Midregional-proAdrenomedullin as a prognostic tool in sepsis and septic shock: A systematic review and meta-analysis.

BACKGROUND: Midregional-proAdrenomedullin (MR-proADM) has been recently proposed as a tool in patients with sepsis and septic shock. Our aim was to evaluate the prognostic role of MR-proADM in hospitalized patients with sepsis and septic shock. METHODS: PRISMA guideline was followed. MEDLINE and EMBASE were searched up to June 2023. Primary outcome was mean difference in MR-proADM among survivors and nonsurvivors, secondary outcome mean difference in MR-proADM according to infection severity and type. Risk of bias was evaluated using Newcastle-Ottawa scale for observational studies and Cochrane tool for randomized trials. Pooled mean differences (MD) with corresponding 95% confidence intervals (CIs) were calculated in a random-effects model. RESULTS: Twenty-four studies included 6730 adult patients (1208 nonsurvivors and 5522 survivors) and three studies included 195 paediatric patients (30 nonsurvivors and 165 survivors). A total of 10, 4 and 13 studies included, respectively, patients with sepsis (3602 patients), septic shock (386 patients) and a mixed population (2937 patients). Twenty-one studies included patients with different source of infection, three with pneumonia and one with a catheter-related infection. Most studies (n = 12) had a follow-up of 28 days. In adult cohort, pooled mean difference between nonsurvivors and survivors of MR-proADM was 2.55 mmol/L (95% CI: 1.95-3.15) with higher values in patients with septic shock (4.25 mmol/L; 95% CI, 2.23-6.26 mmol/L) than in patients with sepsis (1.77 mmol/L; 95% CI: 1.11-2.44 mmol/L). In paediatric cohort, pooled mean difference was 3.11 mmol/L (95% CI: -0.02-6.24 mmol/L). CONCLUSIONS: Higher values of MR-proADM are detectable in nonsurvivors adult and paediatric-hospitalized patients with sepsis or septic shock.

Cilostazol for peripheral arterial disease - a position paper from the Italian Society for Angiology and Vascular Medicine.

Cilostazol is a quinolinone-derivative selective phosphodiesterase inhibitor and is a platelet-aggregation inhibitor and arterial vasodilator for the symptomatic treatment of intermittent claudication (IC). Cilostazol has been shown to improve walking distance for patients with moderate to severe disabling intermittent claudication who do not respond to exercise therapy and who are not candidates for vascular surgical or endovascular procedures. Several studies evaluated the pharmacological effects of cilostazol for restenosis prevention and indicated a possible effect on re-endothelialization mediated by hepatocyte growth factor and endothelial precursor cells, as well as inhibiting smooth muscle cell proliferation and leukocyte adhesion to endothelium, thereby exerting an anti-inflammatory effect. These effects may suggest a potential effectiveness of cilostazol in preventing restenosis and promoting the long-term outcome of revascularization interventions. This review aimed to point out the role of cilostazol in treating patients with peripheral arterial disease, particularly with IC, and to explore its possible role in restenosis after lower limb revascularization.

Correction to: Venous thromboembolism and heparin use in COVID-19 patients: juggling between pragmatic choices, suggestions of medical societies and the lack of guidelines.

In the original version of the article, the article title was processed incorrectly. The correct article title is "Venous Thromboembolism and Heparin Use in COVID-19 Patients: Juggling between Pragmatic Choices, Suggestions of Medical Societies and the Lack of Guidelines". This has been corrected with this erratum and the original article has also been updated to reflect the change in article title.

Upper extremity deep vein thrombosis treated with direct oral anticoagulants: a multi-center real world experience.

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.

Microparticles Carrying Sonic Hedgehog Are Increased in Humans with Peripheral Artery Disease.

Sonic hedgehog (Shh) is a prototypical angiogenic agent with a crucial role in the regulation of angiogenesis. Experimental studies have shown that Shh is upregulated in response to ischemia. Also, Shh may be found on the surface of circulating microparticles (MPs) and MPs bearing Shh (Shh + MPs) have shown the ability to contribute to reparative neovascularization after ischemic injury in mice. The goal of this study was to test the hypothesis that, in humans with peripheral artery disease (PAD), there is increased number of circulating Shh + MPs. This was done by assessing the number of Shh + MPs in plasma of patients with PAD and control subjects without PAD. We found significantly higher number of Shh + MPs in plasma of subjects with PAD, compared to controls, while the global number of MPs-produced either by endothelial cells, platelets, leukocytes, and erythrocytes-was not different between PAD patients and controls. We also found a significant association between the number of Shh + MPs and the number of collateral vessels in the ischemic limbs of PAD patients. Interestingly, the concentration of Shh protein unbound to MPs-which was measured in MP-depleted plasma-was not different between subjects with PAD and the controls, indicating that, in the setting of PAD, the call for Shh recapitulation does not lead to secretion of protein into the blood but to binding of the protein to the membrane of MPs. These findings provide novel information on Shh signaling during ischemia in humans, with potentially important biological and clinical implications.

