MiRNA 126 as a New Predictor Biomarker in Venous Thromboembolism of Persistent Residual Vein Obstruction: A Review of the Literature Plus a Pilot Study.

Venous thromboembolism (VTE) is the third most common cardiovascular disease. Interleukins (ILs) and micro-ribonucleic acids (miRNAs) have been proposed as molecules able to modulate endothelial inflammation and platelet hyperactivity. At present, no early biomarkers are available to predict the outcome of VTE. We investigated in a pilot study a selected number of miRNAs and ILs as prognostic VTE biomarkers and reviewed literature in this setting. Twenty-three patients (aged 18-65) with a new diagnosis of non-oncological VTE and free from chronic inflammatory diseases were enrolled. Twenty-three age- and sex-matched healthy blood donors were evaluated as control subjects. Serum miRNAs (MiRNA 126, 155, 17.92, 195), inflammatory cytokines (IL-6, tumor necrosis factor-α, IL-8), and lymphocyte subsets were evaluated in patients at enrolment (T0) and in controls. In VTE patients, clinical and instrumental follow-up were performed assessing residual vein obstruction, miRNA and ILs evaluation at 3 months' follow-up (T1). At T0, IL-8, activated T lymphocytes, Treg lymphocytes, and monocytes were higher in patients compared with healthy controls, as were miRNA 126 levels. Moreover, miRNA 126 and IL-6 were significantly increased at T0 compared with T1 evaluation in VTE patients. Higher levels of MiR126 at T0 correlated with a significant overall thrombotic residual at follow-up. In recent years an increasing number of studies (case-control studies, in vivo studies in animal models, in vitro studies) have suggested the potential role of miRNAs in modulating the cellular and biohumoral responses involved in VTE. In the frame of epidemiological evidence, this pilot study with a novel observational approach supports the notion that miRNA can be diagnostic biomarkers of VTE and first identifies miRNA 126 as a predictor of outcome, being associated with poor early recanalization.

Incidence of major adverse cardiovascular events among patients with provoked and unprovoked venous thromboembolism: Findings from the Registro Informatizado de Enfermedad Tromboembólica Registry.

OBJECTIVE: Overlap exists between the risk factors for coronary artery disease and venous thromboembolism (VTE). However, a paucity of data is available on the incidence of major acute cardiovascular events (MACE) and major adverse limb events (MALE) among patients presenting with VTE. Moreover, it is unknown whether the rate of cardiovascular outcomes differs among patients with unprovoked vs provoked VTE. METHODS: We analyzed the data from 2009 to 2017 in the Registro Informatizado de Enfermedad Tromboembólica registry, an ongoing, multicenter, international registry of consecutive patients with a diagnosis of objectively confirmed VTE. The query was restricted it to patients with data entry for the arterial outcomes. The baseline prevalence of coronary artery disease risk factors was compared between patients with provoked (ie, immobility, cancer, surgery, travel >6 hours, hormonal causes) and unprovoked VTE. After the initial VTE event, we followed up patients for the composite primary outcome of incident MACE (ie, stroke, myocardial infarction, unstable angina) and/or MALE (ie, major limb events). We used the χ2 test for baseline associations and a Cox proportional hazard for multivariate analysis. We used IBM SPSS, version 24 (IBM Corp, Armonk, NY) for statistical analysis. A P value of <.05 was considered statistically significant. RESULTS: We analyzed the data from 41,259 patients with VTE, of whom 22,633 (55.6%) had experienced a provoked VTE. During follow-up, the patients with provoked VTE were more likely to develop MACE or MALE than were patients with unprovoked VTE (hazard ratio [HR], 1.3; 95% confidence interval [CI], 1.1-1.5). The association of arterial events with recent immobility (HR, 1.4; 95% CI, 1.5-12.1) and cancer (HR, 1.7; 95% CI, 1.4-1.9) was strong. After adjusting for multiple conventional cardiovascular risk factors, provoked VTE, compared with unprovoked VTE, was significantly associated with an increased hazard for MACE (HR, 1.4; 95% CI, 1.1-1.7). Cancer remained a significant adjusted predictor for both MACE (HR, 1.7; 95% CI, 1.4-2.1) and MALE (HR, 2.1; 95% CI 1.01-4.6) in those with provoked VTE. CONCLUSIONS: Among patients with VTE, provoked cases, specifically those with cancer-associated VTE, have an increased risk of major arterial events.

Statin and all-cause mortality in patients receiving anticoagulant therapy for venous thromboembolism. Data from the RIETE registry.

