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Chronic kidney disease (CKD) patients have an accelerated atherosclerosis, increased risk of thrombotic-ischemic complications, and excessive mortality rates when compared with the general population. There is also evidence of an endothelial damage in which the proinflammatory state, the enhanced oxidative stress, or the accumulation of toxins due to their reduced renal clearance in uremia play a role. Further, there is evidence that uremic endothelial cells are both involved in and victims of the activation of the innate immunity. Uremic endothelial cells produce danger associated molecular patterns (DAMPS), which by binding to specific pattern recognition receptors expressed in multiple cells, including endothelial cells, induce the expression of adhesion molecules, the production of proinflammatory cytokines and an enhanced production of reactive oxygen species in endothelial cells, which constitute a link between immunity and inflammation. The connection between endothelial damage, inflammation and defective immunity in uremia will be reviewed here.
Maribel Diaz-Ricart; Sergi Torramadé-Moix; Georgina Pascual; Marta Palomo; Ana Belen Moreno-Castaño; Julia Martinez-Sanchez; Manel Vera; Aleix Cases; Gines Escolar. Endothelial Damage, Inflammation and Immunity in Chronic Kidney Disease. Toxins 2020, 12, 1 .
AMA StyleMaribel Diaz-Ricart, Sergi Torramadé-Moix, Georgina Pascual, Marta Palomo, Ana Belen Moreno-Castaño, Julia Martinez-Sanchez, Manel Vera, Aleix Cases, Gines Escolar. Endothelial Damage, Inflammation and Immunity in Chronic Kidney Disease. Toxins. 2020; 12 (6):1.
Chicago/Turabian StyleMaribel Diaz-Ricart; Sergi Torramadé-Moix; Georgina Pascual; Marta Palomo; Ana Belen Moreno-Castaño; Julia Martinez-Sanchez; Manel Vera; Aleix Cases; Gines Escolar. 2020. "Endothelial Damage, Inflammation and Immunity in Chronic Kidney Disease." Toxins 12, no. 6: 1.
Circulating platelet microparticles (PMP) are the most abundant in bloodstream, are highly procoagulant and contribute to cross-talk with inflammatory cells. The aim of the present study was to investigate the interactions of PMP with platelets and explore the involvement of toll-like receptor 4 (TLR-4). PMP were separated by ultracentrifugation of expired platelet concentrates and added to: i) washed platelets, to confirm uptake, by flow cytometry and confocal and transmission electron microscopy, ii) platelet rich plasma (PRP), to assess changes in platelet function due to uptake by aggregometry in response to ADP; and iii) whole blood, to evaluate heterotypic aggregate (HA) formation by flow cytometry. Moreover, whole blood previously enriched with platelets with internalized PMP was used to explore modifications in thromboelastometry parameters (ROTEM). The inhibitory action of anti-TLR-4 was investigated. Confocal and ultrastructural microscopy studies revealed PMP internalization by platelets. Flow cytometry showed PMP-platelet association (p < 0.01 vs controls, at different PMP dilutions). PMP, at 1/20 dilution, increased HA (p < 0.05 vs controls), the percentage of maximal platelet aggregation to ADP (p < 0.05 vs controls), and accelerated clotting and clot formation times (p < 0.05 vs controls). Incubation of platelets with anti-TLR-4 prior to exposure to PMP reduced PMP-platelet association (p < 0.05 vs absence of the antibody), prevented HA formation, reduced maximal platelet aggregation and normalized ROTEM parameters. Platelets exhibit internalization ability towards their own PMP, a process that potentiates their thrombogenicity and is partially mediated by the innate immunity receptor TLR-4.
Didac Jerez-Dolz; Sergi Torramadé-Moix; Marta Palomo; Ana Moreno-Castaño; Irene Lopez-Vilchez; Rosa Hernandez; Juan Jose Badimon; M. Urooj Zafar; Maribel Diaz-Ricart; Gines Escolar. Internalization of microparticles by platelets is partially mediated by toll-like receptor 4 and enhances platelet thrombogenicity. Atherosclerosis 2019, 294, 17 -24.
AMA StyleDidac Jerez-Dolz, Sergi Torramadé-Moix, Marta Palomo, Ana Moreno-Castaño, Irene Lopez-Vilchez, Rosa Hernandez, Juan Jose Badimon, M. Urooj Zafar, Maribel Diaz-Ricart, Gines Escolar. Internalization of microparticles by platelets is partially mediated by toll-like receptor 4 and enhances platelet thrombogenicity. Atherosclerosis. 2019; 294 ():17-24.
Chicago/Turabian StyleDidac Jerez-Dolz; Sergi Torramadé-Moix; Marta Palomo; Ana Moreno-Castaño; Irene Lopez-Vilchez; Rosa Hernandez; Juan Jose Badimon; M. Urooj Zafar; Maribel Diaz-Ricart; Gines Escolar. 2019. "Internalization of microparticles by platelets is partially mediated by toll-like receptor 4 and enhances platelet thrombogenicity." Atherosclerosis 294, no. : 17-24.
