Nuestros investigadores

José María Hermida Santos

Departamento
. Fundación para la Investigación Médica Aplicada
Hematología
Facultad de Medicina. Universidad de Navarra
Índice H
21, (Scopus, 23/03/2019)

Publicaciones científicas más recientes (desde 2010)

Autores: Figueroa, Rocío; Alfonso, Ana; López-Picazo, José María; et al.
Revista: CLINICAL AND TRANSLATIONAL ONCOLOGY
ISSN 1699-048X  Vol. 21  Nº 6  2019  págs. 805 - 809
PURPOSE: Thromboprophylaxis use among medical inpatients, including cancer patients, is suboptimal. We aimed to evaluate the impact of a novel multiscreen version (v2.0) of an e-alert system for VTE prevention in hospitalised cancer medical patients compared to the original software. METHODS: Prospective study including 989 consecutive adult cancer patients with high-risk of VTE. Patients were followed-up 30 days post-discharge. Two periods were defined, according to the operative software. RESULTS: E-alert v2.0 was associated with an increase in the use of LMWH prophylaxis (65.5% vs. 72.0%); risk difference (95% CI) 0.064 (0.0043-0.12). Only 16% of patients in whom LMWH prophylaxis was not prescribed lacked a contraindication. No significant differences in the rates of VTE (2.9% vs. 3.2%) and major bleeding (2.7% vs. 4.0%) were observed. CONCLUSIONS: E-alert v2.0 further increased the use of appropriate thromboprophylaxis in hospitalised cancer patients, although was not associated with a reduction in VTE incidence.
Autores: Figueroa, Rocío; Alfonso, Ana; López-Picazo, José María; et al.
Revista: PLOS ONE
ISSN 1932-6203  Vol. 13  Nº 8  2018  págs. e0200220
Hospitalized cancer patients are at high risk of venous thromboembolism (VTE). Despite current recommendations in clinical guidelines, thromboprophylaxis with low molecular weight heparin (LMWH) is underused. We performed an observational prospective study to analyse factors influencing prophylaxis use, VTE events and mortality in cancer-hospitalized patients. 1072 consecutive adult cancer patients were included in an University Hospital from April 2014 to February 2017, and followed-up for 30 days after discharge. The rate of LMWH prophylaxis was 67.6% (95% confidence interval [CI]64.7% to 70.4%), with a 2.8% rate of VTE events (95% CI 1.9% to 3.9%) and 3.5% rate of major bleeding events (95% CI 2.5% to 4.8%). 80% of VTE events occurred despite appropriate thromboprophylaxis. Overall, 30-day mortality rate was 13.2% (95% C111.2% to 15.3%). Active chemotherapy treatment, hospital stay >= 4 days, and metastatic disease were associated with a higher use of LMWH. On the contrary, patients with hematologic malignancies,anemia or thrombocytopenia were less prone to receive thromboprophylaxis. The main reasons for not prescribing LMWH prophylaxis were thrombocytopenia (23.9%) and active/recent bleeding (21.8%). The PRETEMED score, used for VTE risk stratification, correlated with 30-day mortality. There is room for improvement in thromboprophylaxis use among hospitalized-cancer patients, especially among those with hematologic malignancies. A relevant number of VTE events occurred despite prophylaxis with LMWH. Therefore, identification of risk factors for thromboprophylaxis failure is needed.
Autores: Allender, M.; Lecumberri, Ramón; et al.
Revista: THROMBOSIS AND HAEMOSTASIS
ISSN 0340-6245  Vol. 117  Nº 9  2017  págs. 1722 - 1729
Antithrombotic medications target coagulation factors. Their use is associated with an increased bleeding risk. Safer drugs are needed. The heat shock protein 70 (Hsp70) exhibits antithrombotic properties that do not influence bleeding. By using murine models, we aimed to test the hypothesis that overexpressing Hsp70 with CM-695, a first in class dual inhibitor of HDAC6 and phosphodiesterase 9, protects against thrombosis while leaves bleeding tendency unaltered. CM-695 was used to induce Hsp70 overexpression. Hsp70 overexpressing mice were submitted to three thrombosis-triggering procedures. The ferric chloride carotid artery model was used to compare the antithrombotic role of CM-695 and rivaroxaban, a direct oral anticoagulant. The mouse tail transection model was used to compare the bleeding tendency upon CM-695 or rivaroxaban administration. Intraperitoneal (i.p.) 20 mg/kg CM-695 increased Hsp70 expression markedly in the murine aortic tissue. This treatment delayed thrombosis in the collagen/epinephrine [p=0.04 (Log-Rank test), n=10], Rose Bengal/laser [median vessel occlusion time (OT): 58.6 vs 39.0 minutes (min) in the control group (CG), p=0.008, n >= 10] and ferric chloride (OT: 14.7 vs 9.2 min in the CG, p=0.032, n >= 10) models. I.p. 80 mg/kg CM-695 (n >= 9) and intravenous 3 mg/kg rivaroxaban (n >= 8) significantly delayed thrombosis. CM-695 did not induce bleeding [median bleeding time (BT): 8.5 vs 7.5 min in the CG, n >= 10]. However, BT was dramatically increased by rivaroxaban (30.0 vs 13.7 min in the CG, p=0.001, n=10). In conclusion, CM-695 is a new antithrombotic small molecule devoid of bleeding risk that may be envisioned as a useful clinical tool.
Autores: Martinez Canarias, S.; et al.
