Endothelial ILK induces cardioprotection by preventing coronary microvascular dysfunction and endothelial-to-mesenchymal transition.

Endothelial dysfunction is an early event in coronary microvascular disease. Integrin-linked kinase (ILK) prevents endothelial nitric oxide synthase (eNOS) uncoupling and, thus, endothelial dysfunction. However, the specific role of endothelial ILK in cardiac function remains to be fully elucidated. We hypothesised that endothelial ILK plays a crucial role in maintaining coronary microvascular function and contractile performance in the heart. We generated an endothelial cell-specific ILK conditional knock-out mouse (ecILK cKO) and investigated cardiovascular function. Coronary endothelial ILK deletion significantly impaired cardiac function: ejection fraction, fractional shortening and cardiac output decreased, whilst left ventricle diastolic internal diameter decreased and E/A and E/E' ratios increased, indicating not only systolic but also diastolic dysfunction. The functional data correlated with extensive extracellular matrix remodelling and perivascular fibrosis, indicative of adverse cardiac remodelling. Mice with endothelial ILK deletion suffered early ischaemic-like events with ST elevation and transient increases in cardiac troponins, which correlated with fibrotic remodelling. In addition, ecILK cKO mice exhibited many features of coronary microvascular disease: reduced cardiac perfusion, impaired coronary flow reserve and arterial remodelling with patent epicardial coronary arteries. Moreover, endothelial ILK deletion induced a moderate increase in blood pressure, but the antihypertensive drug Losartan did not affect microvascular remodelling whilst only partially ameliorated fibrotic remodelling. The plasma miRNA profile reveals endothelial-to-mesenchymal transition (endMT) as an upregulated pathway in endothelial ILK conditional KO mice. Our results show that endothelial cells in the microvasculature in endothelial ILK conditional KO mice underwent endMT. Moreover, endothelial cells isolated from these mice and ILK-silenced human microvascular endothelial cells underwent endMT, indicating that decreased endothelial ILK contributes directly to this endothelial phenotype shift. Our results identify ILK as a crucial regulator of microvascular endothelial homeostasis. Endothelial ILK prevents microvascular dysfunction and cardiac remodelling, contributing to the maintenance of the endothelial cell phenotype.

Statins and psoriasis: Position statement by the Psoriasis Task Force of the European Academy of Dermatology and Venerology.

BACKGROUND: Psoriasis is associated with an increased mortality risk, with cardiovascular disease being the leading excess cause (in a dose-response manner with psoriasis severity). Statins have demonstrated a reduction in all-cause mortality with no excess of adverse events among the general population. The underuse of interventions in cardiovascular prevention, such as statins, for patients with psoriasis may be the result of an insufficient evaluation. OBJECTIVES: To provide the dermatologist with a tool for systematizing the treatment of dyslipidemia in psoriasis, which generally escapes the scope of dermatological practice, and to facilitate decision-making about the referral and treatment of patients. METHODS: The Psoriasis Task Force of the European Academy of Dermatology and Venereology performed this two-phase study to achieve a consensus and create recommendations on the use of statin therapy in patients with psoriasis. The first phase included a systematic review to identify a list of outline concepts and recommendations according to guidelines. The second phase consisted in a two-round Delphi study to evaluate those recommendations not literally taken from guidelines. RESULTS: A list of 47 concepts and recommendations to be followed by dermatologists involved in the treatment of patients with moderate-severe psoriasis was created. It included six main concepts about cardiovascular risk and psoriasis, six items related with the role of low-density lipoprotein cholesterol (LDL-c) and the benefits of statin treatment in psoriasis patients, eight recommendations about how cardiovascular risk should be assessed, three on the role of non-invasive cardiovascular imaging, three on LDL-c thresholds, eight key points related to statin prescription, 10 on statin treatment follow-up and three on patient referral to another specialist. CONCLUSIONS: The application of this position statement (close final list of concepts and recommendations) will help dermatologists to manage dyslipidemia and help psoriasis patients to reduce their cardiovascular risk.

Impact of dapagliflozin on cardiac remodelling in patients with chronic heart failure: The DAPA-MODA study.

