Corrigendum: The new Italian registry of infantile thrombosis (RITI): a reflection on its journey, challenges and pitfalls.

[This corrects the article DOI: 10.3389/fped.2023.1094246.].

Clinical evidence and rationale of mesoglycan to treat chronic venous disease and hemorrhoidal disease: a narrative review.

Chronic venous disease (CVD) and hemorrhoidal disease (HD) are among the most common vascular diseases in the world, with CVD affecting 22-41% of the population in Europe and HD having a point prevalence of 11-39%. The burden is substantial in terms of the effect of symptoms on patients' health-related quality of life (HRQoL) and direct/indirect medical costs. Treatment begins with lifestyle changes, compression in CVD and topical therapies in HD, and escalates as needed through oral therapies first and eventually to surgery for severe disease. CVD and HD share etiological features and pathological changes affecting the structure and function of the tissue extracellular matrix. Mesoglycan, a natural glycosaminoglycan (GAG) preparation composed primarily of heparan sulfate and dermatan sulfate, has been demonstrated to positively impact the underlying causes of CVD and HD, regenerating the glycocalyx and restoring endothelial function, in addition to having antithrombotic, profibrinolytic, anti-inflammatory, antiedema and wound-healing effects. In clinical trials, oral mesoglycan reduced the severity of CVD signs and symptoms, improved HRQoL, and accelerated ulcer healing. In patients with HD, mesoglycan significantly reduced the severity of signs and symptoms and the risk of rectal bleeding. In patients undergoing excisional hemorrhoidectomy, adding mesoglycan to standard postoperative care reduced pain, improved HRQoL, reduced incidence of thrombosis, and facilitated an earlier return to normal activities/work, compared with standard postoperative care alone. The clinical effects of mesoglycan in patients with CVD or HD are consistent with the agent's known mechanisms of action.

Developmental or Procedural Vena Cava Interruption and Venous Thromboembolism: A Review.

The inferior vena cava (IVC) and superior vena cava are the main conduits of the systemic venous circulation into the right atrium. Developmental or procedural interruptions of vena cava might predispose to stasis and deep vein thrombosis (DVT) distal to the anomaly and may impact the subsequent rate of pulmonary embolism (PE). This study aimed to review the various etiologies of developmental or procedural vena cava interruption and their impact on venous thromboembolism. A systematic search was performed in PubMed according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines per each clinical question. For management questions with no high-quality evidence and no mutual agreements between authors, Delphi methods were used. IVC agenesis is the most common form of congenital vena cava interruption, is associated with an increased risk of DVT, and should be suspected in young patients with unexpected extensive bilateral DVT. Surgical techniques for vena cava interruption (ligation, clipping, and plication) to prevent PE have been largely abandoned due to short-term procedural risks and long-term complications, although survivors of prior procedures are occasionally encountered. Vena cava filters are now the most commonly used method of procedural interruption, frequently placed in the infrarenal IVC. The most agreed-upon indication for vena cava filters is for patients with acute venous thromboembolism and coexisting contraindications to anticoagulation. Familiarity with different forms of vena cava interruption and their local and systemic adverse effects is important to minimize complications and thrombotic events.

Efficacy and safety of direct oral anticoagulants in splanchnic vein thrombosis: a pooled analysis of literature studies.

BACKGROUND: Limited evidence is available on management of splanchnic vein thrombosis (SVT). OBJECTIVES: This study aimed to evaluate safety and efficacy of direct oral anticoagulants (DOACs) for SVT treatment. METHODS: Studies were systematically searched in the PubMed, Web of Science, and Scopus databases according to PRISMA guidelines. We assessed any recanalization, full recanalization, recurrence, mortality, and major bleeding as outcomes of interest. Results were reported as weighted mean prevalence (WMP) with 95% CI. Subgroup analyses and meta-regressions have been performed to address heterogeneity and adjust for potential confounders. RESULTS: We included a total of 16 studies (17 datasets) on 648 patients with SVT treated with DOACs. We found any recanalization in 60.3% (95% CI: 41.8%-76.3%; I2 = 84.9%; P < .001) and full recanalization in 51.7% (95% CI: 36.0%-67.0%; I2 = 87.4%; P < .001). Recurrent venous thromboembolism occurred in 2.8% (95% CI: 1.4%-5.9%; I2 = 0%; P = .787) and death in 3.4% (95% CI: 1.6%-7.3%; I2 = 13.2%; P = .318) of patients. Major bleeding was reported by 5.8% (95% CI: 3.7%-8.9%; I2 = 29.2%; P = .125) of patients. Results were consistent when separately analyzing prospective studies, retrospective studies, studies on cirrhotic patients, and studies enrolling patients with portal vein thrombosis. Meta-regression analyses showed that an increasing age and cancer impacted the rate of recanalization. Cirrhosis was associated with a higher rate of major bleeding and mortality. CONCLUSION: The results of the present study, mostly based on observational studies, suggest good safety and efficacy profiles of DOACs in patients with SVT. Randomized studies are needed to corroborate our findings.

