Revistas
Revista:
JOURNAL OF CLINICAL MEDICINE
ISSN:
2077-0383
Año:
2023
Vol.:
12
N°:
4
Págs.:
1399
Thromboinflammation or immunothrombosis is a concept that explains the existing link between coagulation and inflammatory response present in many situations, such as sepsis, venous thromboembolism, or COVID-19 associated coagulopathy. The purpose of this review is to provide an overview of the current data regarding the mechanisms involved in immunothrombosis in order to understand the new therapeutic strategies focused in reducing thrombotic risk by controlling the inflammation.
Revista:
FRONTIERS IN CELL AND DEVELOPMENTAL BIOLOGY
ISSN:
2296-634X
Año:
2023
Vol.:
11
Págs.:
1128534
Aged muscles accumulate satellite cells with a striking decline response to damage. Although intrinsic defects in satellite cells themselves are the major contributors to aging-associated stem cell dysfunction, increasing evidence suggests that changes in the muscle-stem cell local microenvironment also contribute to aging. Here, we demonstrate that loss of the matrix metalloproteinase-10 (MMP-10) in young mice alters the composition of the muscle extracellular matrix (ECM), and specifically disrupts the extracellular matrix of the satellite cell niche. This situation causes premature features of aging in the satellite cells, contributing to their functional decline and a predisposition to enter senescence under proliferative pressure. Similarly, reduction of MMP-10 levels in young satellite cells from wild type animals induces a senescence response, while addition of the protease delays this program. Significantly, the effect of MMP-10 on satellite cell aging can be extended to another context of muscle wasting, muscular dystrophy. Systemic treatment of mdx dystrophic mice with MMP-10 prevents the muscle deterioration phenotype and reduces cellular damage in the satellite cells, which are normally under replicative pressure. Most importantly, MMP-10 conserves its protective effect in the satellite cell-derived myoblasts isolated from a Duchenne muscular dystrophy patient by decreasing the accumulation of damaged DNA. Hence, MMP-10 provides a previously unrecognized therapeutic opportunity to delay satellite cell aging and overcome satellite cell dysfunction in dystrophic muscles.
Autores:
Llau, J. V. (Autor de correspondencia); Aldecoa, C.; Guasch, E.; et al.
Revista:
REVISTA ESPAÑOLA DE ANESTESIOLOGÍA Y REANIMACION
ISSN:
0034-9356
Año:
2023
Vol.:
70
N°:
7
Págs.:
409 - 421
This document is an update of the multidisciplinary document HEMOMAS, published in 2016 with the endorsement of the Spanish Scientific Societies of Anaesthesiology (SEDAR), Intensive Care (SEMICYUC) and Thrombosis and Haemostasis (SETH). The aim of this document was to review and update existing recommendations on the management of massive haemorrhage. The methodology of the update was based on several elements of the ADAPTE method by searching and adapting guidelines published in the specific field of massive bleeding since 2014, plus a literature search performed in PubMed and EMBASE from January 2014 to June 2021. Based on the review of 9 guidelines and 207 selected articles, the 47 recommendations in the original article were reviewed, maintaining, deleting, or modifying each of them and the accompanying grades of recommendation and evidence. Following a consensus process, the final wording of the article and the resulting 41 recommendations were approved by all authors.
Autores:
Llau, Juan V. (Autor de correspondencia); Aldecoa, C.; Guasch, E.; et al.
Revista:
MEDICINA INTENSIVA
ISSN:
0210-5691
Año:
2023
Vol.:
47
N°:
8
Págs.:
454 - 467
This document is an update of the multidisciplinary document HEMOMAS, published in 2016 with the endorsement of the Spanish Scientific Societies of Anaesthesiology (SEDAR), Intensive Care (SEMICYUC) and Thrombosis and Haemostasis (SETH). The aim of this document was to review and update existing recommendations on the management of massive haemorrhage. The methodology of the update was based on several elements of the ADAPTE method by searching and adapting guidelines published in the specific field of massive bleeding since 2014, plus a literature search performed in PubMed and EMBASE from January 2014 to June 2021. Based on the review of 9 guidelines and 207 selected articles, the 47 recommendations in the original article were reviewed, maintaining, deleting, or modifying each of them and the accompanying grades of recommendation and evidence. Following a consensus process, the final wording of the article and the resulting 41 recommendations were approved by all authors.
Revista:
ATHEROSCLEROSIS
ISSN:
1879-1484
Año:
2023
Vol.:
385
Págs.:
117343
BACKGROUND AND AIMS: Peripheral arterial disease (PAD) is a leading cause of morbimortality worldwide. Lipocalin-2 (LCN2) has been associated with higher risk of amputation or mortality in PAD and might be involved in muscle regeneration. Our aim is to unravel the role of LCN2 in skeletal muscle repair and PAD.
METHODS AND RESULTS: WT and Lcn2-/- mice underwent hindlimb ischemia. Blood and crural muscles were analyzed at the inflammatory and regenerative phases. At day 2, Lcn2-/- male mice, but not females, showed increased blood and soleus muscle neutrophils, and elevated circulating pro-inflammatory monocytes (p<0.05), while locally, total infiltrating macrophages were reduced (p<0.05). Moreover, Lcn2-/- soleus displayed an elevation of Cxcl1 (p<0.001), and Cxcr2 (p<0.01 in males), and a decrease in Ccl5 (p<0.05). At day 15, Lcn2 deficiency delayed muscle recovery, with higher density of regenerating myocytes (p<0.04) and arterioles (alphaSMA+, p<0.025). Reverse target prediction analysis identified miR-138-5p as a potential regulator of LCN2, showing an inverse correlation with Lcn2 mRNA in skeletal muscles (rho=-0.58, p<0.01). In vitro, miR-138-5p mimic reduced Lcn2 expression and luciferase activity in murine macrophages (p<0.05). Finally, in human serum miR-138-5p was inversely correlated with LCN2 (p¿0.001 adjusted, n=318), and associated with PAD (Odds ratio 0.634, p=0.02, adjusted, PAD n=264, control n=54).
CONCLUSIONS: This study suggests a possible dual role of LCN2 in acute and chronic conditions, with a probable role in restraining inflammation early after skeletal muscle ischemia, while being associated with vascular damage in PAD, and identifies miR-138-5p as one potential post-transcriptional regulator of LCN2.
Revista:
THROMBOSIS AND HAEMOSTASIS
ISSN:
0340-6245
Año:
2022
Vol.:
122
N°:
08
Págs.:
1314 - 1325
Background: Intracranial hemorrhage (ICH) is one of the major devastating complications of anticoagulation. Matrix metalloproteinase (MMP) inhibition has been proposed as a novel pharmacological approach for ICH treatment.
Objectives: We evaluated the effects of CM-352 (MMP-fibrinolysis inhibitor) in an experimental ICH model associated with oral anticoagulants as compared with clinically used prothrombin complex concentrate (PCC).
Methods: ICH was induced by collagenase injection into the striatum of wild type (C57BL/6J) anticoagulated mice (warfarin or rivaroxaban) and Mmp10 -/- mice. Hematoma volume and neurological deficits were measured 24 hours later by diaminobenzidine staining and different behavioral tests. Circulating plasminogen activator inhibitor-1 (PAI-1) activity and interleukin-6 (IL-6) were measured in plasma samples and local inflammation was assessed by neutrophil infiltration. Finally, fibrinolytic effects of MMP-10 and rivaroxaban were evaluated by thromboelastometry and thrombin-activatable fibrinolysis inhibitor (TAFI) activation assays.
Results: Only PCC reduced hemorrhage volume and improved functional outcome in warfarin-ICH, but both PCC and CM-352 treatments diminished hemorrhage volume (46%, p < 0.01 and 64%, p < 0.001, respectively) and ameliorated functional outcome in rivaroxaban-ICH. We further demonstrated that CM-352, but not PCC, decreased neutrophil infiltration in the hemorrhage area at 24 hours. The effect of CM-352 could be related to MMP-10 inhibition since Mmp10 -/- mice showed lower hemorrhage volume, better neurological score, reduced IL-6 levels and neutrophil infiltration, and increased PAI-1 after experimental ICH. Finally, we found that CM-352 reduced MMP-10 and rivaroxaban-related fibrinolytic effects in thromboelastometry and TAFI activation.
Conclusion: CM-352 treatment, by diminishing MMPs and rivaroxaban-associated fibrinolytic effects, might be a novel antihemorrhagic strategy for rivaroxaban-associated ICH.
Revista:
MEDICINA CLINICA
ISSN:
0025-7753
Año:
2022
Vol.:
158
N°:
2
Págs.:
82 - 89
Autores:
Fernández-Alonso, S.; Martínez-Aguilar, E.; Ravassa, S; et al.
Revista:
LIFE
ISSN:
2075-1729
Año:
2022
Vol.:
12
N°:
6
Págs.:
823
Predicting the progression of small aneurysms is a main challenge in abdominal aortic aneurysm (AAA) management. The combination of circulating biomarkers and image techniques might provide an alternative for risk stratification. We evaluated the association of plasma TAT complexes (TAT) and D-dimer with AAA severity in 3 groups of patients: group 1, without AAA (n = 52), group 2, AAA 40-50 mm (n = 51) and group 3, AAA > 50 mm (n = 50). TAT (p < 0.001) and D-dimer (p < 0.001) were increased in patients with AAA (groups 2 and 3) vs. group 1. To assess the association between baseline TAT and D-dimer concentrations, and AAA growth, aortic diameter and volume (volumetry) were measured by computed tomography angiography (CTA) in group 2 at recruitment (baseline) and 1-year after inclusion. Baseline D-dimer and TAT levels were associated with AAA diameter and volume variations at 1-year independently of confounding factors (p <= 0.044). Additionally, surgery incidence, recorded during a 4-year follow-up in group 2, was associated with larger aneurysms, assessed by aortic diameter and volumetry (p <= 0.036), and with elevated TAT levels (sub-hazard ratio 1.3, p <= 0.029), while no association was found for D-dimer. The combination of hemostatic parameters and image techniques might provide valuable tools to evaluate AAA growth and worse evolution.
Revista:
REUMATOLOGIA CLINICA
ISSN:
1699-258X
Año:
2022
Vol.:
18
N°:
1
Págs.:
1 - 4
The haemostatic system acts in concert with inflammation, so that after inflammatory response various mediators activate the haemostatic system through endothelial dysfunction, platelet activation and coagulation promoting thrombosis, which is termed thromboinflammation. In this process, the inflammasome acquires special relevance; its stimulation promotes innate and adaptive immune responses. Inflamma some activation plays an important physiopathological role in several disorders with inflammatory and thrombotic phenomena. The role of thromboinflammation has become relevant in the COVID-19 pandemic, in which a cytokine storm has been described as one of the mechanisms responsible.
Revista:
REUMATOLOGIA CLINICA
ISSN:
1699-258x
Año:
2022
Vol.:
18
N°:
1
Págs.:
1 - 4
The haemostatic system acts in concert with inflammation, so that after inflammatory response various mediators activate the haemostatic system through endothelial dysfunction, platelet activation and coagulation promoting thrombosis, which is termed thromboinflammation. In this process, the inflammasome acquires special relevance; its stimulation promotes innate and adaptive immune responses. Inflamma some activation plays an important physiopathological role in several disorders with inflammatory and thrombotic phenomena. The role of thromboinflammation has become relevant in the COVID-19 pandemic, in which a cytokine storm has been described as one of the mechanisms responsible.
Revista:
EUROPEAN JOURNAL OF VASCULAR AND ENDOVASCULAR SURGERY
ISSN:
1078-5884
Año:
2022
Vol.:
63
N°:
4
Págs.:
648 - 656
Objective: Peripheral arterial disease (PAD) is the most prevalent cardiovascular (CV) condition globally. Despite the high CV risk of PAD patients, no reliable predictors of adverse clinical evolution are yet available. In this regard, previous transcriptomic analyses revealed increased expression of calprotectin (S100A8/A9) and lipocalin-2 (LCN2) in circulating extracellular vesicles (EVs) of patients with PAD. The aim of this study was to determine the prognostic value of LCN2 and calprotectin for CV risk assessment in PAD. Methods: LCN2 and the S100A9 subunit of calprotectin were examined in human femoral plaques by immunohistochemistry and qPCR. LCN2 and calprotectin were determined by ELISA in PAD (CHN cohort, n = 331, Fontaine IIeIV, serum), and PAD diagnosed by population based screening (VIVA trial, n = 413, the majority Fontaine 0eI, plasma). Patients were followed up for a mean of four years, recording the primary outcomes; CV death or amputation in the CHN cohort and CV death or major lower limb events (MALE) in the VIVA population. Secondary outcomes were all cause death or amputation, and all cause death or MALE, respectively. Results: LCN2 and S100A9 were detected in human plaques in regions rich in inflammatory cells. LCN2 and calprotectin levels were 70% and 64% lower in plasma than in serum. In the CHN cohort, high serum levels of LCN2 and calprotectin increased the risk of primary and secondary outcomes 5.6 fold (p < .001) and 1.8 fold (p = .034), respectively, after covariable adjustment. Similarly, elevated plasma levels of LCN2 and calprotectin increased by three fold the risk of primary and secondary outcomes (p <.001) in the VIVA cohort. Moreover, addition of the combined variable to basal models, considering clinically relevant risk factors, improved reclassification for the primary outcome in both cohorts (p <= .024). Conclusion: Combined assessment of the inflammatory biomarkers LCN2 and calprotectin might be useful for risk stratification in advanced and early PAD.
Autores:
Mostaza, J. M. (Autor de correspondencia); Pinto, X.; Armario, P.; et al.
Revista:
CLINICA E INVESTIGACION EN ARTERIOSCLEROSIS
ISSN:
0214-9168
Año:
2022
Vol.:
34
N°:
3
Págs.:
130 - 179
One of the objectives of the Spanish Society of Arteriosclerosis is to contribute to better knowledge of vascular disease, its prevention and treatment. It is well known that cardiovascular diseases are the leading cause of death in our country and entail a high degree of disability and health care costs. Arteriosclerosis is a multifactorial disease and therefore its prevention requires a global approach that takes into account the different risk factors with which it is associated. Therefore, this document summarizes the current level of knowledge and includes recommendations and procedures to be followed in patients with established cardiovascular disease or at high vascular risk. Specifically, this document reviews the main symptoms and signs to be evaluated during the clinical visit, the laboratory and imaging procedures to be routinely requested or requested for those in special situations. It also includes vascular risk estimation, the diagnostic criteria of the different entities that are cardiovascular risk factors, and makes general and specific recommendations for the treatment of the different cardiovascular risk factors and their final objectives. Finally, the document includes aspects that are not usually referenced in the literature, such as the organization of a vascular risk consultation.
Revista:
LIFE
ISSN:
2075-1729
Año:
2021
Vol.:
11
N°:
5
Págs.:
414
BACKGROUND: Atherosclerosis is the main etiology of cardiovascular diseases (CVD), associated to systemic inflammation. Matrix metalloproteinases (MMPs) are related to atherosclerosis progression through the SDF1/CXCR4 axis promoting macrophages recruitment within the vascular wall. The goal was to assess new circulatory inflammatory markers in relation to atherosclerosis. METHODS: Measurement of SDF1, MMP12 and CRP in blood samples of 298 prospective patients with cardiovascular risk. To explore atherosclerosis progression, CXCR4/SDF1 axis and MMP12 expression were determined by RT-qPCR and by immunohistochemistry in the aorta of accelerated and delayed atherosclerosis mice models (Apoe-/- and Apoe-/-Mmp10-/-). RESULTS: SDF1, MMP12 and CRP were elevated in patients with clinical atherosclerosis, but after controlling by confounding factors, only SDF1 and CRP remained increased. Having high levels of both biomarkers showed 2.8-fold increased risk of presenting clinical atherosclerosis (p = 0.022). Patients with elevated SDF1, MMP12 and CRP showed increased risk of death in follow-up (HR = 3.2, 95%CI: 1.5-7.0, p = 0.004). Gene and protein expression of CXCR4 and MMP12 were increased in aortas from Apoe-/- mice. CONCLUSIONS: The combination of high circulating SDF1, MMP12 and CRP identified patients with particular inflammatory cardiovascular risk and increased mortality. SDF1/CXCR4 axis and MMP12 involvement in atherosclerosis development suggests that they could be possible atherosclerotic targets.