Developments during the past few years have resulted in multiple kinds of platelet products for transfusion. This involves different collection methods, containers, preservative solutions, modifications of storage temperatures and durations, and additional treatments such as pathogen reduction. Much experience has been obtained testing these processes in vitro to seek indications of in vivo effectiveness. Availability of an in vitro method that correlated with in vivo effectiveness would be extremely valuable for these different kinds of platelet products and as more innovation in platelet preparation occurs in the future. This report reviews the methods for in vitro platelet testing with a view to their in vivo implications and whether such testing could be helpful in projecting the clinical effectiveness of different platelet products.
Gines Escolar; Jeffrey McCullough. Platelet in vitro assays: their correspondence with their in vivo hemostatic potential. Transfusion 2019, 59, 3783 -3793.
AMA StyleGines Escolar, Jeffrey McCullough. Platelet in vitro assays: their correspondence with their in vivo hemostatic potential. Transfusion. 2019; 59 (12):3783-3793.
Chicago/Turabian StyleGines Escolar; Jeffrey McCullough. 2019. "Platelet in vitro assays: their correspondence with their in vivo hemostatic potential." Transfusion 59, no. 12: 3783-3793.
In the case of vascular injury, a complex process (of clotting) starts, involving mainly platelets and coagulation factors. This process in healthy humans is known as hemostasis, but when it is deregulated (thrombosis), it can be the cause of important cardiovascular diseases. Nowadays, the aging of the population and unhealthy lifestyles increase the impact of thrombosis, and therefore there is a need for tools to provide a better understanding of the hemostasis mechanisms, as well as more cost-effective diagnosis and control devices. This study proposes a novel microflow chamber, with interchangeable biomimetic surfaces to evaluate global hemostasis, using reduced amounts of blood sample and reagents, and also a minimized time required to do the test. To validate the performance of this novel device, a study on the new oral anticoagulant Apixaban (APIX) has been performed and compared to previous conventional techniques. The test shows an excellent agreement, while the amount of the required sample has been reduced (only 100 µL is used), and the amount of reagent as well. An imprinted electrode embedded in the chamber in order to measure the impedance during the coagulation process. This approach distinguishes the impedance behavior of plasma poor in platelets (PPP) and plasma rich in platelets (PRP) for the first time.
Shadi Karimi; Josep Farré-Lladós; Enrique Mir; Ginés Escolar; Jasmina Casals-Terré. Hemostasis-On-a-Chip: Impedance Spectroscopy Meets Microfluidics for Hemostasis Evaluation. Micromachines 2019, 10, 534 .
AMA StyleShadi Karimi, Josep Farré-Lladós, Enrique Mir, Ginés Escolar, Jasmina Casals-Terré. Hemostasis-On-a-Chip: Impedance Spectroscopy Meets Microfluidics for Hemostasis Evaluation. Micromachines. 2019; 10 (8):534.
Chicago/Turabian StyleShadi Karimi; Josep Farré-Lladós; Enrique Mir; Ginés Escolar; Jasmina Casals-Terré. 2019. "Hemostasis-On-a-Chip: Impedance Spectroscopy Meets Microfluidics for Hemostasis Evaluation." Micromachines 10, no. 8: 534.
BACKGROUND Comparative studies on the restoration of hemostasis with different reversal agents after dabigatran therapy have not been performed. We compared the efficacy and prothrombotic potential of the specific antidote idarucizumab with that of previously recommended non‐specific procoagulant concentrates. STUDY DESIGN AND METHODS We explored the in vitro effects of dabigatran (184 ng/mL) on fibrin and platelet‐aggregate formation onto a damaged vessel under flow conditions (600 s−1). The reversal mechanisms and efficacy of idarucizumab (0.3–3 mg/mL) were compared with that of the non‐specific procoagulant concentrates aPCC (25–75 U/Kg), PCC (70 U/Kg), or rFVIIa (120 μg/Kg). Generation of thrombin and prothrombin fragment (F1 + 2), and thromboelastometry parameters of clot formation were measured. RESULTS Dabigatran caused pronounced reductions in fibrin (87%) and platelet interactions (36%) with damaged vessels (p < 0.01) and significantly impaired thrombin generation and thromboelastometric parameters (delayed dynamics and reduced firmness). Idarucizumab completely normalized rates of fibrin and platelet coverage to baseline values in flow studies; and reversed the alterations in thrombin generation, F1 + 2 and thromboelastometry parameters produced by dabigatran. In comparison, aPCC and PCC only partially compensated for the dabigatran‐induced alterations in fibrin deposition, but were unable to fully restore them to baseline values. Reversal with aPCC or PCC improved the majority of alterations in coagulation‐related tests, but tended to overcompensate thrombin generation kinetics and significantly increased F1 + 2 levels. CONCLUSION Idarucizumab antagonizes alterations of direct and indirect biomarkers of hemostasis caused by dabigatran. In our studies, idarucizumab was clearly more efficacious than strategies with non‐specific procoagulant concentrates and devoid of the excessive procoagulant tendency observed with the latter.
Eduardo Arellano‐Rodrigo; Victor Fernandez‐Gallego; Irene López‐Vilchez; Patricia Molina; Maribel Díaz‐Ricart; M. Urooj Zafar; Juan J. Badimon; Joanne Van Ryn; Ginés Escolar. Idarucizumab, but not procoagulant concentrates, fully restores dabigatran‐altered platelet and fibrin components of hemostasis. Transfusion 2019, 59, 2436 -2445.