Prevention of Venous Thromboembolism in Medical Patients with Thrombocytopenia or with Platelet Dysfunction: The Last 10 Years.

Current guideline recommendations for primary prophylaxis of venous thromboembolism (VTE) are based on randomized clinical trials that usually exclude subjects at a potentially high risk of bleeding complications. For this reason, no specific guideline is available for thromboprophylaxis in hospitalized patients with thrombocytopenia and/or platelet dysfunction. However, except in patients with absolute contraindications to anticoagulant drugs, antithrombotic prophylaxis should always be considered, for example, in hospitalized cancer patients with thrombocytopenia, especially in those with multiple VTE risk factors. Low platelet number, platelet dysfunction, and clotting abnormalities are also very common in patients with liver cirrhosis, but these patients have a high incidence of portal venous thrombosis, implying that cirrhotic coagulopathy does not fully protect against thrombosis. These patients may benefit from antithrombotic prophylaxis during hospitalization. Patients hospitalized for COVID-19 need prophylaxis, but frequently experience thrombocytopenia or coagulopathy. In patients with antiphospholipid antibodies, a high thrombotic risk is usually present, even in the presence of thrombocytopenia. VTE prophylaxis in high-risk conditions is thus suggested in these patients. At variance with severe thrombocytopenia (< 50,000/mm3), mild/moderate thrombocytopenia (≥ 50,000/mm3) should not interfere with VTE prevention decisions. In patients with severe thrombocytopenia, pharmacological prophylaxis should be considered on an individual basis. Aspirin is not as effective as heparins in lowering the risk of VTE. Studies in patients with ischemic stroke demonstrated that thromboprophylaxis with heparins is safe in these patients also during antiplatelet treatment. The use of direct oral anticoagulants in the prophylaxis of VTE in internal medicine patients has been recently evaluated, but no specific recommendation exists for patients with thrombocytopenia. The need for VTE prophylaxis in patients on chronic treatment with antiplatelet agents should be evaluated after assessing the individual risk of bleeding complications. Finally, the selection of patients who require post-discharge pharmacological prophylaxis remains debated. New molecules currently under development (such as the inhibitors of factor XI) may contribute to improve the risk/benefit ratio of VTE primary prevention in this setting of patients.

Venous thromboembolism and major bleeding in severe and critical COVID-19 hospitalized patients.

Venous thromboembolism (VTE) and major bleeding (MB) are life-threatening complications described in COVID-19 hospitalized patients and they can be considered as two sides of the same coin. This retrospective study aims to evaluate the risk factors for VTE and MB in COVID-19 patients admitted to two Italian hospitals. The medical records of all COVID-19 patients (males 139; 62.3%, mean age 67.2±13.6 years, body weight 88.2±20.6 kg) hospitalized from March 11th to July 31st, 2020 to the Federico II University Hospital and to Sea Hospital, Naples, Italy, were analyzed. The COVID-19 patients were classified into four groups: COVID-19 patients developing VTE and/or MB, COVID-19 patients developing only VTE, COVID-19 patients developing only MB, and COVID-19 patients not developing neither VTE nor MB. During the hospitalization, 53 COVID-19 patients (24.7%; males 40; 75.5%, mean age 67.2±13.6 years, weight 88.2±20.6 kg) developed VTE, 33 COVID-19 patients (15.3 %; males 17; 51.5, mean age 67.3±14.9 years, weight 74.1±14.3 kg) developed MB, and 129 COVID-19 patients not developed neither TVP nor MB. No parameters to identify severe COVID-19 complicated by VTE and/or MB were found. However, some clinical and biochemical parameters can be evaluated to predict the risk of MB in order to modify the treatment and take prompt action to reduce mortality.

The new Italian registry of infantile thrombosis (RITI): A reflection on its journey, challenges and pitfalls.