Revista:
JOURNAL OF NEUROINFLAMMATION
ISSN:
1742-2094
Año:
2021
Vol.:
18
N°:
1
Págs.:
3
Background Inflammatory response plays an important role in many processes related to acute ischemic stroke (AIS). Calprotectin (S100A8/S100A9), released by monocytes and neutrophils, is a key protein in the regulation of inflammation and thrombosis. The purpose of this study is to evaluate the association of circulating calprotectin with other inflammatory biomarkers and AIS prognosis, as well as the calprotectin content in stroke thrombi. Methods Among the 748 patients treated at a comprehensive stroke center between 2015 and 2017, 413 patients with confirmed acute ischemic injury were prospectively evaluated. Patients with systemic inflammation or infection at onset were excluded. Plasma calprotectin was measured by ELISA in blood samples of AIS patients within the first 24 h. Univariate and multivariate logistic regression models were performed to evaluate its association with mortality and functional independence (FI) at 3 months (defined as modified Rankin Scale < 3) and hemorrhagic transformation (HT) after ischemic stroke. Further, S100A9 was localized by immunostaining in stroke thrombi (n = 44). Results Higher calprotectin levels were associated with 3-month mortality, HT, and lower 3-month FI. After adjusting for potential confounders, plasma calprotectin remained associated with 3-month mortality [OR (95% CI) 2.31 (1.13-4.73)]. Patients with calprotectin >= 2.26 mu g/mL were 4 times more likely to die [OR 4.34 (1.95-9.67)]. Addition of calprotectin to clinical variables led to significant improvement in the discrimination capacity of the model [0.91 (0.87-0.95) vs 0.89 (0.85-0.93); p < 0.05]. A multimarker approach demonstrated that patients with increased calprotectin, CRP, and NLR had the poorest outcome with a mortality rate of 42.3% during follow-up. S100A9 protein, as part of the heterodimer calprotectin, was present in all thrombi retrieved from AIS patients. Mean S100A9 content was 3.5% and tended to be higher in patients who died (p = 0.09). Moreover, it positively correlated with platelets (Pearson r 0.46, p < 0.002), leukocytes (0.45, p < 0.01), and neutrophil elastase (0.70, p < 0.001) thrombus content. Conclusions Plasma calprotectin is an independent predictor of 3-month mortality and provides complementary prognostic information to identify patients with poor outcome after AIS. The presence of S100A9 in stroke thrombi suggests a possible inflammatory mechanism in clot formation, and further studies are needed to determine its influence in resistance to reperfusion.
Revista:
JOURNAL OF THROMBOSIS AND THROMBOLYSIS
ISSN:
0929-5305
Año:
2021
Vol.:
51
N°:
3
Págs.:
633 - 636
Revista:
FRONTIERS IN NEUROLOGY
ISSN:
1664-2295
Año:
2021
Vol.:
12
Págs.:
599498
Background: Actual clinical management of ischemic stroke (IS) is based on restoring cerebral blood flow using tissue plasminogen activator (tPA) and/or endovascular treatment (EVT). Mechanical thrombectomy has permitted the analysis of thrombus structural and cellular classic components. Nevertheless, histological assessment of hemostatic parameters such as thrombin-activatable fibrinolysis inhibitor (TAFI) and matrix metalloproteinase 10 (MMP-10) remains unknown, although their presence could determine thrombus stability and its response to thrombolytic treatment, improving patient's outcome. Methods: We collected thrombi (n = 45) from large vessel occlusion (LVO) stroke patients (n = 53) and performed a histological analysis of different hemostatic parameters [TAFI, MMP-10, von Willebrand factor (VWF), and fibrin] and cellular components (erythrocytes, leukocytes, macrophages, lymphocytes, and platelets). Additionally, we evaluated the association of these parameters with plasma levels of MMP-10, TAFI and VWF activity and recorded clinical variables. Results: In this study, we report for the first time the presence of MMP-10 and TAFI in all thrombi collected from LVO patients. Both proteins were localized in regions of inflammatory cells, surrounded by erythrocyte and platelet-rich areas, and their content was significantly associated (r = 0.41, p < 0.01). Thrombus TAFI was lower in patients who died during the first 3 months after stroke onset [odds ratio (OR) (95%CI); 0.59 (0.36-0.98), p = 0.043]. Likewise, we observed that thrombus MMP-10 was inversely correlated with the amount of VWF (r = -0.30, p < 0.05). Besides, VWF was associated with the presence of leukocytes (r = 0.37, p < 0.05), platelets (r = 0.32, p < 0.05), and 3 months mortality [OR (95%CI); 4.5 (1.2-17.1), p = 0.029]. Finally, plasma levels of TAFI correlated with circulating and thrombus platelets, while plasma MMP-10 was associated with cardiovascular risk factors and functional dependence at 3 months. Conclusions: The present study suggests that the composition and distribution of thrombus hemostatic components might have clinical impact by influencing the response to pharmacological and mechanical therapies as well as guiding the development of new therapeutic strategies.
Revista:
PEDIATRIA INTEGRAL
ISSN:
1135-4542
Año:
2021
Vol.:
25
N°:
5
Págs.:
265.e1 - 265.e11
La hemostasia comprende un complejo sistema de reacciones en cadena, sinérgicas y coordinadas, cuya finalidad última es mantener la sangre fluida en el interior de los vasos sanguíneos. Para ello, existe un delicado equilibrio entre los factores procoagulantes y anticoagulantes. Disponemos de una amplia variedad de pruebas analíticas que exploran el sistema hemostático en sus distintas fases (hemostasia primaria, hemostasia secundaria y fibrinólisis). Para poder solicitarlas con criterio y saber interpretarlas, es preciso tener unas nociones básicas de la fisiología de la hemostasia. En el presente artículo, se explican las bases fisiológicas de la coagulación, haciendo hincapié en las peculiaridades de la ¿hemostasia del desarrollo¿ del niño y se exponen las pruebas de estudio disponibles, sus indicaciones y su interpretación.
Revista:
JOURNAL OF BONE AND MINERAL RESEARCH
ISSN:
0884-0431
Año:
2021
Vol.:
36
N°:
11
Págs.:
2203 - 2213
The remodeling of the extracellular matrix is a central function in endochondral ossification and bone homeostasis. During secondary fracture healing, vascular invasion and bone growth requires the removal of the cartilage intermediate and the coordinate action of the collagenase matrix metalloproteinase (MMP)-13, produced by hypertrophic chondrocytes, and the gelatinase MMP-9, produced by cells of hematopoietic lineage. Interfering with these MMP activities results in impaired fracture healing characterized by cartilage accumulation and delayed vascularization. MMP-10, Stromelysin 2, a matrix metalloproteinase with high homology to MMP-3 (Stromelysin 1), presents a wide range of putative substrates identified in vitro, but its targets and functions in vivo and especially during fracture healing and bone homeostasis are not well defined. Here, we investigated the role of MMP-10 through bone regeneration in C57BL/6 mice. During secondary fracture healing, MMP-10 is expressed by hematopoietic cells and its maximum expression peak is associated with cartilage resorption at 14 days post fracture (dpf). In accordance with this expression pattern, when Mmp10 is globally silenced, we observed an impaired fracture-healing phenotype at 14 dpf, characterized by delayed cartilage resorption and TRAP-positive cell accumulation. This phenotype can be rescued by a non-competitive transplant of wild-type bone marrow, indicating that MMP-10 functions are required only in cells of hematopoietic linage. In addition, we found that this phenotype is a consequence of reduced gelatinase activity and the lack of proMMP-9 processing in macrophages. Our data provide evidence of the in vivo function of MMP-10 during endochondral ossification and defines the macrophages as the lead cell population in cartilage removal and vascular invasion. (c) 2021 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).
Revista:
SCIENTIFIC REPORTS
ISSN:
2045-2322
Año:
2020
Vol.:
10
N°:
1
Págs.:
10329
Matrix metalloproteinases (MMPs) are proteolytic zinc-endopeptidases regulated by tissue Inhibitors of matrix metalloproteinases (TIMPs). We evaluated the potential of MMPs and TIMPs as clinical tools for Intracranial Haemorrhage (ICH). Spontaneous non-traumatic ICH patients were recruited from two hospitals: Complejo Hospitalario de Navarra (CHN=29) and Vall d ' Hebron (VdH=76). Plasmatic levels of MMP-1, -2, -7, -9, -10 and TIMP-1 and their relationship with clinical, radiological and functional variables were evaluated. We further studied the effect of TIMP-1 (0.05-0.2mg/Kg) in an experimental tail-bleeding model. In CHN, TIMP-1 was associated with admission-hematoma volume and MMP-7 was elevated in patients with deep when compared to lobar hematoma. In VdH, admission-hematoma volume was associated with TIMP-1 and MMP-7. When data from both hospitals were combined, we observed that an increase in 1ng/ml in TIMP-1 was associated with an increase of 0.14ml in haemorrhage (combined beta =0.14, 95% CI=0.08-0.21). Likewise, mice receiving TIMP-1 (0.2mg/Kg) showed a shorter bleeding time (p<0.01). Therefore, the association of TIMP-1 with hematoma volume in two independent ICH cohorts suggests its potential as ICH biomarker. Moreover, increased TIMP-1 might not be sufficient to counterbalance MMPs upregulation indicating that TIMP-1 administration might be a beneficial strategy for ICH.
Revista:
ANALES DEL SISTEMA SANITARIO DE NAVARRA
ISSN:
1137-6627
Año:
2020
Vol.:
43
N°:
2
Págs.:
245 - 249
One of the most significant negative prognostic factors in patients suffering from the disease caused by SARS-CoV-2 (COVID-19) is the development of coagulopathy, associated with abnormal laboratory findings, such as increased D-dimer, and venous thromboembolic complications, requiring thromboprophylactic strategies. The main clinical characteristics of COVID-19 patients are revised here as compared to other coronavirus infections, such as Severe Acute Respiratory Syndrome (SARS) and Middle East Respiratory Syndrome (MERS), emphasizing clinical, diagnostic and therapeutic aspects.
Revista:
JOURNAL OF EXTRACELLULAR VESICLES
ISSN:
2001-3078
Año:
2020
Vol.:
9
N°:
1
Págs.:
1729646
Peripheral arterial disease (PAD) is associated with a high risk of cardiovascular events and death and is postulated to be a critical socioeconomic cost in the future. Extracellular vesicles (EVs) have emerged as potential candidates for new biomarker discovery related to their protein and nucleic acid cargo. In search of new prognostic and therapeutic targets in PAD, we determined the prothrombotic activity, the cellular origin and the transcriptomic profile of circulating EVs. This prospective study included control and PAD patients. Coagulation time (Procoag-PPL kit), EVs cellular origin and phosphatidylserine exposure were determined by flow cytometry in platelet-free plasma (n = 45 PAD). Transcriptomic profiles of medium/large EVs were generated using the MARS-Seq RNA-Seq protocol (n = 12/group). The serum concentration of the differentially expressed gene S100A9, in serum calprotectin (S100A8/A9), was validated by ELISA in control (n = 100) and PAD patients (n = 317). S100A9 was also determined in EVs and tissues of human atherosclerotic plaques (n = 3). Circulating EVs of PAD patients were mainly of platelet origin, predominantly Annexin V positive and were associated with the procoagulant activity of platelet-free plasma. Transcriptomic analysis of EVs identified 15 differentially expressed genes. Among them, serum calprotectin was elevated in PAD patients (p < 0.05) and associated with increased amputation risk before and after covariate adjustment (mean follow-up 3.6 years, p < 0.01). The combination of calprotectin with hs-CRP in the multivariate analysis further improved risk stratification (p < 0.01). Furthermore, S100A9 was also expressed in femoral plaque derived EVs and tissues. In summary, we found that PAD patients release EVs, mainly of platelet origin, highly positive for AnnexinV and rich in transcripts related to platelet biology and immune responses. Amputation risk prediction improved with calprotectin and was significantly higher when combined with hs-CRP. Our results suggest that EVs can be a promising component of liquid biopsy to identify the molecular signature of PAD patients.
Revista:
SCIENTIFIC REPORTS
ISSN:
2045-2322
Matrix metalloproteinases have been implicated in diabetic microvascular complications. However, little is known about the pathophysiological links between MMP-10 and the renin-angiotensin system (RAS) in diabetic kidney disease (DKD). We tested the hypothesis that MMP-10 may be up-regulated in early stage DKD, and could be down-regulated by angiotensin II receptor blockade (telmisartan). Serum MMP-10 and TIMP-1 levels were measured in 268 type 2 diabetic subjects and 111 controls. Furthermore, histological and molecular analyses were performed to evaluate the renal expression of Mmp10 and Timp1 in a murine model of early type 2 DKD (db/db) after telmisartan treatment. MMP-10 (473¿±¿274¿pg/ml vs. 332¿±¿151; p¿=¿0.02) and TIMP-1 (573¿±¿296¿ng/ml vs. 375¿±¿317; p¿<¿0.001) levels were significantly increased in diabetic patients as compared to controls. An early increase in MMP-10 and TIMP-1 was observed and a further progressive elevation was found as DKD progressed to end-stage renal disease. Diabetic mice had 4-fold greater glomerular Mmp10 expression and significant albuminuria compared to wild-type, which was prevented by telmisartan. MMP-10 and TIMP-1 are increased from the early stages of type 2 diabetes. Prevention of MMP-10 upregulation observed in diabetic mice could be another protective mechanism of RAS blockade in DKD.
Autores:
Lou-Mercade, A. C.; Gavin, O.; Oros, D.; et al.
Revista:
ULTRASOUND IN OBSTETRICS AND GYNECOLOGY
ISSN:
0960-7692
Año:
2020
Vol.:
56
N°:
1
Págs.:
111 - 112
Revista:
CLINICA E INVESTIGACION EN ARTERIOSCLEROSIS
ISSN:
0214-9168
Año:
2019
Vol.:
31
N°:
4
Págs.:
152 - 159
Introduction: Monocytes play an important role in atherosclerotic progression having both pro and anti-inflammatory effects depending on different circulating monocyte subpopulations. The objective of this study is to characterize these subpopulations and their association with cardiovascular risk factors.
Methods: Transversal study including 102 selected patients, mean age: 65 years-old (range 41-86), 69% males. A set of specific antibodies against classical monocytes (Mont, CD14+CD16- CD300e+HLADR+), intermediate (Mon2, CD14+CD16+CD300e+HLADR+) and nonclassical (Mon3, CD14 CD16+CD300e+HLADR+) was assayed. Three groups of patients were included: 17 asymptomatic with more than one cardiovascular risk factor (group 1), 56 subjects asymptomatic but with vascular pathology assessed by ultrasound or microalbuminuria (group 2) and 19 patients with a previous atherothrombotic event (group 3). The cardiovascular risk was determined by Framingham and REGICOR scores.
Results: An association between study groups and the percentage of Mon1 and Mon2 was observed (ANOVA, p <.05), being independent of age and sex for Mon2. Likewise Mont and Mon2 subpopulations were associated with cardiovascular adverse events (beta=0.86, p=.02 beta-0.1 p=.002, respectively), independently of age and sex in the case of Mon2. Moreover the percentage of Mon3 was associated with the presence of several cardiovascular risk factors ((3 = 0.21, p =.04) in the univariate analysis. In addition, there was a correlation between the levels of Mon1 and Mon2 and leukocytes (r =0.7, p <.001 and r =0.26, p =.01, respectively).
Conclusions: The analysis of monocyte subpopulations may be clinically useful to stratify the inflammatory profile related to the different cardiovascular risk groups.
Revista:
TH OPEN
ISSN:
2512-9465
Año:
2019
Vol.:
3
N°:
2
Págs.:
e153 - e156
Autores:
Lorente, L. (Autor de correspondencia); Martin, M. M. ; Ramos, L.; et al.
Revista:
BMC NEUROLOGY
ISSN:
1471-2377
Año:
2019
Vol.:
19
Págs.:
167
Background: Higher circulating levels of tissue inhibitor of matrix metalloproteinases (TIMP)-1 early after ischemic stroke have been associated with lower survival. The objectives of this study were to determine serum TIMP-1 levels during the first week of a severe cerebral infarction in surviving and non-surviving patients, and whether those levels during the first week could be used as a mortality biomarker for these patients. Methods: We included patients with severe malignant middle cerebral artery infarction (MMCAI) defined as computer tomography showing ischaemic changes in more than 50% of the middle cerebral artery territory and Glasgow Coma Scale (GCS) <= 8. We measured serum levels of matrix metalloproteinases (MMP)-9 and TIMP-1. End-point study was 30-day mortality. Results: We found higher TIMP-1 concentrations at days 1 (p < 0.001), 4 (p = 0.001), and 8 (p = 0.03) of MMCAI in non-urviving (n = 34) than in surviving (n = 34) patients. We found lower serum MMP-9 concentrations at day 1 (p = 0.03) of MMCAI and no significant differences at days 4 and 8. ROC curve analysis of TIMP-1 concentrations performed at days 1, 4, and 8 of MMCAI showed an area under curve to predict 30-day mortality of 81% (p < 0.001), 80% (p < 0.001) and 72% (p = 0.07) respectively. Conclusions: The new findings of our study were that non-surviving MMCAI patients showed higher serum TIMP-1 levels during the first week of MMCAI that surviving patients, and those levels during the first week of MMCAI could be used as mortality biomarkers.
