Background: Direct oral anticoagulants (DOACs) are largely prescribed, and the lack of need for a laboratory monitoring was the main reason for their large diffusion. However, a wide inter-individual variability has been described, and the need for blood levels measurement when a thrombotic or hemorrhagic event occurred has been suggested. Materials and methods: In 2022, a survey was conducted among the Italian centers affiliated with the Italian Federation of Centers for the Diagnosis of Thrombotic Disorders and the Surveillance of the Antithrombotic Therapies - FCSA, recording that only few centers provided DOACs testing. In 2025, a second survey was performed to evaluate if a change in that area have occurred. Results: We observed a rapid increase in the number of centers providing DOAC testing, from 39/124 (31.0%) in 2022 to 72/122 (59.0%) in 2025; 26% of centers not providing DOAC testing, claimed no funding for testing. In 70/72 (97.2%) of centers, DOAC testing was limited to selected conditions, such as thrombotic or hemorrhagic complications. Conclusions: Data derived from our survey are relevant in developing adequate anticoagulation stewardship programs, that are increasingly required.

BACKGROUND:Splanchnic vein thrombosis (SVT) is a rare type of venous thromboembolism but relatively common in patients with myeloproliferative neoplasms (MPNs). Studies on management and outcomes for patients with MPN-SVT, including comparisons with non-MPN-SVT, are scarce. OBJECTIVES:We assessed anticoagulant management and recurrent thrombosis, bleeding, and survival outcomes in SVT patients with and without MPN. METHODS:We conducted a multicenter comparative cohort study in adults with SVT using individual patient data from 3 published studies and 2 hospital cohorts. Anticoagulant management after SVT diagnosis was evaluated; 6-month cumulative incidences of recurrent thrombosis, bleeding, and death were calculated. We used propensity score weighting to compare outcomes between patients with and without MPN. A subanalysis excluding patients with cirrhosis or solid cancer was performed. RESULTS:We investigated 1189 patients with SVT, 187 with underlying MPN. Anticoagulation was started in 76.1% of patients within 30 days after SVT diagnosis, 78.6% were still anticoagulated at 6 months; this was similar between patients with and without MPN. The 6-month cumulative incidence of recurrent thrombosis and bleeding was 2.5% and 4.5%, respectively. Overall survival was 93.7% at the 6-month follow-up. No significant differences were observed in clinical outcomes between patients with and without MPN, also confirmed by subanalyses. CONCLUSION:In this large cohort, incidences of recurrent thrombosis, bleeding and survival 6 months after SVT were similar in patients with and without MPN. This suggests that MPN-related SVT could be regarded similarly to noncirrhotic, nonmalignant SVT for anticoagulant management and outcomes. Prospective studies with long-term follow-up are still needed for MPN-related patients with SVT.

INTRODUCTION:According to the new In Vitro Diagnostic Medical Device Regulation (EU) (IVDR) an In Vitro Medical Device (IVD) is considered as a laboratory developed test (LDT) if used outside of intended use. It is therefore essential that the information given by the manufacturer about the intended use is clear, precise, and well documented. For now, the only source of information for laboratories is the instructions for use (IFU). Our primary aim was to analyze the IFU provided by several manufacturers for a large panel of coagulation assays. The secondary objective was to provide a list of minimum information that must be accessible to clinical laboratories. METHODS:We analyzed 195 IFU for the main assays used in European hemostasis clinical laboratories commercialized by 12 manufacturers. RESULTS:The "intended use" section appears in almost all IFU, but the information given in this section is very heterogeneous. We observed disagreement for each of the assays assessed with some intended uses not supported by guidance or guidelines. Some indications in use by clinical laboratories are not provided by the manufacturers. We only found information on clinical performance for a limited number of assays. For some assays, data are available in the literature but are not reported in the IFU. The matrix and the importance of a pre-test probability are not systematically mentioned. CONCLUSIONS:We urgently request access to the necessary information to know the intended use of a reagent according to the IVDR. We define the minimum information that should be available to laboratories. We call for joint discussions to maintain innovation and ensure the quality, safety, and accessibility of innovative diagnostics.

