Edoxaban for the Long-Term Therapy of Venous Thromboembolism: Should the Criteria for Dose Reduction be Revised?

Edoxaban is used for venous thromboembolism (VTE) treatment. Real-life data are lacking about its use in long-term therapy. We aimed to assess the efficacy and the safety of edoxaban for long-term VTE treatment in a real-life setting. Patients with VTE included in the Registro Informatizado Enfermedad TromboEmbólica (RIETE) registry, receiving edoxaban 60 or 30 mg daily were prospectively followed up to validate the benefit of using different dosages. The main outcome was the composite of VTE recurrences or major bleeding in patients with or without criteria for dose reduction. Multivariable analysis to identify predictors for the composite outcome was performed. From October 2015 to November 2019, 562 patients received edoxaban for long-term therapy. Most (94%) of the 416 patients not meeting criteria for dose reduction received 60 mg daily, and 92 patients meeting criteria (63%) received 30 mg daily. During treatment, two patients developed recurrent VTE, six had major bleeding and nine died (2 from fatal bleeding). Among patients not meeting criteria for dose reduction, those receiving 30 mg daily had a higher rate of the composite event (hazard ratio (HR) 8.37; 95% confidence interval (CI) 1.12-42.4) and a significant higher mortality rate (HR 31.1; 95% CI 4.63-262) than those receiving 60 mg. Among patients meeting criteria for dose reduction, those receiving 60 mg daily had no events, and a nonsignificantly higher mortality rate (HR 5.04; 95% CI 0.54-133) than those receiving 30 mg daily. In conclusion, edoxaban seems to be effective and safe for long-term VTE treatment in real life. Criteria for dose reduction should be reformulated.

Outcomes after Vena Cava Filter Use in Patients with Cancer-Associated Venous Thromboembolism and Contraindications to Anticoagulation.

BACKGROUND: The association between the use of inferior vena cava filters (IVCFs) and outcomes among patients with cancer-associated thromboembolism (CT) and contraindications to anticoagulation remains unclear. METHODS: In this prospective cohort study of patients with CT from the Registro Informatizado de la Enfermedad TromboEmbólica Registry, we assessed the association between IVCF insertion due to contraindication to anticoagulation and the outcomes of all-cause mortality, pulmonary embolism (PE)-related mortality, recurrent thromboembolism, and major bleeding rates through 30 days after initiation of treatment. We used propensity score matching to adjust for the likelihood of receiving a filter. For outcomes assessment, we implemented generalized estimating equation methods to incorporate the matched-pairs design, and adjusted for covariates that remained unbalanced after matching. RESULTS: Of the 17,005 patients with CT, 270 underwent IVCF placement because of contraindication to anticoagulation. Of those, 247 were successfully matched with 247 patients treated without a filter. Propensity score-matched pairs showed a nonsignificantly lower risk of all-cause death (12.2% vs. 17.0%; p = 0.13), and a significantly lower risk of PE-related mortality (0.8% vs. 4.0%; p = 0.04) for patients receiving IVCFs compared with those who did not. While there was no significant difference in the rate of major bleeding (6.1% vs. 5.7%; p = 0.85), risk-adjusted recurrent rates were higher for patients who received IVCFs compared with those who did not (7.3% vs. 3.2%; p = 0.05). CONCLUSION: In patients with CT and a contraindication to anticoagulation, IVCF insertion was associated with a lower risk of PE-related death, and a higher risk of recurrences.

Outcomes after venous thromboembolism in patients with gastric cancer: Analysis of the RIETE Registry.

Gastric cancer is the fifth most common malignancy worldwide. Venous thromboembolism is an independent predictor of death among patients with gastric cancer. We aimed to describe the factors associated with mortality, thrombosis recurrence, and bleeding complications in patients with gastric cancer who develop venous thromboembolism. We included 612 patients with gastric cancer and venous thromboembolism in the Registro Informatizado de la Enfermedad TromboEmbólica (RIETE) registry from 2001 to 2018. We used Cox proportional hazard ratios and a Fine-Gray model to define factors associated with outcomes. The overall mortality at 6 months was 44.4%. Factors associated with increased 6-month mortality included immobility (HR 1.8, 95% CI 1.3-2.4; p < 0.001), anemia (HR 1.4, 95% CI 1.1-1.8; p < 0.02), and leukocytosis (HR 1.8, 95% CI 1.4-2.3; p < 0.001). Recurrent thrombosis occurred in 6.5% of patients and major bleeding complications in 8.5% of the cohort. Male sex was the main factor associated with thrombosis recurrence (HR 2.1, 95% CI 1.1-4.0; p < 0.02) and hemoglobin below 10 g/dL (HR 1.6, 95% CI 1.05-2.50; p = 0.03) the main factor associated with bleeding. In conclusion, patients with gastric cancer who develop venous thrombosis have a very high likelihood of death. Low hemoglobin in this population is associated with poor outcomes.

