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COVID-19 infection causes respiratory pathology with severe interstitial pneumonia and extra-pulmonary complications; in particular, it may predispose to thromboembolic disease. The current guidelines recommend the use of thromboprophylaxis in patients with COVID-19, however, the optimal heparin dosage treatment is not well-established. We conducted a multicentre, Italian, retrospective, observational study on COVID-19 patients admitted to ordinary wards, to describe clinical characteristic of patients at admission, bleeding and thrombotic events occurring during hospital stay. The strategies used for thromboprophylaxis and its role on patient outcome were, also, described. 1091 patients hospitalized were included in the START-COVID-19 Register. During hospital stay, 769 (70.7%) patients were treated with antithrombotic drugs: low molecular weight heparin (the great majority enoxaparin), fondaparinux, or unfractioned heparin. These patients were more frequently affected by comorbidities, such as hypertension, atrial fibrillation, previous thromboembolism, neurological disease, and cancer with respect to patients who did not receive thromboprophylaxis. During hospital stay, 1.2% patients had a major bleeding event. All patients were treated with antithrombotic drugs; 5.4%, had venous thromboembolism [30.5% deep vein thrombosis (DVT), 66.1% pulmonary embolism (PE), and 3.4% patients had DVT + PE]. In our cohort the mortality rate was 18.3%. Heparin use was independently associated with survival in patients aged ≥ 59 years at multivariable analysis. We confirmed the high mortality rate of COVID-19 in hospitalized patients in ordinary wards. Treatment with antithrombotic drugs is significantly associated with a reduction of mortality rates especially in patients older than 59 years.

Coronavirus disease 2019 (COVID-19) has been shown to be strongly associated with increased risk for venous thromboembolism events (VTE) mainly in the inpatient but also in the outpatient setting. Pharmacologic thromboprophylaxis has been shown to offer significant benefits in terms of reducing not only VTE events but also mortality, especially in acutely ill patients with COVID-19. Although the main source of evidence is derived from observational studies with several limitations, thromboprophylaxis is currently recommended for all hospitalized patients with acceptable bleeding risk by all national and international guidelines. Recently, high quality data from randomized controlled trials (RCTs) further support the role of thromboprophylaxis and provide insights into the optimal thromboprophylaxis strategy. The aim of this statement is to systematically review all the available evidence derived from RCTs regarding thromboprophylaxis strategies in patients with COVID-19 in different settings (either inpatient or outpatient) and provide evidence-based guidance to practical questions in everyday clinical practice. Clinical questions accompanied by practical recommendations are provided based on data derived from 20 RCTs that were identified and included in the present study. Overall, the main conclusions are: (i) thromboprophylaxis should be administered in all hospitalized patients with COVID-19, (ii) an optimal dose of inpatient thromboprophylaxis is dependent upon the severity of COVID-19, (iii) thromboprophylaxis should be administered on an individualized basis in post-discharge patients with COVID-19 with high thrombotic risk, and (iv) thromboprophylaxis should not be routinely administered in outpatients. Changes regarding the dominant SARS-CoV-2 variants, the wide immunization status (increasing rates of vaccination and reinfections), and the availability of antiviral therapies and monoclonal antibodies might affect the characteristics of patients with COVID-19; thus, future studies will inform us about the thrombotic risk and the optimal therapeutic strategies for these patients.

Background: This guideline (GL) on carotid surgery as updating of "Stroke: Italian guidelines for Prevention and Treatment" of the ISO-SPREAD Italian Stroke Organization-Group, has recently been published in the National Guideline System and shared with the Italian Society of Vascular and Endovascular Surgery (SICVE) and other Scientific Societies and Patient's Association. Methods: GRADE-SIGN version, AGREE quality of reporting checklist. Clinical questions formulated according to the PICO model. Recommendations developed based on clinical questions by a multidisciplinary experts' panel and patients' representatives. Systematic reviews performed for each PICO question. Considered judgements filled by assessing the evidence level, direction, and strength of the recommendations. Results: The panel provided indications and recommendations for appropriate, comprehensive, and individualized management of patients with carotid stenosis. Diagnostic and therapeutic processes of the best medical therapy, carotid endarterectomy (CEA), carotid stenting (CAS) according to the evidences and the judged opinions were included. Symptomatic carotid stenosis in elective and emergency, asymptomatic carotid stenosis, association with ischemic heart disease, preoperative diagnostics, types of anesthesia, monitoring in case of CEA, CEA techniques, comparison between CEA and CAS, post-surgical carotid restenosis, and medical therapy are the main topics, even with analysis of uncertainty areas for risk-benefit assessments in the individual patient (personalized medicine [PM]). Conclusions: This GL updates on the main recommendations for the most appropriate diagnostic and medical-surgical management of patients with atherosclerotic carotid artery stenosis to prevent ischemic stroke. This GL also provides useful elements for the application of PM in good clinical practice.