AIMS: Dapagliflozin improves the prognosis of patients with heart failure (HF), regardless of left ventricular ejection fraction (LVEF). However, its effect on cardiac remodelling parameters, specifically left atrial (LA) remodelling, is not well established. METHODS AND RESULTS: The DAPA-MODA trial (NCT04707352) is a multicentre, single-arm, open-label, prospective and interventional study that aimed to evaluate the effect of dapagliflozin on cardiac remodelling parameters over 6 months. Patients with stable chronic HF receiving optimized guideline-directed therapy, except for any sodium-glucose cotransporter 2 inhibitor, were included. Echocardiography was performed at baseline, 30 and 180 days, and analysed by a central core-lab in a blinded manner to both patient and time. The primary endpoint was the change in maximal LA volume index (LAVI). A total of 162 patients (64.2% men, 70.5 ± 10.6 years, 52% LVEF >40%) were included in the study. At baseline, LA dilatation was observed (LAVI 48.1 ± 22.6 ml/m2 ) and LA parameters were similar between LVEF-based phenotypes (≤40% vs. >40%). LAVI showed a significant reduction at 180 days (-6.6% [95% confidence interval -11.1, -1.8], p = 0.008), primarily due to a decrease in reservoir volume (-13.8% [95% confidence interval -22.5, -4], p = 0.007). Left ventricular geometry improved with significant reductions in left ventricular mass index (-13.9% [95% confidence interval -18.7, -8.7], p < 0.001), end-diastolic volume (-8.0% [95% confidence interval -11.6, -4.2], p < 0.001) and end-systolic volume (-11.9% [95% confidence interval -16.7, -6.8], p < 0.001) at 180 days. N-terminal pro-B-type natriuretic peptide (NT-proBNP) showed a significant reduction at 180 days (-18.2% [95% confidence interval -27.1, -8.2], p < 0.001), without changes in filling Doppler measures. CONCLUSION: Dapagliflozin administration in stable out-setting patients with chronic HF and optimized therapy results in global reverse remodelling of cardiac structure, including reductions in LA volumes and improvement in left ventricular geometry and NT-proBNP concentrations.

Management of cardiac disease in cancer patients throughout oncological treatment: ESMO consensus recommendations.

Cancer and cardiovascular (CV) disease are the most prevalent diseases in the developed world. Evidence increasingly shows that these conditions are interlinked through common risk factors, coincident in an ageing population, and are connected biologically through some deleterious effects of anticancer treatment on CV health. Anticancer therapies can cause a wide spectrum of short- and long-term cardiotoxic effects. An explosion of novel cancer therapies has revolutionised this field and dramatically altered cancer prognosis. Nevertheless, these new therapies have introduced unexpected CV complications beyond heart failure. Common CV toxicities related to cancer therapy are defined, along with suggested strategies for prevention, detection and treatment. This ESMO consensus article proposes to define CV toxicities related to cancer or its therapies and provide guidance regarding prevention, screening, monitoring and treatment of CV toxicity. The majority of anticancer therapies are associated with some CV toxicity, ranging from asymptomatic and transient to more clinically significant and long-lasting cardiac events. It is critical however, that concerns about potential CV damage resulting from anticancer therapies should be weighed against the potential benefits of cancer therapy, including benefits in overall survival. CV disease in patients with cancer is complex and treatment needs to be individualised. The scope of cardio-oncology is wide and includes prevention, detection, monitoring and treatment of CV toxicity related to cancer therapy, and also ensuring the safe development of future novel cancer treatments that minimise the impact on CV health. It is anticipated that the management strategies discussed herein will be suitable for the majority of patients. Nonetheless, the clinical judgment of physicians remains extremely important; hence, when using these best clinical practices to inform treatment options and decisions, practitioners should also consider the individual circumstances of their patients on a case-by-case basis.

Oral anticoagulation and left atrial appendage closure: a new strategy for recurrent cardioembolic stroke.