Revista: JOURNAL OF HEMATOLOGY AND ONCOLOGY
ISSN 1756-8722  Vol. 10  Nº 1  2017  págs. 23
Background: Activated protein C/endothelial protein C receptor (APC/EPCR) axis is physiologically involved in anticoagulant and cytoprotective activities in endothelial cells. Emerging evidence indicates that EPCR also plays a role in breast stemness and human tumorigenesis. Yet, its contribution to breast cancer progression and metastasis has not been elucidated. Methods: Transcriptomic status of EPCR was examined in a cohort of 286 breast cancer patients. Cell growth kinetics was evaluated in control and EPCR and SPARC/osteonectin, Cwcv, and kazal-like domains proteoglycan (SPOCK1/testican 1) silenced breast cancer cells in 2D, 3D, and in co-culture conditions. Orthotopic tumor growth and lung and osseous metastases were evaluated in several human and murine xenograft breast cancer models. Tumor-stroma interactions were further studied in vivo by immunohistochemistry and flow cytometry. An EPCR-induced gene signature was identified by microarray analysis. Results: Analysis of a cohort of breast cancer patients revealed an association of high EPCR levels with adverse clinical outcome. Interestingly, EPCR knockdown did not affect cell growth kinetics in 2D but significantly reduced cell growth in 3D cultures. Using several human and murine xenograft breast cancer models, we showed that EPCR silencing reduced primary tumor growth and secondary outgrowths at metastatic sites, including the skeleton and the lungs. Interestingly, these effects were independent of APC ligand stimulation in vitro and in vivo. Transcriptomic analysis of EPCR-silenced tumors unveiled an effect mediated by matricellular secreted proteoglycan SPOCK1/testican 1. Interestingly, SPOCK1 silencing suppressed in vitro 3D growth. Moreover, SPOCK1 ablation severely decreased orthotopic tumor growth and reduced bone metastatic osteolytic tumors. High SPOCK1 levels were also associated with poor clinical outcome in a subset breast cancer patients. Our results suggest that EPCR through SPOCK1 confers a cell growth advantage in 3D promoting breast tumorigenesis and metastasis. Conclusions: EPCR represents a clinically relevant factor associated with poor outcome and a novel vulnerability to develop combination therapies for breast cancer patients.
Autores: Figueroa, Rocío; Alfonso, Ana; et al.
Revista: HAEMATOLOGICA
ISSN 0390-6078  Vol. 102  Nº Supl. 2  2017  págs. 161 - 161
Autores: Guruceaga, Elisabet; José R. González-Porras; Joan C. Reverter; et al.
Revista: EUROPEAN JOURNAL OF HAEMATOLOGY
ISSN 0902-4441  Vol. 97  Nº 2  2016  págs. 128-136
For the first time an association between ACSF2 expression and the risk of recurrent DVT is suggested. Should this association be confirmed in larger prospective studies, ACSF2 could become useful for the selection of patients requiring extended anticoagulant therapy.
Autores: Guruceaga, Elisabet; et al.
Revista: CARDIOVASCULAR RESEARCH
ISSN 0008-6363  Vol. 110  Nº 3  2016  págs. 309 - 318
AIMS: Atrial fibrillation (AF) is a major risk factor for cardio-embolic stroke. Anticoagulant drugs are effective in preventing AF-related stroke. However, the high frequency of anticoagulant-associated major bleeding is a major concern. This study sought to identify new targets to develop safer antithrombotic therapies. METHODS AND RESULTS: Here, microarray analysis in peripheral blood cells in eight patients with AF and stroke and eight AF subjects without stroke brought to light a stroke-related gene expression pattern. HSPA1B, which encodes for heat-shock protein 70 kDa (Hsp70), was the most differentially expressed gene. This gene was down-regulated in stroke subjects, a finding confirmed further in an independent AF cohort of 200 individuals. Hsp70 knock-out mice subjected to different thrombotic challenges developed thrombosis significantly earlier than their wild-type (WT) counterparts. Remarkably, the tail bleeding time was unchanged. Accordingly, both TRC051384 and tubastatin A, i.e. two Hsp70 inducers via different pathways, delayed thrombus formation in WT mice, the tail bleeding time still being unaltered. Most interestingly, Hsp70 inducers did not increase the bleeding risk even when aspirin was concomitantly administered. Hsp70 induction was associated with an increased vascular thrombomodulin expression and higher circulating levels of activated protein C upon thrombotic stimulus. CONCLUSIONS: Hsp70 induction is a novel approach to delay thrombus formation with minimal bleeding risk, and is especially promising for treating AF patients and in other situations where there is also a major bleeding hazard.
Autores: Allende, M.; Gonzalez-Porras, J. R. ; et al.
Revista: STROKE
ISSN 0039-2499  Vol. 47  Nº 3  2016  págs. 863 - 865
Background and Purpose- The risk of cardioembolic stroke in patients with atrial fibrillation (AF) cannot be accurately assessed and novel tools are needed to improve prediction. We hypothesize that telomere shortening constitutes a novel risk factor for cardioembolic stroke in patients with AF. Methods- The peripheral blood leukocyte telomere length (LTL) was determined by real-time polymerase chain reaction in 187 patients with AF, 93 of them without stroke history and 94 of them having suffered 1 cardioembolic stroke. Percentiles were calculated according to LTL values in the nonstroke group to estimate the cardioembolic stroke risk associated with LTL using logistic regression models. Results- Short LTL values were independently and dose-dependently associated with an increased risk of cardioembolic stroke, with an odds ratio (95% confidence interval) of 2.93 (1.24-6.94) and 6.26 (2.01-19.52), respectively, for sex, hypertension, diabetes mellitus, heart failure, and age-adjusted models using the LTL 10th and 5th percentile cut-offs, respectively. Conclusions- Telomere shortening is associated with cardioembolic stroke risk in patients with AF. Prospective studies are encouraged to establish the value of LTL to improve prediction tools to categorize cardioembolic stroke risk in AF.