AMA StyleEduardo Arellano‐Rodrigo, Victor Fernandez‐Gallego, Irene López‐Vilchez, Patricia Molina, Maribel Díaz‐Ricart, M. Urooj Zafar, Juan J. Badimon, Joanne Van Ryn, Ginés Escolar. Idarucizumab, but not procoagulant concentrates, fully restores dabigatran‐altered platelet and fibrin components of hemostasis. Transfusion. 2019; 59 (7):2436-2445.
Chicago/Turabian StyleEduardo Arellano‐Rodrigo; Victor Fernandez‐Gallego; Irene López‐Vilchez; Patricia Molina; Maribel Díaz‐Ricart; M. Urooj Zafar; Juan J. Badimon; Joanne Van Ryn; Ginés Escolar. 2019. "Idarucizumab, but not procoagulant concentrates, fully restores dabigatran‐altered platelet and fibrin components of hemostasis." Transfusion 59, no. 7: 2436-2445.
We read with interest the article by Gerrits et al on the incomplete reversibility of platelet inhibition following prolonged exposure to treatment with ticagrelor [1]. The results are intriguing and somewhat surprising, considering the reversible nature of the binding of ticagrelor with the platelet P2Y12 receptors. The study reported that prolonged exposure (24 hours) to ticagrelor decreased the reversibility of platelet function compared to short exposure (30 minutes) and the degree of this effect varied in the different testing methodologies used in the study. This article is protected by copyright. All rights reserved.
M. Urooj Zafar; Juan José Badimon; G. Escolar; Gines Escolar Gines. Incomplete reversibility of platelet inhibition following prolonged exposure to ticagrelor: comment. Journal of Thrombosis and Haemostasis 2018, 16, 605 -606.
AMA StyleM. Urooj Zafar, Juan José Badimon, G. Escolar, Gines Escolar Gines. Incomplete reversibility of platelet inhibition following prolonged exposure to ticagrelor: comment. Journal of Thrombosis and Haemostasis. 2018; 16 (3):605-606.
Chicago/Turabian StyleM. Urooj Zafar; Juan José Badimon; G. Escolar; Gines Escolar Gines. 2018. "Incomplete reversibility of platelet inhibition following prolonged exposure to ticagrelor: comment." Journal of Thrombosis and Haemostasis 16, no. 3: 605-606.
M. Díaz-Ricart; I.M. Isola; G. Escolar. Emicizumab for routine prophylaxis to prevent bleeding episodes in patients with hemophilia A. Drugs of Today 2018, 54, 591 .
AMA StyleM. Díaz-Ricart, I.M. Isola, G. Escolar. Emicizumab for routine prophylaxis to prevent bleeding episodes in patients with hemophilia A. Drugs of Today. 2018; 54 (10):591.
Chicago/Turabian StyleM. Díaz-Ricart; I.M. Isola; G. Escolar. 2018. "Emicizumab for routine prophylaxis to prevent bleeding episodes in patients with hemophilia A." Drugs of Today 54, no. 10: 591.
SummaryType-2 Diabetes Mellitus [T2DM] is associated with increased platelet reactivity and hypo-response to antiplatelet drugs. Ticagrelor, with its faster and more potent antiplatelet effects, was shown to reduce adverse events more than clopidogrel in the overall CAD patient population of PLATO trial, but the benefits did not reach statistical significance in the T2DM subgroup. To better understand these findings, we compared the antithrombotic effects of ticagrelor versus with clopidogrel in T2DM patients with cardiovascular disease. In a randomized, 2 treatment-sequence, crossover-design, T2DM patients (n=20, 57±8 years, 60% male) received a loading-dose [LD] plus one week of daily-therapy [DT] of clopidogrel or ticagrelor. Treatment effects were assessed by measuring thrombus formation (Badimon Chamber) and platelet aggregation (Multiple Electrode Aggregometry (MEA) Analyzer and VerifyNow®) at 2- and 6-hour post-LD and on Day-7 of DT, in comparison with pre-treatment baseline. After 2 weeks of washout, patients switched to the second treatment under identical testing conditions. Ticagrelor significantly reduced thrombus formation versus baseline at 2- and 6-hour post-LD and Day-7 of DT (33%, 40% and 31%, respectively, pClinical Trial Registration: Unique Identifier: NCT01823510.Supplementary Material to this article is available online at www.thrombosis-online.com.
M. Urooj Zafar; Usman Baber; Donald A. Smith; Samantha Sartori; Johanna Contreras; Juan Rey-Mendoza; Carlos A. Linares-Koloffon; Gines Escolar; Roxana Mehran; Valentin Fuster; Juan J. Badimon. Antithrombotic potency of ticagrelor versus clopidogrel in type-2 diabetic patients with cardiovascular disease. Thrombosis and Haemostasis 2017, 117, 1981 -1988.