Introduction: Thrombotic events in neonates and children represent a rare although severe occurrence in view of the associated risk of mortality and sequelae. Quality evidence is limited in this field, and registry studies provide an essential base for research. The aim of this paper is to present the new Italian Registry of Infantile Thrombosis (RITI), set it into the scene of international thrombosis and stroke registries, and provide some insight on the challenges associated with registry management. Methods: We present the detailed structure and content of the new RITI registry, a brief overview of its main data, and a reflection on its features, pitfalls and the main challenges related to its management. Results: The RITI, initially started in 2007 and officially re-launched in 2017 after structural modifications, is a non-interventional retrospective and prospective registry study collecting data on neonatal and pediatric patients (0-18 years) who experienced a systemic or cerebral thrombotic event in Italy. The RITI is managed by a multidisciplinary team with expertise in pediatric thrombosis, and participation is open to all Italian physicians, on a voluntary basis. The overall aim of the registry is to acquire new evidence to better characterize the population of children with thrombotic events and improve their management and outcome. 48 Italian pediatric and intensive care units are actively involved in the RITI, including 85 medical doctors from 16 Italian regions. A total of 1,001 neonates and children affected by cerebral or systemic thrombosis have been enrolled. Discussion: The RITI is one of the largest available European registries of neonatal and pediatric thrombosis. National registries like the RITI represent a model for the study of rare conditions based on multidisciplinary and multicenter collaboration, aimed at overcoming the limitations due to small populations of patients, and creating a network of experts for patient referral and continuous education. Moreover, registry studies have a pivotal role in the research on pediatric thrombosis, due to the limited feasibility of high-quality studies. In our experience, the main critical stages, pitfalls and challenges in registry management include adequate registry designing, diffusion, data completeness and quality control.

Safety of the pulmonary embolism rule-out criteria rule: Findings from the Registro Informatizado de la Enfermedad TromboEmbolica venosa (RIETE) registry.

BACKGROUND: The diagnostic strategy for pulmonary embolism (PE) includes a D-dimer test when PE probability is low or intermediate, but false-positive D-dimer results are frequent and can result in an unnecessary computed tomography pulmonary angiogram. The PE rule-out criteria (PERC) rule excludes PE without D-dimer testing when pretest probability is <15%. The aim of this study was to assess the safety of the PERC rule strategy in patients included in the Registro Informatizado de la Enfermedad TromboEmbolica venosa (RIETE) registry. METHODS: This retrospective cohort study used data from the RIETE registry, an ongoing, international prospective registry of patients with objectively confirmed venous thromboembolism. The primary outcome was the failure rate of the PERC strategy, represented by the proportion of PERC-negative (PERC-N) patients with a PE included in the registry. Secondary outcomes were a comparison of the clinical characteristics, treatment strategy, and outcome of PERC-N versus PERC-positive (PERC-P) patients at 3 months. RESULTS: From 2001 to 2021, a total of 49,793 patients with acute PE were enrolled in the RIETE registry. We included 48,903 in the final analysis after exclusion of 890 patients with an undetermined PERC status. Only 346 patients were PERC-N with a failure rate of 0.7% (95% confidence interval 0.6%-0.8%). PERC-N patients presented more frequently with chest pain but less often with dyspnea, syncope, or hypotension. They also had subsegmental or segmental PE more frequently, were more often treated with direct oral anticoagulants, and received mechanical or pharmacological thrombolysis less often. In addition, PERC-N patients had a lower incidence of recurrent deep vein thrombosis, major bleeding, and death attributed to PE during the 3-month follow-up. CONCLUSIONS: A low failure rate of the PERC rule was observed in the RIETE registry, thus supporting its use to safely identify patients with an unlikely probability of PE.

Validation of PLASMIC score in a cohort of patients with suspected thrombotic microangiopathy in an academic medical centre.

BACKGROUND: The PLASMIC score is a rapid and inexpensive clinical assessment tool for predicting severe ADAMTS13 deficiency (<10% activity) in patients with suspected thrombotic thrombocytopenic purpura (TTP). The score includes 7 parameters: absence of active cancer, patient not having received stem cell transplant or organ transplant, platelet count <30×109/L, hemolysis, mean corpuscular volume <90 fl, International Normalized Ratio <1.5, and serum creatinine <2 mg/dL. MATERIALS AND METHODS: In this retrospective study, we evaluated a cohort of 59 consecutive patients with suspected thrombotic microangiopathy who had been referred to the Hemostasis and Thrombosis Center of the "Federico II" University of Naples, Italy, for measurement of ADAMTS13 activity. Relevant clinical and laboratory information were collected for all patients. RESULTS: The PLASMIC score was calculated in 52 of the 59 patients included in the study. In the high-risk group (PLASMIC score 6 or 7), 12 out of 20 patients (60%) had ADAMTS13 <10%. Interestingly, all 6 patients (100%) with PLASMIC score 7 had ADAMTS13 <5%. In the intermediate risk group (score 5), only one case out of 17 (5.9%) had ADAMTS 13 <10%. In the low-risk group (score 0-4), none of the patients had severe ADAMTS13 deficiency. The collected data enabled the sensitivity and specificity of PLASMIC score in TTP to be calculated, achieving 92% (95% CI: 0.80-0.98) and 79% (95% CI: 0.66-0.89), respectively. The PLASMIC score was seen to be a very efficient tool in distinguishing between patients with severe ADAMTS13 deficiency from those without, with an AUC of 0.92 (95% CI: 0.82-1.0; p<0.001). DISCUSSION: In our cohort, a high-risk PLASMIC score successfully predicted patients with severe ADAMTS13 deficiency, allowing the clinician to quickly define the best therapeutic approach, especially useful for those clinicians not used to the diagnosis and treatment of thrombotic microangiopathies.