Revista:
CLINICAL AND TRANSLATIONAL ONCOLOGY
ISSN:
1699-048X
Año:
2019
Vol.:
21
N°:
6
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.
Revista:
TRANSLATIONAL STROKE RESEARCH
ISSN:
1868-4483
Año:
2019
Vol.:
10
N°:
4
Págs.:
389 - 401
Diabetes is an important risk factor for ischemic stroke (IS). Tissue-type plasminogen activator (tPA) has been associated with less successful revascularization and poor functional outcome in diabetes. We assessed whether a new thrombolytic strategy based on MMP10 was more effective than tPA in a murine IS model of streptozotocin (STZ)-induced diabetes. Wild-type mice were administered a single dose of streptozotocin (STZ) (180mg/kg) to develop STZ-induced diabetes mellitus. Two weeks later, IS was induced by thrombin injection into the middle cerebral artery and the effect of recombinant MMP10 (6.5 mu g/kg), tPA (10mg/kg) or tPA/MMP10 on brain damage and functional outcome were analysed. Motor activity was assessed using the open field test. Additionally, we studied plasminogen activator inhibitor-1 (PAI-1) and thrombin-antithrombin complex levels (TAT) by ELISA and oxidative stress and blood-brain barrier (BBB) integrity by immunohistochemistry and western blot. MMP10 treatment was more effective at reducing infarct size and neurodegeneration than tPA 24h and 3days after IS in diabetic mice. Locomotor activity was impaired by hyperglycemia and ischemic injury, but not by the thrombolytic treatments. Additionally, TAT, oxidative stress and BBB permeability were reduced by MMP10 treatment, whereas brain bleeding or PAI-1 expression did not differ between treatments. Thrombolytic treatment with MMP10 was more effective than tPA at reducing stroke and neurodegeneration in a diabetic murine model of IS, without increasing haemorrhage. Thus, we propose MMP10 as a potential candidate for the clinical treatment of IS in diabetic patients.
Revista:
MEDICINA CLINICA
ISSN:
0025-7753
Año:
2019
Vol.:
153
N°:
2
Págs.:
78 - 81
Autores:
Rabadan, I. R.; de Lecinana, M. A.; Martin, R. B.; et al.
Revista:
CLINICA E INVESTIGACION EN ARTERIOSCLEROSIS
ISSN:
0214-9168
Año:
2019
Vol.:
31
N°:
6
Págs.:
263 - 270
A multidisciplinary panel of cardiologists, neurologists, internal medicine and specialists in hemostasis and thrombosis has elaborated this document showing recent scientific evidences supporting a better profile of direct oral anticoagulants (DOACs) versus vitamin K antagonists (VKA), as well as the indications of specific antidotes and hemostatic agents to reverse the anticoagulant effects of DOACs. The analysis reinforces the best profile of DOACs and its special benefit in patients with basal high hemorrhagic risk.
Autores:
Lorente, L. (Autor de correspondencia); Martin, M. M.; Ramos, L.; et al.
Revista:
JOURNAL OF CRITICAL CARE
ISSN:
0883-9441
Año:
2019
Vol.:
51
Págs.:
117 - 121
Purpose: Previously, higher circulating levels of matrix metalloproteinase (MMP)-9 and tissue inhibitor matrix metalloproteinases (TIMP)-1 were reported in the first hours after TBI in blood samples from patients with poor prognosis. Thus, the objectives of this study were to determine whether MMP-9 and TIMP-1 levels during the first week of a severe TBI could be used as biomarker predictive of mortality. Methods: We included patients with severe TBI (defined as Glasgow Coma Scale lower than 9), and with Injury Severity Score in non-cranial aspects lower than 9. We determined serum concentrations of MMP-9 and TIMP-1 at days 1, 4 and 8 of TBI. Results: TIMP-1 concentrations at days 1 (p < .001), 4 (p = .001), and 8 (p = .01) of TBI were higher in nonsurviving (n = 34) than in surviving (n = 90) patients. ROC curve analyses showed an area under curve of TIMP-1 concentrations at days 1, 4, and 8 of TBI to predict 30-day mortality of 78% (p < .001), 76% (p <.001) and 71% (p= .02) respectively. Conclusions: The most relevant new findings of our study were that TIMP-1 levels during the first week of a severe TBI were higher in non-surviving than in surviving patients and that could be used as biomarker predictive of mortality. (C) 2019 Elsevier Inc. All rights reserved.
Revista:
REVISTA ESPAÑOLA DE ENFERMEDADES DIGESTIVAS
ISSN:
1130-0108
Año:
2019
Vol.:
111
N°:
6
Págs.:
437 - 444
Introduction: portal vein thrombosis is a relatively common complication of advanced cirrhosis that increases perioperative risk in liver transplant recipients. This condition was characterized in a cohort of patients, including risk factors and their influence on survival. Material and methods: a retrospective study of liver transplant recipients at the Clinica Universidad de Navarra was performed between 2000 and 2015. Differences in clinical and biological characteristics and survival were analyzed in subjects with and without portal vein thrombosis. A predictive index was also developed. Results: a total of 288 patients were included in the study, portal vein thrombosis was recorded in 46 (16%) cases and seven (15.2%) had stage 3/4 disease according to Yerdel's classification. Factors associated with the presence of esophageal/gastric varices (OR = 3.7; p = 0.03) included variceal ligation or sclerotherapy (OR = 2.3; p = 0.01), being overweight/obesity (OR = 2.1; p = 0.04) and thrombocytopenia (OR = 3.6; p = 0.04). There were no significant differences between the groups with and without portal vein thrombosis in terms of survival according to Kaplan-Meier curve analysis (p = 0.7). However, the mortality rate was higher for Yerdel stages 3-4 (p < 0.01). A predictive index was developed that included varices, body mass index (BMI), thrombocytopenia and activated partial thromboplastin time (APTT). This index had a sensitivity of 76.1% and a specificity of 53.7% for the development of portal thrombosis. Conclusions: the presence of esophageal/gastric varices, variceal ligation/sclerotherapy, thrombocytopenia and being overweight/obesity was associated with a higher rate of portal vein thrombosis. Advanced stages had an impact on survival.
Revista:
TRANSFUSION MEDICINE
ISSN:
0958-7578
Año:
2019
Vol.:
29
N°:
4
Págs.:
268 - 274
Objective To evaluate the effectiveness and safety of prothrombin complex concentrates (PCCs) in approved and off-label indications. Background PCCs are approved for the urgent reversal of vitamin K antagonists (VKAs). Data concerning the efficacy, safety and dosing for off-label indications are limited, but they are included in massive bleeding protocols. Methods This was a retrospective review of cases treated with four-factor PCCs (4F-PCCs) between January 2009 and 2016. Efficacy end-points include: (i) VKA reversal efficacy assessed by international normalised ratio (INR) normalisation (<1 center dot 5) and (ii) clinical efficacy as bleeding cessation and/or decreased number of transfused blood components and 24-h mortality in bleeding coagulopathy. The safety end-point is the incidence of thromboembolic events. Results A total of 328 patients were included (51 center dot 8% male, median age 78 years old). Indications were as follows: VKA reversal (66 center dot 6%), bleeding coagulopathy (30 center dot 5%) and direct anticoagulant (DOAC) reversal due to bleeding (2 center dot 5%). VKA reversal was effective in 97 center dot 1% of patients, and 76 center dot 5% demonstrated complete reversal (INR < 1 center dot 5); only 34 center dot 3% patients needed hemoderivatives. Prior to emergency procedures, PCCs achieved global responses in 83% of patients, with no bleeding complication during intervention. DOAC reversal was effective in 88 center dot 9% of patients. Bleeding cessation was associated with the dose administered (P = 0 center dot 002). In coagulopathy bleeding, haemorrhage cessation, established by the International Society of Thrombosis and Haemostais (ISTH) definition, occurred in 56 center dot 7% of massive bleeding events and in 42 center dot 5% of other coagulopathies; 24-h mortality was 30%, mainly related to active bleeding. Ten thrombotic episodes were observed (3 center dot 1%). Conclusion 4F-PCC was effective as adjuvant treatment with an acceptable safety profile, not only for the emergent reversal of VKAs but also for refractory coagulopathy associated with major bleeding.
Revista:
SCIENTIFIC REPORTS
ISSN:
2045-2322
Año:
2019
Vol.:
9
Págs.:
15580
Peripheral artery disease (PAD) is a major cause of acute and chronic illness, with extremely poor prognosis that remains underdiagnosed and undertreated. Trimethylamine-N-Oxide (TMAO), a gut derived metabolite, has been associated with atherosclerotic burden. We determined plasma levels of TMAO by mass spectrometry and evaluated their association with PAD severity and prognosis. 262 symptomatic PAD patients (mean age 70 years, 87% men) categorized in intermittent claudication (IC, n = 147) and critical limb ischemia (CLI, n = 115) were followed-up for a mean average of 4 years (min 1-max 102 months). TMAO levels were increased in CLI compared to IC (P < 0.001). Receiver operating characteristic (ROC) curves for severity (CLI) rendered a cutoff of 2.26 mu mol/L for TMAO (62% sensitivity, 76% specificity). Patients with TMAO > 2.26 mu mol/L exhibited higher risk of cardiovascular death (sub-hazard ratios >= 2, P < 0.05) that remained significant after adjustment for confounding factors. TMAO levels were associated to disease severity and CV-mortality in our cohort, suggesting an improvement of PAD prognosis with the measurement of TMAO. Overall, our results indicate that the intestinal bacterial function, together with the activity of key hepatic enzymes for TMA oxidation (FMO3) and renal function, should be considered when designing therapeutic strategies to control gut-derived metabolites in vascular patients.
Revista:
CLINICA E INVESTIGACION EN ARTERIOSCLEROSIS
ISSN:
0214-9168
Año:
2018
Vol.:
30
N°:
3
Págs.:
133 - 136
Recent research has revealed that clonal hematopoyesis of indeterminate potential (CHIP) characterized by the acquisition of somatic mutations in hematopoietic stem cells, is not only a common age-related disorder and a premalignant condition, but it is also associated with the development of atherosclerotic vascular diseases. Mutations in DNMT3A, TET2 and ASXL1 were each individually associated with coronary heart disease, stroke and coronary calcification. Therefore, CHIP emerges as a new risk factor for atherosclerotic vascular pathologies and its detection may be relevant as a new therapeutic target in order to modify the natural course of the disease. (C) 2018 Sociedad Espanola de Arteriosclerosis. Published by Elsevier Espana, S.L.U. All rights reserved.
Revista:
PLOS ONE
ISSN:
1932-6203
Año:
2018
Vol.:
13
N°:
8
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.
Revista:
ATHEROSCLEROSIS
ISSN:
0021-9150
Año:
2018
Vol.:
278
Págs.:
124 - 134
Background and aims: Matrix metalloproteinases (MMPs) have been implicated in atherosclerosis and vascular calcification. Among them, we reported that MMP10 is present in human atheroma, associated with atherosclerosis. However, it remains unclear whether MMP10 is involved in atherogenesis and vascular calcification. Methods: MMP10 was measured in serum from patients with subclinical atherosclerosis and analyzed in carotid endarterectomies by immunostaining. ApoE-deficient mice (Apoe(-/-)) were crossed to MMP10-deficient (Mmp10(-/-)) mice and followed up to 20 months. Plaque area and composition were assessed by histology and immunohistochemistry. Inflammatory markers were measured in atherosclerotic plaques by RT-qPCR, and leukocyte subpopulations were analyzed by flow cytometry. In vitro calcification assays were performed in aortic vascular smooth muscle cells (VSMC). Results: MMP10 serum levels were associated with coronary calcification in subjects with subclinical atherosclerosis. Immunostaining revealed MMP10 expression in human atheromas, spatially associated with calcification areas, and complicated plaques released higher amounts of MMP10 than non-diseased segments. Interestingly, vascular MMP10 expression was confined to the atherosclerotic lesion in Apoe(-/-) mice, and Apoe(-/-) Mmp10(-/-) showed a substantial reduction in atherosclerotic lesion size, macrophage content and plaque calcification. Reduced local and systemic inflammatory markers could be demonstrated in Apoe(-/-) Mmp10(-/-) by gene expression and flow cytometry analysis. Calcium phosphate deposition and vascular calcification markers were downregulated in VSMC from Apoe(-/-) Mmp10(-/-) mice. Conclusions: Delayed plaque progression and altered cellular composition in the absence of MMP10 suggests that MMP10 plays a role in atherosclerosis, favoring inflammation, development and complication of the plaque.
Autores:
de Miguel, I.; Orbe, J; Sanchez-Arias, J. A. ; et al.
Revista:
ACS MEDICINAL CHEMISTRY LETTERS
ISSN:
1948-5875
Año:
2018
Vol.:
9
N°:
5
Págs.:
428 - 433
In an effort to find novel chemical series as antifibrinolytic agents, we explore alpha-phenylsulfonyl-alpha-spiropiperidines bearing different zinc-binding groups (ZBGs) to target those metalloproteinases involved in the fibrinolytic process: MMP3 and MMP10. Surprisingly, all these new chemical series were inactive against these metalloproteinases; however, several new molecules retained the antifibrinolytic activity in a phenotypic functional assay using thromboelastometry and human whole blood. Further optimization led to compound 38 as a potent antifibrinolytic agent in vivo, three times more efficacious than the current standard-of-care (tranexamic acid, TXA) at 300 times lower dose. Finally, in order to decipher the underlying mode-of action leading to this phenotypic response, an affinity-based probe 39 was successfully designed to identify the target involved in this response: a potentially unknown mechanism-of-action in the fibrinolytic process.
Revista:
THROMBOSIS RESEARCH
ISSN:
0049-3848
Año:
2018
Vol.:
170
Págs.:
1 - 9
Introduction: Wound healing after myocardial infarction (MI) is mediated by different cell types, secreted proteins, components of the extracellular matrix (ECM) and, as increasing evidences suggest, extracellular vesicles (EVs). We aim to determine the dynamics of release and origin of EVs after MI, as well as their biological activity on endothelial cells (ECs).
Methods: MI was induced in WT mice and blood and tissues collected at baseline, 3, 15 and 30 days post-ligation for cardiac function (echocardiography) and histological evaluation. Circulating EVs subpopulations were measured by flow cytometry in mouse, and in a small cohort of patients with ST-segment elevation MI (STEMI, n= 6). In vitro, EVs were isolated from a cardiomyocyte cell line (HL1) and their function assayed on ECs.
Results: Leukocyte and endothelial EVs increased concomitant to inflammatory and angiogenic processes triggered by ischemia. More strikingly, cardiomyocyte EVs (connexin43+) were detected in STEMI patients and in murine MI, where a significant increase in their levels was reported at day 15 post-ischemia (p < 0.05 vs baseline). In vitro, HL1EVs induced ECs migration (p= 0.05) and proliferation (p < 0.05), but impaired tube formation. These apparent contradictory results could be partially explained by the upregulation of MMP3, and the apoptosis and senescence genes, p53 and p16, induced by HL1EVs on ECs (p < 0.05).
Conclusions: MI induces the release of different EVs subpopulations, including those of cardiac origin, in a preclinical model of MI and STEMI patients. In vitro, cardiomyocyte derived EVs are able to modulate endothelial function, suggesting their active role in heart repair after ischemia.
Revista:
MEDICINA CLINICA
ISSN:
0025-7753
Año:
2018
Vol.:
151
N°:
5
Págs.:
207 - 209
Revista:
JOURNAL OF MAGNETIC RESONANCE IMAGING
ISSN:
1053-1807
Año:
2017
Vol.:
46
N°:
6
Págs.:
1810 - 1817
To investigate whether arterial spin labeling (ASL) MRI could detect renal hemodynamic impairment in diabetes mellitus (DM) along different stages of chronic kidney disease (CKD).
