Author Correction: Meta-analyses of sulodexide and other drugs in prevention and treatment of post-thrombotic syndrome.

Correction to: Eur Rev Med Pharmacol Sci 2022; 26 (24): 9372-9381. DOI: 10.26355/eurrev_202212_30688-PMID: 36591846-published online on December 21, 2022. After publication, the authors found a typo in the discussion section. The sentence to amend is the following one: ·       In meta-analyses of observational studies, we found a low incidence of PTS, with 9% of patients presenting PTS among patients receiving sulodexide and a 50% reduction in the risk of PTS in patients receiving rivaroxaban. The "9%" in the sentence below should be changed to "15%" (in order to align the Discussion section with the Results section and the Abstract. There are amendments to this paper. The Publisher apologizes for any inconvenience this may cause. https://www.europeanreview.org/article/30688.

Meta-analyses of sulodexide and other drugs in prevention and treatment of post-thrombotic syndrome.

OBJECTIVE: Post-thrombotic syndrome (PTS) is a common chronic complication of deep vein thrombosis. Elastic compression (ECS) is the common pillar for PTS prevention and treatment, while the pharmacological approach for PTS includes direct oral anticoagulants (DOACs) and venoactive drugs (VADs) for prevention and treatment, respectively. Sulodexide can be used both in long-term prevention and in the treatment of PTS. To better understand the efficacy of the main drugs used in the prevention (sulodexide or DOACs) and treatment of PTS (sulodexide or VADs), pairwise meta-analyses of observational studies and RCTs were conducted. MATERIALS AND METHODS: A literature search in MEDLINE, Embase, and Cochrane Library for observational studies and RCTs was performed. Incidence of PTS, reduction in PTS signs or symptoms and proportion of patients with complete venous ulcers healing were the primary outcomes for prevention and treatment of PTS, respectively. Fixed and Random effect model meta-analyses were performed. Heterogeneity and publication bias were assessed. R® software was used for the analysis. RESULTS: 893 articles were identified during the search. 8 observational studies (6 for DOACs and 2 for sulodexide) and 2 RCTs for sulodexide, out of the 11 studies included in the qualitative synthesis, were included for the prevention and treatment of PTS, respectively. Meta-analyses of observational studies showed an overall incidence of PTS of 15% (95% CI, 11-19) for sulodexide, and a 50% reduction of PTS signs and/or symptoms for rivaroxaban compared to warfarin (OR, 0.50; 95% CI, 0.38-0.65). The overall estimate of the two sulodexide RCTs showed a significant improvement in complete ulcer healing, with an OR of 2.32 (95% CI, 1.49-3.63). CONCLUSIONS: In prevention of PTS, sulodexide and rivaroxaban showed a low incidence and reduced risk of PTS respectively, while in PTS treatment, sulodexide was significantly effective in the complete ulcers healing. These results confirm the need to move from the traditional single-pillar approach with elastic compression stockings to a more effective multi-pillar approach, tailoring the treatment to each individual patient.

Abnormal ankle-brachial index (ABI) predicts primary and secondary cardiovascular risk and cancer mortality.

BACKGROUND: An abnormal ankle-brachial pressure index (ABI) is a marker of the risk for increased total and cardiovascular (CV) mortality. However, it is not clear whether it is associated with an even worse prognosis in patients with previous CV events or with cancer mortality. MATERIALS AND METHODS: Consecutive subjects undergoing ABI assessment for suspected peripheral artery disease or for stratification of CV risk in ten centers in the Veneto Region (northeast Italy), between 2011 and 2014 were enrolled. The ABI was expressed as normal ≥0.9 to ≤1.3, and abnormal <0.9 or >1.3. All-cause mortality and CV or cancer mortality and hospitalizations for CV disease were collected from administrative databases up to December 2018. RESULTS: The study enrolled 1,177 patients. ABI was abnormal in 57.2%. Median follow-up was 61.6 months (53.4-70.1). All-cause, CV and cancer mortality were higher in patients with abnormal than normal ABI, with hazard ratios (HR) respectively 2.0 (95% CI 1.48-2.69), 1.98 (95% CI 1.24-3.17) and 1.85 (95% CI 1.09-3.15). Among subjects with abnormal ABI, the risk of overall mortality, HR 1.57 (95% CI 1.17-2.12), and CV mortality, HR 2.39 (95% CI 1.43-3.99), was higher in those with previous CV events. These latter also had a higher risk of hospitalization for myocardial infarction and stroke: HR 1.85 (95% CI 1.023.37) and 2.17 (95% CI 1.10-4.28). CONCLUSIONS: The co-existence of abnormal ABI and a history of CV events identifies subjects at higher risk, who call for a more aggressive approach. Abnormal ABI is also a predictor of cancer mortality.