AMA StyleM. Urooj Zafar, Usman Baber, Donald A. Smith, Samantha Sartori, Johanna Contreras, Juan Rey-Mendoza, Carlos A. Linares-Koloffon, Gines Escolar, Roxana Mehran, Valentin Fuster, Juan J. Badimon. Antithrombotic potency of ticagrelor versus clopidogrel in type-2 diabetic patients with cardiovascular disease. Thrombosis and Haemostasis. 2017; 117 (10):1981-1988.
Chicago/Turabian StyleM. Urooj Zafar; Usman Baber; Donald A. Smith; Samantha Sartori; Johanna Contreras; Juan Rey-Mendoza; Carlos A. Linares-Koloffon; Gines Escolar; Roxana Mehran; Valentin Fuster; Juan J. Badimon. 2017. "Antithrombotic potency of ticagrelor versus clopidogrel in type-2 diabetic patients with cardiovascular disease." Thrombosis and Haemostasis 117, no. 10: 1981-1988.
The main drawbacks of cardiovascular bare‐metal stents (BMS) are in‐stent restenosis and stent thrombosis as a result of an incomplete endothelialization after stent implantation. Nano‐ and microscale modification of implant surfaces is a strategy to recover the functionality of the artery by stimulating and guiding molecular and biological processes at the implant/tissue interface. In this study, cobalt‐chromium (CoCr) alloy surfaces are modified via direct laser interference patterning (DLIP) in order to create linear patterning onto CoCr surfaces with different periodicities (≈3, 10, 20, and 32 µm) and depths (≈20 and 800 nm). Changes in surface topography, chemistry, and wettability are thoroughly characterized before and after modification. Human umbilical vein endothelial cells' adhesion and spreading are similar for all patterned and plain CoCr surfaces. Moreover, high‐depth series induce cell elongation, alignment, and migration along the patterned lines. Platelet adhesion and aggregation decrease in all patterned surfaces compared to CoCr control, which is associated with changes in wettability and oxide layer characteristics. Cellular studies provide evidence of the potential of DLIP topographies to foster endothelialization without enhancement of platelet adhesion, which will be of high importance when designing new BMS in the future.
Romain Schieber; Federico Lasserre; Michael Hans; Marc Fernández Yagüe; Maribel Díaz-Ricart; Gines Escolar; Maria-Pau Ginebra; Frank Mücklich; Marta Pegueroles. Direct Laser Interference Patterning of CoCr Alloy Surfaces to Control Endothelial Cell and Platelet Response for Cardiovascular Applications. Advanced Healthcare Materials 2017, 6, 1 .
AMA StyleRomain Schieber, Federico Lasserre, Michael Hans, Marc Fernández Yagüe, Maribel Díaz-Ricart, Gines Escolar, Maria-Pau Ginebra, Frank Mücklich, Marta Pegueroles. Direct Laser Interference Patterning of CoCr Alloy Surfaces to Control Endothelial Cell and Platelet Response for Cardiovascular Applications. Advanced Healthcare Materials. 2017; 6 (19):1.
Chicago/Turabian StyleRomain Schieber; Federico Lasserre; Michael Hans; Marc Fernández Yagüe; Maribel Díaz-Ricart; Gines Escolar; Maria-Pau Ginebra; Frank Mücklich; Marta Pegueroles. 2017. "Direct Laser Interference Patterning of CoCr Alloy Surfaces to Control Endothelial Cell and Platelet Response for Cardiovascular Applications." Advanced Healthcare Materials 6, no. 19: 1.
The aim of the present study was to explore whether there is enhanced endothelial dysfunction in patients developing acute GvHD (aGvHD) after allogeneic hematopoietic cell transplantation (allo-HCT) and to identify biomarkers with predictive and/or diagnostic value. In in vitro experiments, endothelial cells (ECs) were exposed to serum from patients with (aGvHD, n=31) and without (NoGvHD, n=13) aGvHD, to evaluate changes in surface adhesion receptors, the reactivity of the extracellular matrix by measuring the presence of Von Willebrand factor (VWF) and platelet adhesion, and the activation of intracellular signaling proteins. Plasma levels of VWF, ADAMTS-13, TNF receptor 1 (TNFR1), soluble vascular cell adhesion molecule 1 and soluble intercellular adhesion molecule 1 were also measured. In vitro results showed a more marked proinflammatory and prothrombotic phenotype in ECs in association with aGvHD. Regarding circulating biomarkers, levels of VWF and TNFR1 above an optimal cutoff score, taken independently or combined, at day 7 after allo-HCT, would be able to positively predict that around 90% of patients will develop aGvHD. Our results demonstrate that endothelial damage is aggravated in those allo-HCT recipients developing aGvHD, and that VWF and TNFR1 are promising predictive aGvHD biomarkers. These findings could contribute to improve the understanding of the pathophysiology of aGvHD.Bone Marrow Transplantation advance online publication, 26 June 2017; doi:10.1038/bmt.2017.121.
E Mir; M Palomo; M Rovira; A Pereira; G Escolar; O Penack; E Holler; E Carreras; Maribel Diaz-Ricart. Endothelial damage is aggravated in acute GvHD and could predict its development. Bone Marrow Transplantation 2017, 52, 1317 -1325.
