Maribel Diaz-Ricart

Hospital Clínic de Barcelona, Barcino, Catalonia, Spain

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Publications (127)528.52 Total impact

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    ABSTRACT: The mobilization pattern and functionality of endothelial progenitor cells after an acute ischemic event remain largely unknown. The aim of our study was to characterize and compare the short-and long-term mobilization of endothelial progenitor cells and circulating endothelial cells after acute myocardial infarction or atherothrombotic stroke, and to determine the relationship between these cell counts and plasma concentrations of vascular cell adhesion molecule (VCAM-1) and Von Willebrand factor (VWF) as surrogate markers of endothelial damage and inflammation. In addi-tion, we assessed whether endothelial progenitor cells behave like functional endothelial cells. We included 150 pa-tients with acute myocardial infarction or atherothrombotic stroke and 145 controls. Endothelial progenitor cells [CD45−, CD34+, KDR+, CD133+], circulating endothelial cells [CD45−, CD146+, CD31+], VWF, and VCAM-1 levels were measured in controls (baseline only) and in patients within 24 h (baseline) and at 7, 30, and 180 days after the event. Myocardial infarction patients had higher counts of endothelial progenitor cells and circulating endo-thelial cells than the controls (201.0/mL vs. 57.0/mL; p b 0.01 and 181.0/mL vs. 62.0/mL; p b 0.01). Endothelial progen-itor cells peaked at 30 days post-infarction (201.0/mL vs. 369.5/mL; p b 0.01), as did VCAM-1 (573.7 ng/mL vs. 701.8 ng/mL; p b 0.01). At 180 days post-infarction, circulating endothelial cells and VWF decreased, compared to base-line. In stroke patients, the number of endothelial progenitor cells — but not circulating endothelial cells — was higher than in controls (90.0/mL vs. 37.0/mL; p = 0.01; 105.0/mL vs. 71.0/mL; p = 0.11). At 30 days after stroke, however, VCAM-1 peaked (628.1/mL vs. 869.1/mL; p b 0.01) but there was no significant change in endothelial progenitor cells (90/mL vs. 78/mL; p b 0.34). At 180 days after stroke, circulating endothelial cells and VWF decreased, compared to baseline. Cultured endothelial progenitor cells from controls and myocardial infarction patients had endothelial phe-notype characteristics and exhibited functional differences in adhesion and Ca 2+ influx, but not in proliferation and vasculogenesis. In myocardial infarction patients, VCAM-1 levels and mobilization of endothelial progenitor cells peaked at 30 days after the ischemic event. Although a similar VCAM-1 kinetic was observed in stroke patients, endo-thelial progenitor cells did not increase. Endothelial progenitor cells had mature endothelial capabilities in vitro.
    Journal of Molecular and Cellular Cardiology 01/2015; Volume 80:146–155. · 5.22 Impact Factor
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    ABSTRACT: Background:Despite the good safety of rivaroxaban, there is limited information on strategies for urgent reversal of its antihemostatic effects.Methods and Results:Alterations of hemostasis induced by rivaroxaban (230 ng/ml) were assessed by using several tests applied to steady and circulating human blood. Effects on thrombin generation (TG) and thromboelastometry (TEM) parameters were measured. Modifications in platelet adhesive, aggregating and procoagulant activities were evaluated in studies with circulating blood. The potential reversal of prothrombin complex concentrates (PCCs; 50 IU/kg), activated PCCs (aPCCs; 75 IU/kg), or recombinant factor VIIa (rFVIIa; 270 μg/kg) was evaluated. Impairment of TG parameters induced by rivaroxaban were corrected by the different concentrates (aPCC≥PCC>rFVIIa). Prolonged clotting times and reduced clot firmness caused by rivaroxaban on TEM tests were improved by different concentrates (rFVIIa≥aPCC>PCC). Rivaroxaban significantly reduced platelets and fibrin interactions with damaged vascular surfaces in perfusion studies. While alterations of platelet interactions were favourably counteracted by rFVIIa or aPCCs, reductions in fibrin formation were only partially restored by the different factor concentrates (rFVIIa>aPCC≥PCC).Conclusions:Rivaroxaban-induced alterations on coagulation parameters measured through assays performed under static conditions were easily reversed by the different concentrates. Studies under flow conditions revealed that these concentrates normalized the action of rivaroxaban on platelets, and significantly improved fibrin formation; although in the later case, levels were not restored to the pre-treatment value.