Autores: Alfonso, Ana; García-Mouriz A; et al.
Revista: THROMBOSIS RESEARCH
ISSN 0049-3848  Vol. 136  Nº 6  2015  págs. 1145-1148
Although the type of malignancy appears as the most relevant variable for decision-making, additional efforts are required to identify patients at particular high thrombosis risk.
Autores: Petersen, J. E. V., (Autor de correspondencia); Bouwens, E. A. M. ; et al.
Revista: THROMBOSIS AND HAEMOSTASIS
ISSN 0340-6245  Vol. 114  Nº 5  2015  págs. 1038 - 1048
The Endothelial Protein C receptor (EPCR) is essential for the anticoagulant and cytoprotective functions of the Protein C (PC) system. Selected variants of the malaria parasite protein, Plasmodium falciparum Erythrocyte Membrane Protein 1 (PfEMP1) associated with severe malaria, including cerebral malaria, specifically target EPCR on vascular endothelial cells. Here, we examine the cellular response to PfEMP1 engagement to elucidate its role in malaria pathogenesis. Binding of the CIDR alpha 1.1 domain of PfEMP1 to EPCR obstructed activated PC (APC) binding to EPCR and induced a loss of cellular EPCR functions. CIDR alpha 1.1 severely impaired endothelial PC activation and effectively blocked APC-mediated activation of protease-activated receptor- 1 (PAR1) and associated barrier protective effects of APC on endothelial cells. A soluble EPCR variant (E86A-sEPCR) bound CIDR alpha 1.1 with high affinity and did not interfere with (A) PC binding to cellular EPCR. E86A-sEPCR used as a decoy to capture PfEMP1, permitted normal PC activation on endothelial cells, normal barrier protective effects of APC, and greatly reduced cytoadhesion of infected erythrocytes to brain endothelial cells. These data imply important contributions of PfEMP1-induced protein C pathway defects in the pathogenesis of severe malaria. Furthermore, the E86A-sEPCR decoy provides a proof-of-principle strategy for the development of novel adjunct therapies for severe malaria.
Autores: Gleeson, E. M. ; Dichiara, M. G.; Salicio, Agustina; et al.
Revista: BLOOD
ISSN 0006-4971  Vol. 126  Nº 7  2015  págs. 915 - 919
Activated protein C (APC) is an anticoagulant protease that initiates cell signaling via protease-activated receptor 1 (PAR1) to regulate vascular integrity and inflammatory response. In this study, a recombinant APC variant (APC(N329Q)) mimicking the naturally occurring APC-beta plasma glycoform was found to exhibit superior PAR1 proteolysis at a cleavage site that selectively mediates cytoprotective signaling. APC(N329Q) also enhanced integrin alpha(M)beta(2)-dependent PAR1 proteolysis to exert significantly improved antiinflammatory activity on macrophages compared with wild-type APC. Recent therapeutic applications of recombinant APC in ischemic stroke models have used APC variants with limited anticoagulant activity to negate potential bleeding side effects. Using a mouse model of ischemic stroke and late t-PA intervention, the neuroprotective activity of a murine APC variant with limited anticoagulant activity (mAPC(PS)) was compared with an identical APC variant except for the absence of glycosylation at the APC-beta sequon (mAPC(PS/N329Q)). Remarkably, mAPC(PS/N329Q) limited cerebral ischemic injury and reduced brain lesion volume significantly more effectively than mAPC(PS). Collectively, this study reveals the importance of APC glycosylation in controlling the efficacy of PAR1 proteolysis by APC and demonstrates the potential of novel APC variants with superior cytoprotective signaling function as enhanced therapeutic agents for the treatment of ischemic stroke.
Autores: Alfonso, Ana; Garcia-Mouriz, A.; et al.
Revista: JOURNAL OF THROMBOSIS AND HAEMOSTASIS
ISSN 1538-7933  Vol. 13  Nº Supl 2  2015  págs. 551
Autores: Lecumberri, Ramón; Montes, R.; Guruceaga, Elisabet; et al.
Revista: JOURNAL OF THROMBOSIS AND HAEMOSTASIS
ISSN 1538-7933  Vol. 13  Nº Supl 2  2015  págs. 683
Autores: Velasco, S. E.; Puy, C. ; et al.