AMA StyleE Mir, M Palomo, M Rovira, A Pereira, G Escolar, O Penack, E Holler, E Carreras, Maribel Diaz-Ricart. Endothelial damage is aggravated in acute GvHD and could predict its development. Bone Marrow Transplantation. 2017; 52 (9):1317-1325.
Chicago/Turabian StyleE Mir; M Palomo; M Rovira; A Pereira; G Escolar; O Penack; E Holler; E Carreras; Maribel Diaz-Ricart. 2017. "Endothelial damage is aggravated in acute GvHD and could predict its development." Bone Marrow Transplantation 52, no. 9: 1317-1325.
INTRODUCTION AND AIMS: Atypical hemolytic uremic syndrome (aHUS) is a rare, progressive, life-threatening form of thrombotic microangiopathy (TMA). aHUS is caused by dysregulation of the alternative complement pathway over the cell surfaces. Nonetheless, there is wide evidence that complement activation has a role in other causes of TMA. A reliable method is needed to evaluate complement activation to monitor eculizumab (E) therapy in aHUS patients and to explore the posible indication of this treatment in other TMA.
Miquel Blasco; Marta Palomo; Patricia Molina; Ginés Escolar; Luis Quintana; Lida Rodas; Esteban Poch; Maribel Diaz-Ricart; Josep Campistol. MP055C5B9 DEPOSITS ON ENDOTHELIAL CELLS FOR THE EVALUATION OF COMPLEMENT FUNCTION IN THROMBOTIC MICROANGIOPATHIES OF DIFFERENT ORIGIN & THERAPY MONITORIZATION. Nephrology Dialysis Transplantation 2017, 32, iii445 -iii446.
AMA StyleMiquel Blasco, Marta Palomo, Patricia Molina, Ginés Escolar, Luis Quintana, Lida Rodas, Esteban Poch, Maribel Diaz-Ricart, Josep Campistol. MP055C5B9 DEPOSITS ON ENDOTHELIAL CELLS FOR THE EVALUATION OF COMPLEMENT FUNCTION IN THROMBOTIC MICROANGIOPATHIES OF DIFFERENT ORIGIN & THERAPY MONITORIZATION. Nephrology Dialysis Transplantation. 2017; 32 (suppl_3):iii445-iii446.
Chicago/Turabian StyleMiquel Blasco; Marta Palomo; Patricia Molina; Ginés Escolar; Luis Quintana; Lida Rodas; Esteban Poch; Maribel Diaz-Ricart; Josep Campistol. 2017. "MP055C5B9 DEPOSITS ON ENDOTHELIAL CELLS FOR THE EVALUATION OF COMPLEMENT FUNCTION IN THROMBOTIC MICROANGIOPATHIES OF DIFFERENT ORIGIN & THERAPY MONITORIZATION." Nephrology Dialysis Transplantation 32, no. suppl_3: iii445-iii446.
Aleix Cases; Manel Vera; Marta Palomo; Sergi Torramade; Gines Escolar; Maribel Diaz-Ricart. TO021DIRECT FACTOR Xa INHIBITOR APIXABAN PREVENTS ENDOTHELIAL ACTIVATION AND DAMAGE ASSOCIATED WITH CHRONIC KIDNEY DISEASE. Nephrology Dialysis Transplantation 2017, 32, 1 .
AMA StyleAleix Cases, Manel Vera, Marta Palomo, Sergi Torramade, Gines Escolar, Maribel Diaz-Ricart. TO021DIRECT FACTOR Xa INHIBITOR APIXABAN PREVENTS ENDOTHELIAL ACTIVATION AND DAMAGE ASSOCIATED WITH CHRONIC KIDNEY DISEASE. Nephrology Dialysis Transplantation. 2017; 32 (suppl_3):1.
Chicago/Turabian StyleAleix Cases; Manel Vera; Marta Palomo; Sergi Torramade; Gines Escolar; Maribel Diaz-Ricart. 2017. "TO021DIRECT FACTOR Xa INHIBITOR APIXABAN PREVENTS ENDOTHELIAL ACTIVATION AND DAMAGE ASSOCIATED WITH CHRONIC KIDNEY DISEASE." Nephrology Dialysis Transplantation 32, no. suppl_3: 1.
Mechanisms of action of direct oral anticoagulants (DOAC) suggest a potential therapeutic use in the prevention of thrombotic complications in arterial territories. However, effects of DOACs on platelet activation and aggregation have not been explored in detail. We have investigated the effects of apixaban on platelet and fibrin components of thrombus formation under static and flow conditions. We assessed the effects of apixaban (10, 40 and 160 ng/mL) on: 1) platelet deposition and fibrin formation onto a thrombogenic surface, with blood circulating at arterial shear-rates; 2) viscoelastic properties of forming clots, and 3) thrombin generation in a cell-model of coagulation primed by platelets. In studies with flowing blood, only the highest concentration of apixaban, equivalent to the therapeutic Cmax, was capable to significantly reduce thrombus formation, fibrin association and platelet-aggregate formation. Apixaban significantly prolonged thromboelastometry parameters, but did not affect clot firmness. Interestingly, results in a platelet-based model of thrombin generation under more static conditions, revealed a dose dependent persistent inhibitory action by apixaban, with concentrations 4 to 16 times below the therapeutic Cmax significantly prolonging kinetic parameters and reducing the total amount of thrombin generated. Our studies demonstrate the critical impact of rheological conditions on the antithrombotic effects of apixaban. Studies under flow conditions combined with modified thrombin generation assays could help discriminating concentrations of apixaban that prevent excessive platelet accumulation, from those that deeply impair fibrin formation and may unnecessarily compromise hemostasis.
