Blasco M, Martínez-Roca A, Rodríguez-Lobato LG, Garcia-Herrera A, Rosiñol L, Castro P, Fernández S, Quintana LF, Cibeira MT, Bladé J, Fernández de Larrea C, Tovar N, Jimenez R, Poch E, Guillen E, Campistol JM, Carreras E, Diaz-Ricart M, Palomo M
Complement as the enabler of carfilzomib-induced thrombotic microangiopathy.
Br. J. Haematol.29 May 2020, . Epub 29 May 2020
Carfilzomib has been associated with the development of thrombotic microangiopathy (TMA) in relapsed/refractory multiple myeloma patients, a severe disease with no currently available aetiological treatment. We evaluated the potential role of terminal complement pathway in four patients with carfilzomib-induced TMA. Membrane attack complex (C5b-9) deposition on endothelial cells in culture exposed to plasma from patients during the acute phase of the disease suggests complement overactivation as a mechanism of potential endothelial damage in three out of four patients. If confirmed in larger cohorts, C5b-9 evaluation will allow early identification of patients who could benefit from complement blockade and treatment monitoring.
Martinez-Sanchez J, Palomo M, Torramade-Moix S, Moreno-Castaño AB, Rovira M, Gutiérrez-García G, Fernández-Avilés F, Escolar G, Penack O, Rosiñol L, Carreras E, Diaz-Ricart M
The induction strategies administered in the treatment of multiple myeloma exhibit a deleterious effect on the endothelium.
Bone Marrow Transplant.13 May 2020, . Epub 13 May 2020
Multiple myeloma induction treatment includes proteasome inhibitors (PI) and immunomodulatory agents at present. The incidence of engraftment syndrome, a transplant complication potentially related to endothelium, has increased in the last years. Our aim was to investigate whether bortezomib (Velcade, V), thalidomide (T), and dexamethasone (D) affect the endothelium, and explore defibrotide (DF) as protective agent. Endothelial cells (ECs) in culture were exposed to the compounds separately or in combination, without (VTD) and with DF (VTD + DF). Changes in markers of: (i) inflammation (ICAM-1 expression and leukocyte adhesion), (ii) VWF production, (iii) cell permeability (VE-cadherin expression and cell monolayer integrity), and (iv) oxidative stress (ROS production and eNOS expression) were measured. ICAM-1 and VWF expression increased significantly in VTD but were similar to controls in VTD + DF. Separately, bortezomib was the main deleterious agent whereas dexamethasone showed no harmful effect. Leukocyte adhesion showed similar trends. VE-cadherin expression was lower in VTD and normalized in VTD + DF. EC permeability increased only with bortezomib. No changes were observed in oxidative stress markers. Our results demonstrate that bortezomib damages the endothelium, and DF prevents this effect. A better knowledge of the induction drugs impact will allow the design of measures to protect the endothelium.
Hajek R, Pour L, Ozcan M, Martin Sánchez J, García Sanz R, Anagnostopoulos A, Oriol A, Cascavilla N, Terjung A, Lee Y, Briso EM, Dobkowska E, Hauns B, Špička I
A phase 2 study of ibrutinib in combination with bortezomib and dexamethasone in patients with relapsed/refractory multiple myeloma.
Eur. J. Haematol.May 2020, 104(5)435-442. Epub 7 Mar 2020
We evaluated ibrutinib, a once-daily inhibitor of Bruton's tyrosine kinase, combined with bortezomib and dexamethasone in patients with relapsed or relapsed/refractory multiple myeloma who had received 1-3 prior therapies.
Is sickle cell disease-related neurotoxicity a systemic endotheliopathy?
Hematol Oncol Stem Cell Ther13 Mar 2020, . Epub 13 Mar 2020
The aim of the present article is to review the role of endothelial damage and dysfunction in the vaso-occlusive episodes associated with sickle cell disease (SCD). This inherited hematological disorder leads to irreversible damage of multiple organs through a wide variety of mechanisms, such as sickling of red cells, oxidative state due to ischemic-reperfusion episodes, inflammation, hypercoagulation state, and platelet activation, among others. In SCD, the endothelium arises as the key entity where most of these processes, which eventually lead to increased morbidly and mortality, interact. This review begins with the already accepted idea that organ-specific vasculopathy precedes clinical manifestation, and briefly explains one of the main triggers of vaso-occlusive episodes, the complex interplay between blood cells and the dysfunctional endothelium. Endothelial protective strategies emerge as a potential tool for the prevention of organ-specific disease in SCD. Actually, this knowledge is currently used for the development of potential pharmacologic interventions to improve the lives of SCD patients.
Palomo M, Vera M, Martin S, Torramadé-Moix S, Martinez-Sanchez J, Belen Moreno A, Carreras E, Escolar G, Cases A, Díaz-Ricart M
Up-regulation of HDACs, a harbinger of uraemic endothelial dysfunction, is prevented by defibrotide.
J. Cell. Mol. Med.28 Nov 2019, . Epub 28 Nov 2019
Endothelial dysfunction is an earlier contributor to the development of atherosclerosis in chronic kidney disease (CKD), in which the role of epigenetic triggers cannot be ruled out. Endothelial protective strategies, such as defibrotide (DF), may be useful in this scenario. We evaluated changes induced by CKD on endothelial cell proteome and explored the effect of DF and the mechanisms involved. Human umbilical cord vein endothelial cells were exposed to sera from healthy donors (n = 20) and patients with end-stage renal disease on haemodialysis (n = 20). Differential protein expression was investigated by using a proteomic approach, Western blot and immunofluorescence. HDAC1 and HDAC2 overexpression was detected. Increased HDAC1 expression occurred at both cytoplasm and nucleus. These effects were dose-dependently inhibited by DF. Both the HDACs inhibitor trichostatin A and DF prevented the up-regulation of the endothelial dysfunction markers induced by the uraemic milieu: intercellular adhesion molecule-1, surface Toll-like receptor-4, von Willebrand Factor and reactive oxygen species. Moreover, DF down-regulated HDACs expression through the PI3/AKT signalling pathway. HDACs appear as key modulators of the CKD-induced endothelial dysfunction as specific blockade by trichostatin A or by DF prevents endothelial dysfunction responses to the CKD insult. Moreover, DF exerts its endothelial protective effect by inhibiting HDAC up-regulation likely through PI3K/AKT.
