical and pathological studies, immunoassay, and molecular analyses were combined to study a patient suffering from progressive muscle weakness. Clinical features included axial and proximal limb muscle weakness, subclinical heart involvement, minimal skin hyperextensibility, no joint abnormalities, and a history of easy bruising. Skeletal muscle biopsy disclosed striking muscle consistency and the abnormal presence of myotendinous junctions in the muscle belly. TNX immunostaining was markedly reduced in muscle and skin, and serum TNX levels were undetectable. Compound heterozygous mutations were identified: a previously reported 30kb deletion and a non-synonymous novel missense mutation in the TNXB gene. This study identifies a TNX-deficient patient presenting with a primary muscle disorder, thus expanding the phenotypic spectrum of TNX-related abnormalities. Biopsy findings provide evidence that TNX deficiency leads to muscle softness and to mislocalization of myotendinous junctions.
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http://dx.doi.org/10.1016/j.nmd.2013.04.009DOI Listing
August 2013

Oral fondaparinux: use of lipid nanocapsules as nanocarriers and in vivo pharmacokinetic study.

Int J Nanomedicine 2011 21;6:2941-51. Epub 2011 Nov 21.

LUNAM Université, Ingénierie de la Vectorisation Particulaire, Inserm U-646, Angers, France.

Oral anticoagulant therapy could be advanced using lipid-based nanoparticulate systems. This study examined lipid nanocapsules for their oral absorption potential as the first step in developing oral fondaparinux (Fp) novel carriers. Using phase inversion method and cationic surfactants such as hexadecyltrimethyl ammonium bromide (CTAB) or stearylamine (SA), cationic lipid nanocapsules (cLNCs), loaded with Fp on their surface, were prepared and characterized (zeta potential, size and Fp association efficiency and content). In vivo studies were conducted after single oral increasing doses of Fp-loaded cLNCs (0.5 to 5 mg/kg of Fp) in rats and the concentration of Fp in the plasma was measured by anti-factor Xa activity assay. The monodisperse, (~50 nm), positively charged Fp-cLNCs with high drug loadings demonstrated linear pharmacokinetic profiles of the drug with an increased oral absolute bioavailability (up to ~21%) compatible with therapeutic anticoagulant effect (>0.2 μg/mL).
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http://dx.doi.org/10.2147/IJN.S25791DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3230563PMC
June 2012

Thrombin inhibition during kidney ischemia-reperfusion reduces chronic graft inflammation and tubular atrophy.

Transplantation 2010 Sep;90(6):612-21

Inserm U927, Ischémie-Reperfusion en Transplantation Rénale; Université de Poitiers Faculté de Medecine et de Pharmacie, Poitiers, France.

Background: Ischemia-reperfusion injury (IRI) is an unavoidable component of transplantation and correlates with delayed graft function, acute rejection, chronic fibrosis, and graft loss. Currently, new donor pools are considered to alleviate pressure on waiting lists, such as deceased after cardiac death donors (DCD) and extended criteria donors. Because these organs are particularly sensitive to IRI, there is a need for novel preservation paradigms. We assessed the effect of anticoagulation therapy during graft preservation on IRI and graft outcome.

Methods: In a large white autotransplanted pig model, kidneys underwent warm ischemia for 60 min, mimicking DCD, then were preserved for 24 hr at 4°C, in University of Wisconsin solution. Animals were followed up 3 months, functional, histologic, and molecular parameters were assessed. In treated groups, antithrombin was added to collection and preservation protocols.

Results: Treatment improved chronic graft function, reduced tubular atrophy, and substantially increased animal survival. Quantitative polymerase chain reaction analysis determined that markers of inflammation, such as interferon-[gamma], tumor necrosis factor-[alpha], interleukin (IL)-2, -1Rn, and -10, were significantly reduced in treated grafts. Histologic analysis revealed a lowering of CD3+ invasion. P selectin and C3 mRNA expressions were reduced in treated groups, indicative of lowered complement production and endothelial cell activation. Vascular endothelium growth factor protein expression was up-regulated, suggesting vascular network remodeling.

Conclusion: Inhibition of thrombin during preservation of DCD graft preserved renal integrity and function, protecting against chronic inflammation and tissue damage. Thus, coagulation seems to be a critical target for the development of therapeutic strategies to improve kidney quality for transplantation.
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http://dx.doi.org/10.1097/tp.0b013e3181d72117DOI Listing
September 2010

[Automated hematology analysers and spurious counts. Part 1. Platelets].

Ann Biol Clin (Paris) 2010 Jul-Aug;68(4):393-407

Laboratoire d'hématologie, CHU d'Angers.