Revista:
AMERICAN HEART ASSOCIATION. JOURNAL. CARDIOVASCULAR AND CEREBROVASCULAR DISEASE
ISSN:
2047-9980
Año:
2017
Vol.:
6
N°:
6
Págs.:
e006042
BACKGROUND:
Intracerebral hemorrhage (ICH) is an acute neurological disorder with high mortality and no effective treatment. In addition to the initial bleeding event, rebleeding and hematoma expansion are associated with poor outcome in these patients. We studied the effectiveness of the new antifibrinolytic agent CM352, a short-half-life matrix metalloproteinase inhibitor, for achieving early hemostasis and improving functional recovery in a rat model of collagenase-induced ICH.
METHODS AND RESULTS:
ICH was induced by striatal injection of collagenase, and 1 hour later, rats received an intravenous injection of saline (n=6) or CM352 (1 mg/kg, n=6). Hematoma (basal and after 3 and 24 hours) and lesion (14 days) volumes were quantified on T2-weighted (T2) magnetic resonance images. Neurological and functional recovery was evaluated by using Bederson score and a cylinder test (basal, 24 hours, and 14 days). Early treatment (1 hour) with CM352 was efficient reducing hematoma expansion at 3 hours (P<0.01) and, more markedly, at 24 hours (P<0.01). Decreased bleeding after antifibrinolytic treatment was accompanied by reduced interleukin-6 levels at 3 hours (P<0.05) and smaller lesion volume at 14 days (P<0.01). CM352 drastically reduced sensorimotor impairment (cylinder test) after ICH in rats at 24 hours (P<0.01) and 14 days (P<0.01). Similarly, it also attenuated neurological deficit (Bederson scale) at 24 hours (P<0.01) and 14 days (P<0.01). Interestingly, late (3 hours) CM352 administration also resulted in reduced lesion size and better functional outcome.
CONCLUSIONS:
CM352, a new antifibrinolytic agent and matrix metalloproteinase inhibitor, effectively prevented hematoma growth and reduced lesion size in ICH in association with improved functional and neurological recovery.
Revista:
JOURNAL OF MEDICAL CASE REPORTS
ISSN:
1752-1947
Año:
2017
Vol.:
11
N°:
1
Págs.:
115
BACKGROUND:
Chemotherapy is considered the most appropriate treatment for metastatic uterine sarcoma, despite its limited efficacy. No other treatment has been conclusively proved to be a real alternative, but some reports suggest that anti-hormonal therapy could be active in a small subset of patients. We report the case of a patient with metastatic uterine carcinosarcoma with positive hormonal receptors and a complete pathological response.
CASE PRESENTATION:
A 54-year-old white woman presented to our emergency room with hypovolemic shock and serious vaginal bleeding. After stabilization, she was diagnosed as having a locally advanced uterine carcinosarcoma with lymph nodes and bone metastatic disease. In order to control the bleeding, palliative radiotherapy was administered. Based on the fact that positive hormone receptors were found in the biopsy, non-steroidal aromatase inhibitor therapy with letrozole was started. In the following weeks, her general status improved and restaging imaging tests demonstrated a partial response of the primary tumor. Ten months after initiating aromatase inhibitor therapy, she underwent a radical hysterectomy and the pathological report showed a complete response. After completing 5 years of treatment, aromatase inhibitor therapy was stopped. She currently continues free of disease, without further therapy, and maintains a normal and active life.
CONCLUSIONS:
This case shows that patients with uterine carcinosarcoma and positive hormone receptors may benefit from aromatase inhibitor therapy. A multidisciplinary strategy that includes local therapies such as radiation and/or surgery should be considered the mainstay of treatment. Systemic therapies such as hormone inhibitors should be taken into consideration and deserve further clinical research in the era of precision medicine.
Revista:
CARDIOVASCULAR RESEARCH
ISSN:
0008-6363
Año:
2017
Vol.:
113
N°:
10
Págs.:
1219 - 1229
Aims Early reperfusion with tissue-type plasminogen activator (tPA) is an effective therapeutic strategy to treat acute ischemic stroke, but only 1/3 of tPA-treated patients recover and are free from disability. tPA has also shown neurotoxicity in experimental models of cerebral ischemia. Considering that MMP-10 improves stroke injury, we have examined the therapeutic and protective effect of MMP10 and tPA/MMP10 as clot-dissolving and neuroprotective agent in an experimental model of ischemic stroke and studied in vitro the molecular pathways involved in MMP10-mediated effects. Methods and results Cerebral ischemia was induced by the local injection of thrombin into the middle cerebral artery followed by reperfusion with MMP10 (6.5 mu g/kg) and tPA (10 mg/kg) alone or in combination with MMP10. Cell cultures were also performed to determine the effect of MMP10 and tPA/MMP10 on brain endothelial cells and neurons. tPA/MMP10 significantly reduced the infarct size in the ischemic stroke model compared with tPA alone (P < 0.05). In vitro, MMP10 reduced the tPA-promoted endothelial ionic permeability, preserved the expression of claudin-5 and decreased ERK1/2 activation. Moreover, combination of tPA/MMP10 prevented tPA-mediated neuronal excitotoxicity and calcium influx. These effects were reversed by blocking MMP10 activity with a monoclonal antibody. Conclusion These results show that MMP10, either alone or in combination with tPA, might represent a new strategy for thrombolysis in ischemic stroke, providing higher protection against cerebrovascular damage.
Revista:
CLINICA E INVESTIGACION EN ARTERIOSCLEROSIS
ISSN:
0214-9168
Año:
2017
Vol.:
29
N°:
4
Págs.:
166 - 167
Revista:
ANALES DEL SISTEMA SANITARIO DE NAVARRA
ISSN:
1137-6627
Año:
2017
Vol.:
40
N°:
1
Págs.:
35 - 42
Background. Most acute coronary syndromes are caused by the fracture of a vulnerable atherosclerotic plaque. These plaques are thin cap fibroatheromas, which can only be detected with invasive coronary imaging techniques. It is necessary to find a non-invasive biomarker of these vulnerable plaques in order to identify patients at risk without a coronary angiography. Metalloproteinase-1 is an enzyme involved in extracellular matrix metabolism which has been correlated with the rupture of atherosclerotic plaques. Its serum levels in patients with vulnerable plaques remain unknown. Methods. Patients with suspected stable coronary artery disease undergoing coronary angiography in our hospital were included. The coronary arteries were studied with optical coherence tomography to detect vulnerable plaques. Blood samples were taken from a peripheral vein and from the coronary sinus, to assess metalloproteinase-1 levels. Results. Fifty-one patients were included, 13 of whom had at least one vulnerable plaque. There were not significant differences in clinical characteristics, lipid profile or C reactive protein levels, between patients with or without vulnerable plaques. Patients with vulnerable plaques had significant higher metalloproteinase-1 levels both in peripheral (7330 5541 vs 2894 1783 pg/ml, p=0.025) and coronary sinus serum (6012 3854 vs 2707 1252 pg/ml, p=0.047). Conclusions. Patients with vulnerable plaques had significantly higher metalloproteinase-1 serum levels. Further studies with clinical follow up are needed to assess the prognostic value of serum metalloproteinase-1.
Revista:
JOURNAL OF VASCULAR SURGERY
ISSN:
0741-5214
Año:
2017
Vol.:
66
N°:
5
Págs.:
1527 - 1533
Objective The prognosis of patients with peripheral arterial disease (PAD) is characterized by an exceptionally high risk for myocardial infarction, ischemic stroke, and death; however, studies in search of new prognostic biomarkers in PAD are scarce. Even though low levels of high-density lipoprotein cholesterol (HDL-C) have been associated with higher risk of cardiovascular (CV) complications and death in different atherosclerotic diseases, recent epidemiologic studies have challenged its prognostic utility. The aim of this study was to test the predictive value of HDL-C as a risk factor for ischemic events or death in symptomatic PAD patients. Methods Clinical and demographic parameters of 254 symptomatic PAD patients were recorded. Amputation, ischemic coronary disease, cerebrovascular disease, and all-cause mortality were recorded during a mean follow-up of 2.7 years. Results Multivariate analyses showed that disease severity (critical limb ischemia) was significantly reduced in patients with normal HDL-C levels compared with the group with low HDL-C levels (multivariate analysis odds ratio, 0.09; 95% confidence interval [CI], 0.03-0.24). A decreased risk for mortality (hazard ratio, 0.46; 95% CI, 0.21-0.99) and major adverse CV events (hazard ratio, 0.38; 95% CI, 0.16-0.86) was also found in patients with normal vs reduced levels of HDL-C in both Cox proportional hazards models and Kaplan-Meier estimates, after adjustment for confounding factors. Conclusions Reduced HDL-C levels were significantly associated with higher risk for development of CV complications as well as with mortality in PAD patients. These findings highlight the usefulness of this simple test for early identification of PAD patients at high risk for development of major CV events.
Autores:
J.V. Llau; F.J. Acosta; G. Escobar; et al.
Revista:
REVISTA ESPAÑOLA DE ANESTESIOLOGIA Y REANIMACION
ISSN:
0034-9356
Año:
2016
Vol.:
63
N°:
1
Págs.:
e1 - e22
La hemorragia masiva es una entidad frecuente que se asocia a una elevada morbimortalidad. Ante la necesidad de la implementación y estandarización de su manejo, se realizó una revisión sistemática de la literatura, con extracción de recomendaciones en base a las evidencias existentes. A partir de las mismas se redactó un documento de consenso multidisciplinar. Desde las definiciones de hemorragia masiva y transfusión masiva, se establecen recomendaciones de actuación estructuradas en las medidas generales de manejo de las mismas (valoración clínica de la hemorragia, manejo de la hipotermia, reposición de la volemia, reanimación hipotensiva y cirugía de contención de daños), monitorización de la volemia, administración de hemocomponentes (concentrado de hematíes, plasma fresco, plaquetas, y óptima relación de administración entre ellos), y de hemostáticos (complejo protrombínico, fibrinógeno, factor VIIa, antifibrinolíticos).
Autores:
Orset, C.; Haelewyn, B.; Allan, S. M.; et al.
Revista:
STROKE
ISSN:
0039-2499
Año:
2016
Vol.:
47
N°:
5
Págs.:
1312 - 1318
Background and Purpose The debate over the fact that experimental drugs proposed for the treatment of stroke fail in the translation to the clinical situation has attracted considerable attention in the literature. In this context, we present a retrospective pooled analysis of a large data set from preclinical studies, to examine the effects of early versus late administration of intravenous recombinant tissue-type plasminogen activator.
Methods We collected data from 26 individual studies from 9 international centers (13 researchers; 716 animals) that compared recombinant tissue-type plasminogen activator with controls, in a unique mouse model of thromboembolic stroke induced by an in situ injection of thrombin into the middle cerebral artery. Studies were classified into early (<3 hours) versus late (3 hours) drug administration. Final infarct volumes, assessed by histology or magnetic resonance imaging, were compared in each study, and the absolute differences were pooled in a random-effect meta-analysis. The influence of time of administration was tested.
Results When compared with saline controls, early recombinant tissue-type plasminogen activator administration was associated with a significant benefit (absolute difference, -6.63 mm(3); 95% confidence interval, -9.08 to -4.17; I-2=76%), whereas late recombinant tissue-type plasminogen activator treatment showed a deleterious effect (+5.06 mm(3); 95% confidence interval, +2.78 to +7.34; I-2=42%; P-int<0.00001). Results remained unchanged after subgroup analyses.
Conclusions Our results provide the basis needed for the design of future preclinical studies on recanalization therapies using this model of thromboembolic stroke in mice. The power analysis reveals that a multicenter trial would require 123 animals per group instead of 40 for a single-center trial.
Revista:
EUROPEAN JOURNAL OF HAEMATOLOGY
ISSN:
0902-4441
Año:
2016
Vol.:
97
N°:
2
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.
Revista:
MEDICINA INTENSIVA
ISSN:
0210-5691
Año:
2016
Vol.:
40
N°:
9
Págs.:
550 - 559
Objective: To audit the impact upon mortality of a massive bleeding management protocol (MBP) implemented in our center since 2007. Design: A retrospective, single-center study was carried out. Patients transfused after MBP implementation (2007-2012, Group 2) were compared with a historical cohort (2005-2006, Group 1). Background: Massive bleeding is associated to high mortality rates. Available MBPs are designed for trauma patients, whereas specific recommendations in the medical/surgical settings are scarce. Patients: After excluding patients who died shortly (<6 h) after MBP activation (n=20), a total of 304 were included in the data analysis (68% males, 87% surgical). Interventions: Our MBP featured goal-directed transfusion with early use of adjuvant hemostatic medications. Variables of interest: Primary endpoints were 24-h and 30-day mortality. Fresh frozen plasma to-red blood cells (FFP:RBC) and platelet-to-RBC (PLT:RBC) transfusion ratios, time to first FFP unit and the proactive MBP triggering rate were secondary endpoints. Results: After MBP implementation (Group 2; n=222), RBC use remained stable, whereas FFP and hemostatic agents increased, when compared with Group 1 (n=82). Increased FFP:RBC ratio (p = 0.053) and earlier administration of FFP (p = 0.001) were also observed, especially with proactive MBP triggering. Group 2 patients presented lower rates of 24-h (0.5% vs. 7.3%; p = 0.002) and 30-day mortality (15.9% vs. 30.2%; p = 0.018) - the greatest reduction corresponding to non-surgical patients. Logistic regression showed an independent protective effect of MBP implementation upon 30-day mortality (OR = 0.3; 95% CI 0.15-0.61). Conclusions: These data suggest that the implementation of a goal-directed MBP for prompt and aggressive management of non-trauma, massive bleeding patients is associated to reduced 24-h and 30-day mortality rates. (C) 2016 Elsevier Espana, S.L.U. y SEMICYUC. All rights reserved.
Revista:
ANGIOLOGIA
ISSN:
0003-3170
Año:
2016
Vol.:
68
N°:
5
Págs.:
359 - 361
Revista:
CLINICA E INVESTIGACION EN ARTERIOSCLEROSIS
ISSN:
0214-9168
Año:
2016
Vol.:
29
N°:
1
Págs.:
46 - 50
As it is well-known, a thrombus evolving into a disrupted/eroded atherosclerotic plaque causes most acute coronary syndromes. Plaque stabilization via reduction of the lipid core and/or thickening of the fibrous cap is one of the possible mechanisms accounted for the clinical benefits displayed by different anti-atherosclerotic strategies. The concept of plaque stabilization was developed to explain how lipid-lowering agents could decrease adverse coronary events without substantial modifications of the atherosclerotic lesion ('angiographic paradox'). A number of imaging modalities (vascular ultrasound and virtual histology, MRI, optical coherence tomography, positron tomography, etc.) are used for non-invasive assessment of atherosclerosis; most of them can identify plaque volume and composition beyond lumen stenosis. An 'aggressive' lipid-lowering strategy is able to reduce the plaque burden and the incidence of cardiovascular events; this may be attributable, at least in part, to plaque-stabilizing effects.
Revista:
REVISTA ESPAÑOLA DE CARDIOLOGIA
ISSN:
0300-8932
Año:
2015
Vol.:
68
N°:
7
Págs.:
638-640
Nuestra experiencia indica que, para los pacientes con asistencia ventricular que sufran TIH sin trombosis asociada, en ausencia de test de activación plaquetaria disponible, la reexposición precoz a HNF exclusivamente durante el trasplante cardiaco podría ser una alternativa al uso de inhibidores directos de la trombina durante la CEC, siempre y cuando el recuento plaquetario se haya recuperado previamente y tras la intervención se reinicie un tratamiento anticoagulante alternativo a la heparina.
Revista:
JOURNAL OF MEDICINAL CHEMISTRY
ISSN:
0022-2623
Año:
2015
Vol.:
58
N°:
5
Págs.:
2465 - 2488
Growing evidence suggests that matrix metalloproteinases (MMP) are involved in thrombus dissolution; then, considering that new therapeutic strategies are required for controlling hemorrhage, we hypothesized that MMP inhibition may reduce bleeding by delaying fibrinolysis. Thus, we designed and synthesized a novel series of MMP inhibitors to identify potential candidates for acute treatment of bleeding. Structure-based and knowledge-based strategies were utilized to design this novel chemical series, ¿-spiropiperidine hydroxamates, of potent and soluble (>75 ¿g/mL) pan-MMP inhibitors. The initial hit, 12, was progressed to an optimal lead 19d. Racemic 19d showed a remarkable in vitro phenotypic response and outstanding in vivo efficacy; in fact, the mouse bleeding time at 1 mg/kg was 0.85 min compared to 29.28 min using saline. In addition, 19d displayed an optimal ADME and safety profile (e.g., no thrombus formation). Its corresponding enantiomers were separated, leading to the preclinical candidate 5 (described in Drug Annotations series, J. Med. Chem. 2015, ).