Correction to: Efficacy of Ronopterin (VAS203) in Patients with Moderate and Severe Traumatic Brain Injury (NOSTRA phase III trial): study protocol of a confirmatory, placebocontrolled, randomised, double blind, multi-centre study.

After publication of our article [1] the authors have notified us that one of the names has been incorrectly spelled.

Efficacy of Ronopterin (VAS203) in Patients with Moderate and Severe Traumatic Brain Injury (NOSTRA phase III trial): study protocol of a confirmatory, placebo-controlled, randomised, double blind, multi-centre study.

BACKGROUND: Traumatic brain injury is a leading cause of death and disability worldwide. The nitric oxide synthase inhibitor Ronopterin was shown to improve clinical outcome by enhancing neuroprotection in a phase IIa trial. METHODS/DESIGN: The NOSTRA phase III trial (Ronopterin in traumatic brain injury) is a multi-centre, prospective, randomised, double-blinded, placebo-controlled, phase III trial in Europe. It aims at determining whether the administration of Ronopterin compared to placebo improves neurological outcome in patients with moderate or severe traumatic brain injury at 6 months after injury. The trial is designed to recruit patients between 18 and 60 years of age with moderate or severe traumatic brain injury (Glasgow Coma Scale score ≥ 3) and requiring insertion of an intracranial pressure probe. Trial patients will receive a 48-h intravenous infusion of either Ronopterin or placebo starting at the earliest 6 h and at the latest 18 h after injury. The primary outcome will be the extended Glasgow Outcome Score (eGOS) at 6 months. Secondary outcomes will include the Quality of Life Index (QOLIBRI) at 6 months after the injury and the eGOS at 3 months after the injury. Additionally, effects on mortality, intracranial pressure and cerebral perfusion pressure are evaluated. DISCUSSION: The trial aims to provide evidence on the efficacy and safety of Ronopterin in patients with traumatic brain injury. TRIAL REGISTRATION: EudraCT, 2013-003368-29. Registered on 9 March 2016. ClinicalTrials.gov, NCT02794168. Registered on 8 June 2016. Protocol version 14.0 from 05 November 2018.

Direct Oral Anticoagulants or Standard Anticoagulant Therapy in Fragile Patients with Venous Thromboembolism.

Background The efficacy and safety of the direct oral anticoagulants (DOACs) in fragile patients (age ≥ 75 years and/or creatinine clearance levels ≤ 50 mL/min and/or body weight ≤ 50kg) with venous thromboembolism (VTE) has not been evaluated. Methods We used the RIETE database to compare the rates of the composite of VTE recurrences or major bleeding during anticoagulation in fragile patients with VTE, according to the use of DOACs or standard anticoagulant therapy. Results From January 2013 to April 2018, 24,701 patients were recruited. Of these, 10,054 (41%) were fragile. Initially, 473 fragile patients (4.7%) received DOACs and 8,577 (85%) low-molecular-weight heparin (LMWH). For long-term therapy, 1,298 patients (13%) received DOACs and 5,038 (50%) vitamin K antagonists (VKAs). Overall, 95 patients developed VTE recurrences and 262 had major bleeding. Patients initially receiving DOACs had a lower rate of the composite outcome (hazard ratio [HR]: 0.32; 95% confidence interval [CI]: 0.08-0.88) than those on LMWH. Patients receiving DOACs for long-term therapy had a nonsignificantly lower rate of the composite outcome (HR: 0.70; 95% CI: 0.46-1.03) than those on VKAs. On multivariable analysis, patients initially receiving DOACs had a nonsignificantly lower risk for the composite outcome (HR: 0.36; 95% CI: 0.11-1.15) than those on LMWH, while those receiving DOACs for long-term therapy had a significantly lower risk (HR: 0.61; 95% CI: 0.41-0.92) than those on VKAs. Conclusions Our data suggest that the use of DOACs may be more effective and safe than standard therapy in fragile patients with VTE, a subgroup of patients where the risk for bleeding is particularly high.