    Circulation Journal 12/2014; · 3.69 Impact Factor
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    ABSTRACT: Thrombotic microangiopathies (TMA) are disorders defined by the presence of a microangiopathic hemolytic anemia (with the characteristic hallmark of schistocytes in the peripheral blood smear), thrombocytopenia and organ malfunction of variable intensity. Thrombotic thrombocytopenic purpura and hemolytic uremic syndrome are the most important forms of TMA and, without the adequate treatment, they are associated with high morbimortality. In recent years, significant advances in the knowledge of the pathophysiology of TMA have occurred. Those advances have allowed us to move from a syndromic diagnosis with a similar treatment to all entities to the search of etiologic diagnosis which would lead to a specific treatment, finally leading to a better outcome of the patient. This document pretends to summarize the current status of knowledge of the pathophysiology of TMA and the therapeutic options available, and to offer a diagnostic and therapeutic practical tool to the professionals caring for the patients. Copyright © 2014 Elsevier España, S.L.U. All rights reserved.
    Medicina clinica. 11/2014;
  • International Journal of Cardiology 10/2014; 178C:221-222. · 6.18 Impact Factor
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    ABSTRACT: Background Serotonergic mechanisms have been suggested as a link between major depression and cardiovascular risk. We investigated the existence of a prothrombotic condition in depressed patients and its possible modulation during treatment with a selective serotonin-reuptake inhibitor (SSRI). Methods Modifications in a series of biomarkers of platelet and coagulation activation were evaluated in blood from 19 patients with a major depression disorder (MDD) at the time of diagnosis, and at 8 and 24 weeks of treatment with escitalopram. Response of blood aliquots recirculated through a thrombogenic surface was assessed in a thrombosis model. Results were compared with those of 20 healthy-matched controls. Results In comparison with controls, platelets from MDD patients showed elevated volumes (p<0.01), significantly enhanced aggregating response to arachidonic acid and augmented expression of GPIb, fibrinogen, factor V, and anionic phospholipids by flow cytometry (p<0.05). Clot firmness and procoagulant activity of platelet-associated tissue factor were also significantly elevated (p<0.05). Studies with circulating blood revealed increased fibrin formation in early diagnosed patients (71.1±9.5% vs. 45.8±5.3%; p<0.05 vs. controls). After 24 weeks of treatment with escitalopram, the majority of the alterations observed were normalized, except for a residual increased expression of GPIIbIIIa (p<0.05) and persistent alterations in thromboelatometic parameters. Limitations Despite the reduced number of followed-up patients our findings were consistent reaching statistical significance. Conclusions Our results reveal a prothrombotic phenotype in MDD patients. While continuous treatment with an SSRI downregulated the majority of the biomarkers analyzed, alterations in viscoelastic parameters of clot formation remained unaffected by the antidepressant treatment.
    Journal of Affective Disorders 04/2014; 159:39–45. · 3.76 Impact Factor
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    ABSTRACT: Introduction: Thromboembolic diseases will become the most important contributors to mortality and morbidity for modern societies. Current antithrombotic strategies using heparins or vitamin K antagonists are inconvenient, with limitations and inherent side effects. A series of new oral anticoagulants with powerful and reliable antithrombotic actions have been developed in the last decade. Areas covered: Edoxaban is a direct and specific inhibitor of activated factor X, delivered orally. This article reviews literature from PubMed and articles referenced within. The text explores the pharmacological aspects of its antithrombotic action. Pharmacokinetics, metabolism and drug interactions are examined. The review places the results of recent clinical trials that have evaluated the antithrombotic potential of edoxaban versus standard antithrombotic therapies in the prophylaxis and treatment of venous thromboembolism into perspective. The possible relationship between the pharmacokinetic profile of edoxaban and the favorable results in clinical trials is discussed. Expert opinion: Edoxaban is perceived as a major advance, compared to vitamin K antagonists, in the prevention and treatment of thromboembolic disease given its favorable efficacy, safety, pharmacokinetic profile and renal clearance. The results of ongoing large international trials exploring the prevention of thrombotic complications in patients in different clinical settings should ensure the approval of edoxaban to treat new indications.