Revista: JOURNAL OF THROMBOSIS AND HAEMOSTASIS
ISSN 1538-7933  Vol. 12  Nº 11  2014  págs. 1921 - 1927
BackgroundEndothelial proteinC receptor (EPCR) must be bound to a molecule of phosphatidylcholine (PC) to be fully functional, i.e. to interact with proteinC/activated proteinC (APC) properly. PC can be replaced with other lipids, such as lysophosphatidylcholine or platelet-activating factor, by the action of groupV secretory phospholipaseA2 (sPLA2-V), an enzyme that is upregulated in a variety of inflammatory conditions. Studies in purified systems have demonstrated that the substitution of PC notably impairs EPCR function in a process called EPCR encryption. ObjectivesTo analyze whether sPLA2-V was able to regulate EPCR-dependent proteinC activation invivo, and its impact on thrombosis and the hemostatic system. MethodsMice were transfected with sPLA2-V by hydrodynamic gene delivery. The effects on thrombosis were studied with the laser carotid artery occlusion model, and APC generation capacity was measured with ELISA. Global hemostasis was analyzed with thromboelastometry. ResultsWe found that sPLA2-V overexpression in mice significantly decreased their ability to generate APC. Furthermore, a murine carotid artery laser thrombosis model revealed that higher sPLA2-V levels were directly associated with faster artery thrombosis. ConclusionssPLA2-V plays a thrombogenic role by impairing the ability of EPCR to promote proteinC activation.
Autores: Nantes, O., (Autor de correspondencia); Montes, R.; et al.
Revista: GASTROENTEROLOGIA Y HEPATOLOGIA
ISSN 0210-5705  Vol. 37  Nº 6  2014  págs. 334 - 341
In the last few years, the number of anticoagulated patients has significantly increased and, as a consequence, so have hemorrhagic complications due to this therapy. We analyzed gastrointestinal (GI) bleeding because it is the most frequent type of major bleeding in these patients, and we hypothesized that they would have lesions responsible for GI bleeding regardless of the intensity of anticoagulation, although excessively anticoagutated patients would have more serious hemorrhages. Objectives: To study the characteristics of anticoagulated patients with GI bleeding and the relationship between the degree of anticoagulation and a finding of causative lesions and bleeding severity. Patients and methods: We prospectively studied 96 patients, all anticoagulated with acenocoumarol and consecutively admitted to hospital between 01/01/2003 and 09/30/2005 because of acute GI bleeding. We excluded patients with severe liver disease, as well as nine patients with incomplete details. Results: The incidence of GI bleeding requiring hospitalization was 19.6 cases/100,000 inhabitants-year. In 90% of patients, we found a causative (85% of upper GI bleeding and 50% of lower GI bleeding) or potentially causative lesion, and 30% of them required endoscopic treatment, without differences depending on the intensity of anticoagulation. No relationship was found between the type of lesions observed and the degree of anticoagulation in these patients. Patients who received more intense anticoagulation therapy had more severe hemorrhages (23% of patients with an INR >= 4 had a life-threatening bleed versus only 4% of patients with INR < 4). Conclusions: We found an incidence of 20 severe GI bleeding episodes in anticoagulated patients per 100,000 inhabitants-year, with no difference in localization or in the frequency of causative lesions depending on the intensity of anticoagulation. Patients receiving more intense anticoagulation had more severe GI bleeding episodes. (C) 2013 Elsevier Espana, S.L. and AEEH y AEG. All rights reserved.
Autores: Rotellar, Fernando, (Autor de correspondencia); Benito, Alberto; et al.
Revista: HPB
ISSN 1365-182X  Vol. 16  Nº 4  2014  págs. 320 - 326
ObjectivesThe laparoscopic approach is widely used in abdominal surgery. However, the benefits of laparoscopy in liver surgery have hitherto been insufficiently established. This study sought to investigate these benefits and, in particular, to establish whether or not the laparoscopic approach is beneficial in patients with lesions involving the posterosuperior segments of the liver. MethodsOutcomes in a cohort of patients undergoing mostly minor hepatectomy (50 laparoscopic and 52 open surgery procedures) between January 2000 and December 2010 at the University Clinic of Navarra were analysed. The two groups displayed similar clinical characteristics. ResultsPatients submitted to laparoscopic liver resection (LLR) had a lower risk for complications [odds ratio (OR) = 0.24, 95% confidence interval (CI) 0.07-0.74; P = 0.013] and shorter hospital stay (OR = 0.08, 95% CI 0.02-0.27; P < 0.001) independently of the presence of classical risk factors for complications. In the cohort of patients with lesions involving posterosuperior liver segments (20 laparoscopic, 21 open procedures), LLR was associated with significantly fewer complications (OR = 0.16, 95% CI 0.04-0.71) and a lower risk for a long hospital stay (OR = 0.1, 95% CI 0.02-0.43). ConclusionsThis study confirms that the laparoscopic approach to hepatic resection decreases the risk for post-surgical complications and lengthy hospitalization in patients undergoing minor liver resections. This beneficial effect is observed even in patients with lesions located in segments that require technically difficult resections.
Autores: Petersen, J. E. V.; Bouwens, E. A.; et al.
Revista: BLOOD
ISSN 0006-4971  Vol. 124  Nº 21  2014 
Autores: Hermida, José; Goñi, M.J.; et al.
Revista: DIABETOLOGIA
ISSN 0012-186X  Vol. 56  Nº 12  2013  págs. 2743-2752
MMP-10 is involved in the development of microvascular complications in type 1 diabetes and emerges as a potential therapeutic target for slowing down the evolution of diabetic nephropathy and retinopathy.
Autores: Lecumberri, Ramón; Marques, Margarita; et al.