BACKGROUND AND PURPOSE: There are no recommendations regarding how to treat cardioembolic recurrent strokes when patients are well anticoagulated. We evaluated the safety and efficacy of combining oral anticoagulation (OAC) with percutaneous left atrial appendage closure (LAAC) in patients with well-anticoagulated atrial fibrillation (AF) with recurrent strokes. METHODS: In an explorative, prospective, observational study, LAAC was performed in patients with AF with at least two ischaemic strokes in the previous year, despite good anticoagulation using the Amplatzer Cardiac Plug (St Jude Medical, St Paul, MN, USA) or Amulet Abbot device (Abbot Vascular, Santa Clara, CA, USA). We recorded age, type of AF, CHA2 DS2 -VASC and HAS-BLED scores, types of OAC and risk factors. After closure, treatment with aspirin (100 mg/day) was continued for 3 months in combination with indefinite OAC. Clinical status, recurrent embolisms and bleeding complications were recorded during follow-up. RESULTS: A total of 19 patients were included (mean age, 72.1 ± 9.6 years; mean CHA2 DS2 -VASC score, 5.3 ± 1.48; mean number of previous strokes, 2.78 ± 1.15). Thirteen had spontaneous echocardiographic contrast and all had dilatation of the left atrium. Eighteen patients had a multilobulated left atrial appendage, 17 with 'chicken-wing' morphology and one patient had a left atrial appendage thrombus. There were no complications during the procedure. Only one patient had a transient ischaemic attack and no major bleeding occurred during a mean follow-up of 17.4 ± 11.5 months. CONCLUSION: Combination therapy with indefinite OAC plus LAAC in patients with AF with recurrent strokes despite good anticoagulation should be considered in order to prevent a new stroke.

State of play and future direction with NOACs: An expert consensus.

Atrial fibrillation (AF) and venous thromboembolism (VTE) are cardiovascular conditions significant in contemporary practice. In both, the use of anticoagulation with vitamin K antagonists (VKAs) has been traditionally used to prevent adverse events. However, VKA therapy is associated with challenges relating to dose maintenance, the need to monitor anticoagulation, and bleeding risks. The non-vitamin K oral anticoagulants (NOACs) are becoming accepted as a clear alternative to VKA therapy for both AF and VTE management. The aim of this paper was to review contemporary evidence on the safety of NOACs in both conditions. A comprehensive literature review was conducted to explore key safety issues and expert consensus was achieved from eight professionals specialised in AF and VTE care. Consensus-based statements were formulated where available evidence was weak or contradictory. The expert statements in this paper form a key overview of the safety of NOACs compared with VKA therapy, and the comparative safety of different NOACs. It is apparent that a detailed patient work-up is required in order to identify and manage individual risk factors for bleeding and thrombosis prior to NOAC therapy. Additional measures, such as dose reductions, may also be used to maintain the safety of NOACs in practice.

Recommendations on managing lenvatinib and everolimus in patients with advanced or metastatic renal cell carcinoma.

INTRODUCTION: There are several second-line treatment options for patients with renal cell carcinoma after first-line failure of a tyrosine kinase inhibitor, especially with the recent approvals of cabozantinib, nivolumab, and the lenvatinib plus everolimus combination. A lack of reliable biomarkers and an overall lack of prospective head-to-head comparisons make it a challenge to choose a second-line treatment in the clinic. Areas covered: In this review/meta-opinion, we describe the safety profile of the lenvatinib plus everolimus combination in renal cell carcinoma. The combination of lenvatinib plus everolimus has achieved the highest rates of objective responses and the longest progression free and overall survival in cross-comparison trials. At the same time, the safety profile of this combination, including the rate of total and severe adverse events, the percentage of dose reductions required, and the rate of treatment discontinuation, was less favorable compared with available monotherapy options, suggesting that better management could help to maximize the activity of this combination while protecting patients from undue harm. Expert opinion: Herein, we aim to postulate multidisciplinary recommendations on the advice to offer to patients and caregivers before starting treatment and how to manage the combination from the perspective of daily clinical practice.

Identifying the needs for competency-based education in Europe: a needs assessment of cardiologists across 52 countries.

Objective: This international needs assessment was mandated by the European Society of Cardiology (ESC) to obtain an in-depth understanding of the current gaps and challenges of European cardiology professionals, with the aim to provide evidence for the development of needs-driven educational and professional development activities. Methods: This ethics-approved needs assessment was conducted among cardiologists from all sub-specialties across 56 countries of Europe and the Mediterranean basin. A mixed-methods research approach was used, combining qualitative in-depth interviews and focus groups with a quantitative survey. Results: Seventy-four (74) cardiologists participated in the qualitative phase and 866 completed the survey. Respondents represented 52 of the 56 targeted countries. Three themes were identified: 1) Challenges in the clinical decision-making process, 2) Challenges in establishing the patient-physician relationship, and 3) Sub-optimal team communication and collaboration. Specific gaps and causalities related to each challenge were found. Although most of the gaps were common across countries and sub-specialties, some significant differences were noted. Conclusion: The findings of this needs assessment indicate gaps and challenges in clinical practice across countries and across sub-specialities. Taking cardiology as an example, this study identifies clear areas of focus, especially around issues of collaboration and communication, for targeted competency-based education in Europe.