    Expert Opinion on Drug Metabolism &amp Toxicology 01/2014; · 2.94 Impact Factor
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    ABSTRACT: Apixaban is a new oral anticoagulant with a specific inhibitory action on FXa. No information is available on the reversal of the antihemostatic action of apixaban in experimental or clinical settings. We have evaluated the effectiveness of different factor concentrates at reversing modifications of hemostatic mechanisms induced by moderately elevated concentrations of apixaban (200 ng/ml) added in vitro to blood from healthy donors (n = 10). Effects on thrombin generation (TG) and thromboelastometry (TEM) parameters were assessed. Modifications in platelet adhesive, aggregating and procoagulant activities were evaluated in studies with blood circulating through damaged vascular surfaces, at a shear rate of 600 s(-1). The potential of prothrombin complex concentrates (PCCs; 50 IU/kg), activated prothrombin complex concentrates (aPCCs; 75 IU/kg), or activated recombinant factor VII (rFVIIa; 270 μg/kg), at reversing the antihemostatic actions of apixaban, were investigated. Apixaban interfered with TG kinetics. Delayed lag phase, prolonged time to peak and reduced peak values, were improved by the different concentrates, though modifications in TG patterns were diversely affected depending on the activating reagents. Apixaban significantly prolonged clotting times (CTs) in TEM studies. Prolongations in CTs were corrected by the different concentrates with variable efficacies (rFVIIa≥aPCC>PCC). Apixaban significantly reduced fibrin and platelet interactions with damaged vascular surfaces in perfusion studies (p<0.05 and p<0.01, respectively). Impairments in fibrin formation were normalized by the different concentrates. Only rFVIIa significantly restored levels of platelet deposition. Alterations in hemostasis induced by apixaban were variably compensated by the different factor concentrates investigated. However, effects of these concentrates were not homogeneous in all the tests, with PCCs showing more efficacy in TG, and rFVIIa being more effective on TEM and perfusion studies. Our results indicate that rFVIIa, PCCs and aPCCs have the potential to restore platelet and fibrin components of the hemostasis previously altered by apixaban.
    PLoS ONE 11/2013; 8(11):e78696. · 3.53 Impact Factor
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    ABSTRACT: Endothelial dysfunction seems to be a key factor in the development of several complications observed early after hematopoietic stem cell transplantation (HSCT). The conditioning regimen and many other factors associated with the procedure are responsible for this endothelial damage. The effects of immunosuppressive agents on endothelial function have not been explored in detail. We evaluated the effects of three of the drugs commonly used in HSCT: two calcineurin inhibitors, cyclosporine A (CSA) and tacrolimus (TAC), and an inhibitor of mTOR, sirolimus (SIR). We also evaluated the effect of the combination of TAC and SIR (TAC+SIR), which is used increasingly in clinical practice. Microvascular endothelial cells (HMEC-1) were exposed to these drugs to evaluate changes in: i) ICAM-1 expression on the cell surface, assessed by immunofluorescence labeling and expressed as the mean gray value (MGV); ii) reactivity of the extracellular matrix (ECM) toward platelets, upon exposure of the ECM to circulating blood; and iii) whole-blood clot formation, assessed by thromboelastometry. Studies were conducted in the absence and presence of defibrotide (DF) to assess its possible protective effect. The exposure of HMEC-1 to CSA and TAC+SIR significantly increased the expression of ICAM-1 (157.5±11.6 and 153.4±9.5 MGV, respectively, vs. 105.7±6.5 MGV in controls (both P<0.05)). TAC applied alone increased ICAM-1 slightly (120.3±8.2 MGV), and SIR had no effect (108.9±7.4 MGV). ECM reactivity increased significantly only in response to CSA (surface covered by platelets of 41.2%±5.4% vs. 30.1%±2.0%, P<0.05). DF attenuated all of these changes. No significant changes in the viscoelastic properties of clot formation were observed in any condition with blood samples incubated in vitro. In conclusion, CSA and TAC+SIR had a proinflammatory effect, but only CSA exhibited an additional prothrombotic effect. Interestingly, DF exerted clear protective anti-inflammatory and antithrombotic effects on the endothelium.