Direct oral anticoagulants (DOAC) have similar efficacy for stroke prevention in patients with non-valvular atrial fibrillation (AF) with improved safety. Recently, a higher bleeding risk was reported when elderly AF patients were switched from VKAs to DOACs. AF patients aged ≥ 75 years who were maintained on VKA treatment or who were switched from VKAs to DOACs at the time of enrollment in the START-AF Register were followed. Bleedings, thrombotic events, and deaths that occurred during follow-up were collected. We included 4230 AF patients, 2930 (69.3

BACKGROUND:Frailty influences the effectiveness and safety of anticoagulant therapy in patients with atrial fibrillation (AF). The age-weighted Charlson comorbidity index may offer a valuable tool to assess the risk of adverse events in AF patients treated with direct oral anticoagulants (DOACs). This sub-analysis of MAS trial data aimed to assess whether using the Charlson index, instead of the standard criteria, would have led to different dosing and improved adverse event occurrence during treatment. METHODS:The MAS study looked for a relationship between DOAC levels assessed at baseline and adverse events during follow-up. The study is described in detail elsewhere. RESULTS:Among the 1,657 patients studied, 832 (50.2 %) had a relatively low Charlson index (up to 6, general median class), of whom 132 (15.9 %) were treated with reduced doses. Conversely, among the 825 patients with a high Charlson index (≥7), 257 (31.1 %) received standard doses. A weak but statistically significant positive correlation (r = 0.1413, p < 0.0001 by ANOVA) was observed between increasing Charlson classes and DOAC levels standardized to allow comparability among drug results. However, no significant differences were found in the incidence or number of adverse events during follow-up, or in other parameters, between patients with low and high Charlson's scores. CONCLUSIONS:Utilizing the Charlson index would have led to notable differences in DOAC dosing compared to standard criteria. However, we found no evidence that its use would have improved the prediction of adverse events in AF patients enrolled in the MAS study.

Since early 2022 the Omicron variant has rapidly spread worldwide, becoming the dominant variant to date. The study aimed to investigate the clinical and epidemiological characteristics of COVID-19 patients and reconstruct the genomic epidemiology of main SARS-CoV-2 Omicron sublineages in Italy in 2022. A total of 8970 SARS-CoV-2 samples were studied, and phylogenetic analyses were focused on BA.1, BA.2, and BA.5 subvariants. More than half of subjects received three doses of vaccine and experienced a reinfection. A significant larger proportion of unvaccinated subjects presented reinfection compared with vaccinated. Clusters presented a tMRCA between September-November 2021 (BA.1), November 2021-January 2022 (BA.2), and October 2021-May 2022 (BA.5). Re values showed the highest level between September-October, January-February 2022, and May 2022 for BA.1, BA.2 and BA.5, respectively. Limited number of studied variant sequences are included in clusters. The spread rate of the studied variant exceeded its evolutionary rate. No single sublineage had sufficient time to differentiate into large clusters, but only into small and fragmented groups sharing the same recent ancestor. These analyses dissect the epidemiological dynamics of Omicron sublineages in Italy over a period of great epidemiological changes in the COVID-19 epidemic.

Anticoagulants are life-saving drugs used to prevent and treat thrombosis, and a wide use of these drugs is increasing overtime. However, anticoagulants are one of the most common causes of drug-related adverse events in- and out-of-hospital. The need for empowering clinicians and patients, enhancing compliance and favoring multidisciplinary collaboration, has been widely outlined. Programs of Anticoagulation Stewardship (ACS) have been implemented worldwide. It has been widely demonstrated that ACS is associated with reduction of hospital-acquired blood clots, drug-drug interactions, bleeding events, hospital readmissions, length of hospital stay and other healthcare costs. Although ACS is widely discussed, no ACS model has been extensively and officially realized in the Italian healthcare system. Since its constitution, the Italian Federation of Centers for the Diagnosis of Thrombotic Disorders and the Surveillance of the Antithrombotic Therapies (i.e. FCSA) supported healthcare professionals providing educational programs, aimed to improve anticoagulation quality and to decrease associated risks and costs. In 2021, FCSA developed an app for mobile phones named FCSApp, which was distributed to affiliated physicians. Aim of this study is to describe this experience. FCSApp was actively used for three years by 100 of 232 registered users, with approximately 3200 messages. The channels of main interest were the so-called ‘Clinical Cases’ with 1671 messages [52.3