Ultrasound elastography is useful to distinguish acute and chronic deep vein thrombosis.

Essentials Ultrasound elastography uses tissue deformation to assess the relative quantification of its elasticity. Compression and duplex ultrasonography may be unable to correctly determine the thrombus age. Ultrasound elastography may be useful to distinguish between acute and chronic deep vein thrombosis. The exact determination of the thrombus age could have both therapeutic and prognostic implications. BACKGROUND: Background Ultrasound elastography (UE) imaging is a novel sonographic technique that is commonly employed for relative quantification of tissue elasticity. Its applicability to venous thromboembolic events has not yet been fully established; in particular, it is unclear whether this technique may be useful in determining the age of deep vein thrombosis (DVT). Thus, the aim of this study was to assess the role of UE in distinguishing acute from chronic DVT. Methods Consecutive patients with a first unprovoked acute and chronic (3 months old) DVT of the lower limbs were analyzed. Patients with recurrent DVT or with a suspected recurrence were excluded. The mean elasticity index (EI) values of acute and chronic popliteal and femoral vein thrombosis were compared. The accuracy of the EI in distinguishing acute from chronic DVT was also assessed by measuring the sensitivity, specificity, positive and negative predictive values, and likelihood ratios. Results One-hundred and forty-nine patients (mean age 63.9 years, standard deviation 13.6; 73 males) with acute and chronic DVT were included. The mean EI of acute femoral DVT was higher than that of chronic femoral DVT (5.09 versus 2.46), and the mean EI of acute popliteal DVT was higher than that of chronic popliteal DVT (4.96 versus 2.48). An EI value of > 4 resulted in a sensitivity of 98.9% (95% confidence interval [CI] 93.3-99.9), a specificity of 99.1% (95% CI 94.8-99.9), a positive predictive value of 91.1% (95% CI 77.9-97.1), a negative predictive value of 98.6% (95% CI 91.3-99.9), a positive likelihood ratio of 13.23 (95% CI 93-653) and a negative likelihood ratio of 0.001 (95% CI 0.008-0.05) for acute DVT. Conclusions UE appears to be a promising technique for distinguishing between acute and chronic DVT. Larger prospective studies are warranted to confirm our preliminary findings.

Thrombosis of abdominal aorta in congenital afibrinogenemia: case report and review of literature.

Thrombotic events in congenital hypo-afibrinogenemia have been rarely reported, either in association or not with replacement therapy or thrombotic risk factors. We describe clinical findings and management of thrombosis of abdominal aorta with peripheral embolism in a patient with congenital afibrinogenemia. A review of arterial thrombosis in inherited hypo-afibrinogenemia was also performed. The patient with a severe bleeding history requiring prophylaxis with fibrinogen concentrates (FC) was admitted for ischaemia of the 4th right toe. An angio-CT of abdominal aorta showed a thrombosis from the origin of renal arteries to the carrefour with a distal floating part. No thrombotic risk factors were found; a previous traumatic lesion of aortic wall might have triggered the thrombus formation, whereas the role of FC prophylaxis remains uncertain. The patient was successfully treated with FC, enoxaparin followed by fondaparinux, and low-dose aspirin without bleeding or thrombosis recurrence. After 2 years, aortic thrombus was almost completely recovered. Sixteen hypo/afibrinogenemia patients with arterial thrombosis were found in Literature, showing that thrombosis often occurs at a young age, involves large vessels, its recurrence is not unusual, and therapeutic strategy is not defined yet. Our therapeutic approach was effective and also safe, but further studies are needed to improve the knowledge of pathogenesis and the anti-thrombotic management in this peculiar setting.