Microparticles Produced by Activated Platelets Carry a Potent and Functionally Active Angiogenic Signal in Subjects with Crohn's Disease.

Microparticles (MPs) are submicron vesicles shed from various cell types upon activation, stimulation, and death. Activated platelets are an important source of circulating MPs in subjects with inflammatory diseases, including Crohn's disease (CD). Angiogenesis is a hallmark of inflammation in CD and plays an active role in sustaining disease progression, while targeting angiogenesis may be an effective approach to block colitis. In this study, we analyzed the angiogenic content of the MPs produced by activated platelets in subjects with CD. We also evaluated whether the angiogenic signal carried by these MPs was functionally active, or able to induce angiogenesis. We found that, in subjects with CD, MPs produced by activated platelets contain significantly higher levels of angiogenic mRNAs, such as epidermal growth factor (EGF), platelet-derived growth factor-α (PDGFα), fibroblast growth factor (FGF-2), and angiopoietin-1 (ANGPT1), compared to MPs isolated from control subjects. They also contain significantly higher levels of prototypical angiogenic proteins, including vascular endothelial growth factor (VEGF), angiopoietin-1, endoglin, endothelin-1, pentraxin 3, platelet factor-4, plasminogen activator inhibitor-1 (PAI-1), tissue inhibitor of metalloproteinases-1 (TIMP-1), and thrombospondin 1. The protein content of these MPs is functionally active, since it has the ability to induce a robust angiogenic process in an endothelial cell/interstitial cell co-culture in vitro assay. Our results reveal a potential novel mechanism through which the angiogenic signal is delivered in subjects with CD, with potentially important clinical and therapeutic implications.

Risk of venous thromboembolism and arterial events in patients with hypoalbuminemia: a comprehensive meta-analysis of more than 2 million patients.

BACKGROUND: Albumin has antiplatelet and anticoagulant functions. Hypoalbuminemia, as defined by serum values of <3.5 g/dL, is associated with arterial thrombosis; its impact on venous thromboembolism (VTE) is unclear. OBJECTIVES: The objective of this meta-analysis is to assess the VTE risk in patients with hypoalbuminemia. METHODS: MEDLINE and EMBASE were searched up to January 2024 for observational studies and randomized trials reporting data of interest. Primary outcome was the risk of VTE, while secondary outcomes were myocardial infarction and stroke risk in patients with hypoalbuminemia versus those without hypoalbuminemia. The risk of bias was evaluated using Newcastle-Ottawa scale and Cochrane tool. Risk ratios (RRs) with 95% confidence intervals (CIs) were calculated in a random-effects model. RESULTS: Forty-three studies for a total of 2 531 091 patients (39 738 medical and 2 491 353 surgical) were included in primary analysis; 79.1% of the studies used 3.5 g/dL cut-off value for hypoalbuminemia definition. Follow-up duration was 30 days in 60.5% of studies. Patients with hypoalbuminemia had a higher risk of VTE (RR, 1.88; 95% CI, 1.66-2.13). RRs were similar in both medical (RR, 1.87; 95% CI, 1.53-2.27) and surgical patients (RR, 1.87; 95% CI, 1.61-2.16) and in patients with (RR, 1.86; 95% CI, 1.66-2.10) and without cancer (RR, 1.89; 95% CI, 1.47-2.44). Risk of myocardial infarction (RR, 1.88; 95% CI, 1.54-2.31) and stroke (RR, 1.77; 95% CI, 1.26-2.48) was higher in patients with hypoalbuminemia. CONCLUSION: Hypoalbuminemia is a risk factor for VTE in both medical and surgical patients irrespective of cancer coexistence. Serum albumin analysis may represent a simple and cheap tool to identify patients at VTE risk.

Clinical Correlates of In-Hospital Mortality in Patients Undergoing Inferior Vena Cava Filter Placement for Acute Deep Vein Thrombosis.