A Rare Case of Tricuspid Valve Libman-Sacks Endocarditis in a Pregnant Woman with Primary Antiphospholipid Syndrome.

Antiphospholipid Antibody Syndrome (APS) is a systemic autoimmune disease characterized by acquired hypercoagulability with the possible development of venous, arterial, and microvascular thrombosis. We report a rare case of Libman-Sacks tricuspid valve endocarditis in a 38-year-old pregnant woman at 15 weeks gestation with unknown primary antiphospholipid syndrome. During a routine cardiac examination and echocardiography performed for a previous episode of pleuropericarditis, a large, mobile mass with irregular edges was found at the level of the tricuspid valve. Three main differential diagnoses for intramyocardial mass were examined: tumor, infective endocarditis, and nonbacterial thrombotic endocarditis (NTBE). Cardiac magnetic resonance imaging (CMR) with contrast raised the suspicion of a thrombus. The woman was hospitalized urgently at the Cardiac Intensive Care Unit of the Federico II University Hospital, and anticoagulant and antiplatelet therapy were started. The thrombophilic screening performed and medical history confirmed the diagnosis of primary antibody syndrome (APS). A multidisciplinary consultation with obstetricians, cardiologists, anesthetists, and cardiac surgeons was required. The patient decided not to terminate the pregnancy despite the risk to her health and to undergo cardiac surgery during pregnancy. Histological examination confirmed the presence of nonbacterial thrombotic endocarditis. Weekly obstetric scans were performed after surgery to verify fetal well-being. An emergency cesarean section was performed at the 35th week of gestation due to repeated deceleration and abnormal short-term variability on c-CTG in a pregnancy complicated by fetal growth restriction and gestational hypertension. A newborn weighing 1290 g was born. She was hospitalized in Neonatal Intensive Care and discharged after two months; currently, she enjoys good health. The management of patients with antiphospholipid antibody syndrome has not yet been standardized, but there is a general consensus that patients who do not have thrombocytopenia, thromboembolic phenomena, or pregnancy should not undergo any treatment or should take only low doses of acetylsalicylic acid. In the presence of any of the above conditions, various treatment regimens have been used based on the severity and individuality of the case.

Optimizing antithrombotic therapy for atrial fibrillation in cancer.

Atrial fibrillation (AF) may be a pre-existing disease before cancer diagnosis, may be a direct effect of the neoplasm or, more often, appears as a post-surgical complication, especially after thoracic surgery. AF may also develop as a consequence of chemotherapy or radiotherapy. The management of the anticoagulation in cancer patients with AF is challenging, and data on these patients are lacking. The use of vitamin K antagonists (VKAs) may be problematic because of the unpredictable therapeutic response and high bleeding risk in patients with active cancer who are undergoing chemotherapy and who may experience thrombocytopenia and/or changes in renal or hepatic function. Low molecular weight heparins and direct oral anticoagulants (DOACs) could be preferred. However, the possible pharmacological interactions of DOACs with anti-cancer and anti-arrhythmic drugs and the bleeding risks in thrombocytopenic patients should be considered. Based on these considerations, a careful evaluation of the antithrombotic strategy with the best efficacy/safety ratio is always needed in cancer patients and anticoagulation for AF should be tailored individually. An ongoing consultation of oncologists/hematologists with cardiologists and coagulation experts in a multidisciplinary approach, with a periodic re-assessment of the benefits of anticoagulation with changes in cancer status/advancement and treatment plans is needed.

Correction: Di Micco et al. Clinical Differences between COVID-19 and a COVID-like Syndrome. J. Clin. Med. 2021, 10, 2519.

Incorrect Affiliation [...].