Background Long-term anticoagulation is recommended in patients with venous thromboembolism (VTE) deemed at high risk for recurrence (HRR). Limited information is available on patients with recurrent VTE and/or severe thrombophilia. In addition, these patients were not included in studies evaluating long-term treatment with low doses of direct oral anticoagulants (DOACs). Objectives The aims of our study were to (1) record the drugs and dosages used in HRR patients, and (2) to record adverse events occurring during follow-up. Methods Among 2520 VTE patients enrolled in the Survey on anTicoagulated pAtients RegisTry 2, we retrospectively analyzed the management of patients with a history of recurrent VTE and/or severe thrombophilia (HRR patients). Results A total of 487 HRR patients were analyzed. Anticoagulants were stopped in 11 of 487 patients (2.3%), full-dose DOACs were continued in 176 patients (36.1%), and 311 patients (63.9%) were shifted to low-dose DOACs (61.4% with apixaban 2.5 mg twice a day and 38.6% with rivaroxaban 10 mg once a day) after a median time of 1.3 years (range, 0.5-20.2 years). During follow-up, no adverse events were recorded in patients who stopped treatment. Among patients who continued treatment, 10 had recurrent VTE (rate, 0.4 × 100 patient-years) and 19 had bleeding (rate, 0.9 × 100 patient-years). The risk of recurrent VTE was similar between patients on full-dose and low-dose anticoagulation. Patients on full-dose anticoagulation had a trend toward a higher bleeding risk (relative risk, 2.2; 95% CI, 0.7-9.0). Conclusion HRR patients with a history of unprovoked recurrent VTE and/or patients with severe thrombophilia treated with long-term low-dose DOACs showed a low risk for recurrence and bleeding events.

In the era of direct oral anticoagulants, vitamin K antagonists retain a clinically relevant role in thrombotic disorders. In Italy, approximately 20% of the patients on anticoagulant therapies receives a VKA, in most cases warfarin. The optimal management of this drug is challenging and cannot disregard its intricate and unpredictable pharmacokinetic properties and patient's thrombotic and bleeding risk. Several clinical issues encountered during warfarin treatment are still unanswered and are tentatively addressed by physicians. In this regard, the Italian Federation of Centers for the diagnosis of thrombotic disorders and the Surveillance of the Antithrombotic therapies (FCSA) provides some experience-based good clinical practice's suggestions on the following topics: (1) how to start the anticoagulant treatment with warfarin and warfarin induction regimen; (2) how to manage a subtherapeutic INR value; (3) how to manage a supratherapeutic INR value in asymptomatic patients; and (4) how to manage the association of warfarin with interfering drugs.

Background D-dimer testing may help deciding the duration of anticoagulation in subjects at high risk of venous thromboembolism (VTE) recurrence. Two management studies on this issue have been published (DULCIS in 2014 and APIDULCIS in 2022). They had similar designs but had important different results. Aim of this article is to compare their results. Methods Both studies were finalized to extend anticoagulation [with vitamin K anticoagulants (VKAs) in DULCIS or apixaban 2.5 mg BID (kindly provided by BMS-Pfizer Collaboration) in APIDULCIS] only in patients with positive D-dimer results. Results More D-dimer assays resulted positive in APIDULCIS than in DULCIS (61.1 % vs 47.7 %, respectively; p < 0.0001). While only 4 (0.5 %) refused low dose apixaban in APIDULCIS, the 22.6 % of patients with positive D-dimer refused to resume VKAs in DULCIS; their rates of recurrence were 187 and 8.8 per 100 person-years, respectively (incidence rate ratio [IRR]: 21.2). The incidence of bleeding was low in those receiving apixaban vs those who resumed VKAs () (0.4 vs 2.3 per 100 person-years, respectively; IRR 0.17;). While the recurrence rate was low and similar in the studies in subjects who resumed anticoagulation, it was significantly higher in APIDULCIS than in DULCIS in those who stopped anticoagulation for negative D-dimer (5.6 vs 3.0 per 100 person-years, respectively; IRR 1.9). Conclusion The low dose Apixaban for extended VTE treatment is effective and safe, and well accepted by patients. Why subjects who stopped anticoagulation for negative D-dimer had a higher recurrence rate in APIDULCIS than in DULCIS remains to be explained.