BACKGROUND: The clinical outcomes during the course of anticoagulation in patients with venous thromboembolism (VTE) using statins remain controversial. METHODS: We used the RIETE (Registro Informatizado Enfermedad TromboEmbólica) registry to compare the risk for VTE recurrences, major bleeding or death during anticoagulation, according to the use of statins at baseline. We used propensity score-matching (PSM) to adjust for confounding variables. RESULTS: From February 2009 to January 2018, 32,062 VTE patients were included. Of these, 7,085 (22%) were using statins. Statin users were 10 years older (73±11 vs. 63±19 years, respectively) and more likely to have comorbidities or to be using antiplatelets or corticosteroids at baseline than non-users. During the course of anticoagulation (median, 177 days), 694 patients developed VTE recurrences, 848 bled and 3,169 died (fatal pulmonary embolism 176, fatal bleeding 121). Statin users had a similar rate of VTE recurrences (hazard ratio [HR]: 0.98; 95%CI: 0.82-1.17), a higher rate of major bleeding (HR: 1.29; 95%CI: 1.11-1.50) and a similar mortality rate (HR: 1.01; 95%CI: 0.93-1.10) than non-users. On PSM analysis, statin users had a significantly lower risk for death (HR: 0.62; 95%CI: 0.48-0.79) and a similar risk for VTE recurrences (HR: 0.98; 95%CI: 0.61-1.57) or major bleeding (HR: 0.85; 95%CI: 0.59-1.21) than non-users. CONCLUSIONS: During anticoagulation for VTE, patients using statins at baseline had a lower risk to die than non-users.

Surgical Treatment of a High-Flow Femoro-Femoral Arteriovenous Fistula in an Intravenous Drug Abuser.

BACKGROUND: We report the surgical treatment of a high-flow femoro-femoral arteriovenous fistula (AVF), a rare complication of intravenous drug abuse. METHODS: A 36-year-old woman with history of intravenous heroin and cocaine abuse presented with right lower limb edema, inguinal bruit, and heart failure. Duplex ultrasound examination (DUS) and computed tomography angiography showed a large, high-flow AVF involving the common femoral vein and the superficial femoral artery, which is associated with thrombosis of the great saphenous vein and an important inflammation in the right groin, without active bleeding. Under general anesthesia, the patient underwent open surgical repair of the AVF through a right-groin cutdown. The 3-cm-long AVF was repaired with the interposition of a bovine pericardium patch that is sewn from inside the femoral vein through a longitudinal venotomy with a continuous 5-0 polypropylene suture. RESULTS: The venotomy was repaired with a 5-0 polypropylene running suture. No perioperative or postoperative complications were recorded. The inguinal bruit resolved, the arteries recovered good pulsatility, and the lower limb edema promptly reduced. A 6-month DUS confirmed the patency of the femoral arteries and veins and the absence of AVF or infection signs in the right groin. CONCLUSIONS: Surgical repair of femoro-femoral AVF in drug abusers by biologic patch interposition is a challenging, but feasible, and effective technique with encouraging midterm results in terms of patency and resistance to infections.

The Schmidt Syndrome.

Addison's disease (AD) is a rare endocrine condition related to adrenal insufficiency. Autoimmune adrenalitis is commonly associated with autoimmune diseases. Autoimmune Addison's Disease (AAD) describes Autoimmune Polyendocrine Syndrome (APS) in 60% of patients with an important immunitary pathogenesis imprinting. We describes a case of Autoimmune Polyendocrine Syndrome charachterize by adrenal insufficiency and thyroid disease (Schmidt Syndrome). In this case report, Addison's disease had a slow onset in absence of the typical weight loss. In our considerations this is due to the concomitant hypothyroidism that masked some typical signs and also limited acute presentation.

Real-life Use of Anticoagulants in Venous Thromboembolism With a Focus on Patients With Exclusion Criteria for Direct Oral Anticoagulants.

We assessed the real-life use of direct oral anticoagulants (DOACs) in patients with venous thromboembolism (VTE) and exclusion criteria for randomized trials. From 2013 to 2016, 3,578 of 18,853 patients (19%) had exclusion criteria. Irrespective of which anticoagulant was chosen, they had more VTE recurrences (hazard ratio (HR): 3.10; 95% confidence interval (CI): 2.47-3.88), major bleeds (HR: 4.10; 95% CI: 3.38-4.96), and deaths (HR: 9.47; 95% CI: 8.46-10.6) than those without exclusion criteria. During initial therapy, no patient with exclusion criteria on DOACs (n = 115) recurred, but those on rivaroxaban bled less often (adjusted HR: 0.18; 95% CI: 0.04-0.79) than those on unfractionated heparin (n = 224) and similar to those (n = 3,172) on low-molecular-weight (LMWH) heparin. For long-term therapy, patients on rivaroxaban (n = 151) had nonsignificantly fewer VTE recurrences (adjusted HR: 0.74; 95% CI: 0.08-1.32) and major bleeds (adjusted HR: 0.41; 95% CI: 0.15-1.15) than those on LMWH (n = 2,071). The efficacy and safety of DOACs were similar to standard therapy.