Revista: THROMBOSIS AND HAEMOSTASIS
ISSN 0340-6245  Vol. 110  Nº 1  2013  págs. 184-190
Many cancer patients are at high risk of venous thromboembolism (VTE) during hospitalisation; nevertheless, thromboprophylaxis is frequently underused. Electronic alerts (e-alerts) have been associated with improvement in thromboprophylaxis use and a reduction of the incidence of VTE, both during hospitalisation and after discharge, particularly in the medical setting. However, there are no data regarding the benefit of this tool in cancer patients. Our aim was to evaluate the impact of a computer-alert system for VTE prevention in patients with cancer, particularly in those admitted to the Oncology/Haematology ward, comparing the results with the rest of inpatients at a university teaching hospital. The study included 32,167 adult patients hospitalised during the first semesters of years 2006 to 2010, 9,265 (28.8%) with an active malignancy. Appropriate prophylaxis in medical patients, significantly increased over time (from 40% in 2006 to 57% in 2010) and was maintained over 80% in surgical patients. However, while e-alerts were associated with a reduction of the incidence of VTE during hospitalisation in patients without cancer (odds ratio [OR] 0.31; 95% confidence interval [CI], 0.15-0.64), the impact was modest in cancer patients (OR 0.89; 95% CI, 0.42-1.86) and no benefit was observed in patients admitted to the Oncology/Haematology Departments (OR 1.11; 95% CI, 0.45-2.73). Interestingly, 60% of VTE episodes in cancer patients during recent years developed despite appro
Autores: Lecumberri, Ramón; Marques, Margarita; Alfonso, Ana; et al.
Revista: JOURNAL OF THROMBOSIS AND HAEMOSTASIS
ISSN 1538-7933  Vol. 11  Nº Supl 2  2013  págs. 381
Many cancer patients are at high risk of venous thromboembolism (VTE) during hospitalisation; nevertheless, thromboprophylaxis is frequently underused. Electronic alerts (e-alerts) have been associated with improvement in thromboprophylaxis use and a reduction of the incidence of VIE, both during hospitalisation and after discharge, particularly in the medical setting. However, there are no data regarding the benefit of this tool in cancer patients. Our aim was to evaluate the impact of a computer-alert system for VTE prevention in patients with cancer, particularly in those admitted to the Oncology/Haematology ward, comparing the results with the rest of inpatients at a university teaching hospital. The study included 32,167 adult patients hospitalised during the first semesters of years 2006 to 2010, 9,265 (28.8%) with an active malignancy. Appropriate prophylaxis in medical pa, tents, significantly increased over time (from 40% in 2006 to 57% in 2010) and was maintained over 80% in surgical patients. However,; while e-alerts were associated with a reduction of the incidence of VTE during hospitalisation in patients without cancer (odds ratio [OR] 0.31; 95% confidence interval [CI], 0.15-0.64), the impact was modest in cancer patients (OR 0.89; 95% CI, 0.42-1.86) and no benefit was observed in patients admitted to the Oncology/Haematology Departments (OR 1.11; 95% CI, 0.45-2.73). Interestingly, 60% of VIE episodes in cancer patients during recent years developed despite app
Autores: Montes, R., (Autor de correspondencia); Puy, C.; et al.
Revista: THROMBOSIS AND HAEMOSTASIS
ISSN 0340-6245  Vol. 107  Nº 5  2012  págs. 815 - 826
In the last decade, the endothelial cell protein C/activated protein C receptor (EPCR) has received considerable attention. The role initially attributed to EPCR, i.e. the enhancement of protein C (PC) activation by the thrombin-thrombomodulin complex on the surface of the large vessels, although important, did not go beyond the haemostasis scenario. However, the discovery of the cytoprotective, anti-inflammatory and anti-apoptotic features of the activated PC (APC) and the required involvement of EPCR for APC to exert such actions did place the receptor in a privileged position in the crosstalk between coagulation and inflammation. The last five years have shown that PC/APC are not the only molecules able to interact with EPCR. Factor VII/VIIa (FVII/VIIa) and factor Xa (FXa), two other serine proteases that play a central role in haemostasis and are also involved in signalling processes influencing wound healing, tissue remodelling, inflammation or metastasis, have been reported to bind to EPCR. These observations have paved the way for an exploration of unsuspected new roles for the receptor. This review aims to offer a new image of EPCR in the light of its extended panel of ligands. A brief update of what is known about the APC-evoked EPCR-dependent cell signalling mechanisms is provided, but special care has been taken to assemble all the information available about the interaction of EPCR with FVII/VIIa and FXa.
Autores: Díez, J; Hermida, José;
Revista: JOURNAL OF THROMBOSIS AND HAEMOSTASIS
ISSN 1538-7933  Vol. 10  Nº 9  2012  págs. 1733-1735
Autores: Hermida, José; Toledo, Estefanía Ainhoa; et al.
Revista: ANALES DEL SISTEMA SANITARIO DE NAVARRA
ISSN 1137-6627  Vol. 35  Nº 3  2012  págs. 425 - 432
BACKGROUND: Type 1 diabetes is associated with vascular morbidity. The aim of this study was to evaluate the role of polymorphisms rs1410996 CFH and rs10490924 ARMS2 with proliferative diabetic retinopathy and coronary disease in type 1 diabetes patients. MATERIAL AND METHODS: We present a retrospective study that analyses the clinical characteristics and the polymorphisms rs1410996 CFH and rs10490924 ARMS2 of 147 type 1 diabetes patients. RESULTS: The patients who developed proliferative diabetic retinopathy in the first 20 years carried the rs1410996 CFH polymorphism. The overall risk-allele frequency was significantly higher among patients with coronary artery disease than in those without it (75 vs. 53%, p<0.001). CONCLUSIONS: rs1410996 CFH polymorphism could be associated with both proliferative diabetic retinopathy and coronary artery disease in type 1 diabetes patients. However, rs10490924 ARMS2 does not seem to be associated either with retinopathy or coronary artery disease.