Background: It is reasonable to place an Inferior Vena Cava Filter (IVCF) when an acute deep vein thrombosis (DVT) of the lower limbs occurs in a patient with absolute contraindication to therapeutic anticoagulation. An additional potential reason for placing an IVCF is the need to stop therapeutic anticoagulation in a patient with acute DVT who must undergo urgent non-deferrable surgery. However, IVCFs are often used outside of such established indications and many authors argue about their actual utility, especially in terms of survival. In this retrospective study, we looked for clinical correlates of in-hospital mortality among patients who underwent IVCF placement, limiting our analysis to the cases for which a correct indication to IVCF placement existed. Methods: We retrospectively analyzed the electronic database of our University Hospital, searching for consecutive hospitalized patients who had acute DVT and underwent IVCF placement because of an established contraindication to therapeutic anticoagulation and/or because it was necessary to stop anticoagulation due to urgent surgery. The search covered the period between 1 January 2010 and 31 December 2020. Results: The search resulted in the identification of 168 individuals. An established contraindication to therapeutic anticoagulation was present in 116 patients (69.0%), while urgent non-deferrable surgery was the reason for IVCF placement in 52 patients (31.0%). A total of 24 patients (14.3%) died during the same hospital stay in which the IVCF was placed. Mortality rate was significantly higher in patients with a contraindication to anticoagulation than in patients who underwent IVCF placement because of urgent surgery (19.0% vs. 3.8%, OD 5.85 vs. 0.17). In-hospital mortality was also significantly higher among patients with chronic kidney disease and those who needed blood cell transfusion during hospitalization. Conclusions: This study provides novel information on clinical correlates of in-hospital mortality among patients with acute DVT who undergo IVCF. Prospective observational studies are needed to substantiate these findings.

Safety and effectiveness of oral anticoagulants in patients with atrial fibrillation and stage 4 chronic kidney disease: a real-world experience.

It is still uncertain whether direct oral anticoagulants (DOACs) perform better than vitamin K antagonists (VKAs) in subjects with non-valvular atrial fibrillation (NVAF) and advanced chronic kidney disease (CKD). The aim of the study was to compare safety and effectiveness of DOACs and VKAs in patients with NVAF and stage 4 CKD (creatinine clearance 15-29 mL/min). We searched the hospital databases of two academic centers to retrospectively identify patients with stage 4 CKD who were on treatment with DOACs or VKAs for NVAF. Safety was the primary outcome of the study and was assessed in terms of incidence of major bleeding (MB). Secondary outcomes were clinically relevant non-major bleeding (CRNMB) and death for any cause. A total of 176 patients (102 on DOACs and 74 on VKAs) were found and included in the analysis. The incidence rate of MB was not statistically different between groups (8.6 per 100 patients-year in the DOAC group and 5.6 per 100 patients-year in the VKA group). Rates of IS/SSE and CRNMB were statistically similar in the two treatment groups, as well. There were less deaths for any cause in the DOAC group than in the VKA group (8.6 and 15.8 per 100 patients-year, respectively), but the difference was not statistically significant. This study found no difference in terms of safety and effectiveness between patients with NVAF and stage 4 CKD treated with DOACs and VKAs. Larger prospective or randomized studies are needed to confirm these findings.

Factor V Leiden, prothrombin, MTHFR, and PAI-1 gene polymorphisms in patients with arterial disease: A comprehensive systematic-review and meta-analysis.

INTRODUCTION: The role of inherited thrombophilia in arterial disease is uncertain. We performed a systematic-review and meta-analysis of inherited thrombophilia in cerebrovascular (CVD), coronary heart (CHD), and peripheral artery disease (PAD) patients. MATERIALS AND METHODS: MEDLINE and EMBASE were searched up to February 2022. Pooled prevalences (PPs) and odds ratios (ORs) with 95 % confidence intervals (95%CI) were calculated in a random-effects model. Factor V Leiden (G1691A), prothrombin (G20210A), MTHFR C677T/A1298C and PAI-1 4G/5G were evaluated. RESULTS: 377 studies for 98,186 patients (32,791 CVD, 62,266 CHD, 3129 PAD) and 108,569 controls were included. Overall, 37,249 patients had G1691A, 32,254 G20210A, 42,546 MTHFR C677T, 8889 MTHFR A1298C, and 19,861 PAI-1 4G/5G gene polymorphisms. In CVD patients, PPs were 6.5 % for G1691A, 3.9 % for G20210A, 56.4 % for MTHFR C677T, 51.9 % for MTHFR A1298C, and 77.6 % for PAI-1. In CHD, corresponding PPs were 7.2 %, 3.8 %, 52.3 %, 53.9 %, and 76.4 %. In PAD, PPs were 6.9 %, 4.7 %, 55.1 %, 52.1 %, and 75.0 %, respectively. Strongest ORs in CVD were for homozygous G1691A (2.76; 95 %CI, 1.83-4.18) and for homozygous G20210A (3.96; 95 %CI, 2.05-7.64). Strongest ORs in CHD were for homozygous G1691A (OR 1.68; 95%CI, 1.02-2.77) and G20210A (heterozygous 1.49 95%CI, 1.22-1.82; homozygous 1.54 95%CI, 0.79-2.99). The OR for PAI-1 4G/4G in PAD was 5.44 (95%CI, 1.80-16.43). Specific subgroups with higher PPs and ORs were identified according to age and region. CONCLUSIONS: Patients with arterial disease have an increased prevalence and odds of having some inherited thrombophilia. Some thrombophilia testing may be considered in specific subgroups of patients.