Palomo M, Blasco M, Molina P, Lozano M, Praga M, Torramade-Moix S, Martinez-Sanchez J, Cid J, Escolar G, Carreras E, Paules C, Crispi F, Quintana LF, Poch E, Rodas L, Goma E, Morelle J, Espinosa M, Morales E, Avila A, Cabello V, Ariceta G, Chocron S, Manrique J, Barros X, Martin N, Huerta A, Fraga-Rodriguez GM, Cao M, Martin M, Romera AM, Moreso F, Manonelles A, Gratacos E, Pereira A, Campistol JM, Diaz-Ricart M
Complement Activation and Thrombotic Microangiopathies.
Clin J Am Soc Nephrol6 Nov 2019, . Epub 6 Nov 2019
Atypical hemolytic uremic syndrome is a form of thrombotic microangiopathy caused by dysregulation of the alternative complement pathway. There is evidence showing complement activation in other thrombotic microangiopathies. The aim of this study was to evaluate complement activation in different thrombotic microangiopathies and to monitor treatment response.
Angiogenesis and endothelial activation and dysfunction have been associated with acute graft-vs.-host disease (aGVHD), pointing to the endothelium as a potential target for pharmacological intervention. Defibrotide (DF) is a drug with an endothelium-protective effect that has been approved for the treatment of veno-occlusive disease/sinusoidal obstruction syndrome after allogeneic hematopoietic cell transplantation. Clinical data suggest that DF also reduces the incidence of aGVHD; however, the mechanisms of DF-mediated aGVHD regulation have not been examined. To investigate possible DF-mediated prophylactic and therapeutic mechanisms in aGVHD, we performed
Corbacioglu S, Carreras E, Ansari M, Balduzzi A, Cesaro S, Dalle JH, Dignan F, Gibson B, Guengoer T, Gruhn B, Lankester A, Locatelli F, Pagliuca A, Peters C, Richardson PG, Schulz AS, Sedlacek P, Stein J, Sykora KW, Toporski J, Trigoso E, Vetteranta K, Wachowiak J, Wallhult E, Wynn R, Yaniv I, Yesilipek A, Mohty M, Bader P
Diagnosis and severity criteria for sinusoidal obstruction syndrome/veno-occlusive disease in pediatric patients: a new classification from the European society for blood and marrow transplantation.
Bone Marrow Transplant.Feb 2018, 53(2)138-145. Epub 31 Jul 2017
The advances in hematopoietic cell transplantation (HCT) over the last decade have led to a transplant-related mortality below 15%. Hepatic sinusoidal obstruction syndrome/veno-occlusive disease (SOS/VOD) is a life-threatening complication of HCT that belongs to a group of diseases increasingly identified as transplant-related, systemic endothelial diseases. In most cases, SOS/VOD resolves within weeks; however, severe SOS/VOD results in multi-organ dysfunction/failure with a mortality rate >80%. A timely diagnosis of SOS/VOD is of critical importance, given the availability of therapeutic options with favorable tolerability. Current diagnostic criteria are used for adults and children. However, over the last decade it has become clear that SOS/VOD is significantly different between the age groups in terms of incidence, genetic predisposition, clinical presentation, prevention, treatment and outcome. Improved understanding of SOS/VOD and the availability of effective treatment questions the use of the Baltimore and Seattle criteria for diagnosing SOS/VOD in children. The aim of this position paper is to propose new diagnostic and severity criteria for SOS/VOD in children on behalf of the European Society for Blood and Marrow Transplantation.
Mir E, Palomo M, Rovira M, Pereira A, Escolar G, Penack O, Holler E, Carreras E, Diaz-Ricart M
Endothelial damage is aggravated in acute GvHD and could predict its development.
Bone Marrow Transplant.Sep 2017, 52(9)1317-1325. Epub 26 Jun 2017
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.
Martínez C, Millán O, Rovira M, Fernández-Avilés F, López A, Suárez-Lledó M, Carreras E, Urbano-Ispízua Á, Brunet M
Pharmacodynamics of T cell function for monitoring pharmacologic immunosuppression after allogeneic hematopoietic stem cell transplantation.
Int. J. Hematol.23 Nov 2016, . Epub 23 Nov 2016
Information on pharmacodynamic monitoring after allogeneic hematopoietic cell transplantation (allo-SCT) to evaluate individual responses to immunosuppressive drugs is scarce. We studied the relationship between a panel of pharmacodynamic markers monitored during the first 3 months after transplant and the occurrence of graft-versus-host disease (GVHD). Lymphocyte activation assessed by intracellular ATP concentration in CD4(+) T cells, a high percentage of CD8(+) effector T cells, and a low percentage of CD4(+) regulatory T (Treg) cells correlated significantly with GVHD. A cutoff value of 0.5 for the CD8(+) effector T/Treg ratio provided the most accurate diagnosis of GVHD (sensitivity 58.8%, specificity 91%). These pharmacodynamic markers may provide an efficient complement to standard pharmacokinetic monitoring of immunosuppressive drugs after allo-SCT.