Autores: Lopez-Sagaseta, J. ; Puy, C.; et al.
Revista: BLOOD
ISSN 0006-4971  Vol. 119  Nº 12  2012  págs. 2914 - 2921
The endothelial protein C receptor (EPCR) plays an important role in cardiovascular disease by binding protein C/activated protein C (APC). EPCR structure contains a hydrophobic groove filled with an unknown phospholipid needed to perform its function. It has not been established whether lipid exchange takes place in EPCR as a regulatory mechanism of its activity. Our objective was to identify this phospholipid and to explore the possibility of lipid exchange as a regulatory mechanism of EPCR activity driven by the endothelially expressed secretory group V phospholipase A(2) (sPLA(2)-V). We identified phosphatidylcholine (PCh) as the major phospholipid bound to human soluble EPCR (sEPCR). PCh in EPCR could be exchanged for lysophosphatidylcholine (lysoPCh) and platelet activating factor (PAF). Remarkably, lysoPCh and PAF impaired the protein C binding ability of sEPCR. Inhibition of sPLA(2)-V, responsible for lysoPCh and PAF generation, improved APC binding to endothelial cells. EPCR-dependent protein C activation and APC antiapoptotic effect were thus significantly enhanced. In contrast, endothelial cell supplementation with sPLA(2)-V inhibited both APC generation and its antiapoptotic effects. We conclude that APC generation and function can be modulated by changes in phospholipid occupancy of its endothelial cell receptor. (Blood. 2012;119(12):2914-2921)
Autores:  et al.
Revista: AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE
ISSN 1073-449X  Vol. 186  Nº 1  2012  págs. 96 - 105
Rationale: Efficient metastasis requires survival and adaptation of tumor cells to stringent conditions imposed by the extracellular milieu. Identification of critical survival signaling pathways in tumor cells might unveil novel targets relevant in disease progression. Objectives: To investigate the contribution of activated protein C (APC) and its receptor (endothelial protein C receptor [EPCR]) in animal models of lung cancer metastasis and in patients with lung adenocarcinoma. Methods: Signaling pathway triggered by APC/EPCR and its relevance in apoptosis was studied in vitro. Functional significance was assessed by silencing and blocking antibodies in several in vivo models of lung cancer metastasis in athymic nude Foxn1(nu) mice. We examined EPCR levels using a microarray dataset of 107 patients. Immunohistochemical analysis was performed in an independent cohort of 295 patients with lung adenocarcinoma. Measurements and Main Results: The effects of APC binding to EPCR rapidly triggered Akt and extracellular signal-regulated kinase signaling pathways, leading to attenuated in vitro apoptosis. In vivo, silencing of EPCR expression or blocking APC/EPCR interaction reduced infiltration in the target organ, resulting in impaired prometastatic activity. Moreover, overexpression of EPCR induced an increased metastatic activity to target organs. Analysis of clinical samples showed a robust association between high EPCR levels and poor prognosis, particularly in stage I patients. Conclusions: EPCR and its ligand APC promote cell survival that contributes to tumor cell endurance to stress favoring prometastatic activity of lung adenocarcinoma. EPCR/APC is a novel target of relevance in the clinical outcome of early-stage lung cancer.
Autores: Toni, M. ; Hermida, José; Toledo, Estefanía Ainhoa; et al.
Revista: ANALES DEL SISTEMA SANITARIO DE NAVARRA
ISSN 1137-6627  Vol. 35  Nº 3  2012  págs. 425 - 432
Background. Type 1 diabetes is associated with vascular morbidity. The aim of this study was to evaluate the role of polymorphisms rs1410996 CFH and rs10490924 ARMS2 with proliferative diabetic retinopathy and coronary disease in type 1 diabetes patients. Material and methods. We present a retrospective study that analyses the clinical characteristics and the polymorphisms rs1410996 CFH and rs10490924 ARMS2 of 147 type 1 diabetes patients. Results. The patients who developed proliferative diabetic retinopathy in the first 20 years carried the rs1410996 CFH polymorphism. The overall risk-allele frequency was significantly higher among patients with coronary artery disease than in those without it (75 vs. 53%, p<0.001). Conclusions. rs1410996 CFH polymorphism could be associated with both proliferative diabetic retinopathy and coronary artery disease in type 1 diabetes patients. However, rs10490924 ARMS2 does not seem to be associated either with retinopathy or coronary artery disease.
Autores: Segura, Victoriano; Gavira, Juan José; et al.