Revista:
JOURNAL OF MEDICINAL CHEMISTRY
ISSN:
0022-2623
Año:
2015
Vol.:
58
N°:
7
Págs.:
2941 - 2957
Discovery of potent and safe therapeutics that improve upon currently available antifibrinolytics, e.g., tranexamic acid (TXA, 1) and aprotinin, has been challenging. Matrix metalloproteinases (MMPs) participate in thrombus dissolution. Then we designed a novel series of optimized MMP inhibitors that went through phenotypic screening consisting of thromboelastometry and mouse tail bleeding. Our optimized lead compound, CM-352 (2), inhibited fibrinolysis in human whole blood functional assays and was more effective than the current standard of care, 1, in the tail-bleeding model using a 30¿000 times lower dose. Moreover, 2 reduced blood loss during liver hepatectomy, while 1 and aprotinin had no effect. Molecule 2 displayed optimal pharmacokinetic and safety profiles with no evidence of thrombosis or coagulation impairment. This novel mechanism of action, targeting MMP, defines a new class of antihemorrhagic agents without interfering with normal hemostatic function. Furthermore, 2 represents a preclinical candidate for the acute treatment of bleeding.
Revista:
THROMBOSIS RESEARCH
ISSN:
0049-3848
Año:
2015
Vol.:
136
N°:
6
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:
Muñoz Gómez, M. ; E. Bisbe Vives; M. Basora Macaya; et al.
Revista:
MEDICINA INTENSIVA
ISSN:
0210-5691
Año:
2015
Vol.:
39
N°:
9
Págs.:
552 - 562
In recent years, several safety alerts have questioned or restricted the use of some pharmacological alternatives to allogeneic blood transfusion in established indications. In contrast, there seems to be a promotion of other alternatives, based on blood products and/or antifibrinolytic drugs, which lack a solid scientific basis. The Multidisciplinary Autotransfusion Study Group and the Anemia Working Group España convened a multidisciplinary panel of 23 experts belonging to different healthcare areas in a forum for debate to: 1) analyze the different safety alerts referred to certain transfusion alternatives; 2) study the background leading to such alternatives, the evidence supporting them, and their consequences for everyday clinical practice, and 3) issue a weighted statement on the safety of each questioned transfusion alternative, according to its clinical use. The members of the forum maintained telematics contact for the exchange of information and the distribution of tasks, and a joint meeting was held where the conclusions on each of the items examined were presented and discussed. A first version of the document was drafted, and subjected to 4 rounds of review and updating until consensus was reached (unanimously in most cases). We present the final version of the document, approved by all panel members, and hope it will be useful for our colleagues.
Revista:
FASEB JOURNAL
ISSN:
0892-6638
Año:
2015
Vol.:
29
N°:
3
Págs.:
960 - 972
We studied the role of matrix metalloproteinase-10 (MMP-10) during skeletal muscle repair after ischemia using a model of femoral artery excision in wild-type (WT) and MMP-10 deficient (Mmp10(-/-)) mice. Functional changes were analyzed by small animal positron emission tomography and tissue morphology by immunohistochemistry. Gene expression and protein analysis were used to study the molecular mechanisms governed by MMP-10 in hypoxia. Early after ischemia, MMP-10 deficiency resulted in delayed tissue reperfusion (10%, P < 0.01) and in increased necrosis (2-fold, P < 0.01), neutrophil (4-fold, P < 0.01), and macrophage (1.5-fold, P < 0.01) infiltration. These differences at early time points resulted in delayed myotube regeneration in Mmp10(-/-) soleus at later stages (regenerating myofibers: 30 ± 9% WT vs. 68 ± 10% Mmp10(-/-), P < 0.01). The injection of MMP-10 into Mmp10(-/-) mice rescued the observed phenotype. A molecular analysis revealed higher levels of Cxcl1 mRNA (10-fold, P < 0.05) and protein (30%) in the ischemic Mmp10(-/-) muscle resulting from a lack of transcriptional inhibition by MMP-10. This was further confirmed using siRNA against MMP-10 in vivo. Our results demonstrate an important role of MMP-10 for proper muscle repair after ischemia, and suggest that chemokine regulation such as Cxcl1 by MMP-10 is involved in muscle regeneration
Autores:
De Gonzalo-Calvo, D.; Llorente-Cortés, V.; Orbe, J; et al.
Revista:
INTERNATIONAL JOURNAL OF CARDIOLOGY
ISSN:
0167-5273
Año:
2015
Vol.:
178
Págs.:
102 - 104
Revista:
CLINICAL AND APPLIED THROMBOSIS-HEMOSTASIS
ISSN:
1076-0296
Año:
2015
Vol.:
21
N°:
7
Págs.:
684 - 687
The purpose of the study was to analyze a systemic activation of hemostasis and concentration of matrix metalloproteinase 10 (MMP-10) in patients with primary varicose veins (PVVs). A study group consisted of 41 patients with noncomplicated PVVs. A control group consisted of 30 age- and sex-matched healthy individuals without varicose veins. The concentration of d-dimers (DD), prothrombin fragments 1 and 2 (F1+2), antigen of von Willebrand factor (vWF), and activity of plasminogen activator inhibitor (PAI-1) in plasma and concentration of MMP-10 in serum were analyzed. In patients with PVVs, higher concentrations of DD (P < .001), F1+2 (P < .001), vWF (P = .027), MMP-10 (P = .006), and higher activity of PAI-1 (P < .001) were observed. However, no correlation between the concentrations of MMP-10 and prothrombotic markers was found. Noncomplicated PVVs are associated with systemic, prothrombotic activation of hemostasis and increased concentration of MMP-10, suggesting a prothrombotic and proinflammatory state.
Revista:
THROMBOSIS RESEARCH
ISSN:
0049-3848
Año:
2015
Vol.:
136
N°:
2
Págs.:
445 - 450
BACKGROUND:
Thrombin-activatable fibrinolysis inhibitor (TAFI) plays an important role in coagulation and fibrinolysis. Whereas TAFI deficiency may lead to a haemorrhagic tendency, data from TAFI knockout mice (TAFI-/-) are controversial and no differences have been reported in these animals after ischemic stroke. There are also no data regarding the role of circulating microparticles (MPs) in TAFI-/-.
OBJECTIVES:
to examine the effect of tPA on the rate of intracranial haemorrhage (ICH) and on MPs generated in a model of ischemic stroke in TAFI-/- mice.
METHODS:
Thrombin was injected into the middle cerebral artery (MCA) to analyse the effect of tPA (10mg/Kg) on the infarct size and haemorrhage in the absence of TAFI. Immunofluorescence for Fluoro-Jade C was performed on frozen brain slides to analyse neuronal degeneration after ischemia. MPs were isolated from mouse blood and their concentrations calculated by flow cytometry.
RESULTS:
Compared with saline, tPA significantly increased the infarct size in TAFI-/- mice (p<0.05). Although plasma fibrinolytic activity (fibrin plate assay) was higher in these animals, no macroscopic or microscopic ICH was detected. A positive signal for apoptosis and degenerating neurons was observed in the infarct area, being significantly higher in tPA treated TAFI-/- mice (p<0.05). Interestingly, higher numbers of MPs were found in TAFI-/- plasma as compared to wild type, after stroke (p<0.05).
CONCLUSIONS:
TAFI deficiency results in increased brain damage in a model of thrombolysis after ischemic stroke, which was not associated with bleeding but with neuronal degeneration and MP production.
Revista:
HEPATOLOGY
ISSN:
0270-9139
Año:
2015
Vol.:
62
N°:
1
Págs.:
166 - 178
Matrix metalloproteinases (MMPs) participate in tissue repair after acute injury, but also participate in cancer by promoting a protumorigenic microenvironment. Previously, we reported on a key role for MMP10 in mouse liver regeneration. Herein, we investigated MMP10 expression and function in human hepatocellular carcinoma (HCC) and diethylnitrosamine (DEN)-induced mouse hepatocarcinogenesis. MMP10 was induced in human and murine HCC tissues and cells. MMP10-deficient mice showed less HCC incidence, smaller histological lesions, reduced tumor vascularization, and less lung metastases. Importantly, expression of the protumorigenic, C-X-C chemokine receptor-4 (CXCR4), was reduced in DEN-induced MMP10-deficient mice livers. Human HCC cells stably expressing MMP10 had increased CXCR4 expression and migratory capacity. Pharmacological inhibition of CXCR4 significantly reduced MMP10-stimulated HCC cell migration. Furthermore, MMP10 expression in HCC cells was induced by hypoxia and the CXCR4 ligand, stromal-derived factor-1 (SDF1), through the extracellular signal-regulated kinase 1/2 pathway, involving an activator protein 1 site in MMP10 gene promoter.
CONCLUSION:
MMP10 contributes to HCC development, participating in tumor angiogenesis, growth, and dissemination. We identified a new reciprocal crosstalk between MMP10 and the CXCR4/SDF1 axis contributing to HCC progression and metastasis. To our knowledge, this is the first report addressing the role of a MMP in hepatocarcinogenesis in the corresponding genetic mouse model.
Autores:
Martínez-Aguilar, E.; Gómez-Rodríguez, V.; Orbe, J; et al.
Revista:
JOURNAL OF VASCULAR SURGERY
ISSN:
0741-5214
Año:
2015
Vol.:
61
N°:
2
Págs.:
428 - 435
Objective: Peripheral arterial disease ( PAD) is associated with poor prognosis in terms of cardiovascular (CV) morbidity and mortality. Matrix metalloproteinases (MMPs) contribute to vascular remodeling by degrading extracellular matrix components and play a role in atherosclerosis as demonstrated for MMP-10 (stromelysin-2). This study analyzed MMP-10 levels in PAD patients according to disease severity and CV risk factors and evaluated the prognostic value of MMP-10 for CV events and mortality in lower limb arterial disease after a follow-up period of 2 years.
Methods: MMP-10 was measured by enzyme-linked immunosorbent assay in 187 PAD patients and 200 sex-matched controls.
Results: PAD patients presented with increased levels of MMP-10 (702 +/- 326 pg/mL control vs 946 +/- 473 pg/mL PAD; P < .001) and decreased levels of tissue inhibitor of matrix metalloproteinase 1 (312 +/- 117 ng/mL control vs 235 +/- 110 ng/mL PAD; P <.001) compared with controls. Among PAD patients, those with critical limb ischemia (n = 88) showed higher levels of MMP-10 (1086 6 478 pg/mL vs 822 6 436 pg/mL; P < .001) compared with those with intermittent claudication (n = 99), whereas the MMP-10/tissue inhibitor of matrix metalloproteinase 1 ratio remained similar. The univariate analysis showed an association between MMP-10, age (P = .015), hypertension (P = .021), and ankle-brachial index (P = .006) in PAD patients that remained significantly associated with PAD severity after adjustment for other CV risk factors. Patients with the highest MMP-10 tertile had an increased incidence of all-cause mortality and CV mortality (P < .03).
Conclusions: Our results suggest that MMP-10 is associated with severity and poor outcome in PAD.
Revista:
LIVER INTERNATIONAL
ISSN:
1478-3223
Año:
2015
Vol.:
35
N°:
5
Págs.:
1590 - 96
BACKGROUND & AIMS:
Radioembolization may rarely induce liver disease resulting in a syndrome that is similar to veno-occlusive disease complicating bone marrow transplantation where inflammation, endothelial cell activation and thrombosis are likely involved. We hypothesized that similar mechanisms could be implicated in radioembolization-induced liver disease (REILD). Moreover, lobar radioembolization may induce hypertrophy of the non-treated hemiliver most probably by inducing liver regeneration.
METHODS:
In patients with hepatocellular carcinoma, we prospectively studied serum levels of markers of liver regeneration, oxidative stress, pro-inflammatory pathways, endothelial activation and coagulation parameters over 2 months after radioembolization.
RESULTS:
Although REILD did not occur among 14 treated patients, a decrease in effective liver blood flow was observed. Radioembolization was followed by a persistent increase in pro-inflammatory (interleukin 6 and 8) and oxidative stress (malondyaldehide) markers, an induction of endothelial injury markers (vW factor and PAI-1) and an activation of the coagulation cascade (factor VIII, PAI-1, D-Dimer) as well as a significant increase in factors related to liver regeneration (FGF-19 and HGF).
CONCLUSION:
Radioembolization activates liver regeneration, produces oxidative stress, activates inflammatory cytokines and induces endothelial injury with partial activation of the coagulation cascade. These findings may have implicati
Autores:
Lorente, L.; Martin, M. M.; Ramos, L.; et al.
Revista:
BMC NEUROLOGY
ISSN:
1471-2377
Año:
2015
Vol.:
15
Págs.:
111
BACKGROUND:
In the last years, circulating matrix metalloproteinases (MMP)-9 levels have been associated with functional outcome in ischemic stroke patients. However the prognostic value of circulating levels of tissue inhibitor of matrix metalloproteinases (TIMP)-1 and MMP-10 in functional outcome of ischemic stroke patients has been scarcely studied. In addition, to our knowledge, serum MMP-9, MMP-10 and TIMP-1 levels in patients with malignant middle cerebral artery infarction (MMCAI) for mortality prediction have not been studied, and these were the objectives of this study.
METHODS:
This was a multicenter, observational and prospective study carried out in six Spanish Intensive Care Units. We included patients with severe MMCAI defined as Glasgow Coma Scale (GCS) lower than 9. We measured circulating levels of MMP-9, MMP-10, TIMP-1, in 50 patients with severe MMCAI at diagnosis and in 50 healthy subjects. Endpoint was 30-day mortality.
RESULTS:
Patients with severe MMCAI showed higher serum levels of MMP-9 (p = 0.001), MMP-10 (p < 0.001), and TIMP-1 (p = 0.02) than healthy subjects. Non-surviving MMCAI patients (n = 26) compared to survivor ones (n = 24) showed higher circulating levels of TIMP-1 (p < 0.001), MMP-10 (p = 0.02) and PAI-1(p = 0.02), and lower MMP-9 levels (p = 0.04). Multiple binomial logistic regression analysis showed that serum TIMP-1 levels > 239 ng/mL are associated with 30-day mortality (OR = 5.82; 95% CI = 1.37-24.73; P = 0.02) controlling for GCS and age. The area under the curve for TIMP-1 as predictor of 30-day mortality was 0.81 (95% CI = 0.67-0.91; P < 0.001). We found an association between circulating levels of TIMP-1 and MMP-10 (rho = 0.45; P = 0.001), plasminogen activator inhibitor (PAI)-1 (rho = 0.53; P < 0.001), and tumor necrosis factor (TNF)-alpha (rho = 0.70; P < 0.001).
CONCLUSIONS:
The most relevant and new findings of our study, were that serum TIMP-1 levels in MMCAI patients were associated with mortality, and could be used as a prognostic biomarker of mortality in MMCAI patients.
Autores:
De Gonzalo-Calvo, D.; Llorente-Cortés, V.; Orbe, J; et al.
Revista:
INTERNATIONAL JOURNAL OF CARDIOLOGY
ISSN:
0167-5273
Año:
2014
Vol.:
173
N°:
2
Págs.:
337 - 338
Revista:
BRITISH JOURNAL OF ANAESTHESIA
ISSN:
0007-0912
Año:
2014
Vol.:
112
Págs.:
766 - 767
Autores:
Lorente, L.; Martín, M. M.; Solé-Violán, J.; et al.
Revista:
PLOS ONE
ISSN:
1932-6203
Año:
2014
Vol.:
9
N°:
4
Págs.:
e94318
Objective: Higher circulating levels of tissue inhibitor of matrix metalloproteinases (TIMP)-1 at the time of severe sepsis diagnosis have been reported in nonsurviving than in surviving patients. However, the following questions remain unanswered: 1) Does TIMP-1/MMP-9 ratio differ throughout the first week of intensive care between surviving and nonsurviving patients? 2) Is there an association between TIMP-1/MMP-9 ratio and sepsis severity and mortality during such period? 3) Could TIMP-1/MMP-9 ratio during the first week be used as an early biomarker of sepsis outcome? 4) Is there an association between TIMP-1/MMP-9 ratio and coagulation state and circulating cytokine levels during the first week of intensive care in these patients? The present study sought to answer these questions.
Methods: Multicenter, observational and prospective study carried out in six Spanish Intensive Care Units (ICUs) of 295 patients with severe sepsis. Were measured circulating levels of TIMP-1, MMP-9, tumour necrosis factor (TNF)-alpha, interleukin (IL)-10 and plasminogen activator inhibitor (PAI)-1 at day 1, 4 and 8. End-point was 30-day mortality.