Lluis Pujadas-Mestres; Irene Lopez-Vilchez; Eduardo Arellano-Rodrigo; Joan Carles Reverter; Antonio Lopez Farre; Maribel Diaz-Ricart; Juan Jose Badimon; Gines Escolar. Differential inhibitory action of apixaban on platelet and fibrin components of forming thrombi: Studies with circulating blood and in a platelet-based model of thrombin generation. PLOS ONE 2017, 12, e0171486 .
AMA StyleLluis Pujadas-Mestres, Irene Lopez-Vilchez, Eduardo Arellano-Rodrigo, Joan Carles Reverter, Antonio Lopez Farre, Maribel Diaz-Ricart, Juan Jose Badimon, Gines Escolar. Differential inhibitory action of apixaban on platelet and fibrin components of forming thrombi: Studies with circulating blood and in a platelet-based model of thrombin generation. PLOS ONE. 2017; 12 (2):e0171486.
Chicago/Turabian StyleLluis Pujadas-Mestres; Irene Lopez-Vilchez; Eduardo Arellano-Rodrigo; Joan Carles Reverter; Antonio Lopez Farre; Maribel Diaz-Ricart; Juan Jose Badimon; Gines Escolar. 2017. "Differential inhibitory action of apixaban on platelet and fibrin components of forming thrombi: Studies with circulating blood and in a platelet-based model of thrombin generation." PLOS ONE 12, no. 2: e0171486.
Activated coagulation factor X (FXa) is a common target for classic and newer anticoagulants. Parenteral anticoagulants with an indirect inhibitory action on FXa (low-molecular-weight heparins) have a well-established clinical efficacy in the prophylaxis and therapy of thromboembolic conditions. More recently developed direct oral anticoagulants (DOACs) have emerged as a new class of antithrombotic drugs. Rivaroxaban, apixaban and edoxaban are direct inhibitors of FXa approved for the management of venous thromboembolism and stroke prevention in atrial fibrillation. Although these DOACs are associated with fewer hemorrhagic side effects than classic vitamin K antagonists, bleeding is still a main complication. FXa antagonists had no specific agents that could reverse their antihemostatic effects. Andexanet alfa is a modified, recombinant human FXa molecule with an enhanced ability to bind to both direct and indirect FXa inhibitors, but unable to contribute to blood coagulation mechanisms. Andexanet alfa is designed to reverse the anticoagulant effects of FXa inhibitors. This review will address the preclinical pharmacology and the main aspects of the clinical development of andexanet alfa for the reversal of anticoagulant therapies with an inhibitory action on FXa. It will also summarize additional completed or ongoing studies on andexanet alfa available to the scientific community until present.
G Escolar; M Diaz-Ricart; E Arellano-Rodrigo. Andexanet alfa: a recombinant mimetic of human factor Xa for the reversal of anticoagulant therapies. Drugs of Today 2017, 53, 271 -282.
AMA StyleG Escolar, M Diaz-Ricart, E Arellano-Rodrigo. Andexanet alfa: a recombinant mimetic of human factor Xa for the reversal of anticoagulant therapies. Drugs of Today. 2017; 53 (5):271-282.
Chicago/Turabian StyleG Escolar; M Diaz-Ricart; E Arellano-Rodrigo. 2017. "Andexanet alfa: a recombinant mimetic of human factor Xa for the reversal of anticoagulant therapies." Drugs of Today 53, no. 5: 271-282.
G Escolar; M. Diaz-Ricart; E. Arellano-Rodrigo. Betrixaban: a direct oral inhibitor of activated factor X for the prophylaxis of venous thromboembolism in patients hospitalized for acute medical illness. Drugs of Today 2017, 53, 423 .
AMA StyleG Escolar, M. Diaz-Ricart, E. Arellano-Rodrigo. Betrixaban: a direct oral inhibitor of activated factor X for the prophylaxis of venous thromboembolism in patients hospitalized for acute medical illness. Drugs of Today. 2017; 53 (8):423.
Chicago/Turabian StyleG Escolar; M. Diaz-Ricart; E. Arellano-Rodrigo. 2017. "Betrixaban: a direct oral inhibitor of activated factor X for the prophylaxis of venous thromboembolism in patients hospitalized for acute medical illness." Drugs of Today 53, no. 8: 423.