INTRODUCTION:Mechanical heart valve (MHV) replacement requires long-life anticoagulation due to the risk of Prosthetic Valve Dysfunction (PVD) and cardioembolism. METHODS:We report data from a prospective observational study conducted on MHV patients in the Khartoum Salam Centre for Cardiac Surgery built by 'Emergency,' an Italian Non-Governmental Organization, to evaluate the occurrence of PVD and associated risk factors. RESULTS:We prospectively followed 3647 patients, and 38 patients (rate 1.04 × 100 pt-years) had PVD during follow-up. The time in therapeutic range (TTR) among patients without PVD was 53 % (IQR 37-67), and it was 43 % (IQR 19-58) among patients with PVD (p = 0.04). Twenty-three over 38 patients (60.5 %) were symptomatic, 18 (47.4 %) had obstructive valvular stenosis, 24 patients (63.2 %) had INR <2.0 at diagnosis, and 21 patients (55.3 %) had been off warfarin for a long time: 3 patients for 1 week, 1 patient for 2 weeks, and 17 patients for >4 weeks (6 patients were off warfarin from 3 to 12 months). Ten were uncompliant to treatment, and 8 were pregnant women. Ten patients (26.3 %) with PVD had had a previous episode of PVD, and 14 patients (36.8 %) had 2 or more associated risk factors. Only in 6 cases were no associate risk factors found. CONCLUSIONS:Among MHV patients on warfarin treatment with a sub-optimal quality of anticoagulation, the rate of PVD is 1.04 % pt-years, and the most frequent associated risk factor for PVD occurrence is warfarin withdrawal lasting more than one week.

Background: Rheumatic heart disease (RHD) with mechanical heart valve (MHV) replacement is common in Africa. However, MHV requires lifelong anticoagulation that could have a particular impact in women in reproductive age.Methods: We report data of a prospective observational cohort study conducted between August 2018 and September 2019 in MHV patients in the Salam Centre for Cardiac Surgery built in Khartoum by Emergency, an Italian Non-Governmental Organization, to evaluate bleeding risk, its associated determinants, and the impact of lifelong anticoagulation in fertile women.Results: We studied 3647 patients (median age 25.1 years; 53.9% female). During follow-up [median time 1.1 (0.1-1.2) years], we recorded 85 major bleedings (rate 2.16 x 100 pt-years), Major bleedings occurred more frequently among women (64/85 cases, 75.3%; rate 3.0 x 100 pt-years), compared to men (21/85 cases, 24.7%; rate 1.16 x 100 pt-years) (RR 2.6; 95% CI 1.6-4.5; p = 0.0001). Multivariate analysis was performed to identify variables associated with major bleeding, and female sex was the only risk factor significantly associated, whereas aspirin treatment and higher INR target showed a non-significant trend for higher bleeding risk. Thirtytwo/85 (37.6%) of major bleedings were metrorrhagias. When we calculate the incidence of major bleedings after the exclusion of gynecological events, no sex differences in the bleeding risk were found (HR 1.3, 95% CI 0.8-2.3; p = 0.3).Conclusions: Bleeding risk of young MHV patients on oral anticoagulant therapy is higher among women, mainly due to metrorrhagia. Women in the reproductive life are at high risk for gynecological bleeding when treated with anticoagulants.