Low-Dose Rivaroxaban to Prevent Recurrences of Venous Thromboembolism in Cancer: A Real-Life Experience with a Focus on Female Patients.

BACKGROUND: The way in which to prevent recurrent venous thromboembolism (VTE) is an unmet clinical need in cancer patients. International guidelines only provide conditional recommendations and do not specify which anticoagulant and dose should be used. In the last 2 years, we have been using low-dose rivaroxaban to prevent VTE recurrences in cancer patients. The results of this real-life experience are presented in this study. METHODS: All patients had cancer and had previously completed a cycle of at least six months of full-dose anticoagulation for the treatment of a VTE index event, before receiving a prescription of low-dose rivaroxaban (10 mg once daily) for secondary prevention of VTE. Effectiveness and safety of this therapeutic regimen were evaluated in terms of VTE recurrences, major bleedings (MB), and clinically relevant non-major bleedings (CRNMB). RESULTS: The analysis included 106 cancer patients. Their median age was 60 years (IQR 50-69). Metastatic cancer was present in 87 patients (82.1%). Six patients (5.7%) had brain metastases. Over a median follow-up time of 333 days (IQR 156-484), the incidence of VTE recurrences was 3.8% (95%CI 1.0-9.4), with a recurrence rate of 4.0 per 100 person-years (95%CI 1.1-10.2). We observed no MB (0.0%) and three CRNMB (2.8%) (95%CI 0.6-8.1). CONCLUSIONS: Low-dose rivaroxaban is potentially effective and safe in cancer patients that require prevention of recurrent VTE. Large-scale studies are needed to confirm these findings.

Gut dysbiosis-related thrombosis in inflammatory bowel disease: Potential disease mechanisms and emerging therapeutic strategies.

Patients with inflammatory bowel disease (IBD) have an increased risk of developing venous thromboembolic events, which have a considerable impact on morbidity and mortality. Chronic inflammation plays a crucial role in the pathogenesis of thrombotic events in patients with IBD. However, many unresolved questions remain, particularly regarding the mechanisms that determine the persistent inflammatory state independent of disease activity. This review explored the role of gut microbiota dysbiosis and intestinal barrier dysfunction, which are considered distinctive features of IBD, in determining pro-thrombotic tendencies. Gut-derived endotoxemia due to the translocation of bacterial lipopolysaccharides (LPS) from the intestine to the bloodstream and the bacterial metabolite trimethylamine-N-oxide (TMAO) are the most important molecules involved in gut dysbiosis-related thrombosis. The pathogenic prothrombotic pathways linked to LPS and TMAO have been discussed. Finally, we present emerging therapeutic approaches that can help reduce LPS-mediated endotoxemia and TMAO, such as restoring intestinal eubiosis, normalizing intestinal barrier function, and counterbalancing the effects of LPS and TMAO.

Antithrombotic treatment for retinal vein occlusion: a systematic review and meta-analysis.

BACKGROUND: Retinal vein occlusion (RVO) represents a common thrombotic disorder. OBJECTIVES: In this meta-analysis, we evaluated the efficacy and safety of anticoagulant and antiplatelet therapy in RVO. METHODS: MEDLINE and EMBASE were searched up to December 2021 for observational studies and randomized controlled trials including patients with RVO. Efficacy outcomes were best-corrected visual acuity improvement, recurrent RVO, fluorescein angiography improvement, cardiovascular events, and safety outcomes were major bleeding and intraocular bleeding. RESULTS: A total of 1422 patients (15 studies) were included. Antiplatelet therapy was administered to 477 patients (13 studies), anticoagulant therapy to 312 patients (12 studies), and 609 (7 studies) patients received no antithrombotic treatment. The treatment duration ranged between 0.5 and 3 months. The median follow-up duration was 12 months. Best-corrected visual acuity improvement was reported in 58% of the patients (95% confidence interval [CI], 45%-69%) overall, 64% (95% CI, 58%-71%) in those on anticoagulant therapy, and 33% (95% CI, 21%-47%) in those on antiplatelet therapy. The rates of recurrent RVO was 11% (95% CI, 7%-17%), 7% (95% CI, 2%-19%), and 15% (95% CI, 8%-28%), respectively. The rate of recurrent RVO in untreated patients was 9% (95% CI, 6%-14%). The rate of major bleeding was 5% (95% CI, 3%-9%) overall, 4% (95% CI, 2%-9%) in those on anticoagulant therapy, and 7% (95% CI, 2%-23%) in those on antiplatelet therapy. CONCLUSION: Anticoagulant therapy was associated with higher visual acuity improvement and fewer recurrent RVO events than antiplatelet therapy, at the cost of an acceptable proportion of bleeding complications.