New anticoagulants for the treatment of venous thromboembolism.

In recent years, the significant limitations associated with the use of vitamin K antagonists (VKA) have encouraged the development of new agents. Based upon the central roles played by the serine proteases thrombin and Factor Xa in the blood coagulation cascade, direct thrombin inhibitors and direct Factor Xa inhibitors have been developed. These agents, which include the direct thrombin inhibitor dabigatran etexilate and the Factor Xa inhibitors rivaroxaban and idrabiotaparinux are free from many of the limitations of VKAs. According to the results of available phase III randomized clinical trials, both dabigatran and rivaroxaban are effective and safe enough to qualify as ideal oral anticoagulants for the initial and long-term treatment of patients with acute venous thromboembolism (VTE). Rivaroxaban does not require an initial parenteral treatment and can be given in once daily administrations after the first three weeks. Both of them have limitations for the treatment of patients with severe renal failure, and require further investigations in cancer patients and in pregnant patients with VTE. Both of them lack an antidote.

The optimal duration of anticoagulation in patients with venous thromboembolism: how long is long enough?

The risk of recurrent venous thromboembolism (VTE) approaches 40% of all patients after 10 years of follow-up. This risk is higher in patients with permanent risk factors of thrombosis such as active cancer, prolonged immobilization from medical diseases, and antiphospholipid syndrome; in carriers of several thrombophilic abnormalities, including deficiencies of natural anticoagulants; and in patients with unprovoked presentation. Patients with permanent risk factors of thrombosis should receive indefinite anticoagulation, consisting of subtherapeutic doses of low-molecular-weight heparin in cancer patients, and oral anticoagulants in all other conditions. Patients whose VTE is triggered by major surgery or trauma should be offered three months of anticoagulation. Patients with unprovoked VTE, including carriers of thrombophilia, and those whose thrombotic event is associated with minor risk factors (such as hormonal treatment, minor injuries, long travel) should receive at least three months of anticoagulation. The decision as to go on or discontinue anticoagulation after this period should be individually tailored and balanced against the haemorrhagic risk. Post-baseline variables, such as the D-dimer determination and the ultrasound assessment of residual thrombosis can help identify those patients in whom anticoagulation can be safely discontinued. As a few emerging anti-Xa and anti-IIa compounds seem to induce fewer haemorrhagic complications than conventional anticoagulation, while preserving at least the same effectiveness, they have the potential to open new scenarios for decisions regarding the duration of anticoagulation in patients with VTE.

Permanent diabetes during the first year of life: multiple gene screening in 54 patients.

AIMS/HYPOTHESIS: The aim of this study was to investigate the genetic aetiology of permanent diabetes mellitus with onset in the first 12 months of age. METHODS: We studied 46 probands with permanent, insulin-requiring diabetes with onset within the first 6 months of life (permanent neonatal diabetes mellitus [PNDM]/monogenic diabetes of infancy [MDI]) (group 1) and eight participants with diabetes diagnosed between 7 and 12 months of age (group 2). KCNJ11, INS and ABCC8 genes were sequentially sequenced in all patients. For those who were negative in the initial screening, we examined ERN1, CHGA, CHGB and NKX6-1 genes and, in selected probands, CACNA1C, GCK, FOXP3, NEUROG3 and CDK4. The incidence rate for PNDM/MDI was calculated using a database of Italian patients collected from 1995 to 2009. RESULTS: In group 1 we found mutations in KCNJ11, INS and ABCC8 genes in 23 (50%), 9 (19.5%) and 4 (8.6%) patients respectively, and a single homozygous mutation in GCK (2.1%). In group 2, we identified one incidence of a KCNJ11 mutation. No genetic defects were detected in other loci. The incidence rate of PNDM/MDI in Italy is estimated to be 1:210,287. CONCLUSIONS/INTERPRETATION: Genetic mutations were identified in ~75% of non-consanguineous probands with PNDM/MDI, using sequential screening of KCNJ11, INS and ABCC8 genes in infants diagnosed within the first 6 months of age. This percentage decreased to 12% in those with diabetes diagnosed between 7 and 12 months. Patients belonging to the latter group may either carry mutations in genes different from those commonly found in PNDM/MDI or have developed an early-onset form of autoimmune diabetes.