Background: Patients with acute venous thromboembolism (VTE) need anticoagulation (AC) therapy for at least 3/6 months (primary treatment); after that period, they should receive a decision on the duration of therapy. Methods: This study examined the complications occurring during two years of follow-up (FU) in patients with a first VTE who were recruited in 20 clinical centers and had discontinued or prolonged AC. They were included in the START2-POST-VTE prospective observational study. Results: A total of 720 patients (53.5% males) who, after the completion of primary treatment, had received the decision to continue (n = 281, 39%; 76.1% with a DOAC) or discontinue (n = 439, 61%) AC were followed up for 2 years (total FU = 1318 years). The decision to prolong or suspend AC was made in similar proportions in patients with unprovoked or provoked index events. Courses of sulodexide treatment or Aspirin (100 mg daily) were prescribed to 20.3% and 4.5%, respectively, of the patients who discontinued AC. The bleeding rate was significantly higher in patients who extended AC (1.6% pt/y) than in those who stopped AC (0.1% pt/y; p = 0.001) and was higher in patients using standard-dose DOACs (3.1% pt/y) than in those using reduced-dose DOACs (0.4% pt/y). The recurrent VTE rates were similar between the two groups (2.2% pt/y during AC vs. 3% pt/y off AC). Conclusion: Physicians’ decisions about AC duration were independent of the unprovoked/provoked nature of the index event. The bleeding rate was higher in patients who continued AC using standard-dose DOACs. Surprisingly, the rate of thrombotic recurrence was not different between those who continued or discontinued AC. Randomized studies comparing different procedures to decide on the duration of AC after a first VTE are needed.

Background: The MAS study (Blood Advances 2024) showed that a high proportion of Italian AF patients treated with direct oral anticoagulants (DOACs) receive reduced doses. This sub-analysis of MAS data aimed to analyze the effects of reduced (appropriate or not)- or standard-dose use on DOAC activity assessed at baseline and the occurrence of thrombotic or bleeding complications during follow-up. Methods: The MAS study design, the methods for DOAC measurement, the results, and the adverse events during follow-up, are described in detail elsewhere. Results: Seven hundred AF patients (42 % of the total 1657) received a reduced dose (considered inappropriate in 140 [20 %]). They were older, more frequently women, with lower body mass index (BMI), hemoglobin levels, and creatinine clearance. They more often had cerebral or cardiovascular diseases, were taking more medications, with higher scores for thrombotic or bleeding risk. Despite the use of low doses, 133 (19.0 %) patients had high standardized C-trough DOAC levels and experienced a high proportion of bleeding events (8.3 % per year). Conversely, some patients (4.7 %) had very low levels, resulting in a high incidence of thrombotic events (6.7 % per year). No difference was detected if the reduced dose was appropriate or not. Conclusion: The unpredictable, highly variable inter-individual anticoagulant effect of DOACs may lead to either too low or too high anticoagulant levels, increasing the risk of thrombotic or bleeding events. This is particularly relevant for patients with high-risk conditions, such as those chosen for reduced-dose treatment. Further studies are needed to investigate this important clinical issue.

The recent pandemic prompted renewed interest in paediatric respiratory infections, including whether co-infections – particularly with RSV – have an adverse prognostic impact. We evaluated the charts of all children presenting with respiratory symptoms to our unit between October 2022 and April 2023, each of whom was subjected to a multiplex PCR assay to detect eight viral targets and one bacterial target and examine the relationships between mono- and co-infections and hospitalization outcomes. We observed that younger age and RSV infection were both associated with the need for hospitalisation and the duration of hospitalisation after adjusting for confounders. Co-infection was, however, not associated with these outcomes. Conclusion: This real-world data add to a growing consensus that RSV increases the risk of hospitalisation, while other co-infections, except for co-infection with SARS-CoV-2, do not. Given the timeframe over which our study was conducted, only a few children had SARS-CoV-2 co-infection, so we could not confirm any significant effect from this interaction.