Immobilization of bioactive peptide sequences on CoCr surfaces is an effective route to improve endothelialization, which is of great interest for cardiovascular stents. In this work, we explored the effect of physical and covalent immoblization of RGDS, YIGSR and their equimolar combination peptides on endothelial cells (EC) and smooth muscle cell (SMC) adhesion and on thrombogenicity. We extensively investigated using RT‐qPCR, the expression by ECs cultured on functionalised CoCr surfaces of different genes. Genes relevant for adhesion (ICAM‐1 and VCAM‐1), vascularization (VEGFA, VEGFR‐1 and VEGFR‐2) and anti‐thrombogenicity (tPA and eNOS) were over‐expressed in the ECs grown to covalently functionalized CoCr surfaces compared to physisorbed and control surfaces. Pro‐thrombogenic genes expression (PAI‐1 and vWF) decreased over time. Cell co‐cultures of ECs/SMCs found that functionalization increased the amount of adhered ECs onto modified surfaces compared to plain CoCr, independently of the used peptide and the strategy of immobilization. SMCs adhered less compared to ECs in all surfaces. All studied peptides showed a lower platelet cell adhesion compared to TCPS. Covalent functionalization of CoCr surfaces with an equimolar combination of RGDS and YIGSR represented prevailing strategy to enhance the early stages of ECs adhesion and proliferation, while preventing SMCs and platelet adhesion. © 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 105A: 973–983, 2017.
Maria Isabel Castellanos; Jordi Guillem-Marti; Carlos Mas-Moruno; Maribel Díaz-Ricart; Gines Escolar; Maria-Pau Ginebra; Francisco Javier Gil; Marta Pegueroles; Jose María Manero. Cell adhesive peptides functionalized on CoCr alloy stimulate endothelialization and prevent thrombogenesis and restenosis. Journal of Biomedical Materials Research Part A 2016, 105, 973 -983.
AMA StyleMaria Isabel Castellanos, Jordi Guillem-Marti, Carlos Mas-Moruno, Maribel Díaz-Ricart, Gines Escolar, Maria-Pau Ginebra, Francisco Javier Gil, Marta Pegueroles, Jose María Manero. Cell adhesive peptides functionalized on CoCr alloy stimulate endothelialization and prevent thrombogenesis and restenosis. Journal of Biomedical Materials Research Part A. 2016; 105 (4):973-983.
Chicago/Turabian StyleMaria Isabel Castellanos; Jordi Guillem-Marti; Carlos Mas-Moruno; Maribel Díaz-Ricart; Gines Escolar; Maria-Pau Ginebra; Francisco Javier Gil; Marta Pegueroles; Jose María Manero. 2016. "Cell adhesive peptides functionalized on CoCr alloy stimulate endothelialization and prevent thrombogenesis and restenosis." Journal of Biomedical Materials Research Part A 105, no. 4: 973-983.
There is a link between depression, cardiovascular events and inflammation. We have explored this connection through endothelial dysfunction, using in vivo and in vitro approaches. We evaluated circulating biomarkers of endothelial dysfunction in patients with major depression at their diagnosis (MD-0) and during antidepressant treatment with the selective serotonin reuptake inhibitor escitalopram, for 8 and 24 weeks (MD-8 and MD-24). Results were always compared with matched healthy controls (CON). We measured in vivo circulating endothelial cells (CECs) and endothelial progenitor cells (EPCs) in blood samples, and assessed plasma levels of soluble von Willebrand factor (VWF) and vascular cell adhesion molecule-1 (VCAM-1). CEC counts, soluble VWF and VCAM-1 were statistically elevated in MD-0 (P<0.01 versus CON) and gradually decreased during treatment. Conversely, EPC levels were lower in MD-0, tending to increase throughout treatment. In vitro studies were performed in human endothelial cells cultured in the presence of sera from each study group. Elevated expression of the inflammation marker intercellular adhesion molecule-1 and oxidative stress, with lower presence of endothelial nitric oxide synthase and higher reactive oxygen species production, were found in cells exposed to MD-0 sera (P<0.05 versus CON). These results were normalized in cells exposed to MD-24 sera. Thrombogenicity of extracellular matrices generated by these cells, measured as expression of VWF, tissue factor and platelet reactivity, showed non-significant differences. We provide a model of cultured endothelial cells reproducing endothelial dysfunction in naive patients with major depression, demonstrating endothelial damage and inflammation at diagnosis, and recovering with selective serotonin reuptake inhibitor treatment for 24 weeks.
I Lopez-Vilchez; M Diaz-Ricart; V Navarro; Sergi Torramadé-Moix; J Zamorano-Leon; Antonio Lopez Farre; A M Galan; C Gasto; Gines Escolar. Endothelial damage in major depression patients is modulated by SSRI treatment, as demonstrated by circulating biomarkers and an in vitro cell model. Translational Psychiatry 2016, 6, e886 -e886.
AMA StyleI Lopez-Vilchez, M Diaz-Ricart, V Navarro, Sergi Torramadé-Moix, J Zamorano-Leon, Antonio Lopez Farre, A M Galan, C Gasto, Gines Escolar. Endothelial damage in major depression patients is modulated by SSRI treatment, as demonstrated by circulating biomarkers and an in vitro cell model. Translational Psychiatry. 2016; 6 (9):e886-e886.
Chicago/Turabian StyleI Lopez-Vilchez; M Diaz-Ricart; V Navarro; Sergi Torramadé-Moix; J Zamorano-Leon; Antonio Lopez Farre; A M Galan; C Gasto; Gines Escolar. 2016. "Endothelial damage in major depression patients is modulated by SSRI treatment, as demonstrated by circulating biomarkers and an in vitro cell model." Translational Psychiatry 6, no. 9: e886-e886.