Management and outcome of major bleeding in patients receiving vitamin K antagonists for venous thromboembolism.

BACKGROUND: The optimal management of major bleeding in patients receiving vitamin K antagonists (VKA) for venous thromboembolism (VTE) is unclear. METHODS: We used the RIETE (Registro Informatizado Enfermedad TromboEmbólica) registry to assess the management and 30-day outcomes after major bleeding in patients receiving VKA for VTE. RESULTS: From January 2013 to December 2017, 267 of 18,416 patients (1.4%) receiving long-term VKA for VTE had a major bleeding (in the gastrointestinal tract 78, intracranial 72, hematoma 50, genitourinary 20, other 47). Overall, 151 patients (57%) received blood transfusion; 110 (41%) vitamin K; 37 (14%) fresh frozen plasma; 29 (11%) pro-haemostatic agents and 20 (7.5%) a vena cava filter. During the first 30 days, 59 patients (22%) died (41 died of bleeding) and 13 (4.9%) had a thrombosis. On multivariable analysis, patients with intracranial bleeding (hazard ratio [HR]: 4.58; 95%CI: 2.40-8.72) and those with renal insufficiency at baseline (HR: 2.73; 95%CI: 1.45-5.15) had an increased mortality risk, whereas those receiving vitamin K had a lower risk (HR: 0.47; 0.24-0.92). On the other hand, patients receiving fresh frozen plasma were at increased risk for thrombotic events (HR: 4.22; 95%CI: 1.25-14.3). CONCLUSIONS: Major bleeding in VTE patients receiving VKA carries a high mortality rate. Intracranial bleeding and renal insufficiency increased the risk. Fresh frozen plasma seems to increase this risk for recurrent VTE.

Raised Fibrinogen Levels and Outcome in Outpatients With Peripheral Artery Disease.

The influence of raised fibrinogen levels on outcome in stable outpatients with peripheral arterial disease (PAD) has not been consistently investigated. We used data from the Factores de Riesgo y ENfermedad Arterial (FRENA) registry to compare ischemic events, major bleeding, and mortality in stable outpatients with PAD, according to their baseline plasma fibrinogen levels. Of 1363 outpatients with PAD recruited in FRENA, 558 (41%) had fibrinogen levels >450 mg/100 mL. Over 18 months, 43 patients presented with acute myocardial infarction, 37 had an ischemic stroke, 51 underwent limb amputation, 19 had major bleeding, and 90 died. Compared to patients with normal levels, those with raised fibrinogen levels had an over 2-fold higher rate of ischemic stroke (rate ratio [RR]: 2.30; 95% confidence interval [CI]: 1.19-4.59), limb amputation (RR: 2.58; 95% CI: 1.46-4.67), or death (RR: 2.27; 95% CI: 1.49-3.51) and an over 3-fold higher rate of major bleeding (RR: 3.90; 95% CI: 1.45-12.1). On multivariate analysis, patients with raised fibrinogen levels had an increased risk of developing subsequent ischemic events (hazard ratio [HR]: 1.61; 95% CI: 1.11-2.32) and major bleeding (HR: 3.42; 95% CI: 1.22-9.61). Stable outpatients with PAD and raised plasma fibrinogen levels had increased rates of subsequent ischemic events and major bleeding.

Gender differences in patients with venous thromboembolism and five common sites of cancer.