Gender and age effects on risk factor-based prediction of coronary artery calcium in symptomatic patients: A Euro-CCAD study.

BACKGROUND AND AIMS: The influence of gender and age on risk factor prediction of coronary artery calcification (CAC) in symptomatic patients is unclear. METHODS: From the European Calcific Coronary Artery Disease (EURO-CCAD) cohort, we retrospectively investigated 6309 symptomatic patients, 62% male, from Denmark, France, Germany, Italy, Spain and USA. All of them underwent risk factor assessment and CT scanning for CAC scoring. RESULTS: The prevalence of CAC among females was lower than among males in all age groups. Using multivariate logistic regression, age, dyslipidaemia, hypertension, diabetes and smoking were independently predictive of CAC presence in both genders. In addition to a progressive increase in CAC with age, the most important predictors of CAC presence were dyslipidaemia and diabetes (ß = 0.64 and 0.63, respectively) in males and diabetes (ß = 1.08) followed by smoking (ß = 0.68) in females; these same risk factors were also important in predicting increasing CAC scores. There was no difference in the predictive ability of diabetes, hypertension and dyslipidaemia in either gender for CAC presence in patients aged <50 and 50-70 years. However, in patients aged >70, only dyslipidaemia predicted CAC presence in males and only smoking and diabetes were predictive in females. CONCLUSIONS: In symptomatic patients, there are significant differences in the ability of conventional risk factors to predict CAC presence between genders and between patients aged <70 and ≥70, indicating the important role of age in predicting CAC presence.

Circulating microRNAs in Huntington's disease: Emerging mediators in metabolic impairment.

Huntington's disease (HD) is a hereditary neurodegenerative disease, with peripheral consequences that negatively contribute to quality of life. Circulating microRNAs (cmiRNAs) are being explored for their roles in intercellular communication and gene expression regulation, which allows gaining insight into the regulation of crosstalk between neuronal and peripheral tissues. Here, we explore the cmiRNA profile of plasma samples from fifteen symptomatic patients, with 40-45 CAG repeats in the HTT gene, and seven healthy matched controls. Isolated miRNAs from plasma samples were run against human miRNome panels, which have sequences for 752 human mature miRNAs. We found that 168 cmiRNAs are altered in symptomatic patients. Considering Bonferroni's correction, miR-877-5p, miR-223-3p, miR-223-5p, miR-30d-5p, miR-128, miR-22-5p, miR-222-3p, miR-338-3p, miR-130b-3p, miR-425-5p, miR-628-3p, miR-361-5p, miR-942 are significantly increased in HD patients as compared with controls. Moreover, after patient's organization according to approved HD scales, miR-122-5p is significantly decreased in HD patients with Unified Huntington's Disease Rating Scale >24, whereas an increase in miR-100-5p levels and a decrease in miR-641 and miR-330-3p levels were recorded when patients were rearranged by Total Functional Capacity. These results suggest that cmiRNA profile could be further modified by disease progression, making cmiRNAs useful as monitoring biomarkers. Analysis of target genes indicated a general overexpression of cmiRNAs implicated in metabolism regulation. Profiling cmiRNA of HD subjects opens the possibility of personalized therapies for different groups of HD patients, based on disease modifiers: regulation of altered pathways might contribute to not only alleviate disease symptoms, but also influence HD progression.

Proton pump inhibitor-responsive oesophageal eosinophilia correlates with downregulation of eotaxin-3 and Th2 cytokines overexpression.