    Biology of blood and marrow transplantation: journal of the American Society for Blood and Marrow Transplantation 07/2013; · 3.15 Impact Factor
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    ABSTRACT: BACKGROUND: The Atreus system (Terumo BCT) automates the preparation of blood components from whole blood donations. Intermediate platelet (PLT) products can be pooled manually or with the OrbiSac (Terumo BCT) and suspended in different PLT additive solutions (PASs) to obtain PLT concentrates (PCs). The aim of our study was to compare the in vitro PLT quality of PCs obtained with either the Atreus 2C+ and the OrbiSac or the Atreus 3C and suspended in PAS-II or PAS-IIIM during storage for up to 7 days. STUDY DESIGN AND METHODS: We prepared eight PCs from buffy coats obtained with Atreus 2C+, pooled with the OrbiSac, and suspended in PAS-II and eight PCs from interim PLT units obtained with the Atreus 3C and suspended either in PAS-II or in PAS-IIIM. We measured volume, PLT content, and mean PLT component and performed metabolic assays (pH, glucose, lactate, pO2 , and pCO2 ) and flow cytometry analyses (GPIb, GPIIbIIIa, GPIV, CD62P, CD63, von Willebrand factor [vWF], fibrinogen, Factor V, and annexin V). RESULTS: PCs prepared with the Atreus 3C showed lower volume and higher PLT concentration when compared with PCs prepared with the Atreus 2C+ and the OrbiSac (p < 0.05). Glucose consumption rate and the expression of CD62P, CD63, and vWF were lower in PCs suspended in PAS-IIIM when compared with PCs suspended in PAS-II (p < 0.05). CONCLUSION: PCs prepared with the Atreus 3C and suspended in PAS-IIIM preserve satisfactorily the in vitro PLT quality during 7-day storage. PLT activation during a 7-day storage period was lower when the storage solution was PAS-IIIM in comparison with PAS-II.
    Transfusion 05/2013; · 3.57 Impact Factor
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    ABSTRACT: INTRODUCTION: The thrombogenic potential of tissue factor (TF) associated to platelets is controversial. We have investigated the in vitro contribution of platelet-associated TF to thrombus formation. MATERIALS AND METHODS: Platelets suspensions were exposed to human TF-rich microvesicles (TF-MV) from placental or recombinant origin. Platelet-associated TF was quantified through coagulometric assays. Adhesive and cohesive properties of platelets containing TF were assessed in perfusion models using two thrombogenic surfaces: 1) type-I collagen, or 2) damaged vascular segments. Perfusion studies were performed with heparinized blood enriched with a 30% of washed platelets exposed to TF-MV vs. washed control platelets. Thrombin generation and thromboelastometric properties of clots were also assessed using a fluorometric assay and ROTEM analysis, respectively. Inhibitory strategies with an antibody to TF were performed in some cases. RESULTS: The addition of 30% of platelets containing TF to blood perfusates resulted in a statistically significant increase in the platelet coverage (%CS) vs. non-exposed platelets on collagen surfaces (%CS: 19.7±0.6 and 23.9±0.7 respectively, vs.14.5±1.4; p<0.01) and on the vascular subendothelium (%CS: 54.0±1.5 and 47.2±6.8 respectively vs. 38.0±3.5, p<0.05), with a statistically significant increase in the size of large platelet aggregates (p<0.05) vs. control platelets. These effects on collagen surfaces were almost totally prevented by an antibody to TF. Platelet-associated TF significantly accelerated thrombin generation and clot formation (p<0.05), effects that were partially prevented by a neutralizing anti-TF. CONCLUSIONS: Platelet-associated TF potentiated adhesive and aggregating properties in in vitro studies with flowing blood and accelerated thrombin generation and clot formation time under steady conditions.
    Thrombosis Research 11/2012; · 2.43 Impact Factor
  • Thrombosis Research 10/2012; 130:S113. · 2.43 Impact Factor
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    ABSTRACT: BACKGROUND: Haemodilution during resuscitation after massive haemorrhage may worsen the coagulopathy and perpetuate bleeding. MATERIALS AND METHODS: Blood samples from healthy donors were diluted (30 and-60%) using crystalloids (saline, Ringer's lactate, Plasmalyte(TM)) or colloids (6% hydroxyethylstarch [HES130/0.4], 5% human albumin, and gelatin). The effects of haemodilution on platelet adhesion (Impact R), thrombin generation (TG), and thromboelastometry (TEM) parameters were analysed as were the effects of fibrinogen, prothrombin complex concentrates (PCC), activated recombinant factor VII (FVIIa), and cryoprecipates on haemodilution. RESULTS: Platelet interactions was already significantly reduced at 30% haemodilution. Platelet reactivity was not improved by addition of any of the concentrates tested. A decrease in TG and marked alterations of TEM parameters were noted at 60% haemodilution. HES130/0.4 was the expander with the most deleterious action. TG was significantly enhanced by PCC whereas rFVIIa only caused a mild acceleration of TG initiation. Fibrinogen restored the alterations of TEM parameters caused by haemodilution including those caused by HES 130/0.4. Cryoprecipitates significantly improved the alterations caused by haemodilution on TG and TEM parameters; the effects on TG disappeared after ultracentrifugation of the cryoprecipitates. DISCUSSION: The haemostatic alterations caused by haemodilution are multifactorial and affect both blood cells and coagulation. In our in vitro approach, HES 130/0.4 had the most deleterious effect on haemostasis parameters. Coagulation factor concentrates did not improve platelet interactions in the Impact R, but did have favourable effects on coagulation parameters measured by TG and TEM. Fibrinogen notably improved TEM parameters without increasing thrombin generation, suggesting that this concentrate may help to preserve blood clotting abilities during haemodilution without enhancing the prothrombotic risk.