Hematology analysers provide now quick, accurate, and reproducible cell blood counts. However, depending on detection methods, spurious counts may occur. If undetected, such spurious counts may lead to inappropriate medical care and to unneeded explorations. Focusing first on platelet counts, situations leading to spurious decrease include several preanalytical considerations, the major one corresponding to EDTA-induced platelet aggregation and to platelet satellitism around polymorphs. In other instances, related to the presence of small particles mimicking platelets, including fragmented red blood cells, lipids, cryoglobulins, fibrin strands, or cytoplasmic fragments of leukocytes, spurious elevation of platelet count may occur. According to the analyser and to the methods used for the determination of the cell blood count, flags or messages related to these spurious changes differ. For each spurious change, the authors describe the mechanism leading to the anomaly, the way the analysers generate flags, and what should be done to provide accurate results.
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http://dx.doi.org/10.1684/abc.2010.0451DOI Listing
September 2010

Direct thrombin inhibitor prevents delayed graft function in a porcine model of renal transplantation.

Transplantation 2009 Jun;87(11):1636-44

Inserm U927, Poitiers, France.

Background: Kidney transplantations from donors after cardiac arrest (DCA) are characterized by an increase in the occurrence of delayed graft function and primary nonfunction. In this study, Melagatran, a selective reversible direct thrombin inhibitor was used to limit renal injury in a DCA pig kidney transplantation model.

Methods: We used a porcine model of DCA to study the effects of treatment with Melagatran in the peri-conservation period. Thromboelastography was used to check Melagatran antithrombin effect on in vitro clot formation. Reverse-transcriptase polymerase chain reaction was used to analyze the peripheral immune cells activation status. Renal function and morphologic study were performed at days 1 and 7. Finally, we analyzed the mechanisms of Melagatran protection on kidney microvasculature primary endothelial cells.

Results: Prolongation of coagulation time (Ex-Tem) was observed 10 min after injection; however, Melagatran did not modulate increases of thrombin-antithrombin complexes following reperfusion. Melagatran significant treatment lowered the proinflammatory status of circulating immune cells. Animal's survival was increased in Melagatran-treated groups (9 of 10 in Melagatran groups vs. 4 of 10 in controls at day 7). Renal injury and inflammation were also significantly reduced in treated groups. We also demonstrated a direct protective effect of Melagatran against endothelial cell activation and inflammation in vitro.

Conclusion: Direct thrombin inhibitor administration in the periconservation period improved graft outcome and reduced renal injury in a model of DCA.
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http://dx.doi.org/10.1097/TP.0b013e3181a5b154DOI Listing
June 2009

Major clinical vascular events and aspirin-resistance status as determined by the PFA-100 method among patients with stable coronary artery disease: a prospective study.

Blood Coagul Fibrinolysis 2008 Apr;19(3):235-9

CHU Poitiers, Department of Cardiology, Research Clinical Center, Laboratory of Hematology, Poitiers, France.

Aspirin inhibits platelet activation and reduces major vascular events in patients with stable coronary artery disease. The extent of platelet inhibition, denoted as aspirin resistance, however, is not always sufficient. A correlation between aspirin resistance as measured by aggregometry and adverse clinical events has been demonstrated. The point-of-care platelet function analyzer PFA-100 is usually used to detect aspirin resistance, but the relation between PFA-100 results and the vascular prognosis is not assessed. We prospectively enrolled 97 patients with stable coronary artery disease who were on aspirin (160 mg per day since 1 month or longer). Aspirin resistance was measured by the PFA-100 analyzer. Median follow-up was 2.5 years and the primary outcome was the composite of death, myocardial infarction, and ischemic cerebral infarction or acute limb ischemia. In our study, 29 patients (29.9%) showed resistance to aspirin, with a higher percentage of female patients (38 vs. 15%; P=0.01). During the follow-up, aspirin resistance was not associated with an increased risk of death, myocardial infarction, or ischemic vascular event compared with the aspirin-sensitive patients (17 vs. 13%; P>0.60). In this cohort of stable coronary artery disease, patients on aspirin dose of 160 mg per day, the aspirin-resistance status based on the PFA-100 results is not associated with a significant increase in major vascular clinical events.
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http://dx.doi.org/10.1097/MBC.0b013e3282f9ade8DOI Listing
April 2008

Monitoring of the antiplatelet drugs effect in patients with coronary artery disease: what is the real clinical impact?

Curr Vasc Pharmacol 2007 Oct;5(4):293-301

Département Médico-Chirurgical de Cardiologie, Centre Hospitalo-Universitaire de Poitiers, Hôpital de la Milétrie, Poitiers, France.