Revista: THROMBOSIS AND HAEMOSTASIS
ISSN 0340-6245  Vol. 108  Nº 4  2012  págs. 742 - 749
The leading cause of cardioembolic stroke is atrial fibrillation (AF), which predisposes to atrial thrombus formation. Although rheological alterations promote a hypercoagulable environment, as yet undefined factors contribute to thrombogenesis. The role of the endocardium has barely been explored. To approach this topic, rapid atrial pacing (RAP) was applied in four pigs to mimic AF. Left and right endocardial cells were isolated separately and their gene expression pattern was compared with that of four control pigs. The AF-characteristic rhythm disorders and endothelial nitric oxide synthase down-regulation were successfully reproduced, and validated RAP to mimic AF. A change was observed in the transcriptonnic endocardial profile after RAP: the expression of 364 genes was significantly altered (p < 0.01), 29 of them having passed the B > 0 criteria. The left atrial endocardium [325 genes (7 genes, B > 0)] was largely responsible for such alterations. Blood coagulation, blood vessel morphogenesis and inflammatory response are among the most significant altered functions, and help to explain the activation of coagulation observed after RAP: D-dimer, 0.49 (1.63) vs. 0.23 (0.24) mg/l [median (interquartile range)] in controls, p=0.02. Furthermore, three genes directly related to thrombotic processes were differentially expressed after RAP: FGL2 [fold change (FC)=0.85; p=0.007], APLP2 (FC=-0.47; p=0.005) and ADAMTS-18 (FC=-0.69; p=0.004). We demonstrate for the first time that AF induces a global expression change in the left atrial endocardium associated with an activation of blood coagulation. The nature of some of the altered functions and genes provides clues to identify new therapeutic targets.
Autores: Hermida, José, (Autor de correspondencia); Lopez, F. L.; Montes, R. ; et al.
Revista: AMERICAN JOURNAL OF CARDIOLOGY
ISSN 0002-9149  Vol. 109  Nº 1  2012  págs. 95 - 99
High-sensitivity C-reactive protein (hs-CRP) is a marker for the risk of cardiovascular and overall mortality. However, information about the association between hs-CRP and mortality in patients with atrial fibrillation is scarce. A total of 293 participants of the Atherosclerosis Risk In Communities study with a history of AF and hs-CRP levels available were studied. During a median follow-up of 9.4 years, 134 participants died (46%). The hazard ratio of all-cause mortality associated with the highest versus the lowest tertile of hs-CRP was 2.52 (95% confidence interval 1.49 to 4.25) after adjusting for age, gender, history of cardiovascular diseases, and cardiovascular risk factors. A similar trend was observed for cardiovascular mortality (57 events; hazard ratio 1.90, 95% confidence interval 0.81 to 4.45). The Congestive heart failure, Hypertension, Age >75 years, Diabetes, and previous Stroke or transient ischemic attack (CHADS2) score was also associated with all-cause and cardiovascular mortality, with an adjusted hazard ratio of 3.39 (95% confidence interval 1.91 to 6.01) and 8.71 (95% confidence interval 2.98 to 25.47), respectively, comparing those with a CHADS2 score >2 versus a CHADS2 score of 0. Adding hs-CRP to a predictive model including the CHADS2 score was associated with an improvement of the C-statistic for total mortality (from 0.627 to 0.677) and for cardiovascular mortality (from 0.700 to 0.718). In conclusion, high levels of hs-CRP constitute an independent marker for the risk of mortality in patients with atrial fibrillation. (C) 2012 Elsevier Inc. All rights reserved. (Am J Cardiol 2012;109:95-99)
Autores: Navarro, S. ; Bonet, E.; Estelles, A. ; et al.
Revista: THROMBOSIS RESEARCH
ISSN 0049-3848  Vol. 128  Nº 5  2011  págs. 410 - 416
The protein C anticoagulant pathway plays a crucial role as a regulator of the blood clotting cascade. Protein C is activated on the vascular endothelial cell membrane by the thrombin-thrombomodulin complex. The endothelial protein C receptor binds protein C and further enhances protein C activation. Once formed, activated protein C down-regulates thrombin formation by inactivating factors Va and VIIIa and exerts cytoprotective effects through endothelial protein C receptor binding. An adequate generation of activated protein C depends on the precise assembly, on the surface of the endothelial cells, of thrombin, thrombomodulin, protein C, and endothelial protein C receptor. Therefore, any change in the efficiency of this assembly may cause a reduction or increase in activated protein C generation and modulate the risk of thrombosis. This review highlights the role of the endothelial protein C receptor in disease and discusses the association of its mutations with the risk of thrombosis. (C) 2011 Elsevier Ltd. All rights reserved.
Autores: Cervero, J. ; Montes, R.; Espana, F. ; et al.
Revista: STROKE
ISSN 0039-2499  Vol. 42  Nº 9  2011  págs. 2622 - 2624
Background and Purpose-Atrial fibrillation is the most important risk factor for cardioembolic stroke. Thrombi form in the left atrial appendage rather than in the right. The causes of this different thrombogenicity are not well-understood. The goal herein was to compare the activation of the anticoagulant protein C and the thrombomodulin and endothelial protein C receptor/activated protein C receptor expression on the endocardium between right and left atria. Methods-We harvested the atria of 6 monkeys (Macaca fascicularis) and quantified their ability to activate protein C ex vivo and we measured the thrombomodulin and endothelial protein C receptor expression by immunofluorescence. Results-We found the ability to activate protein C decreased by half (P = 0.028) and there was lower expression of thrombomodulin in the left atrial endocardium than the right (52.5 +/- 19.9 and 72.1 +/- 18.8 arbitrary intensity units, mean +/- standard deviation; P = 0.028). No differences were detected in endothelial protein C receptor expression. Conclusions-Impaired protein C activation on the left atrial endocardium attributable to low thrombomodulin expression may explain its higher thrombogenicity and play a role in cardioembolic stroke. (Stroke. 2011;42:2622-2624.)
Autores: Puy, C. ; Hermida, José; Montes, R., (Autor de correspondencia)
Revista: JOURNAL OF THROMBOSIS AND HAEMOSTASIS
ISSN 1538-7933  Vol. 9  Nº 6  2011  págs. 1256 - 1257
Autores: Puy, C.; Lopez-Sagaseta, J.; Hermida, José; et al.