BACKGROUND: The outcome of cancer patients with venous thromboembolism (VTE) may differ according to gender. METHODS: We used the RIETE database to compare the rate of VTE recurrences, major bleeding and mortality in patients with lung, colorectal, pancreatic, hematologic or gastric cancer during the course of anticoagulation, according to gender. RESULTS: As of January 2016, 11,055 patients with active cancer were enrolled: 1,727 had lung cancer, 1,592 colorectal, 840 hematologic, 517 pancreatic and 459 had gastric cancer. Compared with men (N = 3,130), women (N = 2,005) were more likely to have colorectal, pancreatic or hematologic cancer, and less likely to have lung cancer. Most patients (91%) were initially treated with low-molecular-weight heparin (LMWH), but women received higher daily doses per body weight. Then, 66% kept receiving LMWH for long-term therapy. During the course of anticoagulation, 302 patients developed recurrent VTE, 220 bled and 1,749 died. Compared with men, women had a similar rate of VTE recurrences or major bleeding, and a lower mortality (risk ratio [RR]: 0.90; 95% CI: 0.82-0.99). When separately comparing outcomes according to cancer site, women with lung cancer had a lower mortality (RR: 0.79; 95% CI: 0.70-0.92), those with colorectal cancer had a higher mortality (RR: 1.25; 95% CI: 1.02-1.54) and those with gastric cancer had a higher rate of VTE recurrences than men (RR: 2.47; 95% CI: 1.04-5.89). CONCLUSIONS: VTE women with lung, colorectal, pancreatic, haematological or gastric cancer experienced a similar outcome during the course of anticoagulant therapy than men with similar cancers.

Clinical Prognosis of Nonmassive Central and Noncentral Pulmonary Embolism: A Registry-Based Cohort Study.

BACKGROUND: Whether the localization of nonmassive pulmonary embolism (PE) is associated with the short-term and long-term prognosis of patients remains unknown. Our aim was to characterize associations of nonmassive PE localization with risks of recurrent VTE, major bleeding, and mortality during and after anticoagulation. METHODS: Among participants of the Registro Informatizado de la Enfermedad ThromboEmbòlica (RIETE) registry with incident symptomatic nonmassive PE diagnosed by CT scan, we compared risks of recurrent VTE, major bleeding, and mortality during and after anticoagulation between central PE (main pulmonary artery) and noncentral PE (more peripheral arteries) using Cox proportional hazard-adjusted models. RESULTS: Of the 6,674 participants, patients with central PE (40.5%) had age (mean 66 years), sex (46.9% male sex), and proportion of idiopathic (45.0%) and cancer-related (22.3%) PE that were similar to those of patients with noncentral PE. During anticoagulation (5,256.1 patient-years), the risk of recurrent VTE was similar between the two groups (2.5 vs 2.1 per 100 patient-years; adjusted hazard ratio [aHR], 1.32; 95% CI, 0.91-1.90), as were risks of major bleeding and mortality. After anticoagulation was discontinued (2,175.4 patient-years), participants with central PE had a borderline greater risk of recurrent VTE than did participants with noncentral PE (11.0 vs 8.0 per 100 patient-years; aHR, 1.34; 95% CI, 1.01-1.78) but not when restricted to participants after unprovoked PE (13.8 vs 11.9 per 100 patient-years; aHR, 1.15; 95% CI, 0.79-1.68; P = .48). Risks of major bleeding and mortality were similar. CONCLUSIONS: In nonmassive PE, central localization of PE is associated with greater risk of recurrent VTE after anticoagulation cessation. However, the low magnitude of this association and the absence of association after unprovoked PE suggest that the clinical relevance of this finding is limited and that the duration of anticoagulation should not be tailored to PE localization after nonmassive unprovoked PE.

Anemia and Outcome in Outpatients With Peripheral Artery Disease.

The influence of anemia on outcome in stable outpatients with peripheral artery disease (PAD) has not been consistently investigated. We used data from the Factores de Riesgo y ENfermedad Arterial (FRENA) Registry to compare ischemic events and mortality rates in stable outpatients with symptomatic PAD and anemia. Of 1663 patients with PAD, 208 (12.5%) had anemia. Over 18 months, patients with anemia had a higher rate of myocardial infarction (MI; rate ratio [RR]: 2.10; 95% confidence interval [CI]: 1.04-3.99), limb amputation (RR: 2.98; 95%CI: 1.70-5.05), and higher mortality (RR: 3.58; 95%CI: 2.39-5.28) than those without anemia. The rates of ischemic stroke (RR: 0.75; 95%CI: 0.23-1.93) and major bleeding (RR: 0.93; 95%CI: 0.15-3.51) were similar. On multivariable analysis, anemia was associated with an increased risk to die (hazard ratio [HR]: 2.32; 95%CI: 1.53-3.50) but not to develop MI (HR: 1.49; 95%CI: 0.73-3.05) or to have limb amputation (HR: 1.49; 95%CI: 0.86-2.59). In stable outpatients with PAD, anemia was associated with increased mortality but not with an increased rate of subsequent ischemic events or major bleeding.