    Blood transfusion = Trasfusione del sangue 09/2012; · 1.90 Impact Factor
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    ABSTRACT: Impaired hemostasis coexists with accelerated atherosclerosis in patients with chronic kidney disease (CKD). The elevated frequency of atherothrombotic events has been associated with endothelial dysfunction. The relative contribution of the uremic state and the impact of the renal replacement therapies have been often disregarded. Plasma markers of endothelial activation and damage were evaluated in three groups of patients with CKD: under conservative treatment (predialysis), on hemodialysis, and on peritoneal dialysis. Activation of p38 MAPK and the transcription factor NFκB was assessed in endothelial cell (EC) cultures exposed to pooled sera from each group of patients. Most of the markers evaluated (VCAM-1, ICAM-1, VWF, circulating endothelial cells) were significantly higher in CDK patients than in controls, being significantly more increased in the group of peritoneal dialysis patients. These results correlated with the activation of both p38 MAPK and NFκB in EC cells exposed to the same sera samples, and also to the peritoneal dialysis fluids. Hemodialysis did not further contribute to the endothelial damage induced by the uremic state observed in predialysis patients, probably due to the improved biocompatibility of the hemodialysis technique in recent years, resulting in lower cellular activation. However, peritoneal dialysis seemed to exert a significant proinflammatory effect on the endothelium that could be related to the high glucose concentrations and glucose degradation products present in the dialysis fluid. Although peritoneal dialysis has been traditionally considered a more physiological technique, our results raise some doubts with respect to inflammation and EC damage.
    PLoS ONE 08/2012; 7(8):e43374. · 3.53 Impact Factor
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    ABSTRACT: BACKGROUND: There were no previous studies about the quality of cryoprecipitate prepared from fresh-frozen plasma (FFP) inactivated with amotosalen and ultraviolet A (UVA) light. The aim of this study was to analyze the quantity and quality of coagulation factors in cryoprecipitate prepared from FFP treated with amotosalen and UVA light. STUDY DESIGN AND METHODS: FFP was obtained from whole blood donations and inactivated with amotosalen and UVA light according to the manufacturer's instructions. Fibrinogen, factor VIII (FVIII), von Willebrand factor antigen (VWF : Ag) and activity (VWF : RCo), the von Willebrand factor cleavage protease activity (ADAMTS-13), and the multimeric structure of VWF were analyzed. RESULTS: The content of fibrinogen, FVIII, and ADAMTS-13 was lower in cryoprecipitates prepared from amotosalen-treated plasma when compared with cryoprecipitates prepared from nontreated plasma (35, 40, and 18% loss, respectively). The quantity and quality of VWF as well as VWF multimer patterns were not affected by the inactivation method. CONCLUSION: Cryoprecipitates prepared from amotosalen-treated FFP contained significantly reduced levels of fibrinogen, FVIII, and ADAMTS-13. However, the VWF quantity and quality was well preserved.