Systemic Catheter-Related Venous Thromboembolism in Children: Data From the Italian Registry of Pediatric Thrombosis.

Background: Central venous catheters (CVCs) represent one of the main risk factors for venous thrombotic events (VTEs) in children. Methods: We studied the Italian Registry of Pediatric Thrombosis (RITI) with regard to systemic radiologically confirmed CVC-related VTEs (CVC-VTEs) occurred during 6.5 years in children aged 29 days to 18 years. Results: A total of 78 CVC-VTEs were included, which occurred in 76 patients (40/76, 53% males). CVC-VTEs comprised 67 non-cardiac VTEs (86%) and 11 intracardiac thrombotic events (ICTEs) (14%); the median age at onset was 19 and 17 months, respectively. The most frequent reason for CVC insertion was supportive therapy. The catheters were placed percutaneously in 85% of cases (56/66) and surgically in the remaining 15% (10/66). Peripherally inserted central catheters (PICCs) were used in 47% (31/66) cases, partially implanted catheters in 42% (28/66), non-implantable catheters in 7% (5/66), and totally implanted catheters (Port) in 2% (1/66). CVC-VTEs were symptomatic in 77% of cases (60/78), while in the remaining 23%, they were incidentally detected on the imaging performed for the underlying condition. The median time between CVC insertion and the onset of symptoms was 10 days in non-cardiac VTEs and 39 days in ICTEs. Doppler ultrasound was the diagnostic technique most frequently used. The venous compartment most frequently affected was the veins of the lower extremities (52%, 43/73). Anti-thrombotic treatment was administered in 96% of CVC-VTEs (75/78). About 2.6% (2/76) of patients experienced a second thrombotic event. At discharge, post-thrombotic syndrome was reported in 13.5% (5/37) events with available data, CVC replacement in 10.8% (4/47), and ischemic necrosis with toe finger amputation in 2.7% (1/37). Three patients died due to an underlying condition; no CVC-VTE-related deaths were reported. Conclusions: We have carried out a registry-based study on CVC-VTEs in the children in Italy, providing the data that may help improve the detection and management of this CVC-related complication.

Role of New Potential Biomarkers in the Risk of Thromboembolism in Atrial Fibrillation.

Ischemic stroke risk in atrial fibrillation differs from patient to patient, depending on numerous variables. Many attempts have been made to translate this difference into simple numbers and to compare it to the hemorrhagic risk of anticoagulation. Different clinical scores have been studied to define a clear strategy. One score, the CHA2DS2-VASc score, has been extensively and successfully applied worldwide. Nevertheless, it is not yet the "perfect instrument". Many proposals have been made to integrate its clinical parameters with some biomarkers to improve its predictive power. This short review describes some of these biomarkers and their possible implications in potentiating the efficacy of clinical scores.

Spontaneous Muscle Hematoma in Patients with COVID-19: A Systematic Literature Review with Description of an Additional Case Series.

Coagulation abnormalities, thrombosis, and endothelial dysfunction have been described in COVID-19 patients. Spontaneous muscle hematoma (SMH) is a rare complication in COVID-19. The aims of this study are to: (1) perform a systematic review of the literature to better define the clinical SMH characteristics, (2) describe the prevalence and the clinical characteristics of SMH in COVID-19 patients referring to a Department of Internal Medicine (IM) (Federico II University of Naples), a Department of Sub-Intensive Care Medicine (SIM) (Ospedale Del Mare), and a Department of Intensive Care Unit (ICU) (Federico II University). The systematic review was performed according to PRISMA criteria. The local prevalence of SMH in COVID-19 was evaluated retrospectively. The medical records of all COVID-19 patients referring to IM and ICU from March 11th, 2020, to February 28th, 2021 were examined for SMH occurrence. In our retrospective analysis, we describe 10 cases of COVID-19 patients with SMH not previously reported in literature, with a prevalence of 2.1%. The literature review, inclusive of our case series, describes a total of 50 SMHs in COVID-19 patients (57.4% males; mean age 68.8 ± 10.0 years). The SMH sites were ileo-psoas, vastus intermedius, gluteus, sternocleidomastoid, and pectoralis major muscles. Males developed SMH earlier than females (9.5 ± 7.8 vs. 17.1 ± 9.7 days). Ileo-psoas hematoma was more frequent in males (69.2 vs. 30.8%), while pectoralis major hematoma occurred only in females. The in-hospital mortality rate of SMH in COVID-19 patients was 32.4%. SMH is a rare but severe complication in COVID-19 hospitalized patients, associated with high mortality. A gender difference seems to be present in the clinical presentation of the disorder.