Impact of residual pulmonary obstruction on the long-term outcome of patients with pulmonary embolism.

The impact of residual pulmonary obstruction on the outcome of patients with pulmonary embolism is uncertain.We recruited 647 consecutive symptomatic patients with a first episode of pulmonary embolism, with or without concomitant deep venous thrombosis. They received conventional anticoagulation, were assessed for residual pulmonary obstruction through perfusion lung scanning after 6 months and then were followed up for up to 3 years. Recurrent venous thromboembolism and chronic thromboembolic pulmonary hypertension were assessed according to widely accepted criteria.Residual pulmonary obstruction was detected in 324 patients (50.1%, 95% CI 46.2-54.0%). Patients with residual pulmonary obstruction were more likely to be older and to have an unprovoked episode. After a 3-year follow-up, recurrent venous thromboembolism and/or chronic thromboembolic pulmonary hypertension developed in 34 out of the 324 patients (10.5%) with residual pulmonary obstruction and in 15 out of the 323 patients (4.6%) without residual pulmonary obstruction, leading to an adjusted hazard ratio of 2.26 (95% CI 1.23-4.16).Residual pulmonary obstruction, as detected with perfusion lung scanning at 6 months after a first episode of pulmonary embolism, is an independent predictor of recurrent venous thromboembolism and/or chronic thromboembolic pulmonary hypertension.

Residual vein thrombosis and serial D-dimer for the long-term management of patients with deep venous thrombosis.

BACKGROUND: The optimal long-term strategy for preventing recurrent venous thromboembolism (VTE) in patients with deep-vein thrombosis (DVT) is uncertain. METHODS: In 620 consecutive outpatients with a first proximal DVT who had completed at least three months of anticoagulation (unprovoked in 483, associated with minor risk factors in 137), the ultrasound presence of residual vein thrombosis (RVT) was assessed and defined as an incompressibility of at least 4mm. In 517 patients without RVT and with negative D-dimer, anticoagulation was stopped and D-dimer was repeated after one and three months. Anticoagulation was resumed in 63 of the 72 patients in whom D-dimer reverted to positivity. RESULTS: During a mean follow-up of three years, recurrent VTE developed in 40 (7.7%) of the 517 patients, leading to an annual rate of 3.6% (95% CI, 2.6 to 4.9): 4.1% (95% CI, 2.9 to 5.7) in individuals with unprovoked DVT, and 2.2% (95% CI, 1.1 to 4.5) in those with DVT associated with minor risk factors. Of the 233 males with unprovoked DVT, 17 (7.3%) developed events in the first year of follow-up. Major bleeding complications occurred in 8 patients while on anticoagulation, leading to an annual rate of 1.2% (95% CI, 0.6 to 2.4). CONCLUSIONS: Discontinuing anticoagulation in patients with a first episode of proximal DVT based on the assessment of RVT and serial D-dimer leads to an overall annual rate of recurrent VTE lower than 5.0%, which is the rate deemed as acceptable by the Subcommittee on Control of Anticoagulation of the ISTH. However, in males with unprovoked DVT there is room for further improving the long-term strategy of VTE prevention. (ClinicalTrials.gov number, NCT01285661).

Gender-related differences in the outcome of patients with venous thromboembolism and thrombophilia.