The value of 64-detector row computed tomography for the exclusion of pulmonary embolism.

Recently, a diagnostic strategy using a clinical decision rule, D-dimer testing and spiral computed tomography (CT) was found to be effective in the evaluation of patients with clinically suspected pulmonary embolism (PE). However, the rate of venous thromboembolic complications in the three-month follow-up of patients with negative CT was still substantial and included fatal events. It was the objective to evaluate the safety of withholding anticoagulants after a normal 64-detector row CT (64-DCT) scan from a cohort of patients with suspected PE. A total of 545 consecutive patients with clinically suspected first episode of PE and either likely pre-test probability of PE (using the simplified Wells score) or unlikely pre-test probability in combination with a positive D-dimer underwent a 64-DCT. 64-DCT scanning was inconclusive in nine patients (1.6%), confirmed the presence of PE in 169 (31%), and ruled out the diagnosis in the remaining 367. During the three-month follow-up of the 367 patients one developed symptomatic distal deep-vein thrombosis (0.27%; 95%CI, 0.0 to 1.51%) and none developed PE (0 %; 95%CI, 0 to 1.0%). We conclude that 64-DCT scanning has the potential to safely exclude the presence of PE virtually in all patients presenting with clinical suspicion of this clinical disorder.

Risk stratification and outcomes in hemodynamically stable patients with acute pulmonary embolism: a prospective, multicentre, cohort study with three months of follow-up.

BACKGROUND: The role of risk stratification in normotensive patients with acute pulmonary embolism (PE) is still unclear. OBJECTIVES: We evaluated, in these patients, the usefulness of six prognostic markers for predicting in-hospital adverse events related to PE and 3-month mortality. PATIENTS/METHODS: Two hundred and one consecutive patients with confirmed acute PE and normal blood pressure, who were administered conventional anticoagulation, were recruited in a multicentre prospective cohort study with 3 months of follow-up. At baseline, they received a comprehensive risk-evaluation including echocardiographic assessment of right ventricular dysfunction, determination of troponin I, brain natriuretic peptide and D-dimer, arterial blood gas analysis and a clinical score. Primary outcome of the study was PE-related in-hospital death or clinical deterioration. Secondary outcomes were in-hospital and 3-month all-cause mortality. RESULTS: The primary outcome occurred in one patient (0.5%), who died from PE during hospitalization. The in-hospital and 3-month all-cause mortality were 2% and 9%, respectively. None of the prognostic markers was predictive of the primary outcome. Clinical score, troponin I and hypoxemia predicted in-hospital all-cause mortality (P = 0.02, 0.01 and < 0.01, respectively). Clinical score (HR, 4.7; 95% CI, 1.9-12.0), D-dimer (4.8; 1.4-16.3), hypoxemia (5.7; 2.1-15.1) and troponin I (7.5; 2.5-22.7) were predictors of 3-month all-cause mortality on univariate analysis. On multivariate analysis clinical score and troponin I remained independently predictive. CONCLUSIONS: We did not find prognostic markers useful as predictors of in-hospital PE-related adverse events. Clinical score, troponin I and hypoxemia predicted in-hospital all-cause mortality. Clinical score and troponin I independently predicted 3-month all-cause mortality.

Venous thromboembolism and the risk of subsequent symptomatic atherosclerosis.