High-dose versus low-dose venous thromboprophylaxis in hospitalized patients with COVID-19: a systematic review and meta-analysis.

BACKGROUND: Hospitalized COVID-19 patients are at high risk of venous thromboembolism (VTE). Standard doses of anticoagulant prophylaxis may not be sufficiently effective for the prevention of VTE. The objective of this systematic-review and meta-analysis was to compare the efficacy and safety of high-dose versus low-dose thromboprophylaxis in hospitalized patients with COVID-19. MATERIAL AND METHODS: MEDLINE and EMBASE were searched up to October 2021 for randomized clinical trials (RCTs) comparing high-dose with low-dose thromboprophylaxis in hospitalized adult patients with COVID-19. The primary efficacy outcome was the occurrence of VTE and the primary safety outcome was major bleeding. RESULTS: A total of 5470 patients from 9 RCTs were included. Four trials included critically ill patients, four non-critically ill patients, and one included both. VTE occurred in 2.9% of patients on high-dose and in 5.7% of patients on low-dose thromboprophylaxis (relative risk [RR] 0.53; 95% confidence intervals [CIs], 0.41-0.69; I2 = 0%; number needed to treat for an additional beneficial outcome, 22). Major bleeding occurred in 2.5% and 1.4% of patients, respectively (RR 1.78; 95% CI, 1.20-2.66; I2 = 0%; number needed to treat for an additional harmful outcome, 100). All-cause mortality did not differ between groups (RR 0.97; 95% CI, 0.75-1.26; I2 = 47%). The risk of VTE was significantly reduced by high-dose thromboprophylaxis in non-critically ill (RR 0.54; 95% CI, 0.35-0.86; I2 = 0%), but not in critically ill patients (RR 0.69; 95% CI, 0.39-1.21; I2 = 36%). DISCUSSION: In hospitalized patients with COVID-19, high-dose thromboprophylaxis is more effective than low-dose for the prevention of VTE but increases the risk of major bleeding.

Anticoagulant treatment for upper extremity deep vein thrombosis: A systematic review and meta-analysis.

BACKGROUND: Data on anticoagulant treatment for upper extremity deep vein thrombosis (UEDVT) are largely derived from studies on usual site venous thromboembolism (VTE). OBJECTIVES: The objective of this meta-analysis was to evaluate the efficacy and safety of anticoagulant therapy for UEDVT. PATIENTS/METHODS: A systematic search of MEDLINE and EMBASE was conducted for studies including patients with UEDVT. Primary outcomes were recurrent VTE and major bleeding. Secondary outcomes included clinically-relevant non-major bleeding and all-cause mortality. Summary estimates with 95% confidence intervals (CIs) were calculated by random-effect meta-analysis. RESULTS: A total of 1473 patients from 11 prospective and nine retrospective studies were included. Sixty percent of patients had an indwelling catheter and 56.1% had cancer. Anticoagulant treatment consisted of direct oral anticoagulants, low molecular weight heparin followed by vitamin K antagonists, and low molecular weight heparin alone in 45.1%, 35.0%, and 19.9% of patients, respectively. During a median follow-up of 13 months, recurrent VTE occurred in 3% of patients (95% CI: 2-4; 21/1334 patients), major bleeding in 3% (95% CI: 2%-5%; 29/1235 patients), clinically-relevant non-major bleeding in 4% (95% CI: 3-6; 40/1075 patients), and all-cause mortality in 9% (95% CI: 5-15; 108/1084 patients). Rates of these outcomes were not significantly different between patients with or without cancer, patients with or without an indwelling catheter, and among those receiving different anticoagulant treatments. CONCLUSIONS: In patients with UEDVT, anticoagulant treatment is associated with a low risk of recurrent VTE and a nonnegligible risk of major bleeding.