BACKGROUND: In patients with venous thromboembolism (VTE) and factor V Leiden (FVL) or prothrombin 20210G-A mutation (PTM), the influence of gender on outcome has not been consistently studied. METHODS: We used the RIETE (Registro Informatizado Enfermedad TromboEmbolica) database to assess the existence of gender differences in the rate of VTE recurrences (deep vein thrombosis [DVT] or pulmonary embolism [PE]) or major bleeding during the course of anticoagulation and after its discontinuation in FVL and PTM carriers. RESULTS: From March 2001 to September 2016, 11,224 VTE patients underwent thrombophilia testing. Of these, 1,563 were FVL carriers (863 men and 700 women) and 1,231 were PTM carriers (659 men and 572 women). During the course of anticoagulant therapy, men with FVL had a 6-fold higher rate of VTE recurrences than major bleeds (31 vs. 5 events). In women with FVL, the rate of VTE recurrences was 2-fold higher (16 vs. 8), as was in men (17 vs. 8) or women (17 vs. 9) with PTM. After discontinuing anticoagulation, men with FVL had a 3-fold higher rate of DVT recurrences than women (hazard ratio [HR]: 3.13; 95% CI: 1.79-5.67), with no differences in PE recurrences. Among patients with PTM, there were no gender differences in the rate of DVT (HR: 1.89; 95% CI: 1.00-3.65) or PE recurrences (HR: 1.82; 95% CI: 0.83-4.12). CONCLUSIONS: During the anticoagulation course, men with FVL are at a much higher risk for VTE recurrences than bleeding. After discontinuing anticoagulation, men with FVL are at an increased risk for DVT recurrences.

Atypical And Severe Enlargement Of Right Atrium.

A 76 year-old woman was admitted to the Emergency Department for recent-onset dyspnea and cough. The electrocardiogram was considered inconclusive. A thoracic X-ray showed global cardiac profile enlargement. Computed tomography, acutely performed in the clinical suspicion of atypical pneumonia/myocarditis or pericardial effusion, showed cardiac enlargement especially of the right chambers. In order to investigate Ebstein's anomaly, pericardial cysts, tumors or other conditions of the right heart a simple trans-thoracic echocardiogram was performed. Four chambers view showed a giant right atrium aneurysm with moderate tricuspid regurgitation without stenosis or typical Ebstein's echocardiographic pattern.

Urgent monitoring of direct oral anticoagulants in patients with atrial fibrillation: a tentative approach based on routine laboratory tests.

The number of patients diagnosed with atrial fibrillation who will be candidates for antithrombotic therapy with direct oral anticoagulants (i.e., dabigatran, rivaroxaban, apixaban and edoxaban) is exponentially arising worldwide, thus posing substantial economic and organizational challenges for their urgent monitoring. Due to long turnaround time and inherent technical complexity, liquid chromatography techniques are unsuitable for rapid assessment of their concentration. Even the use of surrogate tests such as thrombin clotting time or anti-factor Xa activity carries some economic and technical drawbacks. Based on literature data, we have hence developed an algorithm based on first-line tests for urgent screening of the anticoagulant effect of direct oral anticoagulants, which entails activated partial thromboplastin time (aPTT) for dabigatran and prothrombin time (PT) for rivaroxaban. Although these tests also display a concentration-dependent prolongation in patients taking apixaban and edoxaban, neither of them is sufficiently sensitive for providing accurate estimation of the pharmacodynamic effect, so that the measurement of anti-factor Xa activity remains the most suitable approach in patients taking these drugs. According to literature data, this strategy appears suitable to reliably define the thrombotic or bleeding risk in an urgent setting, contextually saving precious laboratory resources.

Thigh-length versus below-knee compression elastic stockings for prevention of the postthrombotic syndrome in patients with proximal-venous thrombosis: a randomized trial.

Although below-knee compression elastic stockings (CES) are effective for the prevention of the postthrombotic syndrome (PTS), a substantial number of patients with deep venous thrombosis still develop PTS. In the present open-label, randomized clinical trial, we compared thigh-length with below-knee CES for the prevention of PTS. A total of 267 patients with the first episode of proximal deep venous thrombosis were randomized to wear either thigh-length or below-knee CES for 2 years. After 3, 6, 12, 18, 24, and 36 months, they were assessed for PTS manifestations according to the Villalta scale. PTS developed in 44 (32.6%) of the 135 patients randomized to thigh-length CES and in 47 (35.6%) of the 132 allocated to below-knee CES, for an adjusted hazard ratio of 0.93 (95% confidence interval, 0.62-1.41). Severe PTS developed in 3 patients in each group. CES-related side effects developed in 55 (40.7%) of the 135 patients allocated to thigh-length CES and in 36 (27.3%) of those randomized to the below-knee group (P = .017), and led to premature discontinuation of their use in 29 (21.5%) and 18 (13.6%) patients, respectively. We conclude that thigh-length CES do not offer a better protection against PTS than below-knee CES and are less well tolerated.

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).

Bleeding complications associated with anticoagulant therapy in patients with cancer.