Results: We found higher TIMP-1/MMP-9 ratio during the first week in non-surviving (n = 98) than in surviving patients (n = 197) (p<0.01). Logistic regression analyses showed that TIMP-1/MMP-9 ratio at days 1, 4 and 8 was associated with mortality. Receiver operating characteristic (ROC) curves showed that TIMP-1/MMP-9 ratio at days 1, 4 and 8 could predict mortality. There was an association between TIMP-1/MMP-9 ratio and TNF-alpha, IL-10, PAI-1 and lactic acid levels, SOFA score and platelet count at days 1, 4 and 8.
Conclusions: The novel findings of our study were that non-surviving septic patients showed persistently higher TIMP-1/MMP-9 ratio than survivors ones during the first week, which was associated with severity, coagulation state, circulating cytokine levels and mortality; thus representing a new biomarker of sepsis outcome.
Revista:
PHLEBOLOGY
ISSN:
0268-3555
Año:
2014
Vol.:
29
N°:
3
Págs.:
154 - 163
Objective: The purpose of this study was to compare the activation of haemostasis and inflammatory response after three different methods of treatment of great saphenous vein (GSV) incompetence.
Material and methods: Forty-five patients with GSV incompetence were assigned to one of the three types of treatment: high ligation and stripping (HL&S), radiofrequency ablation with ClosureFast (RFA) and endovenous laser ablation (EVLA) with 810 nm diode laser with miniphlebectomy if required. Peripheral blood samples were obtained in the morning before the surgery and 24 hours and 10 days after the procedure. The concentrations of C-reactive protein (CRP), D-dimer, prothrombin fragment 1 + 2 (F1 + 2), antigen of tissue plasminogen activator (t-PA) and von Willebrand factor (vWF) antigen and activity of plasminogen activator inhibitor (PAI-1) were determined. The results were statistically analysed with SPSS for Windows 15.0.
Results: Thirty-eight patients completed the study: 13 from RFA, 14 from EVLA and 11 from HL&S group. The baseline data did not differ among groups. There was a significant increase of D-dimer in HL&S group after 24 hours (P = 0.002). The changes in RFA and EVLA groups did not show statistical significance (P = 0.092). PAI-1 decreased in RFA patients after 24 hours (P = 0.02), did not change in EVLA patients, and tended to increase after HL&S (P = 0.08). The highest CRP increase was observed in HL& S group (P = 0.003). No significant changes in F1 + 2, t-PA and vWF were observed in any group of patients at 24 hours. At 10 days, a further significant increase of D-dimer (P = 0.04) and CRP (P = 0.018) concentrations in HL& S but not RFA and EVLA patients was observed.
Conclusions: Endovenous thermal ablation is associated with significantly less activation of haemostasis and inflammatory response when compared with HL&S.
Revista:
ANGIOLOGIA
ISSN:
0003-3170
Año:
2014
Vol.:
66
N°:
3
Págs.:
109 - 111
Revista:
STEM CELL
ISSN:
1945-4570
Año:
2014
Vol.:
32
N°:
2
Págs.:
447 - 461
Matrix metalloproteinases (MMPs), a family of endopeptidases that are involved in the degradation of extracellular matrix components, have been implicated in skeletal muscle regeneration. Among the MMPs, MMP-2 and MMP-9 are upregulated in Duchenne muscular dystrophy (DMD), a fatal X-linked muscle disorder. However, inhibition or overexpression of specific MMPs in a mouse model of DMD (mdx) has yielded mixed results regarding disease progression, depending on the MMP studied. Here, we have examined the role of MMP-10 in muscle regeneration during injury and muscular dystrophy. We found that skeletal muscle increases MMP-10 protein expression in response to damage (notexin) or disease (mdx mice), suggesting its role in muscle regeneration. In addition, we found that MMP-10-deficient muscles displayed impaired recruitment of endothelial cells, reduced levels of extracellular matrix proteins, diminished collagen deposition, and decreased fiber size, which collectively contributed to delayed muscle regeneration after injury. Also, MMP-10 knockout in mdx mice led to a deteriorated dystrophic phenotype. Moreover, MMP-10 mRNA silencing in injured muscles (wild-type and mdx) reduced muscle regeneration, while addition of recombinant human MMP-10 accelerated muscle repair, suggesting that MMP-10 is required for efficient muscle regeneration. Furthermore, our data suggest that MMP-10-mediated muscle repair is associated with VEGF/Akt signaling. Thus, our findings indicate that MMP-10 is
Revista:
ANALES DEL SISTEMA SANITARIO DE NAVARRA
ISSN:
1137-6627
Año:
2014
Vol.:
37
N°:
3
Págs.:
363 - 369
Fundamento: Los concentrados de factores del complejo protrombínico (CCP) están indicados para reversión del efecto de antagonistas de vitamina K (AVK). Recientemente se han utilizado en el manejo de la coagulopatía de la hemorragia masiva. El objetivo del presente trabajo es evaluar la seguridad y eficacia del CCP en dos situaciones clínicas, para reversión de AVK y manejo integral de la hemorragia masiva.
Material y métodos: Revisión retrospectiva de los casos tratados con CCP entre enero de 2010 y febrero de 2013 en un único centro universitario. El objetivo primario fue la seguridad de administración del CCP en cuanto a reacciones inmediatas y episodios trombóticos. El objetivo secundario fue la eficacia, en 2 grupos: 1) Reversión de AVK y 2) Corrección de coagulopatía en hemorragia masiva.
Resultados: El análisis de seguridad incluyó 31 pacientes (22 varones), edad mediana 61 años (rango 30-86). No se registraron reacciones adversas durante la infusión y solo se observó un evento trombótico.
La eficacia en la reversión de AVK fue del 100% (6/6 pacientes), alcanzando normalización del INR en todos los pacientes. En hemorragia masiva, la supervivencia a las 24 horas fue 64% (16/25). Se requirieron procedimientos invasivos adicionales en 28% de los pacientes (7/25). El uso de CCP se asoció a cese de hemorragia en 44% de los pacientes (11/25), que correlacionó positivamente con la supervivencia (p=0,01).
Conclusión: El uso de CCP es una alternativa segura y eficaz, para la reversión urgente del efecto de AVK, así como para el control de sangrado en situación de hemorragia masiva.
Autores:
Llorente-Cortés, V.; De Gonzalo-Calvo, D.; Orbe, J; et al.
Revista:
EUROPEAN JOURNAL OF CLINICAL INVESTIGATION
ISSN:
0014-2972
Año:
2014
Vol.:
44
N°:
6
Págs.:
539 - 548
BACKGROUND:
Peripheral arterial disease is a relevant public health problem associated with increased risk of morbimortality. Most of the patients with this condition are asymptomatic. Therefore, the development of accessible biochemical markers seems to be necessary to anticipate diagnosis. Our hypothesis is that asymptomatic subjects with objectively confirmed femoral artery atherosclerosis could be distinguished from control subjects by gene expression analysis in peripheral blood mononuclear cells (PBMC).
MATERIALS AND METHODS:
A total of 37 asymptomatic males over 50 years old were recruited at the University Clinic of Navarra (Spain). Nineteen participants were free from atherosclerotic vascular disease and 18 participants presented subclinical femoral artery atherosclerosis defined by means of Doppler ultrasound. PBMC were isolated from blood and the RNA extracted. A panel of atherosclerotic-related genes were evaluated by Taqman low-density array.
RESULTS:
In univariate logistic regression models, we found a direct relationship between IL4, ITGAM and TLR2 expression levels in PBMC and femoral atherosclerosis, even when the models were adjusted for age and hypertension prevalence. Multivariate logistic regression models showed that elevated IL4 expression levels were intimately associated with subclinical femoral atherosclerosis after adjusting for the same potential confounders.
CONCLUSIONS:
Current data suggest that gene expression in PBMC, in particular IL4 expression, could be a useful tool in the diagnosis of femoral artery atherosclerosis in asymptomatic patients. Furthermore, in patients with no differences in cardiovascular risk factors except for hypertension, the results point to the immune and inflammatory deregulation as a feature of subclinical peripheral atherosclerosis.
Revista:
THROMBOSIS RESEARCH
ISSN:
0049-3848
Año:
2014
Vol.:
134
N°:
1
Págs.:
182 - 186
BACKGROUND:
Higher plasma plasminogen activator inhibitor-1 (PAI-1) levels have been reported in septic patients. However, some questions remain unanswered, such as whether there is an association between plasma PAI-1 levels and sepsis severity and mortality, and inflammation state during the first week.
METHODS:
Multicenter, observational and prospective study carried out in six Spanish Intensive Care Units of 260 patients with severe sepsis. Circulating levels of PAI-1 and tumour necrosis factor (TNF)-¿ were measured at day 1, 4 and 8. End-point was 30-day mortality.
RESULTS:
Nonsurviving septic patients (n=89) presented higher PAI-1 levels than surviving (n=171) at day 1 (58.4 (33.3-83.8) vs 36.5 (21.1-62.5) ng/mL; p<0.001), 4 (34.0 (14.7-53.3) vs 16.2 (10.2-27.4) ng/mL; p<0.001) and 8 (30.6 (16.2-47.8) vs 18.9 (10.4-29.5) ng/mL; p=0.004). We found a positive correlation of PAI-1 levels with SOFA, lactic acid, aPTT, INR and TNF-¿, and negative with platelet count at day 1, 4 and 8. Logistic regression analyses showed that PAI-1 levels at day 1 (p<0.001), 4 (p<0.001) and 8 (p=0.001) were associated with 30-day mortality. On ROC curve analysis to predict 30- day survival, the area under the curve of PAI-1 levels at day 1, 4 and 8 were 0.65 (95% CI=0.58-0.72; p<0.001), 0.69 (95% CI=0.60-0.78; p<0.001) and 0.65 (95% CI=0.54-0.75; p=0.005) respectively.
CONCLUSIONS:
The most interesting findings of our study, to our knowledge the largest series reporting PAI-1 levels during follow-up in septic patients, were that plasma PAI-1 levels during the first week were associated with inflammation, severity and mortality.
Revista:
STEM CELLS AND DEVELOPMENT
ISSN:
1547-3287
Año:
2014
Vol.:
23
N°:
12
Págs.:
1417-1427
The CXCR4/SDF1 axis participates in various cellular processes, including cell migration, which is essential for skeletal muscle repair. Although increasing evidence has confirmed the role of CXCR4/SDF1 in embryonic muscle development, the function of this pathway during adult myogenesis remains to be fully elucidated. In addition, a role for CXCR4 signaling in muscle maintenance and repair has only recently emerged. Here, we have demonstrated that CXCR4 and stromal cell-derived factor-1 (SDF1) are up-regulated in injured muscle, suggesting their involvement in the repair process. In addition, we found that notexin-damaged muscles showed delayed muscle regeneration on treatment with CXCR4 agonist (AMD3100). Accordingly, small-interfering RNA-mediated silencing of SDF1 or CXCR4 in injured muscles impaired muscle regeneration, whereas the addition of SDF1 ligand accelerated repair. Furthermore, we identified that CXCR4/SDF1-regulated muscle repair was dependent on matrix metalloproteinase-10 (MMP-10) activity. Thus, our findings support a model in which MMP-10 activity modulates CXCR4/SDF1 signaling, which is essential for efficient skeletal muscle regeneration.
Revista:
THROMBOSIS AND HAEMOSTASIS
ISSN:
0340-6245
Año:
2014
Vol.:
111
N°:
1
Págs.:
182
Revista:
MEDICINA CLINICA
ISSN:
0025-7753
Año:
2014
Vol.:
143
N°:
1
Págs.:
20 - 21
Revista:
MEDICINA CLINICA
ISSN:
0025-7753
Año:
2013
Vol.:
141
N°:
5
Págs.:
207 - 209
Revista:
MEDICINE (ELSEVIER)
ISSN:
0304-5412
Año:
2013
Vol.:
11
N°:
46
Págs.:
2723 - 2729
Novel oral anticoagulants, dabigatran, rivaroxaban, apixaban and edoxaban are approved in several indications, such as the prevention of venous thromboembolism after elective hip or knee replacement, treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE), prevention of recurrent DVT and PE and prevention of stroke in patients with non-valvular atrial fibrillation. These agents overcome some limitations of traditional anticoagulants, such as heparins and vitamin K antagonists, are suggested to have no requirement for routine coagulation monitoring and are administered orally. Therefore, they may represent a significant advance in the prophylaxis and treatment of thrombosis.
Autores:
Parrondo, J.; Grande, C.; Ibáñez, J.; et al.
Revista:
FARMACIA HOSPITALARIA
ISSN:
1130-6343
Año:
2013
Vol.:
37
N°:
3
Págs.:
182 - 191
Objetivo: Desarrollar una herramienta de apoyo a la decisión en la selección de agonistas del receptor de trombopoyetina en el tratamiento de pacientes adultos con trombocitopenia inmune primaria crónica (PTI) refractaria. Métodos: Análisis coste-efectividad estocástico con un modelo de Markov de seis estados: estable, sangrado tipo 2, 3 ó 4, post-sangrado 4 y muerte. Cada simulación analiza un escenario aleatoriamente generado que describe las características del paciente, los resultados medidos en años de vida ajustados a calidad (AVACs) y los costes (en ?2011). Se obtuvieron distribuciones a partir de los datos para España de la Encuesta Europea de Salud de 2009, de la estimación de población para 2011 del INE, de los estudios a 6 meses de Eltrombopag y Romiplostim, de las utilidades obtenidas de la bibliografía y de las tarifas oficiales en España para procesos y actividad. Se generaron 10.000 escenarios aleatorios y se simuló la evolución de los pacientes de cada escenario durante un horizonte temporal de cinco años (ciclos de dos semanas). Perspectiva del Sistema Nacional de Salud (SNS). Tasa de descuento anual del 3% para costes y efectos. Resultados: En 9.983 escenarios Eltrombopag mostró mayor efectividad y en 17 no hubo diferencias. Eltombopag fue la alternativa dominante en 7.048 escenarios y la más coste efectiva en otros 19 (umbral 30.000 ?/AVAC). Conclusiones: Eltrombopag es la alternativa más coste-efectiva en el 70,67% de los escenarios simulados, por lo que su uso podría producir menores costes al SNS.
Revista:
THROMBOSIS AND HAEMOSTASIS
ISSN:
0340-6245
Año:
2013
Vol.:
110
N°:
1
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
Revista:
HEMATOLOGIA
ISSN:
2081-0768
Año:
2013
Vol.:
17
N°:
1
Págs.:
1-7
Revista:
LIVER INTERNATIONAL
ISSN:
1478-3223
Año:
2013
Vol.:
34
N°:
7
Págs.:
e257 - e270
Background & Aims Upon tissue injury, the liver mounts a potent reparative and regenerative response. A role for proteases, including serine and matrix metalloproteinases ( MMPs), in this process is increasingly recognized. We have evaluated the expression and function of MMP10 (stromelysin-2) in liver wound healing and regeneration. Methods The hepatic expression of MMP10 was examined in two murine models: liver regeneration after two-thirds partial hepatectomy (PH) and bile duct ligation (BDL). MMP10 was detected in liver tissues by qPCR, western blotting and immunohistochemistry. The effect of growth factors and toll-like receptor 4 (TLR4) agonists on MMP10 expression was studied in cultured parenchymal and biliary epithelial cells and macrophages respectively. The role of MMP10 was evaluated by comparing the response of Mmp10+/+ and Mmp10¿/¿ mice to PH and BDL. The intrahepatic turnover of the extracellular matrix proteins fibrin (ogen) and fibronectin was examined. Results MMP10 mRNA was readily induced after PH and BDL. MMP10 protein was detected in hepatocytes, cholangiocytes and macrophages. In cultured liver epithelial cells, MMP10 expression was additively induced by transforming growth factor-ß and epidermal growth factor receptor ligands. TLR4 ligands also stimulated MMP10 expression in macrophages. Lack of MMP10 resulted in increased liver injury upon PH and BDL. Resolution of necrotic areas was impaired, and Mmp10¿/¿ mice showed increased fibrogenesis and defective turnover of fibrin (ogen) and fibronectin. Conclusions MMP10 expression is induced during mouse liver injury and participates in the hepatic wound healing response. The profibrinolytic activity of MMP10 may be essential in this novel hepatoprotective role.