    Transfusion 06/2012; 53(3). · 3.57 Impact Factor
  • M. Diaz-Ricart, J. Bozzo, G. Escolar
    Drugs of the Future 01/2012; 37(2):135. · 0.25 Impact Factor
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    ABSTRACT: Endothelin-1 (ET-1), circulating endothelial cells (CEC) and endothelial progenitor cells (EPC) are well-known modulators of endothelial function with important cardiac effects after an acute myocardial infarction. However, the relationship between them has never been assessed. The objective of the present study was to establish the relationship between ET-1, CEC, and EPC concentrations after ST-elevation myocardial infarction (STEMI). Endothelin-1, CEC, and EPC levels were measured in 61 patients presenting with a first STEMI. Samples were withdrawn acutely 6-24h and 1week after admission. Assessments included reperfusion outcomes (angiography), left ventricular ejection fraction (echocardiography), and 30-day mortality. Mean age was 60.6±12.6years and 45 (74%) were males. Higher ET-1 plasma levels were associated with lower EPC count after 1week (7.45±2.53pg/ml if EPCs in the first quartile vs 5.72±1.49pg/ml if EPCs in the fourth quartile; P=0.04). In contrast with CEC and EPC count, higher ET-1 concentrations on admission were associated with Killip≥2 (9.92±2.01pg/ml vs 7.32±2.13pg/ml; P<0.001), post-reperfusion thrombolysis in myocardial infarction (TIMI) <3 (8.65±2.86pg/ml vs 5.87±1.93pg/ml; P=0.002), myocardial blush grade (MBG) <3 (7.46±2.48pg/ml vs 5.99±2.01pg/ml; P=0.004) and higher 30-day mortality (10.29±2.02pg/ml vs 6.57±2.20pg/ml; P=0.005). In STEMI patients, high ET-1 levels on admission predict a lower EPC mobilization after 1week. Endothelin-1 provides better clinical, angiographic and echocardiographic information for prognosis than do CEC and EPC concentrations.
    Microvascular Research 09/2011; 82(2):177-81. · 2.43 Impact Factor
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    ABSTRACT: Anaemia and microcytosis are common post kidney transplantation. The aim of this study was to evaluate the potential role of mammalian target of rapamycin (mTOR) inhibition in the development of anaemia and microcytosis in healthy animals and in human erythroid cultures in vitro. Rats with normal kidney function were treated with sirolimus (n = 7) or vehicle (n = 8) for 15 weeks. Hemograms were determined thereafter. In the sirolimus withdrawal part of the study, rats received sirolimus (SRL) for 67 days (n = 4) 1 mg/kg three times per week or for 30 days (n = 4) and were observed until Day 120. Hemograms were performed regularly. Peripheral blood mononuclear cells from healthy controls (HC; n = 8), kidney transplant patients with sirolimus treatment with (SRL + MC; n = 8) or without microcytosis (SRL - MC; n = 8) were isolated and cultured in the absence or presence of SRL (5 ng/mL). SRL-treated animals had a reduced mean corpuscular volume (MCV) and elevated erythrocyte count compared with control animals after 15 weeks of treatment. This effect was evident as early as 4 weeks (MCV: 61.5 ± 1.8 versus 57 ± 1.7 fL; P = 0.0156; Red blood count 7.4 ± 0.3 × 10(9)/L versus 8.6 ± 0.5 × 10(9)/L; P = 0.0156) and was reversible 90 days after SRL withdrawal. SRL in the culture medium of erythroid cultures led to fewer colonies in cultures from HC as well as from kidney transplant patients (without SRL: 34.2 ± 11.4 versus with SRL: 27.5 ± 9.9 BFU-E-derived colonies P = 0.03), regardless if the cultures were derived from recipients with normocytic or with microcytic erythrocytes. The presence of tacrolimus in the culture medium had no influence on the number and size of colonies. mTOR inhibition induces microcytosis and polyglobulia, but not anaemia in healthy rats. This might be caused by growth inhibition of erythroid precursor cells.
    Nephrology Dialysis Transplantation 07/2011; 27(2):537-41. · 3.37 Impact Factor
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    ABSTRACT: Clinical evidence accumulated from hemophilic patients during prophylaxis with recombinant activated factor VII (rFVIIa) suggests that the duration of the hemostatic action of rFVIIa exceeds its predicted plasma half-life. Mechanisms involved in this outcome have not been elucidated. We have investigated in vitro the redistribution of rFVIIa in platelets from healthy donors, patients with FVII deficiency, and one patient with Bernard-Soulier syndrome. Platelet-rich plasma was exposed to rFVIIa (3 to 60 μg/mL). Flow cytometry, immunocytochemistry, and coagulation tests were applied to detect and quantify rFVIIa. The hemostatic effect of rFVIIa associated to platelets was evaluated using perfusion models. Our studies revealed a dose-dependent association of rFVIIa to the platelet cytoplasm with redistribution into the open canalicular system, and α granules. Mechanisms implicated in the internalization are multiple, involve GPIb and GPIV, and require phospholipids and cytoskeletal assembly. After platelet activation with thrombin, platelets exposed rFVIIa on their membrane. Perfusion studies revealed that the presence of 30% of platelets containing FVIIa improved platelet aggregate formation and enhanced fibrin generation (P < 0.01 versus control). Our results indicate that, at therapeutic concentrations, rFVIIa can be internalized into platelets, where it is protected from physiological clearance mechanisms and can still promote hemostatic activity. Redistribution of rFVIIa into platelets may explain the prolonged prophylactic effectiveness of rFVIIa in hemophilia.