Background: The optimal management of patients with isolated distal deep vein thrombosis (IDDVT) is uncertain. Observational studies report similar therapeutic strategies as for patients with proximal DVT or pulmonary embolism (PE), but shorter treatment duration. We compared two different durations of treatment with rivaroxaban in patients with symptomatic IDDVT. Methods: In a randomized, double-blind, placebo-controlled trial, patients with symptomatic IDDVT received 6 weeks of rivaroxaban at standard doses and were assigned to rivaroxaban 20 mg once daily or placebo for additional 6 weeks. Randomization was done using a computer-generated randomization list and was stratified by study center. Primary efficacy outcome was a composite of recurrent IDDVT, proximal DVT, symptomatic or fatal PE. Primary safety outcome was ISTH-defined major bleeding. We here report the results of the 6-month follow-up. Findings: Of the 402 randomized patients, 200 received rivaroxaban and 202 placebo. IDDVT was unprovoked in 41.0% and 42.6% of patients, respectively. The primary efficacy outcome occurred in 5 patients (2.5%) on rivaroxaban and 21 (10.4%) treated with placebo (p=0.001). Recurrent IDDVT occurred in 3 (1.5%) and 16 (7.9%)(p=0.002); proximal DVT or PE in 2 (1.0%) and 5 (2.5%) (p=0.45), respectively. There were 3 (0.7%) major bleeding events prior to randomization, none after randomization. Interpretation: Rivaroxaban administered for 3 months effectively and safely reduces recurrent venous thrombosis as compared to 6 weeks of treatment during a 6-month follow up. The incidence of proximal DVT and PE was low and similar between the two groups. Clinical Trial Registration Details: EudraCT Number: 2016-000958-36. Clinical Trial Gov identifier: NCT02722447. Funding Information: Unrestricted grant from Bayer Italy. Declaration of Interests: None to declare. Ethics Approval Statement: The study was approved by the local institutional review boards or ethics committees of all participating centers and was performed in accordance with the declaration of Helsinki (52nd WMA General Assembly, Edinburgh, Scotland, October 2000) as well as with the International Conference on Harmonisation (ICH) guidelines on Good Clinical Practise (GCP).

Registro Informatizado de Enfermedad Tromboembólica Investigators., [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, [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.

Background We hypothesized that the clinical course of venous thromboembolism in patients with active cancer may differ according to the specificities of primary tumor site. Aim and Methods We used data from RIETE (international registry of patients with venous thromboembolism) to compare the clinical venous thromboembolism-related outcomes during the course of anticoagulation in patients with one of the 4 more frequent cancers (breast, prostate, colorectal, or lung cancer). Results As of September 2014, 3947 cancer patients were recruited, of whom 938 had breast, 629 prostate, 1189 colorectal, and 1191 lung cancer. Overall, 55% had metastatic disease (42%, 36%, 53%, and 72%, respectively). During the course of anticoagulant therapy (mean duration, 139 days), the rate of thromboembolic recurrences was similar to the rate of major bleeding in patients with breast (5.6 [95% confidence interval (CI), 3.8-8.1] vs 4.1 [95% CI, 2.7-5.9] events per 100 patient-years) or colorectal cancer (10 [95% CI, 7.6-13] vs 12 [95% CI, 9.4-15] per 100 patient-years). In contrast, in patients with prostate cancer, the rate of venous thromboembolic recurrences was half the rate of major bleeding (6.9 [95% CI, 4.4-10] vs 13 [95% CI, 9.2-17] events per 100 patient-years), whereas in those with lung cancer, the rate of thromboembolic recurrences was twofold higher than the rate of major bleeding (27 [95% CI, 22-23] vs 11 [95% CI, 8.6-15] per 100 patient-years). Conclusions Significant differences in the clinical profile of venous thromboembolic-related outcomes were observed according to the site of cancer. These findings suggest the development of cancer-specific anticoagulant strategies as an area for further research.