Revista:
MEDICINA CLINICA
ISSN:
0025-7753
Año:
2013
Vol.:
141
N°:
8
Págs.:
346 - 348
Revista:
INTERNATIONAL JOURNAL OF CANCER
ISSN:
0020-7136
Año:
2013
Vol.:
133
N°:
9
Págs.:
2157 - 2164
Extensive screening strategies to detect occult cancer in patients with unprovoked venous thromboembolism (VTE) are complex and no benefit in terms of survival has been reported. FDG-PET/CT (2-[F-18] fluoro-2-deoxy-D-glucose positron emission tomography combined with computed tomography), a noninvasive technique for the diagnosis and staging of malignancies, could be useful in this setting. Consecutive patients ¿ 50 years with a first unprovoked VTE episode were prospectively included. Screening with FDG-PET/CT was performed 3¿4 weeks after the index event. If positive, appropriate diagnostic work-up was programmed. Clinical follow-up continued for 2 years. Blood samples were collected to assess coagulation biomarkers. FDG-PET/CT was negative in 68/99 patients (68.7%), while suspicious FDG uptake was detected in 31/99 patients (31.3%). Additional diagnostic work-up confirmed a malignancy in 7/31 patients (22.6%), with six of them at early stage. During follow-up, two patients with negative FDG-PET/CT were diagnosed with cancer. Sensitivity (S), positive (PPV) and negative predictive values (NPV) of FDG-PET/CT as single tool for the detection of occult malignancy were 77.8% (95% CI: 0.51¿1), 22.6% (95% CI: 0.08¿0.37) and 97.1% (95% CI: 0.93¿1), respectively. Median tissue factor (TF) activity in patients with occult cancer was 5.38 pM vs. 2.40 pM in those without cancer (p = 0.03). ...
Autores:
Leal-Noval, S. R.; Muñoz, M.; Asuero, M.; et al.
Revista:
BLOOD TRANSFUSION
ISSN:
1723-2007
Año:
2013
Vol.:
11
N°:
4
Págs.:
585 - 610
Autores:
Lorente, L.; Martin, M.; Plasencia, F.; et al.
Revista:
CRITICAL CARE
ISSN:
1466-609X
Año:
2013
Vol.:
17
N°:
3
Págs.:
R94
INTRODUCTION:
Previous studies have found higher circulating levels of tissue inhibitor of matrix metalloproteinase (TIMP)-1 in nonsurviving septic patients than in surviving septic patients, and an association between the 372 T/C genetic polymorphism of TIMP-1 and the risk of developing certain diseases. However, the relationship between genetic polymorphisms of TIMP-1, circulating TIMP-1 levels and survival in patients with severe sepsis has not been examined, and this was the objective of the study.
METHODS:
This multicentre, prospective, observational study was carried out in six Spanish ICUs. We determined the 372 T/C genetic polymorphism of TIMP-1 (rs4898), serum levels of TIMP-1, matrix metalloproteinase (MMP)-9, MMP-10, TNF¿, IL-10 and plasma plasminogen activator inhibitor-1 (PAI-1). Survival at 30 days from ICU admission was the endpoint assessed. The association between continuous variables was carried out using Spearman's rank correlation coefficient or Spearman's rho coefficient. Multivariate logistic regression analysis was applied to determine the association between the 372 T/C genetic polymorphism and survival 30 days from ICU admission.
RESULTS:
Of 275 patients with severe sepsis, 80 had genotype CC, 55 had genotype CT and 140 had genotype TT of the 372 T/C genetic polymorphism of TIMP-1. Patients with the T allele showed higher serum levels of TIMP-1 than patients without the T allele (P=0.004). Multiple logistic regression analysis showed that the T allele was associated with higher mortality at 30 days (odds ratio=2.08; 95% confidence interval=1.06 to 4.09; P=0.03). Survival analysis showed that patients with the T allele presented lower 30-day survival than patients without the T allele (¿2=5.77; P=0.016). We found an association between TIMP-1 levels and levels of MMP-9 (¿=-0.19; P=0.002), MMP-10 (¿=0.55; P<0.001), TNF¿ (¿=0.56; P<0.001), IL-10 (¿=0.48; P<0.001) and PAI-1 (¿=0.49; P<0.001).
CONCLUSION:
The novel findings of our study are that septic patients with the T allele in the 372 T/C genetic polymorphism of TIMP-1 showed higher serum TIMP-1 levels and lower survival rate. The determination of the 372 T/C genetic polymorphism of TIMP-1 thus has prognostic implications and could help in the selection of patients who may benefit from modulation of the MMP/TIMP balance.
Revista:
THROMBOSIS AND HAEMOSTASIS
ISSN:
0340-6245
Año:
2013
Vol.:
110
N°:
3
Págs.:
598 - 608
Abstract
A prothrombotic state is one of the hallmarks of malignancy and a major contributor to morbidity and mortality in cancer patients.Tissue factor (TF) is often overexpressed in malignancy and is a prime candidate in predicting the hypercoagulable state. Moreover, increased number of TF-exposing microparticles (MPs) in cancer patients may contribute to venous thromboembolism (VTE). We have conducted a prospective cohort study to determine whether elevated TF antigen, TF activity and TF associated to MPs (MPs-TF) are predictive of VTE and mortality in cancer patients. The studied population consisted of 252 cancer patients and 36 healthy controls. TF antigen and activity and MPs-TF were determined by ELISA and chromogenic assays. During a median follow-up of 10 months, 40 thrombotic events were recorded in 34 patients (13.5%), and 73 patients (28.9%) died. TF antigen and activity were significantly higher in patients than in controls (p<0.01) mainly in patients with advanced stages, whereas no differences were observed for TF activity of isolated MPs. We did not find a statistically significant association of TF variables with the risk of VTE. Multivariate analysis adjusting for age, sex, type of cancer and other confounding variables showed that TF activity (p<0.01) and MPs-TF activity (p<0.05) were independently associated with mortality. In conclusion, while TF variables were not associated with future VTE in cancer patients, we found a strong association of TF and MPs-TF activity with mortality, thus suggesting they might be good prognostic markers in cancer patients.
Revista:
JOURNAL OF THROMBOSIS AND HAEMOSTASIS
ISSN:
1538-7933
Año:
2013
Vol.:
11
N°:
8
Págs.:
1464 - 1473
Background: Matrix metalloproteinases (MMPs) mediate tissue injury during stroke but also neurovascular remodeling and we have shown that MMP-10 is involved in atherothrombosis. Objective: The purpose of this study was to examine the relationship between proMMP-10 and clinical outcome, assessing inflammatory and proteolytic markers, in patients with acute ischemic stroke. Methods: We prospectively studied 76 patients with ischemic stroke treated with tPA within the first 3 h from symptom onset, compared with 202 non-tPA-treated ischemic stroke patients and 83 asymptomatic subjects. Stroke severity was assessed with the National Institutes of Health Stroke Scale (NIHSS). Hemorrhagic transformation (HT) and severe brain edema were diagnosed by cranial CT. Good functional outcome was defined as a modified Rankin scale score ¿ 2 at 90 days. Serum levels of MMP-9, proMMP-10, TIMP-1, tumor necrosis factor-¿ (TNF¿), interleukin-6 and cellular fibronectin were measured at admission. The effect of TNF¿ on endothelial proMMP-10 was assessed in vitro. Results: Serum proMMP-10 concentration in ischemic stroke patients, non-treated or treated with t-PA, which was higher than age-matched healthy subjects (P < 0.0001), was independently associated with higher infarct volume, severe brain edema, neurological deterioration and poor functional outcome at 3 months (all P < 0.05), but not with HT. proMMP-10 levels were also independently and positively associated with circulating levels of TNF¿ (P < 0.0001), which induced its endothelial expression in vitro, both mRNA and protein. MMP-9, however, was only associated with HT and severe edema (all P < 0.05). Conclusions: Increased serum proMMP-10 after acute ischemic stroke, associated with TNF¿, is a new marker of brain damage and poor outcome.
Revista:
CELL TRANSPLANTATION
ISSN:
0963-6897
Año:
2012
Vol.:
21
N°:
5
Págs.:
1023 - 1037
Fresh adipose-derived cells have been shown to be effective in the treatment of acute myocardial infarction (MI), but their role in the chronic setting is unknown. We sought to determine the long-term effect of the adipose derived-stromal vascular fraction (SVF) cell transplantation in a rat model of chronic MI. MI was induced in 82 rats by permanent coronary artery ligation and 5 weeks later rats were allocated to receive an intramyocardial injection of 10(7) GFP-expressing fresh SVF cells or culture media as control. Heart function and tissue metabolism were determined by echocardiography and F-18-FDG-microPET, respectively, and histological studies were performed for up to 3 months after transplantation. SVF induced a statistically significant long-lasting (3 months) improvement in cardiac function and tissue metabolism that was associated with increased revascularization and positive heart remodeling, with a significantly smaller infarct size, thicker infarct wall, lower scar fibrosis, and lower cardiac hypertrophy. Importantly, injected cells engrafted and were detected in the treated hearts for at least 3 months, directly contributing to the vasculature and myofibroblasts and at negligible levels to cardiomyocytes. Furthermore, SVF release of angiogenic (VEGF and HGF) and proinflammatory (MCP-1) cytokines, as well as TIMP1 and TIMP4, was demonstrated in vitro and in vivo, strongly suggesting that they have a trophic effect. These results show the potential of SVF to contribute to the regeneration of ischemic tissue and to provide a long-term functional benefit in a rat model of chronic MI, by both direct and indirect mechanisms.
Revista:
MEDICINE (ELSEVIER)
ISSN:
0304-5412
Año:
2012
Vol.:
11
N°:
22
Págs.:
1337-44
Las púrpuras representan la patología genuina de los trastornos de la hemostasia primaria y se dividen en: a) púrpuras vasculares, con alteración en el componente vascular, con número y función plaquetaria normal y hemorragias cutáneas superficiales; b) púrpuras trombopénicas, causadas por un fallo cuantitativo en el componente plaquetario, de ellas, el cuadro más importante es la trombocitopenia inmune primaria (PTI) causada por autoanticuerpos antiplaquetarios, con una forma infantil autolimitada y otra crónica presente en adultos y cuadro hemorrágico cutaneomucoso; el tratamiento de primera línea de la PTI son los corticoides e inmunoglobulinas, y de segunda línea la esplenectomía y los nuevos agentes trombopoyéticos como romiplostin y eltrombopag y c) púrpuras trombopáticas, causadas por un fallo cualitativo, que pueden ser congénitas, como síndrome de Bernard-Soulier y trombastenia de Glanzmann, o adquiridas (por ejemplo, hepatopatía, enfermedad renal, ingesta de antiplaquetarios, etc.). El tratamiento se basa en la administración de antifibrinolíticos y desmopresina en las formas moderadas y concentrado de plaquetas y factor VII activado recombinante en las formas graves.
Revista:
MEDICINE (ELSEVIER)
ISSN:
0304-5412
Año:
2012
Vol.:
11
N°:
23
Págs.:
1421 - 1427
Thrombotic vascular disorders represent the main cause of mortality in industrialized and developing countries. Activation of the hemostasis with generation of fibrin inside the vessel provokes the reduction of blood flow with the consequent ischemia and thrombosis. The basis of the antithrombotic treatment is anticoagulant drugs, classically represented by low molecular weight heparins and fondaparinux or unfractionated heparin parenterally in the initial phase and the vitamin K antagonists (acenocoumarol [Sintrom® or warfarin]) orally, as long-term strategy. In the last decade, new oral thrombin inhibitors (dabigatran) and of the Xa factor (rivaroxaban and apixaban) whose advantages are that they do not require monitoring and that they have scarce pharmacological interactions have been developed. Recent clinical studies demonstrate their utility in the prevention of venous thromboembolism in major orthopedic surgery and in the prevention of stroke in atrial fibrillation patients and those under treatment for venous thromboembolism. It is likely that in the short term these drugs will replace the vitamin K antagonists in different clinical scenarios that occur with thrombosis.
Revista:
MEDICINE (ELSEVIER)
ISSN:
0304-5412
Año:
2012
Vol.:
11
N°:
22
Págs.:
1359-65
Las coagulopatías adquiridas son procesos muy frecuentes en la práctica clínica. En general, son el resultado del consumo de factores de coagulación, como en la coagulación intravascular diseminada (CID), defecto de síntesis de factores, como en las hepatopatías y déficits de vitamina K, o como resultado de la presencia de anticoagulantes circulantes o de fármacos que alteran la coagulación (antivitaminas K, acenocumarol o warfarina). La intensidad de la hemorragia es muy variable, existiendo una pobre correlación con las alteraciones hemostáticas detectadas en los estudios rutinarios de coagulación (tiempo de protrombina y tromboplastina parcial activado, fibrinógeno, dímero D y recuento de plaquetas). El tratamiento debe ser individualizado y requiere el uso apropiado de hemoderivados, plasma, plaquetas y crioprecipitado, en combinación con agentes farmacológicos, tales como concentrado de factores del complejo protrombínico y antifibrinolíticos. La administración de vitamina K será esencial para corregir el déficit secundario al tratamiento con acenocumarol o warfarina.
Revista:
MEDICINE (ELSEVIER)
ISSN:
0304-5412
Año:
2012
Vol.:
11
N°:
22
Págs.:
1353-58
Las coagulopatías congénitas se caracterizan por trastornos hemorrágicos que aparecen en la infancia y presentan una historia familiar conocida. Las más frecuentes son la enfermedad de von Willebrand, caracterizada por la aparición de hemorragias cutaneomucosas en sujetos de ambos sexos, y la hemofilia A (déficit de FVIII) que se presenta con hemorragias intraarticulares y musculares en los varones. El diagnóstico se realiza con pruebas funcionales, inmunológicas y tests genéticos. El tratamiento es, generalmente, sustitutivo mediante la infusión del factor deficitario en las formas graves complementado con estrategias de profilaxis primaria. La principal complicación del tratamiento de la hemofilia es el desarrollo de inhibidores. En los casos leves el tratamiento de elección es la desmopresina. En otras coagulopatías congénitas infrecuentes, el tratamiento consiste en la administración de plasma fresco congelado, concentrado de factores del complejo protrombínico o factor VII activado recombinante.
Revista:
MEDICINE (ELSEVIER)
ISSN:
0304-5412
Año:
2012
Vol.:
11
N°:
22
Págs.:
1366-70
El tromboembolismo venoso (TEV) es la tercera causa de mortalidad cardiovascular, tras el infarto agudo de miocardio y el ictus. Las secuelas del TEV a largo plazo son el síndrome postrombótico y la hipertensión pulmonar crónica. El diagnóstico se basa en modelos de probabilidad clínica, el dímero D y pruebas de imagen no invasivas, como ecografía para trombosis venosa profunda y angiotomografía computadorizada (TC) para embolismo pulmonar. La base del tratamiento la constituye la anticoagulación, generalmente con heparina no fraccionada o de bajo peso molecular por vía parenteral, seguida por antivitaminas K por vía oral (acenocumarol o warfarina) durante 3¿6 meses, requiriendo una estrecha monitorización del INR (índice normalizado internacional). Se han desarrollado nuevos anticoagulantes orales (dabigatran, rivaroxaban, apixaban) que pueden a corto plazo reemplazar a las heparinas y acenocumarol, con la ventaja de tener una administración oral y sin necesidad de monitorización.
Revista:
MEDICINE (ELSEVIER)
ISSN:
0304-5412
Año:
2012
Vol.:
11
N°:
22
Págs.:
1371 - 1376
El sistema hemostático tiene como función evitar la pérdida de sangre cuando se produce una lesión vascular, con la puesta en marcha de los mecanismos de hemostasia primaria y coagulación, con la finalidad de formar un tapón de plaquetas y fibrina. El sistema fibrinolítico es el encargado de la degradación de la fibrina para mantener la fluidez circulatoria. Un déficit de los mecanismos de coagulación o un aumento de fibrinolisis va a favorecer el desarrollo de complicaciones hemorrágicas. La detección de una diátesis hemorrágica comienza con una correcta anamnesis y exploración física en combinación con pruebas de laboratorio complementarias. Las pruebas de hemostasia se dirigen al estudio de las alteraciones cuantitativas y cualitativas de las plaquetas, pruebas globales de coagulación y fibrinolisis, y pruebas específicas encaminadas a la detección del mecanismo concreto responsable del cuadro hemorrágico.