BACKGROUND: Cancer patients with venous thromboembolism (VTE) have an increased incidence of bleeding complications while on anticoagulant therapy. METHODS: RIETE is an ongoing registry of consecutive patients with acute VTE. We tried to identify which cancer patients are at a higher risk for major bleeding. RESULTS: Up to May 2009, 4,709 patients with active cancer had been enrolled in RIETE registry. During the first 3 months of anticoagulant therapy, 200 (4.2%) patients developed major bleeding. Then, 38 (0.8%) further patients bled beyond the first 90 days of therapy, 3 bled after withholding anticoagulant therapy. The most common sites of bleeding were the gastrointestinal tract (118 patients, 49%), genitourinary system (43 patients, 18%) and the brain (27 patients, 11%). In all, 160 patients (66%) died within 30 days after bleeding: 88 (55%) died of bleeding, 3 (1.9%) died of recurrent pulmonary embolism. CONCLUSIONS: Major bleeding is a frequent and severe complication in cancer patients with VTE, even beyond the third month. One third of the patients who bled died due the bleeding event.

Brain abscess of odontogenic origin in a man with interatrial defect.

A 65-year-old man with previous surgery for cyanotic congenital heart disease was admitted to our hospital with fever, headache and visual disturbances due to a right occipital brain abscess as shown through CT-scan. A comprehensive workup looking for a source of infection was negative except for an orthopantomogram showing multiple dental caries. A transesophageal echocardiogram (TEE) bubble study revealed the permanence of an atrial septal defect with a moderate right-to-left shunt. The culture of the abscess content showed flora commonly found in the oropharynx that responded to antimicrobial therapy. We hypothesize that the underlying mechanism is a significant bacterial load from dental infections that enters the arterial circulation through the interatrial defect. If a brain abscess is identified without any adjacent source of infection, then a transesophageal echocardiogram is indicated to exclude right to left shunt. If a shunt is found, then hematogenous spread of flora normally found in the oropharynx should be suspected. Surgical evacuation followed by antimicrobial therapy is warranted. Once the infection is eliminated, long term anticoagulation or anatomic closure of the interatrial defect with good oral hygiene could be valid strategies for preventing recurrence.

Residual thrombosis on ultrasonography to guide the duration of anticoagulation in patients with deep venous thrombosis: a randomized trial.

BACKGROUND: The optimal duration of oral anticoagulant therapy in patients with deep venous thrombosis (DVT) of the lower extremities remains uncertain. OBJECTIVE: To assess whether tailoring the duration of anticoagulation on the basis of the persistence of residual thrombi on ultrasonography reduces the rate of recurrent venous thromboembolism (VTE) compared with the administration of conventional fixed-duration treatment in adults with proximal DVT. DESIGN: Parallel, randomized trial from 1999 to 2006. Trained physicians who assessed outcomes were blinded to patient assignment status, but patients and providers were not. SETTING: 9 university or hospital centers in Italy. PATIENTS: 538 consecutive outpatients with a first episode of acute proximal DVT at completion of an uneventful 3-month period of anticoagulation. INTERVENTION: Patients were randomly assigned (stratified by center and secondary vs. unprovoked DVT by using a computer-generated list that was accessible only to a trial nurse) to fixed-duration anticoagulation (no further anticoagulation for secondary thrombosis and an extra 3 months for unprovoked thrombosis) or flexible-duration, ultrasonography-guided anticoagulation (no further anticoagulation in patients with recanalized veins and continued anticoagulation in all other patients for up to 9 months for secondary DVT and up to 21 months for unprovoked thrombosis). For the primary outcome assessment, 530 patients completed the trial. MEASUREMENTS: The rate of confirmed recurrent VTE during 33 months of follow-up. RESULTS: Overall, 46 (17.2%) of 268 patients allocated to fixed-duration anticoagulation and 32 (11.9%) of 270 patients allocated to flexible-duration anticoagulation developed recurrent VTE (adjusted hazard ratio [HR], 0.64 [95% CI, 0.39 to 0.99]). For patients with unprovoked DVT, the adjusted HR was 0.61 (CI, 0.36 to 1.02) and 0.81 (CI, 0.32 to 2.06) for those with secondary DVT. Major bleeding occurred in 2 (0.7%) patients in the fixed-duration group and 4 (1.5%) patients in the flexible-duration group (P = 0.67). LIMITATIONS: The trial lacked a double-blind design. The sample size was not powered to detect differences in bleeding between groups and to detect effectiveness of the intervention in the subgroups of patients with unprovoked and secondary DVT. Patients with previous thromboembolism, permanent risk factors for thrombosis, and thrombophilic abnormalities other than factor V Leiden and prothrombin mutation were excluded. CONCLUSION: Tailoring the duration of anticoagulation on the basis of ultrasonography findings reduces the rate of recurrent VTE in adults with proximal DVT. PRIMARY FUNDING SOURCE: None.