Antiplatelet therapy is used to reduce the risk of ischemic events in patients with cardiovascular disease. The balance of benefits and risks of antiplatelet drugs in coronary artery disease has been evaluated in large-scale randomised trials, however the absolute benefit for an individual patient and a specific platelet-active drug need further evaluation. Several well-conducted studies have demonstrated a substantial inter-individual variability in the platelet responsiveness to drugs. The historical "gold standard" test of platelet function (optical aggregation) has well established limitations for measuring the effect of antiplatelet drugs. Other new tests developed (i.e. PFA-100, VerifyNow) may overcome some of these limitations but they do not correlate well with each other. Despite these unresolved methodological questions, several recent clinical studies, but not all, suggest a significant correlation between antiplatelet resistance status and serious vascular events. In these conditions, laboratory monitoring for antiplatelet therapies raises several questions: (i) the necessity for a consensus on the definition of resistance and on the best test for evaluation of the condition, (ii) the demonstration that biological resistance has clinical significance, and (iii) the clinical impact of adapting the antiplatelet therapy. Therefore, it is not currently appropriate to test patients or to change therapy on the basis of such tests, other than in prospective and adequately powered clinical trials.
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http://dx.doi.org/10.2174/157016107782023361DOI Listing
October 2007

A rapid and specific whole blood HPA-1 phenotyping by flow cytometry using two commercialized monoclonal antibodies directed against GP IIIa and GP IIb-IIIa complexes.

Br J Haematol 2004 Jan;124(2):221-3

Laboratoire d'hématologie et des maladies du sang, CHU de Poitiers, hôpital La Miletrie, Poitiers 86021, France.

The human platelet antigen 1 (HPA-1) system has been implicated in rare but severe diseases, such as neonatal alloimmune thrombocytopenic purpura, post-transfusion purpura and immune platelet refractoriness. We developed a flow cytometry assay for HPA-1 phenotyping using two commercial monoclonal antibodies, P2 and SZ21, directed against glycoprotein (GP) IIb-IIIa and GP IIIa respectively. One hundred and twenty-seven healthy controls were studied and ratios of mean fluorescence intensity for P2 and SZ21 discriminated between HPA-1a homozygotes and heterozygotes. These two monoclonal antibodies, coupled with flow cytometry represent a rapid and reliable tool for platelet HPA-1 typing to aid diagnosis.
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http://dx.doi.org/10.1046/j.1365-2141.2003.04757.xDOI Listing
January 2004

Resistance in vitro to low-dose aspirin is associated with platelet PlA1 (GP IIIa) polymorphism but not with C807T(GP Ia/IIa) and C-5T Kozak (GP Ibalpha) polymorphisms.

J Am Coll Cardiol 2003 Sep;42(6):1115-9

Laboratoire d'Hématologie et des maladies du sang, CHU de Poitiers Hôpital La Miletrie, Poitiers, France.

Objectives: We investigated whether three platelet gene polymorphisms, Pl(A1/A2), C807T, and C-5T Kozak (encoding, respectively, for platelet membrane glycoproteins (GP) IIIa, GP Ia/IIa, GP Ibalpha), could contribute to the resistance to a low dose of aspirin (160 mg/day).

Background: Aspirin antiplatelet effect is not uniform in all patients, and the mechanism by which some patients are in vitro resistant to aspirin remains to be determined. However, it has been suggested that polymorphisms of platelet membrane glycoproteins might contribute to aspirin resistance.

Methods: Ninety-eight patients on aspirin (160 mg/day) for at least one month were enrolled. Aspirin resistance was measured by the platelet function analyzer (PFA)-100 analyzer; genotyping of the three polymorphisms was performed using a polymerase chain reaction-based restriction fragment-length polymorphism analysis.

Results: Using a collagen/epinephrine-coated cartridge on the PFA-100, the prevalence of aspirin resistance was 29.6% (n = 29). Aspirin-resistant patients were significantly more often Pl(A1/A1) (86.2%; n = 25) than sensitive patients (59.4%; n = 41; p = 0.01). Of the 29 patients, 25 were reevaluated after having taken 300 mg/day aspirin for at least one month. Only 11 patients still have nonprolonged collagen epinephrine closure time, and these were all Pl(A1/A1). No relation was found between resistance status and C-5T Kozak or C807T genotypes.

Conclusions: Platelets homozygous for the Pl(A1) allele appear to be less sensitive to inhibitory action of low-dose aspirin. This differential sensitivity to aspirin may have potential clinical implications whereby specific antiplatelet therapy may be best tailored according to the patient's Pl(A) genotype.
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http://dx.doi.org/10.1016/s0735-1097(03)00921-5DOI Listing
September 2003
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