Revista:
MEDICINE (ELSEVIER)
ISSN:
0304-5412
Año:
2012
Vol.:
11
N°:
22
Págs.:
1377-81
La trombofilia, una predisposición genética o adquirida a la trombosis, se considera una enfermedad multifactorial resultado de la combinación de factores genéticos y adquiridos. A pesar de su baja prevalencia en la población general, puede encontrarse en hasta en un 10¿50% de los pacientes con eventos tromboembólicos espontáneos y/o mujeres con complicaciones obstétricas. La trombosis idiopática recurrente, en pacientes menores de 50 años con historia familiar o de localización inusual, así como mujeres con abortos recurrentes debe elevar la sospecha clínica y realizar estudios complementarios con pruebas especiales de hipercoagulabilidad: antitrombina, proteínas C y S, factor V Leiden, mutación de la protrombina, anticoagulante lúpico, anticuerpos antifosfolípidos y otras adicionales. Los resultados anormales de las pruebas de trombofilia se deben confirmar siempre, y un hallazgo positivo aconseja estudiar a familiares de primer grado para establecer profilaxis primaria si es pertinente y determinar la conducta terapéutica de cara a la anticoagulación en sujetos con trombosis.
Revista:
MEDICINE (ELSEVIER)
ISSN:
0304-5412
Año:
2012
Vol.:
11
N°:
22
Págs.:
1327 - 1336
La hemostasia representa un mecanismo de defensa del organismo para prevenir la pérdida excesiva de sangre cuando se produce una lesión vascular. Según la hipótesis celular actual, la coagulación sería una sinfonía en la que múltiples sistemas interaccionan simultáneamente en concierto con superficies celulares de las plaquetas y el endotelio vascular para generar un coágulo estable de fibrina. Una alteración del balance hemostático puede favorecer la hemorragia o la trombosis.
La historia clínica será de vital importancia para establecer la naturaleza congénita o adquirida del trastorno hemostático. La interpretación de las pruebas de coagulación y fibrinolisis requiere el conocimiento de las principales vías implicadas, existiendo en la actualidad dispositivos que permiten su determinación a la cabecera del paciente. Las alteraciones hemostáticas pueden afectar a la hemostasia primaria o plaquetaria y cursar con hemorragias cutaneomucosas, o a la coagulación sanguínea (hemostasia secundaria), con hemorragias a nivel muscular, articular o en cavidades.
Revista:
Arteriosclerosis, thrombosis and vascular biology (Print)
ISSN:
1079-5642
Año:
2012
Vol.:
32
N°:
6
Págs.:
1477 - 1487
Revista:
MEDICINE (ELSEVIER)
ISSN:
0304-5412
Año:
2012
Vol.:
11
N°:
22
Págs.:
1345-52
El tromboembolismo venoso (TEV) es una de las causas más importantes de morbilidad y mortalidad en nuestro medio. En su patogenia intervienen las alteraciones de la pared vascular, anomalías del flujo (estasis) y un estado de hipercoagulabilidad (o trombofilia) de la sangre. Los estados trombofílicos pueden ser congénitos, por pérdida de función, como en la deficiencia de anticoagulantes naturales (antitrombina y proteínas C y S), o ganancia de función, como el factor V Leiden o la mutación de la protrombina. El diagnóstico del TEV se realiza mediante la probabilidad clínica, pruebas de imagen no invasivas, como eco-doppler y angio-tomografía computadorizada (TC), y determinación del dímero D. El tratamiento consiste en la administración de heparina de bajo peso molecular por vía subcutánea, seguida de antivitaminas K (acenocumarol o warfarina) por vía oral durante 3¿6 meses o indefinidamente si existen factores de riesgo permanentes. En los últimos años se han desarrollado nuevos anticoagulantes orales, inhibidores directos de la trombina o del factor Xa (dabigatran, rivaroxaban, apixaban), que pueden reemplazar a corto plazo a las antivitaminas K.
Revista:
Medicina clínica. (Ed. impresa)
ISSN:
0025-7753
Año:
2011
Vol.:
137
N°:
10
Págs.:
458 - 453
Autores:
Lorente, L; Martin, M; Varo, N; et al.
Revista:
Critical care medicine
ISSN:
0090-3493
Año:
2011
Vol.:
15
N°:
2
Págs.:
1 - 8
Autores:
Calvayrac, O; Rodriguez-Calvo, R; Alonso, J; et al.
Revista:
ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY
ISSN:
1079-5642
Año:
2011
Vol.:
31
N°:
11
Págs.:
2733 - 2741
Revista:
JOURNAL OF THROMBOSIS AND HAEMOSTASIS
ISSN:
1538-7933
Año:
2011
Vol.:
9
N°:
6
Págs.:
1108-1115
Objectives: The prevention of venous thromboembolism (VTE) is a priority for improved safety in hospitalised patients. Worldwide, there is growing concern over the undersuse of appropriate thromboprophylaxis. Computerised decision support improves the implementation of thromboprophylaxis and reduces inpatient VTE. However, an economic assessment of this approach has not yet been performed. Objectives: To evaluate the economic impact of an electronic alert (e-alert) system to prevent VTE in hospitalised patients over a 4 year period. Patients/methods: All hospitalised patients at a single institution during the first semesters of 2005-2009 (n = 32 280) were included. All cases of VTE developed during hospitalisation were followed and direct costs of diagnosis and management collected. Results: E-alerts achieved a sustained reduction of the incidence of in-hospital VTE, OR 0.50 (95% CI, 0.29-0.84), the impact being especially significant in medical patients, OR 0.44 (95% CI, 0.22-0.86). No increase in prophylaxis-related bleeding was observed. In our setting, the mean direct cost (during hospitalisation and after discharge) of an in-hospital VTE episode is euro7058. Direct costs per single hospitalised patient were reduced after e-alerts from euro21.6 to euro11.8, while the increased use of thromboprophylaxis and the development of e-alerts meant euro3 and euro0.35 per patient, respectively. Thus, the implementation of e-alerts led to a net cost saving of euro6.5 per hospitalised patient. Should all hospitalised patients in Spain be considered, total yearly savings would approach euro30 million. Conclusions: E-alerts are useful and cost-effective tools for thromboprophylaxis strategy in hospitalised patients. Fewer thromboembolic complications and lower costs are achieved by its implementation
Autores:
Casanova-Esteban, Paola; Guiral, Nuria; Andres, Eva; et al.
Revista:
METABOLISM-CLINICAL AND EXPERIMENTAL
ISSN:
0026-0495
Año:
2011
Vol.:
60
N°:
6
Págs.:
830 - 834
Genetic predisposition to hereditary hemochromatosis (HH) is associated with primary hypertriglyceridemia (HTG). If iron overload influences the development of HTG, the management of these patients could be different. However, the metabolic syndrome in primary HTG is frequent; and it could partially confuse the association. The objective was to determine whether periodic bloodletting could decrease triglyceride concentrations in subjects with HH and iron overload. We retrospectively studied 155 genetically defined HH patients (C282Y homozygotes and compound heterozygotes C282Y/H63D) with iron overload and under periodic therapeutic phlebotomy. Hypertriglyceridemia (triglycerides ¿150 mg/dL) was present in 49 subjects at baseline (31.6%). Phlebotomies significantly decreased triglycerides, especially in subjects with basal HTG (from 287 mg/dL at baseline to 133 mg/dL after phlebotomies, P < .001). Blood glucose and total cholesterol did not change with phlebotomies. The triglyceride-lowering effect was obtained until ferritin concentration decreased to less than 200 ¿g/L and transferrin saturation to less than 40%. The triglyceride-lowering effect was obtained for glucose levels both less than and greater than 100 mg/dL. In summary, HH subjects frequently have HTG that improves after therapeutic phlebotomy, independently of basal blood glucose. Our results suggest that therapeutic phlebotomy could be a useful therapeutic approach in patients with HTG and iron overload.
Revista:
Circulation
ISSN:
0009-7322
Año:
2011
Vol.:
124
N°:
25
Págs.:
2909 - 2919
BACKGROUND:
The fibrinolytic and matrix metalloproteinase (MMP) systems cooperate in thrombus dissolution and extracellular matrix proteolysis. The plasminogen/plasmin system activates MMPs, and some MMPs have been involved in the dissolution of fibrin by targeting fibrin(ogen) directly or by collaborating with plasmin. MMP-10 has been implicated in inflammatory/thrombotic processes and vascular integrity, but whether MMP-10 could have a profibrinolytic effect and represent a promising thrombolytic agent is unknown.
METHODS AND RESULTS:
The effect of MMP-10 on fibrinolysis was studied in vitro and in vivo, in MMP-10-null mice (Mmp10(-/-)), with the use of 2 different murine models of arterial thrombosis: laser-induced carotid injury and ischemic stroke. In vitro, we showed that MMP-10 was capable of enhancing tissue plasminogen activator-induced fibrinolysis via a thrombin-activatable fibrinolysis inhibitor inactivation-mediated mechanism. In vivo, delayed fibrinolysis observed after photochemical carotid injury in Mmp10(-/-) mice was reversed by active recombinant human MMP-10. In a thrombin-induced stroke model, the reperfusion and the infarct size in sham or tissue plasminogen activator-treated animals were severely impaired in Mmp10(-/-) mice. In this model, administration of active MMP-10 to wild-type animals significantly reduced blood reperfusion time and infarct size to the same extent as tissue plasminogen activator and was associated with shorter bleeding time and no intracranial hemorrhage. This effect was not observed in thrombin-activatable fibrinolysis inhibitor-deficient mice, suggesting thrombin-activatable fibrinolysis inhibitor inactivation as one of the mechanisms involved in the MMP-10 profibrinolytic effect.
CONCLUSIONS:
A novel profibrinolytic role for MMP-10 in experimental ischemic stroke is described, opening new pathways for innovative fibrinolytic strategies in arterial thrombosis.
Revista:
Medicina clínica. (Ed. impresa)
ISSN:
0025-7753
Año:
2011
Vol.:
137
N°:
11
Págs.:
504 - 508
Revista:
CIRUGIA CARDIOVASCULAR
ISSN:
1134-0096
Año:
2011
Vol.:
18
N°:
1
Págs.:
15 - 19
La trombosis es una de las causas de muerte más importante en los países industrializados. La trombosis arterial es responsable del infarto de miocardio y de los accidentes cerebrovasculares y se genera en zonas de daño arterial. Los antiplaquetarios y anticoagulantes desempeñan un papel fundamental en la prevención y tratamiento. La enfermedad tromboembólica venosa, a través de la trombosis venosa profunda y la embolia pulmonar, es la tercera causa de muerte después de los eventos arteriales. Ésta suele tratarse con anticoagulantes. En este trabajo se revisan los nuevos fármacos antiplaquetarios y anticoagulantes y su impacto en la cirugía cardiovascular.
Thrombosis is the main cause of mortality in the industrialized countries. Arterial thrombosis, responsible of acute myocardial infarction and cerebrovascular accidents are characterized by the presence of rich clots in platelets and with scanty fibrin (called ¿white thrombus¿) that are generated in places of vascular injury. Under these circumstances antiplatelet agents are required for prevention and treatment. Nevertheless, as thrombin is the main enzyme of the coagulation system and is also a powerful platelet activator, anticoagulants are used to prevent arterial thrombosis. Venous tromboembolism, which includes deep venous thrombosis (DVT) and pulmonary embolism (PE), constitutes the third reason of cardiovascular mortality after myocardial infarction and stroke. Venous thrombi result from an activation of the coagulation and are constituted principally by fibrin, in which the red blood cells remain trapped together with scanty platelets (called ¿red thrombus¿); they are generally treated with anticoagulant agents. In this paper we will discuss the new antiplatelet and anticoagulant agents and their impact in cardiovascular surgery.
Revista:
New England Journal of Medicine
ISSN:
0028-4793
Año:
2011
Vol.:
365
N°:
3
Págs.:
278 - 279
Revista:
Medicina clínica. (Ed. impresa)
ISSN:
0025-7753
Año:
2011
Vol.:
137
N°:
10
Págs.:
468 - 471
Revista:
British Journal of Dermatology (Print)
ISSN:
0007-0963
Año:
2010
Vol.:
162
N°:
2
Págs.:
350 - 356
Revista:
HAEMATOLOGICA
ISSN:
1138-0381
Año:
2010
Vol.:
95
N°:
Extra 1
Págs.:
445 - 449
Revista:
HEART INTERNATIONAL
ISSN:
1826-1868
Año:
2010
Vol.:
5
N°:
2
Págs.:
58 - 63
Revista:
ARTIF ORGANS
ISSN:
0160-564X
Año:
2010
Vol.:
34
N°:
2
Págs.:
140 - 146
The aim of this study was to assess platelet dysfunction and damage to organs after extracorporeal circulation using a pump based on a new method that adds a pulsatile flow to the continuous flow provided by a centrifugal pump. The continuous component of the total flow (2-3 L/min) is created by a Bio-Pump centrifugal pump, while the pulsatile component is created by the pulsating of an inner membrane pneumatically controlled by an intra-aortic counterpulsation balloon console (systolic volume of 37.5 mL in an asynchronous way with a frequency of 60 bpm). Six pigs were subjected to a partial cardiopulmonary bypass lasting 180 min and were sacrificed 60 min after extracorporeal circulation was suspended. The hematological study included the measurement of hematocrit, hemoglobin, leukocytes, and platelet function. The new pump did not significantly alter either platelet count or platelet function. In contrast, hematocrit and hemoglobin were significantly reduced during extracorporeal circulation (approximately 5% P = 0.011, and 2 g/dL P = 0.01, respectively). The leukocyte count during extracorporeal circulation showed a tendency to decrease, but this was not significant. In general, the short-term use of the new pump (4 h) did not cause any serious morphological damage to the heart, lung, kidney, or liver. The results suggest that the hemodynamic performance of the new pump is similar to a conventional centrifugal pump and could therefore be appropriate for use in extracorporeal circulation.
Revista:
Advances in clinical chemistry
ISSN:
0065-2423
Año:
2010
Vol.:
51
Págs.:
1 - 23
Prothrombin fragment 1+2 (F1+2), which comes from in vivo cleavage of prothrombin by factor Xa, is considered to be useful for diagnosis of thrombosis. Recognition of the central role of thrombosis in the pathogenesis ofcardiovascular disease has prompted growing interest in the association o F1+2 with cardiovascular clinical syndromes. Increased F1+2 levels have reported in venous thromboembolism, inflammation, cancer, sepsis, acute coronary syndromes, stroke, peripheral arterial disease, atrial fibrillation and during the postoperative period. However, a clear relationship with the appearance of thrombosis has not always been consistently demonstrated. Besides its potential prognostic and diagnostic value, it could also be usefu in assessing the impact of various therapies. However, it should be kept in mind that measurement of hemostasis activation markers has several important biological and methodological disadvantages. Activation markers reflect the presence of thrombosis in any vascular bed, so they are not specific. Furthermore, elevations occur not only in the presence of overt thrombosis but also during the hypercoagulable state. The cutoff level to be used for the definition of elevations is still largely unknown due to the use of different analytical methods, none of which have been standardized until know. Finally, the prognostic value of F1+2 and other markers of coagulation activation remains to be fully defined in future studies.
Revista:
NEPHROLOGY
ISSN:
1320-5358
Año:
2010
Vol.:
15
N°:
2
Págs.:
178 - 183
Revista:
KIDNEY INTERNATIONAL
ISSN:
0085-2538
Año:
2010
Vol.:
78
N°:
12
Págs.:
1275 - 1280
Cardiovascular disease is the leading cause of mortality in chronic kidney disease (CKD). As matrix metalloproteinases have a major role in atherosclerosis, we hypothesized that alterations in metalloproteinases-8, -10 and their tissue inhibitor-1 can be associated with the severity of atherosclerosis in patients with kidney disease. This was evaluated in a cross-sectional, observational study of 111 patients with stages I-V kidney disease, 217 patients on dialysis and 50 healthy controls. The severity of atherosclerosis was estimated with the atherosclerosis score (AS), combining the results of ankle-brachial index and carotid ultrasound. Serum levels of the two metalloproteinases and tissue inhibitor-1 were measured by enzyme-linked immunosorbent assay and were significantly increased in patients with kidney disease compared with the healthy controls, and higher in patients on dialysis than in earlier stages of CKD. The severity of the AS was also more prevalent in the dialysis group, in which serum levels of both metalloproteinases and tissue inhibitor-1 were significantly higher. After multivariate analysis, metalloproteinase-10, dialysis, C-reactive protein, age, and male gender were associated with increased risk of atherosclerosis. Thus, patients with CKD exhibit elevated levels of circulating metalloproteinase-10, and this was independently associated with the severity of atherosclerosis and may represent a new biomarker of atherosclerotic diseases.
Revista:
DRUGS
ISSN:
0012-6667
Año:
2010
Vol.:
70
N°:
Supl. 2
Págs.:
11 - 18
Revista:
BRITISH JOURNAL OF DERMATOLOGY
ISSN:
0007-0963
Año:
2010
Vol.:
162
Págs.:
1156