New strategies for tacrolimus administration that conserve its immunosuppressive effect but avoiding fluctuations in tacrolimus circulating levels are needed. The aim was to analyze if subcutaneous biodegradable tacrolimus-loaded microspheres injection promoted a significant immunosuppressive response in rats. Rats received two subcutaneous tacrolimus-loaded microspheres injections at different days, the first injection was done at day 0 and the second injection was done 12 days after. Plasma circulating levels of tacrolimus, interleukin-2 (IL-2) and calcineurin phosphatase (PP2B) activity in mononuclear cells were measured. Tacrolimus plasma levels were significantly increased from the day after tacrolimus-loaded microspheres injection and remained increased during 10days. Compared to control, plasma IL-2 levels and PP2B activity in mononuclear cells were significantly decreased during ten days. At day 12, a new subcutaneous injection of tacrolimus-loaded microspheres was performed and two days after injection, tacrolimus plasma levels were again increased and both IL-2 plasma levels and PP2B activity decreased. A single subcutaneous tacrolimus-loaded microspheres injection was enough to reduce tacrolimus-related immunosuppressive parameters. These results open the possibility of new therapeutic strategies to administrate calcineurin inhibitors reducing the variability of their circulating levels related to gastrointestinal drug absorption/metabolism modifications.
Jose J. Zamorano-Leon; Ines Hernandez-Fisac; Sandra Guerrero; Jorge Tamarit-Rodriguez; Juana M. Santos-Sancho; Bernardo Sopeña; Ginés Escolar; Irene López-Vilchez; Juan Duarte; Alberto Barrientos; Antonio J. López-Farré. New strategy of tacrolimus administration in animal model based on tacrolimus-loaded microspheres. Transplant Immunology 2016, 36, 9 -13.
AMA StyleJose J. Zamorano-Leon, Ines Hernandez-Fisac, Sandra Guerrero, Jorge Tamarit-Rodriguez, Juana M. Santos-Sancho, Bernardo Sopeña, Ginés Escolar, Irene López-Vilchez, Juan Duarte, Alberto Barrientos, Antonio J. López-Farré. New strategy of tacrolimus administration in animal model based on tacrolimus-loaded microspheres. Transplant Immunology. 2016; 36 ():9-13.
Chicago/Turabian StyleJose J. Zamorano-Leon; Ines Hernandez-Fisac; Sandra Guerrero; Jorge Tamarit-Rodriguez; Juana M. Santos-Sancho; Bernardo Sopeña; Ginés Escolar; Irene López-Vilchez; Juan Duarte; Alberto Barrientos; Antonio J. López-Farré. 2016. "New strategy of tacrolimus administration in animal model based on tacrolimus-loaded microspheres." Transplant Immunology 36, no. : 9-13.
Key Points Specific interaction of DF with EC membranes is followed by its internalization mainly through macropinocytic mechanisms. DF attachment to the cell membrane is sufficient to perform its antiinflammatory and antioxidant effects on the endothelium.
Marta Palomo; Enrique Mir; Montse Rovira; Ginés Escolar; Enric Carreras; Maribel Diaz-Ricart. What is going on between defibrotide and endothelial cells? Snapshots reveal the hot spots of their romance. Blood 2016, 127, 1719 -1727.
AMA StyleMarta Palomo, Enrique Mir, Montse Rovira, Ginés Escolar, Enric Carreras, Maribel Diaz-Ricart. What is going on between defibrotide and endothelial cells? Snapshots reveal the hot spots of their romance. Blood. 2016; 127 (13):1719-1727.
Chicago/Turabian StyleMarta Palomo; Enrique Mir; Montse Rovira; Ginés Escolar; Enric Carreras; Maribel Diaz-Ricart. 2016. "What is going on between defibrotide and endothelial cells? Snapshots reveal the hot spots of their romance." Blood 127, no. 13: 1719-1727.
Juan V. Llau; F.J. Acosta; Gines Escolar; E. Fernández-Mondéjar; E. Guasch; P. Marco; P. Paniagua; José A Paramo; M. Quintana; P. Torrabadella. Documento multidisciplinar de consenso sobre el manejo de la hemorragia masiva (documento HEMOMAS). Revista Española de Anestesiología y Reanimación 2016, 63, e1 -e22.
AMA StyleJuan V. Llau, F.J. Acosta, Gines Escolar, E. Fernández-Mondéjar, E. Guasch, P. Marco, P. Paniagua, José A Paramo, M. Quintana, P. Torrabadella. Documento multidisciplinar de consenso sobre el manejo de la hemorragia masiva (documento HEMOMAS). Revista Española de Anestesiología y Reanimación. 2016; 63 (1):e1-e22.
Chicago/Turabian StyleJuan V. Llau; F.J. Acosta; Gines Escolar; E. Fernández-Mondéjar; E. Guasch; P. Marco; P. Paniagua; José A Paramo; M. Quintana; P. Torrabadella. 2016. "Documento multidisciplinar de consenso sobre el manejo de la hemorragia masiva (documento HEMOMAS)." Revista Española de Anestesiología y Reanimación 63, no. 1: e1-e22.