    American Journal Of Pathology 06/2011; 178(6):2938-48. · 4.60 Impact Factor
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    ABSTRACT:  Obesity is associated with an increased atherothrombotic morbidity/mortality risk. However, there is no direct evidence of subclinical activation of the endothelium in obese subjects without other major cardiometabolic risk factors.  We applied a translational approach to investigate endothelial activation occurring in response to the components secreted by visceral and subcutaneous adipose tissue and their corresponding cell fractions obtained from obese subjects without other major cardiometabolic risk factors, as compared with non-obese controls.  Fat pads and cell fractions were incubated with serum-free medium to obtain their secretomes, which were analyzed by protein arrays. Endothelial cells (ECs) were exposed to the different secretomes to evaluate changes in gene expression, composition and reactivity of the extracellular matrix (ECM), and cell growth and viability.  ECs incubated in the presence of obese secretomes displayed increased proliferation, altered cell morphology, augmented expression of VCAM-1, ICAM-1, and von Willebrand factor, and higher ECM reactivity towards circulating platelets. The visceral secretomes, especially the stromal one, induced the strongest expression of these markers, together with a more reactive ECM. These changes occurred through nuclear factor-κB (NF-κB) activation.  This is the first translational study demonstrating that the cytokines secreted by the adipose tissue from obese individuals without other major cardiometabolic complications have a hazardous effect on the endothelium, through activation of the NF-κB pathway.
    Journal of Thrombosis and Haemostasis 06/2011; 9(6):1236-45. · 6.08 Impact Factor
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    E Carreras, M Diaz-Ricart
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    ABSTRACT: In this review, we analyse the role of the endothelium in the development of several complications that appear soon after haematopoietic SCT (HSCT). Once it had been demonstrated that sinusoidal damage is the initiating event of the sinusoidal obstruction syndrome, it was considered that other short-term complications with overlapping clinical manifestations, such as capillary leak syndrome, engraftment syndrome, transplant-associated microangiopathy, diffuse alveolar haemorrhage and idiopathic pneumonia syndrome, could have an endothelial origin. During HSCT, endothelial cells (ECs) are activated and damaged by several factors, including conditioning, cytokines released by damaged tissues, endotoxins translocated through damaged mucosa, drugs used in the procedure, the engraftment, and--in the allogeneic setting--immunological reactions. The different clinical syndromes that occur could be determined by the predominant phenotypic change in the ECs and the location of this change (organ dependant or systemic). Several translational studies have provided evidence of this endothelial dysfunction on the basis of analysis of soluble markers, soluble forms of adhesion molecules, the enumeration of circulating ECs and microparticles, and morphologic and functional changes induced in cultured ECs. This increased knowledge has opened up a wide range of potential pharmacologic interventions to prevent or treat endothelial damage and, consequently, to improve the outcome of patients receiving HSCT.
    Bone marrow transplantation 04/2011; 46(12):1495-502. · 3.00 Impact Factor

Publication Stats

963 Citations
528.52 Total Impact Points

Institutions

  • 1992–2015
    • Hospital Clínic de Barcelona
      • Servicio de Hemoterapia y Hemostasia
      Barcino, Catalonia, Spain
  • 1990–2014
    • University of Barcelona
      • • Department of Medicine
      • • Facultad de Medicina
      Barcino, Catalonia, Spain
  • 2000–2013
    • IDIBAPS August Pi i Sunyer Biomedical Research Institute
      Barcino, Catalonia, Spain
  • 1996–2008
    • Southern Medical Clinic
      San Fernando, City of San Fernando, Trinidad and Tobago
  • 2007
    • Autonomous University of Barcelona
      • Facultat de Veterinària
      Cerdanyola del Vallès, Catalonia, Spain
  • 1996–1998
    • Kurume University
      • Institute of Life Science
      Куруме, Fukuoka, Japan