BACKGROUND: The molecular basis and effects of proton pump inhibitor (PPI) therapy on PPI-responsive oesophageal eosinophilia (PPI-REE) and eosinophilic oesophagitis (EoE) remain unknown. AIM: To compare symptom-histological and cytokine gene expression in PPI-REE and EoE patients, at baseline and after specific treatment. METHODS: In consecutive adult patients with an EoE phenotype (dysphagia/food impaction, typical endoscopic findings and > 15 eos/HPF), gene expression of eotaxin-3, IL-13, and IL-5 were determined in distal and proximal oesophagus, at baseline and after omeprazole 40 mg b.d. for 8 weeks. PPI-REE was defined by clinicohistological response. PPI nonresponders (EoE) were offered treatment with topical steroids. RESULTS: Fifty three patients were re-evaluated on PPI therapy. 23 patients (43%) had PPI-REE and 30 patients (57%) had EoE. At baseline, eotaxin-3/IL-13/IL-5 gene expression was indistinguishable between EoE and PPI-REE, excepting increased IL-5 expression in proximal oesophagus (12.54 vs. 57, P = 0.029). PPI therapy significantly decreased eotaxin-3/IL-13 in PPI-REE, at both oesophageal sites (P ≤ 0.008), and IL-5 in distal (P = 0.016), but not in proximal oesophagus. Patients with steroid-responsive EoE also showed a significant decrease in eotaxin-3/IL-5 expression at both oesophageal sites. In EoE patients, initial PPI trial significantly decreased distal oesophageal eosinophilia (63.78 to 41.79 eos/HPF, P = 0.025) and led to symptom remission in 16%, but did not influence Th2 markers. CONCLUSIONS: Baseline cytokine gene expression in PPI-REE was nearly indistinguishable from EoE. PPI therapy significantly downregulated oesophageal eotaxin-3/Th2-cytokine gene expression in PPI-REE, similarly to that seen in steroid-responsive EoE. A subset of EoE patients showed clinicohistological improvement on PPI therapy.

[Prevalence of chronic diseases and risk factors among the Spanish prison population]. / Prevalencia de patologías crónicas y factores de riesgo en población penitenciaria española.

BACKGROUND: chronic diseases are responsible for 60% of deaths and 75% of spending on public health. There are few works on the prevalence of this type of pathology in prison. OBJECTIVE: Describe the prevalence of chronic major diseases in the population and the major risk factors observed. METHODS: Multicenter transversal descriptive study. The sample size was 1,170 people, who were selected through sampling stratified with simple allocation by strata among 9 prisons in the country. There were interviews and physical examinations between May and June 2013. Variables were collected: socio-demographic, diagnostic, anthropometric, clinical-analytical and risk factors. A descriptive and subsequent comparative analysis was carried out using non-parametric tests for quantitative variables using the Mann-Whitney test and a Ji-square test for categorical variables. Subsequently, binary logistic regression models to evaluate the influence of factors of risk in major pathologies. The manuscript was approved by the Ethics Committee for clinical research of the University General Hospital of Castellon. RESULTS: 1 of every 2 inmates has some type of chronic disease out of the 1,077 participated (92.1). Median age of 37.4 years IQR (30.0 to 44.8). 95 males, 40.6 foreigners. Prevalence: dyslipidemias (34.8); arterial hypertension (17.8); Diabetes (5.3); asthma (4.6); COPD (2.2); ischaemic heart disease (1.8) and (1.5) cardio-circulatory pathologies. Main risk factors: smoking, obesity, abdominal fat distribution, consumption of cocaine and age. CONCLUSIONS: It would be interesting to establish early diagnosis, encourage giving up smoking, and physical activity and dietary advice to combat the major modifiable risk factors.

Historia natural de la enfermedad tromboembólica venosa en el área mediterránea. Una revisión sistemática / Natural history of venous thromboembolism in patients from the Mediterranean region. A systematic review