Supervised versus non-supervised exercise in patients with recent myocardial infarction: A propensity analysis.

BACKGROUND: The influence of supervised versus non-supervised exercise training on outcome in patients with a recent myocardial infarction (MI) is controversial. DESIGN: Longitudinal observational study. METHODS: FRENA is an ongoing registry of stable outpatients with symptomatic coronary, cerebrovascular or peripheral artery disease. We compared the rate of subsequent ischaemic events (MI, ischaemic stroke or lower limb amputation) and the mortality rate in patients with recent MI, according to the use of supervised versus non-supervised exercise training. The influence of physical activity on outcomes was estimated by using propensity score method in multivariate analysis. RESULTS: As of February 2014, 1124 outpatients with recent MI were recruited, of whom 593 (53%) participated in a supervised exercise training programme. Over a mean follow-up of 15 months, 25 patients (3.3%) developed 26 subsequent ischaemic events - 24 MI, one stroke, one lower-limb amputation - and 12 (1.6%) died. The mortality rate (0.15 vs. 2.89 deaths per 100 patient-years; rate ratio = 0.05; 95% confidence interval, 0.01-0.39) was significantly lower in supervised exercise than in non-supervised exercise patients. On propensity score analysis, the rate of the composite outcome was significantly lower in supervised exercise patients (1.80 vs. 6.51 events per 100 patient-years; rate ratio = 0.28; 95% confidence interval, 0.12-0.64). CONCLUSIONS: The use of supervised exercise training in patients with recent MI was associated with a significant decrease in the composite outcome of subsequent ischaemic events and death.

Cerebrospinal fluid-derived circulating tumour DNA better represents the genomic alterations of brain tumours than plasma.

Cell-free circulating tumour DNA (ctDNA) in plasma has been shown to be informative of the genomic alterations present in tumours and has been used to monitor tumour progression and response to treatments. However, patients with brain tumours do not present with or present with low amounts of ctDNA in plasma precluding the genomic characterization of brain cancer through plasma ctDNA. Here we show that ctDNA derived from central nervous system tumours is more abundantly present in the cerebrospinal fluid (CSF) than in plasma. Massively parallel sequencing of CSF ctDNA more comprehensively characterizes the genomic alterations of brain tumours than plasma, allowing the identification of actionable brain tumour somatic mutations. We show that CSF ctDNA levels longitudinally fluctuate in time and follow the changes in brain tumour burden providing biomarkers to monitor brain malignancies. Moreover, CSF ctDNA is shown to facilitate and complement the diagnosis of leptomeningeal carcinomatosis.

Cardiac rehabilitation and outcome in stable outpatients with recent myocardial infarction.

OBJECTIVE: To compare the mortality rate and the rate of subsequent ischemic events (myocardial infarction [MI], ischemic stroke, or limb amputation) in patients with recent MI according to the use of cardiac rehabilitation or no rehabilitation. DESIGN: Longitudinal observational study. SETTING: Ongoing registry of outpatients. PARTICIPANTS: Patients (N=1043) with recent acute MI were recruited; of these, 521 (50%) participated in cardiac rehabilitation. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Subsequent ischemic events and mortality rates were registered. RESULTS: Over a mean follow-up of 18 months, 50 patients (4.8%) died and 49 (4.7%) developed 52 subsequent ischemic events (MI: n=43, ischemic stroke: n=6, limb amputation: n=3). Both the mortality rate (.16 vs 5.57 deaths per 100 patient-years; rate ratio=.03; 95% confidence interval [CI], 0.0-0.1]) and the rate of subsequent ischemic events (1.65 vs 4.54 events per 100 patient-years; rate ratio=0.4; 95% CI, 0.2-0.7) were significantly lower in cardiac rehabilitation participants than in nonparticipants. Multivariate analysis confirmed that patients in cardiac rehabilitation had a significantly lower risk of death (hazard ratio=.08; 95% CI, .01-.63; P=.016) and a nonsignificant lower risk of subsequent ischemic events (hazard ratio=.65; 95% CI, .30-1.42). CONCLUSIONS: The use of cardiac rehabilitation in patients with recent MI was independently associated with a significant decrease in the mortality rate and a nonsignificant decrease in the rate of subsequent ischemic events.

Predictors of outcome in stable outpatients with peripheral artery disease.