BACKGROUND: Recently, we reported an association between asymptomatic carotid atherosclerosis and venous thromboembolism (VTE) of unknown origin. We hypothesized that patients with VTE of unknown origin would be at a higher risk of developing symptomatic atherosclerosis than patients with VTE induced by known risk factors. METHODS: To examine this hypothesis, we studied 1,919 consecutive patients followed prospectively after their first VTE episode. The primary outcome was non-fatal and fatal symptomatic atherosclerotic disease in patients with VTE of unknown origin as compared to those with secondary VTE. An independent committee assessed all study outcomes, and adjusted hazard ratios (HR) were calculated using the Cox's proportional hazards model. RESULTS: After a median follow-up of 48 and 51 months, respectively, at least one symptomatic atherosclerotic complication was detected in 160 of the 1,063 patients (15.1%) with VTE of unknown origin, and in 73 of the 856 (8.5%) with secondary VTE. After adjusting for age and other risk factors of atherosclerosis, the HR for symptomatic atherosclerotic complications in patients with VTE of unknown origin compared to those with secondary VTE was 1.6 (95% confidence intervals; CI: 1.2-2.0). When the analysis was restricted to patients without previous symptomatic atherosclerosis, the HR became 1.7 (95% CI: 1.1-2.4). CONCLUSIONS: Patients with VTE of unknown origin have a 60% higher risk of developing symptomatic atherosclerotic disease than do patients with secondary venous thrombosis.

The metabolic syndrome and the risk of venous thrombosis: a case-control study.

OBJECTIVE: The results of recent studies have suggested that patients with idiopathic venous thromboembolism (VTE) might be at increased risk of asymptomatic atherosclerosis and cardiovascular events. The metabolic syndrome is a cluster of risk factors for atherosclerosis. Its impact on VTE is unknown. METHODS: In a case-control study, consecutive patients with objectively confirmed deep vein thrombosis (DVT) and control subjects with objectively excluded DVT underwent clinical assessment for the presence of the metabolic syndrome according to the National Cholesterol Education Program criteria. The presence of known risk factors for DVT was documented. Patients with DVT secondary to cancer were excluded. The prevalence of the metabolic syndrome was compared between patients with idiopathic DVT and controls. RESULTS: We enrolled 93 patients with a first episode of idiopathic DVT and 107 controls. The mean age was 65.1 and 63.7 years, respectively. The metabolic syndrome was diagnosed in 50.5% of patients with idiopathic DVT and in 34.6% of controls [odds ratio (OR) 1.93; 95% confidence interval (CI) 1.05, 3.56]. After adjustment for age, sex, body mass index, and smoke, the metabolic syndrome remained independently associated with idiopathic DVT (OR 1.94; 95% CI 1.04, 3.63). In patients with secondary DVT, the prevalence of the metabolic syndrome was 27%. CONCLUSIONS: The metabolic syndrome may play a role in the pathogenesis of idiopathic DVT and may act as link between venous thrombosis and atherosclerosis.

High vs. low doses of low-molecular-weight heparin for the treatment of superficial vein thrombosis of the legs: a double-blind, randomized trial.

In contrast with extensive information on the management of deep vein thrombosis of the lower extremities, little is known on the most appropriate treatment of the superficial vein thrombosis (SVT). In a multicenter, prospective, controlled, double-blind, double-dummy clinical trial, 164 consecutive patients with acute SVT of the great saphenous vein were randomized to receive the s.c. administration of either fixed prophylactic doses (2850 a-Xa IU) or body-weight adjusted therapeutic doses of nadroparin once daily for 1 month. The main study outcome was to compare the rate of asymptomatic and symptomatic extension of SVT and/or venous thromboembolic (VTE) complications during a 3-month follow-up period. Of the 81 patients randomized to the prophylactic doses, seven [8.6%; 95% confidence interval (CI), 3.5-17.0] developed SVT progression or VTE complications as compared with six of the 83 (7.2%; 95% CI, 2.8-15.1) allocated to the treatment group (absolute difference, 1.4; 96% CI, -6.9 to 9.7; P = 0.74). No patient in either group developed major bleeding. Our findings suggest that therapeutic doses of low-molecular-weight heparin, administered for 1 month in patients with SVT of the greater saphenous vein do not improve results obtained by prophylactic doses, administered for the same period, over a 3-month follow-up period.