Antecedentes: El pronóstico de las enfermedades cardiovasculares es mejor en los países mediterráneos que en otras partes del mundo. Se desconoce si estas diferencias también acontecen en la enfermedad tromboembólica venosa (ETV) Métodos: En las bases de datos Medline y EMBASE se revisaron los ensayos clínicos y estudios de cohortes de pacientes con ETV que habían recibido tratamiento anticoagulante durante 3 meses. Dos revisores extrajeron independientemente los datos de forma reglada. Se seleccionaron 24 estudios con un total de 7.225 pacientes incluidos (2.414 del área mediterránea y 4.811 de otras regiones). Resultados: Entre los pacientes del área mediterránea predominaban las mujeres, tenían mayor edad, y la ETV idiopática fue menos frecuente que en otras regiones del mundo. Comparados con otros países, los pacientes del área mediterránea presentaron más recidivas de trombosis venosa profunda (4,35% frente a 2,68%; odds ratio [OR]: 1,65; intervalo de confianza al 95% [IC95%]: 1,27-2,15), recidivas mortales de ETV (0,75% frente a 0,35%; OR: 2,11; IC95%: 1,09-4,12) y sangrado mortal (0,25% frente a 0,06%; OR: 3,99; IC95%: 1-16). En el área mediterránea el porcentaje de recidivas de ETV mortal fue del 12,8%, IC95%: 7,99-19,1 frente al 8,41%, IC95%: 5,15-12,9 en otras zonas del mundo. El porcentaje de hemorragias mortales fue del 11,3%, IC95%: 4,72-22,1 frente al 3,22%, IC95%: 0,83-8,53 en otras zonas geográficas. Conclusiones: Los pacientes con ETV del área mediterránea tienen una mayor mortalidad durante los 3 primeros meses de tratamiento imputable a una mayor incidencia de ETV recidivante y de hemorragias graves (AU)

Background: Patients with cardiovascular diseases living in the Mediterranean area have a better outcome than those in other parts of the world, but it is not known whether these differences also occur with venous thromboembolism (VTE). Methods: We searched the Medline and EMBASE databases to identify clinical trials and cohort studies of patients with VTE who had been treated with anticoagulant therapy for 3 months. Two reviewers independently extracted the data in a standardized manner. A total of 24 studies that included 7,225 patients (2,414 from the Mediterranean region and 4,811 from other regions) were analyzed. Results: The patients from the Mediterranean area were predominately women and older, and the idiopathic VTE was less frequent than in other regions. Compared with patients from other regions, patients from the Mediterranean region had an increased rate of recurrent deep vein thrombosis (4.35% vs. 2.68%; odds ratio [OR], 1.65; 95% confidence interval [95% CI] 1.27-2.15), fatal recurrent VTE (0.75% vs. 0.35%; OR, 2.11; 95% CI 1.09-4.12) and fatal bleeding (0.25% vs. 0.06%; odds ratio: 3.99; 95% CI 1.00-16.0). The case-fatality rate (CFR) for recurrent VTE was 12.8% (95% CI 7.99-19.1) in the Mediterranean region and 8.41% (5.15-12.9) in other areas. The CFR for major bleeding was 11.3% (95% CI 4.72-22.1) and 3.22% (95% CI 0.83-8.53), respectively. Conclusions: Compared to other regions, patients with VTE from the Mediterranean region have greater mortality during the first 3 months of treatment due to a greater incidence of recurrent VTE and severe hemorrhaging (AU)

Natural history of venous thromboembolism in patients from the Mediterranean region. A systematic review.

BACKGROUND: Patients with cardiovascular diseases living in the Mediterranean area have a better outcome than those in other parts of the world, but it is not known whether these differences also occur with venous thromboembolism (VTE). METHODS: We searched the Medline and EMBASE databases to identify clinical trials and cohort studies of patients with VTE who had been treated with anticoagulant therapy for 3 months. Two reviewers independently extracted the data in a standardized manner. A total of 24 studies that included 7,225 patients (2,414 from the Mediterranean region and 4,811 from other regions) were analyzed. RESULTS: The patients from the Mediterranean area were predominately women and older, and the idiopathic VTE was less frequent than in other regions. Compared with patients from other regions, patients from the Mediterranean region had an increased rate of recurrent deep vein thrombosis (4.35% vs. 2.68%; odds ratio [OR], 1.65; 95% confidence interval [95% CI] 1.27-2.15), fatal recurrent VTE (0.75% vs. 0.35%; OR, 2.11; 95% CI 1.09-4.12) and fatal bleeding (0.25% vs. 0.06%; odds ratio: 3.99; 95% CI 1.00-16.0). The case-fatality rate (CFR) for recurrent VTE was 12.8% (95% CI 7.99-19.1) in the Mediterranean region and 8.41% (5.15-12.9) in other areas. The CFR for major bleeding was 11.3% (95% CI 4.72-22.1) and 3.22% (95% CI 0.83-8.53), respectively. CONCLUSIONS: Compared to other regions, patients with VTE from the Mediterranean region have greater mortality during the first 3 months of treatment due to a greater incidence of recurrent VTE and severe hemorrhaging.