Patients with peripheral artery disease (PAD) are at increased risk for subsequent ischemic events. We used data from the FRENA Registry to find predictors of subsequent myocardial infarction (MI), ischemic stroke, and limb amputation in stable outpatients with PAD. As of January 2012, 1,270 patients with PAD were recruited, of whom 1,042 (82 %) had Fontaine stage II; 113 (8.9 %) stage III; and 115 (9.1 %) stage IV. Over a mean follow-up of 14 months, 35 patients developed MI, 25 had stroke, 39 underwent limb amputation, and 91 died. Among patients with Fontaine stage II, the incidence of MI (2.09 events per 100 patient-years; 95 % CI 1.43-2.97) or stroke (0.93; 95 % CI 0.52-1.56) was similar to that of limb amputation (3.22; 95 % CI 2.37-4.29). On multivariate analysis, patients with diabetes [hazard ratio (HR) 2.09; 95 % CI 1.05-4.18], prior coronary disease (HR 5.35; 95 % CI 2.24-12.8), or atrial fibrillation (HR 3.11; 95 % CI 1.52-6.37) were at increased risk for MI; female (HR 2.94; 95 % CI 1.32-6.67), those with prior stroke (HR 5.21; 95 % CI 1.22-22.2) or atrial fibrillation (HR 3.37; 95 % CI 1.45-7.85) at increased risk for stroke; and female (HR 2.38; 95 % CI 1.23-4.55), those with diabetes (HR 3.50; 95 % CI 1.58-7.73) or advanced stages of PAD were at increased risk for limb amputation. Prior coronary artery disease, diabetes and atrial fibrillation predicted subsequent MI; female gender, prior stroke and atrial fibrillation predicted stroke; and female gender, diabetes, and advanced stages of PAD predicted limb amputation.

Pulmonary embolism and 3-month outcomes in 4036 patients with venous thromboembolism and chronic obstructive pulmonary disease: data from the RIETE registry.

BACKGROUND: Patients with chronic obstructive pulmonary disease (COPD) have a modified clinical presentation of venous thromboembolism (VTE) but also a worse prognosis than non-COPD patients with VTE. As it may induce therapeutic modifications, we evaluated the influence of the initial VTE presentation on the 3-month outcomes in COPD patients. METHODS: COPD patients included in the on-going world-wide RIETE Registry were studied. The rate of pulmonary embolism (PE), major bleeding and death during the first 3 months in COPD patients were compared according to their initial clinical presentation (acute PE or deep vein thrombosis (DVT)). RESULTS: Of the 4036 COPD patients included, 2452 (61%; 95% CI: 59.2-62.3) initially presented with PE. PE as the first VTE recurrence occurred in 116 patients, major bleeding in 101 patients and mortality in 443 patients (Fatal PE: first cause of death). Multivariate analysis confirmed that presenting with PE was associated with higher risk of VTE recurrence as PE (OR, 2.04; 95% CI: 1.11-3.72) and higher risk of fatal PE (OR, 7.77; 95% CI: 2.92-15.7). CONCLUSIONS: COPD patients presenting with PE have an increased risk for PE recurrences and fatal PE compared with those presenting with DVT alone. More efficient therapy is needed in this subtype of patients.

Thirty-day mortality rate in women with cancer and venous thromboembolism. Findings from the RIETE Registry.

The influence of the site of cancer on outcome in cancer women with venous thromboembolism (VTE) is poorly understood. Reliable information on its influence might facilitate better use of prevention strategies. We assessed the 30-day outcome in all women with active cancer in the RIETE Registry, trying to identify if differences exist according to the tumor site. Up to May 2010, 2474 women with cancer and acute VTE had been enrolled. The most common sites were the breast (26%), colon (13%), uterus (9.3%), and haematologic (8.6%) cancers. During the 30-day study period, 329 (13%) patients died. Of them, 71 (2.9%) died of pulmonary embolism (PE), 22 (0.9%) died of bleeding. Fatal PE was more common in women with breast, colorectal, lung or pancreatic cancer (59% of the fatal PEs). Fatal bleeding was more frequent in women with colorectal, haematologic, ovarian cancer or carcinoma of unknown origin (55% of fatal bleedings).

Metaloproteinasas de matriz en las lesiones neurológicas: ¿una nueva diana terapéutica? / Matrix metaloproteinases in neurological brain lesions: a new therapeutic target?