Revista: BRITISH JOURNAL OF HAEMATOLOGY
ISSN 0007-1048  Vol. 149  Nº 1  2010  págs. 111 - 117
P>Traces of activated factor VII (FVIIa) are required to maintain haemostasis. Activated factor X (FXa) is the main activator of FVII in the absence of tissue factor. However, little is known about how this mechanism is regulated. We and others reported the interaction between FVII and the endothelial cell protein C receptor (EPCR). We have analysed the role of EPCR in the FXa-dependent FVIIa generation. Activation was performed on the surface of human aortic endothelial cells in the presence or absence of a blocking anti-EPCR monoclonal antibody (mAb). Western-blot analyses revealed that FVII activation was increased twofold upon EPCR blocking. Kinetic analyses revealed that blocking doubled the catalytic efficiency for activation. Protein C was unable to mimic the effect of the anti-EPCR mAb on activation. Surface plasmon resonance experiments revealed that binding of EPCR and phospholipids to FVII were mutually exclusive. The 50% inhibitory concentration value for phospholipids to reduce the binding of FVIIa to EPCR was 57 center dot 67 +/- 0 center dot 11 mu mol/l. Immunofluorescence experiments showed that EPCR and phosphatidylserine are located at different regions of the cell surface. We propose that EPCR downregulates FVII activation by moving it from phosphatidylserine-rich regions. In summary, this study described a new anticoagulant role for EPCR.
Autores: Centelles, Miguel Nöel; Puy, C. ; Lopez-Sagaseta, J.; et al.
Revista: THROMBOSIS AND HAEMOSTASIS
ISSN 0340-6245  Vol. 103  Nº 6  2010  págs. 1239 - 1244
The endothelial protein C receptor (EPCR) plays an anticoagulant role by improving protein C activation. Although low levels of activated protein C (APC) constitute a thrombosis risk factor, the relationship between modulating EPCR function and thrombosis has not been addressed so far. Monoclonal antibodies (mAb) against murine EPCR were raised, and their ability to block protein C/APC binding was tested. The ferric chloride carotid artery injury model in mice was chosen to test the effect of anti-EPCR mAb on thrombus formation. The time to total occlusion of the vessel was analysed in three groups, given an isotype control mAb (IC), a blocking (RCR-16) or a non-blocking (RCR-20) anti-EPCR mAb. RCR-16 prevented the interaction between protein C/APC and EPCR as demonstrated by surface plasmon resonance and flow cytometry, and inhibited the activation of protein C on the endothelium. IC and RCR-20 were unable to induce such effects. In vivo, RCR-16 shortened the time to total vessel occlusion with respect to IC [13.4 +/- 1.0 (mean +/- SD) and 17.8 +/- 3.2 minutes, respectively, p<0.001]. Occlusive thrombi lasting for more than one hour were observed in all RCR-16-treated animals, but only in 43% of IC-treated ones. Results with RCR-20 were indistinguishable from those observed with IC. For the first time, a direct relationship between blocking EPCR and thrombosis is demonstrated. Blocking anti-EPCR autoantibodies can predispose to thrombosis episodes and may constitute a new therapeutic target.
Autores: Catena, R.; Larzábal, Leyre; Larráyoz, Marta; et al.
Revista: MOLECULAR CANCER
ISSN 1476-4598  Vol. 9  Nº 320  2010  págs. 1 - 14
Background: Different isoforms of VEGF-A (mainly VEGF(121), VEGF(165) and VEGF(189)) have been shown to display particular angiogenic properties in the generation of a functional tumor vasculature. Recently, a novel class of VEGF-A isoforms, designated as VEGF(xxx)b, generated through alternative splicing, have been described. Previous studies have suggested that these isoforms may inhibit angiogenesis. In the present work we have produced recombinant VEGF(121/165)b proteins in the yeast Pichia pastoris and constructed vectors to overexpress these isoforms and assess their angiogenic potential. Results: Recombinant VEGF(121/165)b proteins generated either in yeasts or mammalian cells activated VEGFR2 and its downstream effector ERK1/2, although to a lesser extent than VEGF(165). Furthermore, treatment of endothelial cells with VEGF(121/165)b increased cell proliferation compared to untreated cells, although such stimulation was lower than that induced by VEGF165. Moreover, in vivo angiogenesis assays confirmed angiogenesis stimulation by VEGF(121/165)b isoforms. A549 and PC 3 cells overexpressing VEGF(121)b or VEGF(165)b (or carrying the PCDNA3.1 empty vector, as control) and xenotransplanted into nude mice showed increased tumor volume and angiogenesis compared to controls. To assess whether the VEGF(xxx)b isoforms are differentially expressed in tumors compared to healthy tissues, immunohistochemical analysis was conducted on a breast cancer tissue microarray. A significant increase (p < 0.05) in both VEGF(xxx)b and total VEGF-A protein expression in infiltrating ductal carcinomas compared to normal breasts was observed. A positive significant correlation (r = 0.404, p = 0.033) between VEGF(xxx)b and total VEGF-A was found. Conclusions: Our results demonstrate that VEGF(121/165)b are not anti-angiogenic, but weakly angiogenic isoforms of VEGF-A. In addition, VEGF(xxx)b isoforms are up-regulated in breast cancer in comparison with non malignant breast tissues. These results are to be taken into account when considering a possible use of VEGF(121/165)b-based therapies in patients.

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