Upper-extremity deep vein thrombosis (UEDVT) accounts for about 5-10% of all cases of deep vein thrombosis (DVT). It is often associated with cancer and/or presence of a central venous catheter (CVC), but it may also occur in the absence of these favoring conditions. The safety and efficacy of using direct oral anticoagulants (DOACs) in subjects with UEDVT has not been systematically evaluated and the only data available in the literature derive from anecdotal evidence, analysis of registries, and small single-centre studies. In addition, a specific analysis of UEDVT not associated with cancer and/or CVC has never been made. In this study, we specifically focused on patients with no cancer and without a CVC who were diagnosed with a first episode of UEDVT and were treated with a DOAC. We studied 61 patients, treated in six Italian centres between January 2014 and December 2018. Treatment lasted at least 3 months in all patients. In terms of efficacy, no recurrence of thrombosis or pulmonary embolism were recorded, while Doppler ultrasonography, performed after at least three months of treatment, documented in all cases either partial or complete recanalization of obstructed veins. In terms of safety, no cases of major bleedings were recorded. This is the only series available in the literature of patients treated with DOACs for UEDVT not associated with cancer and/or CVC. This small multicenter real world experience supports the concept that DOACs might be safe and effective for treating UEDTV. Further studies are required to better understand the role of DOACs in these patients.

Background— Patients with a first episode of unprovoked venous thromboembolism have a high risk of recurrence after discontinuation of anticoagulant therapy. Extending anticoagulation reduces the risk of recurrence but is associated with increased bleeding. Sulodexide, a glycosaminoglycan, exerts antithrombotic and profibrinolytic actions with a low bleeding risk when administered orally, but its benefit for preventing recurrent venous thromboembolism is not well known. Methods and Results— In this multicenter, double-blind study, 615 patients with first-ever unprovoked venous thromboembolism who had completed 3 to 12 months of oral anticoagulant treatment were randomly assigned to sulodexide 500 lipasemic units twice daily or placebo for 2 years, in addition to elastic stockings. The primary efficacy outcome was recurrence of venous thromboembolism. Major or clinically relevant bleeding was the primary safety outcome. Venous thromboembolism recurred in 15 of the 307 patients who received sulodexide and in 30 of the 308 patients who received placebo (hazard ratio, 0.49; 95% confidence interval [CI], 0.27–0.92; P =0.02). The analysis in which lost to follow-up was assigned to failure yielded a risk ratio among treated versus control subjects of 0.54 (95% confidence interval, 0.35–0.85; P =0.009). No major bleeding episodes occurred; 2 patients in each treatment group had a clinically relevant bleeding episode. Adverse events were similar in the 2 groups. Conclusion— Sulodexide given after discontinuation of anticoagulant treatment reduced the risk of recurrence in patients with unprovoked venous thromboembolism, with no apparent increase of bleeding risk. Clinical Trial Registration— URL: https://www.clinicaltrialsregister.eu/ . Identifier: EudraCT number 2009-016923-77.

SummaryPlatelets critically contribute to atherothrombosis and worsening ischaemia in patients with peripheral arterial disease (PAD), eventually leading to critical limb ischaemia (CLI). Furthermore, persistent platelet activation despite antiplatelet therapy has been reported in this setting. The prostacyclin analogue iloprost is currently recommended in CLI patients for its effects in relieving symptoms by promoting local perfusion. In this study, we investigated the effects of iloprost infusion on urinary 11-dehydro-TXB2 and 8-iso-PGF2α excretion rate, as in vivoindexes of thromboxane-dependent platelet activation and lipid peroxidation, respectively, and on platelet-derived proinflammatory sCD40L and nitric oxide bioavailability in 44 patients with CLI while on chronic treatment with low-dose aspirin. Daily iloprost infusion for one-week significantly decreased urinary 11-dehydro-TXB2 [499 (277 – 807) vs. 380 (189 – 560) pg/mg creatinine, p < 0.0001] and 8-iso-PGF2α [533 (316 – 842) vs. 334 (196 – 540) pg/mg creatinine, p < 0.0001] as well as plasma sCD40L [1540 (1005 – 3015) vs. 948 (845 – 2030) pg/ml, p < 0.0001]. Furthermore, a significant increase in plasma nitrate plus nitrite levels has been observed [26.8 (18.8 – 35.9) vs. 43.7 (33.0 – 75.5) μM, p < 0.0001]. A significant direct correlation was also found between urinary 8-iso-PGF2α and 11-dehydro-TXB2 before and after iloprost treatment (Rho = 0.695, p < 0.0001). In conclusion, we report that a short-term course of iloprost is able to significantly reduce residual thromboxane biosynthesis, oxidative stress, endothelial dysfunction and platelet-derived inflammation in low-dose aspirin treated patients with CLI.