Background: Direct oral anticoagulants (DOACs) are recommended for stroke prevention in non-valvular atrial fibrillation (NVAF) patients. We aimed to describe the prevalence of inappropriate DOACs dose prescription in the START2-AF Registry, the outcomes according to the appropriateness of the dosage, and the factors associated with inappropriate dose prescription. Methods: Patients’ demographics and clinical data were prospectively collected as electronic files in an anonymous form on the website of the START2-Registry; DOACs dosage was determined to be appropriate when prescribed according to the European Heart Rhythm Association Guidelines. Results: We included 5943 NVAF patients on DOACs; 2572 (46.3%) were female patients. The standard dose (SD) was prescribed to 56.9% of patients and the low dose (LD) was prescribed to 43.1% of patients; 38.9% of all NVAF patients received an inappropriate LD DOAC and 0.3% received inappropriate SD. Patients treated with LD DOAC had a significantly higher rate of all bleedings (RR 1.5; 95% CI 1.2–2.0), major bleedings (RR 1.8; 95% CI 1.3–1.7), and mortality (RR 2.8; 95% CI 1.9–4.1) with respect to patients treated with SD DOAC. No difference was found among patients treated with appropriate and inappropriate LD regarding bleeding, thrombotic, and mortality rates. Age, body weight <60 kg, and renal failure were significantly associated with inappropriate LD DOAC prescription. Conclusions: Inappropriate LD DOACs in NVAF patients is not associated with a reduction in bleeding risk, nor with an increased thrombotic risk. Instead, it is associated with higher mortality rate, suggesting that, in clinical practice, underdosing is preferred for patients at particularly high risk for adverse events.

Although effective and safe, treatment with direct oral anticoagulants (DOAC) in atrial fibrillation (AF) is still associated with thrombotic complications. Whether the measurement of DOAC levels may improve treatment ef ficacy is an open issue. We carried out the observational, prospective, multicenter Measure and See (MAS) study. Blood was collected 15 to 30 days after starting DOAC treatment in patients with AF who were followed-up for 1 year. Plasma samples were centralized for DOAC level measurement. Patients ' DOAC levels were converted into drug/dosage standardized values to allow a pooled analysis in a time-dependent, competitive-risk model. The measured values were transformed into standardized values (representing the distance of each value from the overall mean) by subtracting the DOAC-speci fic mean value from the original values and dividing by the standard deviation. Trough and peak DOAC levels were assessed in 1657 and 1303 patients, respectively. In total, 21 thrombotic complications were recorded during 1606 years of follow-up (incidence of 1.31% of patients per year). Of 21 thrombotic events, 17 occurred in patients whose standardized activity levels were below the mean of each DOAC (0); the incidence was the highest (4.82% of patients per year) in patients whose standardized values were in the lowest class ( -1.00 or less). Early measurement of DOAC levels in patients with AF allowed us to identify most of the patients who, having low baseline DOAC levels, subsequently developed thrombotic complications. Further studies are warranted to assess whether thrombotic complications may be reduced by measuring baseline DOAC levels and modifying treatment when indicated. This trial was registered at www.ClinicalTrials.gov as #NCT03803579.

BACKGROUND:The accuracy of available prediction tools for clinical outcomes in patients with atrial fibrillation (AF) remains modest. Machine Learning (ML) has been used to predict outcomes in the AF population, but not in a population entirely on anticoagulant therapy. METHODS AND AIMS:Different supervised ML models were applied to predict all-cause death, cardiovascular (CV) death, major bleeding and stroke in anticoagulated patients with AF, processing data from the multicenter START-2 Register. RESULTS:11078 AF patients (male n = 6029, 54.3%) were enrolled with a median follow-up period of 1.5 years [IQR 1.0-2.6]. Patients on Vitamin K Antagonists (VKA) were 5135 (46.4%) and 5943 (53.6%) were on Direct Oral Anticoagulants (DOAC). Using Multi-Gate Mixture of Experts, a cross-validated AUC of 0.779 ± 0.016 and 0.745 ± 0.022 were obtained, respectively, for the prediction of all-cause death and CV-death in the overall population. The best ML model outperformed CHA2DSVA2SC and HAS-BLED for all-cause death prediction (p < 0.001 for both). When compared to HAS-BLED, Gradient Boosting improved major bleeding prediction in DOACs patients (0.711 vs. 0.586, p < 0.001). A very low number of events during follow-up (52) resulted in a suboptimal ischemic stroke prediction (best AUC of 0.606 ± 0.117 in overall population). Body mass index, age, renal function, platelet count and hemoglobin levels resulted the most important variables for ML prediction. CONCLUSIONS:In AF patients, ML models showed good discriminative ability to predict all-cause death, regardless of the type of anticoagulation strategy, and major bleeding on DOAC therapy, outperforming CHA2DS2VASC and the HAS-BLED scores for risk prediction in these populations.