Introducción. Las metaloproteinasas de matriz (MMP) constituyen una familia de enzimas proteolíticas presentes en la mayoría de tejidos humanos y responsables de degradar la matriz extracelular. Sus principales funciones son mantener la integridad de la matriz extracelular, modular la interacción entre células durante el desarrollo, la remodelación tisular, participar directamente en la angiogénesis y facilitar la migración celular. Dada la importancia de su función en el mantenimiento de la matriz extracelular, su expresión está estrechamente regulada a nivel transcripcional, mediante la activación de la proforma y a partir de inhibidores tisulares. Sin embargo, la regulación de estas proteasas puede alterarse, produciendo una sobreexpresión que puede llegar a alterar e incluso destruir la estructura tisular, como se ha observado en patologías neurológicas como la esclerosis múltiple, la formación de aneurismas y la isquemia cerebral. El papel que las MMP desempeñan en la fisiopatología de las lesiones neurotraumáticas es poco conocido y procede fundamentalmente de estudios experimentales in vitro e in vivo, y de sólo tres estudios en humanos. Algunos estudios experimentales relacionan las alteraciones encefálicas producidas tras la lesión traumática con incrementos de las concentraciones de diversas MMP. Objetivo. Revisar el papel de dichas proteasas en las lesiones cerebrales, incidiendo en la relación de estas proteínas con el traumatismo craneoencefálico y su posible aplicación terapéutica. Desarrollo. Se realizó una búsqueda bibliográfica en la base de datos Medline. Conclusiones. Ciertas MMP podrían relacionarse con la alteración de la barrera hematoencefálica y la formación del edema postraumático, siendo su inhibición una prometedora diana terapéutica (AU)

Introduction. Matrix metalloproteinases (MMP) are a family of proteolytic enzymes that degrade the extracellular matrix and are found in a large amount of human tissues. Their main functions are to maintain the integrity of the extracellular matrix, to modulate the interaction of the cells during development, to contribute to tissue remodeling, to directly participate in angiogenesis and to facilitate cellular migration. Due to the importance of its maintaining extracellular matrix function, MMP expression is tightly regulated at transcriptional level, through proform activation and with the binding to tissular inhibitors. Despite this complex regulation system, MMP regulation can be altered, producing an overexpression of these proteolytic proteins that alter the tissular structure, possibly destroying the tissue, as observed in some neurologic pathologies such as multiple sclerosis, aneurism formation and cerebral ischemia. The role that MMP have in traumatic brain lesions is almost unknown and is derived mainly from in vivo and in vitro experimental studies, and only from three papers performed in humans. There are some experimental studies that relate the brain alterations produced after traumatic brain injury with an increase in the concentration of various MMP. Aim. To review the role of these proteases in human brain lesions, emphasizing on the function of these proteases in traumatic brain injury lesions and their possible therapeutic target. Development. A bibliographic search was performed on Medline database. Conclusions. Some MMP could be related to blood-brain barrier alteration and postraumatic edema formation, turning them into promising therapeutic targets (AU)

Neuropsychological correlates of basal ganglia and medial temporal lobe NAA/Cho reductions in traumatic brain injury.

BACKGROUND: Proton magnetic resonance spectroscopy can assess neurochemical sequelae in traumatic brain injury. Metabolic abnormalities are present in the acute or subacute period in patients with traumatic brain injury and correlate with outcome on clinical scales. OBJECTIVE: To investigate the use of proton magnetic resonance spectroscopy in detecting possible gray subcortical neurochemical impairments and their relationship with neuropsychological performance. DESIGN: Group comparisons and correlations of brain metabolites with clinical and neuropsychological variables. PATIENTS AND METHODS: Metabolite concentrations were acquired from voxels localized to the basal ganglia and medial temporal region in 20 patients with long-term moderate and severe traumatic brain injury and 20 matched control subjects. Both groups underwent neuropsychological assessment. RESULTS: N-acetylaspartate-choline-containing compounds ratios were decreased in patients in the basal ganglia (t = -3.28, P =.002) and medial temporal region (t = -3.52, P =.001). The basal ganglia ratio correlated to measures of speed, motor scanning, and attention. CONCLUSION: Patients with long-term TBI present a regional correlation pattern that may help identify the neurological basis of cognitive sequelae in traumatic brain injury.