SummaryThe natural history of calf deep-vein thrombosis (DVT) is still uncertain and it is debated whether it warrants to be diagnosed and treated. We aimed to investigate the complication rate of untreated isolated calf DVT (ICDVT). Symptomatic outpatients were prospectively managed with serial compression ultrasonography (SCUS). Those without proximal DVT and with likely pre-test clinical probability (PCP) or altered D-dimer received immediate subsequent complete examination of calf deep veins (CCUS) by a different operator. The result of CCUS was kept blind both to the managing doctor and the patient and disclosed after three months. Primary outcome was the rate of venous thromboembolism at three months. We examined 431 subjects (196 males; median age 68.0 years) in whom five outcomes were recorded (1.2%; 95% confidence intervals [CI]: 0.4–2.7). If CCUS results had been available, outcomes would have been recorded in 3/424 patients (0.7%; 95% CI: 0.2–2.1) with two events in subjects negative at both serial and complete CUS. ICDVT was diagnosed in 65 subjects (15.3%; 95% CI: 12–19); of whom 59 remained uneventful (one was lost to follow-up). A significant higher rate of outcomes was recorded in subjects with than without ICDVT (5/64; 7.8%; 95% CI: 3–17 vs. 3/351; 0.8%; 95% CI: 0–2; p=0.003). However, after excluding two events picked at serial CUS in subjects with ICDVT, the difference became barely significant (3/64; 4.7%; 95% CI: 1–13; p=0.049). Thrombotic evolution of untreated ICDVT in high-risk subjects may be relevant. Larger studies are needed to address this issue.

Chronic venous disease is very common and widespread. Chronic Venous Insufficiency (CVI) is a condition characterized by hypertension of the venous system of the lower limbs which manifests itself through a large range of symptoms. The main cause of (CVI) is hypertension of the venous system of lower limbs, which in most cases is due to reflux for the incontinence of the valvar system of veins. Other causes are related to obstruction of the venous outflow, or at a reduced venous emptying due to inefficiency of the system of the veno-muscular pumps of the calf and of the foot. The purpose of this study was to evaluate if the use of a non-invasive rehabilitative model, which is characterized by two different visco-elastic insoles, is effective both to reduce postural imbalances and to improve the efficiency of the veno-muscular pumps of the foot and of the calf using photoplethysmography in reflected light. Fifty (50) patients suffering from flatfoot and ped cavus, were studied doing a stabilometric and baropodometric test to evaluate the angle of the foot and the podalic angle. Patients were evaluated by examining vascular examination and venous reography in basal condition, using corrective visco-elastic insoles for the correction of dysmorphisms that we were studying. An improvement of the angle of the Right and Left axis (p The photoplethysmography examination documented a significant improvement of the venous emptying capacity of foot-calf veno-muscular system due to the use of specific insoles for the studied dysmorphism, with an improving tendency even with the use of non-specific insoles. The hemodynamic improvement is correlated with the improvement of the analyzed biomechanical parameters: contact time, lenght of the halfstep, podalic angle and angle of the foot. The partial normalization of biomechanical parameters allows a reorganization of relationships of forces between ground and foot, as well as the improvement of the function of the subtalar joint, causing a partial recovery of the complex physiological mechanism of activation of the veno-muscular pumps of the foot and of the calf.

Factor XII deficiency is associated with increased risk for both arterial and venous thrombosis. We describe a case of DVT involving superficial femoral and popliteal vein occurred following total hip replacement and despite prophylaxis with low molecular weight heparin in a subject with previous acute myocardial infarction (AMI). Tests of haemostasis documented a slightly prolonged activated partial thromboplastin time (APTT) (45′′) due to mild factor XII deficiency (clotting activity 32%). A therapeutic dose of enoxaparin was started, together with warfarin therapy. The patient was advised to continue oral anticoagulation indefinitely. Although cases of both venous and arterial thrombosis in carriers of severe factor XII deficiency have been already reported, to our knowledge this is the first case in the literature occurred in a carrier of partial factor XII deficiency. In conclusion, factor XII deficiency should be suspected if a patient presents with recurrent arterial and/or venous thrombosis and prolonged APTT. If this defect is diagnosed, in the presence of a history of thrombotic events, lifelong anticoagulation could be considered.

Sedentary lifestyle is a risk factor for the development of cardiovascular disease, and leads to a quantifiable impairment in vascular function and arterial wall stiffening. We tested the hypothesis of oxidative stress as a determinant of arterial stiffness (AS) in physically inactive subjects, and challenged the reversibility of these processes after the completion of an eight-week, high-intensity exercise training (ET). AS was assessed before and after ET, measuring carotid to femoral pulse wave velocity (PWV) with a Vicorder device. At baseline and after ET, participants performed urine collection and underwent fasting blood sampling. Urinary 8-iso-PGF2α, an in vivo marker of lipid peroxidation, total, HDL and LDL cholesterol, and triglyceride concentrations were measured. ET was associated with significantly reduced urinary 8-iso-PGF2α(p

Pressure ulcers are defined as “Localized injury to the skin and/or underlying tissue usually over a bony prominence, as a result of pressure, or pressure in combination with shear” (NPUAP/EPUAP 2009) that generally affected people with impaired mobility. In clinical practice there are several methods to facilitate the healing of pressure ulcer. There is evidence that pressure ulcers are characterized by abnormally low electrical potentials, resulting in voltage gradients compared with the surrounding healthy tissue, for this reason electrical stimulation is used to treat pressure ulcers in medical practice. We conducted a monocentric, double-blind, randomized, prospective clinical trial in our rehabilitation center. 33 patients with pressure ulcers at stage II and III NPUAP/EPUAP classification were enrolled. With the aim to investigate the effect of specific modulation of microcurrent wave therapy (BabytechBH®) on tissue regeneration in pressure ulcers treatment. Our data show a reduction in ulcer initial size in treatment group to a mean of 46% (p

SummaryPhysical activity is associated with cardiovascular risk reduction, but the effects of exercise on platelet activation remain controversial. We investigated the effects of regular high-amount, high intensity aerobic exercise on in vivo thromboxane (TX)-dependent platelet activation and plasma levels of platelet-derived proteins, CD40L and P-selectin, and whether platelet variables changes may be related to changes in high-density lipoprotein (HDL) and in the extent of oxidative stress and oxidative stress-related inflammation, as reflected by urinary isoprostane excretion and endogenous soluble receptor for advanced glycation end-products (esRAGE), respectively. Urinary excretion of 11-dehydro-TXB2 and 8-iso-prostaglandin (PG)F2α and plasma levels of P-selectin, CD40L and esRAGE were measured before and after a eight-week standardised aerobic high-amount–high-intensity training program in 22 sedentary subjects with low-to-intermediate risk. Exercise training had a clear beneficial effect on HDL cholesterol (+10%, p=0.027) and triglyceride (-27%, p=0.008) concentration. In addition, a significant (p

Polycythemia vera (PV) is associated with high morbidity and mortality for thrombosis. We hypothesized that in PV altered sensitivity to aspirin might be related to dysfunction of the endothelial repair and/or of the nitric oxide (NO) system. Urinary thromboxane (TX) A2 metabolite (TXM), endothelial colony-forming cells (ECFCs), plasma asymmetric dimethylarginine (ADMA) and von Willebrand factor (VWF) were measured in 37 PV patients on low-dose aspirin and 12 healthy controls. Patients showed an approximately 2-fold increase in median TXM and plasma ADMA levels (P < .001), while ECFC numbers were reduced by approximately 7-fold (P < .001) as compared with nonaspirinated control. These differences were more pronounced in patients with previous thrombosis. An 8-week course of aspirin did not affect ECFCs in 6 controls. VWF and TXM correlated directly with ADMA, and inversely with ECFCs. By multiple regression analysis, lower ECFC quartiles (beta = −0.39; SE = 0.17; P = .028) and higher VWF levels (beta = 0.338, SE = 0.002, P = .034) were independent predictors of higher TXM quartiles (R2 = 0.39). Serum TXB2, measured in 22 patients, was approximat-ly 10-fold higher than aspirin-treated controls. PV patients appear to have an unbalanced ECFC/NO axis, and an apparent altered sensitivity of platelet TXA2 production, all potentially contributing to aspirin-insensitive TXM formation. Thus, additional antithrombotic strategies may be beneficial in PV.