Different Lung Parenchyma Quantification Using Dissimilar Segmentation Software: A Multi-Center Study for COVID-19 Patients.

BACKGROUND: Chest Computed Tomography (CT) imaging has played a central role in the diagnosis of interstitial pneumonia in patients affected by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and can be used to obtain the extent of lung involvement in COVID-19 pneumonia patients either qualitatively, via visual inspection, or quantitatively, via AI-based software. This study aims to compare the qualitative/quantitative pathological lung extension data on COVID-19 patients. Secondly, the quantitative data obtained were compared to verify their concordance since they were derived from three different lung segmentation software. METHODS: This double-center study includes a total of 120 COVID-19 patients (60 from each center) with positive reverse-transcription polymerase chain reaction (RT-PCR) who underwent a chest CT scan from November 2020 to February 2021. CT scans were analyzed retrospectively and independently in each center. Specifically, CT images were examined manually by two different and experienced radiologists for each center, providing the qualitative extent score of lung involvement, whereas the quantitative analysis was performed by one trained radiographer for each center using three different software: 3DSlicer, CT Lung Density Analysis, and CT Pulmo 3D. RESULTS: The agreement between radiologists for visual estimation of pneumonia at CT can be defined as good (ICC 0.79, 95% CI 0.73-0.84). The statistical tests show that 3DSlicer overestimates the measures assessed; however, ICC index returns a value of 0.92 (CI 0.90-0.94), indicating excellent reliability within the three software employed. ICC was also performed between each single software and the median of the visual score provided by the radiologists. This statistical analysis underlines that the best agreement is between 3D Slicer "LungCTAnalyzer" and the median of the visual score (0.75 with a CI 0.67-82 and with a median value of 22% of disease extension for the software and 25% for the visual values). CONCLUSIONS: This study provides for the first time a direct comparison between the actual gold standard, which is represented by the qualitative information described by radiologists, and novel quantitative AI-based techniques, here represented by three different commonly used lung segmentation software, underlying the importance of these specific values that in the future could be implemented as consistent prognostic and clinical course parameters.

Management of DOAC in Patients Undergoing Planned Surgery or Invasive Procedure: Italian Federation of Centers for the Diagnosis of Thrombotic Disorders and the Surveillance of the Antithrombotic Therapies (FCSA) Position Paper.

Patients on anticoagulant treatment are constantly increasing, with an estimated prevalence in Italy of 2% of the total population. About a quarter of the anticoagulated patients require temporary cessation of direct oral anticoagulants (DOACs) or vitamin K antagonists for a planned intervention within 2 years from anticoagulation inception. Several clinical issues about DOAC interruption remain unanswered: many questions are tentatively addressed daily by thousands of physicians worldwide through an experience-based balancing of thrombotic and bleeding risks. Among possible valuable answers, the Italian Federation of Centers for the diagnosis of thrombotic disorders and the Surveillance of the Antithrombotic therapies (FCSA) proposes some experience-based suggestions and expert opinions. In particular, FCSA provides practical guidance on the following issues: (1) multiparametric assessment of thrombotic and bleeding risks based on patients' individual and surgical risk factor, (2) testing of prothrombin time, activated partial thromboplastin time, and DOAC plasma levels before surgery or invasive procedure, (3) use of heparin, (4) restarting of full-dose DOAC after high risk bleeding surgery, (5) practical nonpharmacological suggestions to manage patients perioperatively. Finally, FCSA suggests creating a multidisciplinary "anticoagulation team" with the aim to define the optimal perioperative management of anticoagulation.

The effect of health literacy on vaccine hesitancy among Italian anticoagulated population during COVID-19 pandemic: the moderating role of health engagement.

Assessing vaccine hesitancy and its determinants is pivotal to optimize vaccine acceptance in anticoagulated patients, given that this population has been described to have a higher risk of severe COVID-19-related complications. This study assessed the moderator role of patients' health engagement on the relationship between health literacy and vaccine hesitancy. A web-based survey was performed in Italy during the first wave (June-August 2020) and the second wave (October 2020-March 2021) of the COVID-19 pandemic, enrolling 288 patients. The rates of vaccine hesitancy reported during the first pandemic wave were 38.4% and 30.8% during the second wave (when a vaccine was available) (p = .164). A moderation analysis was performed to assess the role of health engagement in influencing the relationship from health literacy to vaccine hesitancy. Patients' health engagement enhanced the effects of health literacy on decreasing vaccine hesitancy (p < .001), suggesting that co-construction strategies for communicative action are pivotal.

Best quality indicator of vitamin K antagonist therapy to predict mortality and bleeding in haemodialysis patients with atrial fibrillation.

BACKGROUND: There is a high prevalence of atrial fibrillation (AF) in patients undergoing haemodialysis. Oral anticoagulant therapy with vitamin K antagonists (VKAs) is the only accepted treatment for the prevention of thromboembolism in haemodialysis patients with AF. However, in this population, the risk of bleeding is greatly increased. The aim of the study was to evaluate the ability of treatment quality indicators of VKA therapy to predict mortality and bleedings in a population of haemodialysis patients with AF. MATERIALS AND METHODS: A total of 129 patients were included in this cohort study. Deaths and bleeding events were recorded during a follow-up of 4 years. In all patients, International Normalized Ratio (INR) values were assessed at least once a month. Time in therapeutic range (TTR) and INR variability, as measured by the standard deviation of INR, were updated at each INR measurement. A Cox model with time-dependent co-variates and sandwich variance was applied. RESULTS: During follow-up, 71 patients died and 55 bleeding episodes occurred in 31 patients. INR variability was the only indicator associated with both mortality (hazard ratio [HR]=1.67, 95% confidence interval [CI] 1.12; 2.49, p=0.012) and bleeding (HR=2.85, 95% CI: 1.71; 4.75, p=0.0001). HR of mortality was higher in patients with INR >3 (HR=2.06, 95% CI: 1.09; 3.88, p=0.0259) than in subjects in therapeutic range 2

Managing anticoagulation in the COVID-19 era between lockdown and reopening phases.

Patients on anticoagulant treatment are constantly increasing, with an estimated prevalence in Italy of 2% of the total population. The recent spreadout of the COVID-19 pandemic requires a re-organization of Anticoagulation Clinics to prevent person-to-person viral diffusion and continue to offer the highest possible quality of assistance to patients. In this paper, based on the Italian Federation of Anticoagulation Clinics statements, we offer some advice aimed at improving patient care during COVID-19 pandemic, with particular regard to the lockdown and reopening periods. We give practical guidance regarding the following points: (1) re-thinking the AC organization, (2) managing patients on anticoagulants when they become infected by the virus, (3) managing anticoagulation surveillance in non-infected patients during the lockdown period, and (4) organizing the activities during the reopening phases.

Determinants of health-related quality of life: a cross-sectional investigation in physician-managed anticoagulated patients using vitamin K antagonists.

BACKGROUND: Literature has paid little attention in describing the specific contribution of each modifiable and non-modifiable characteristics on health-related quality of life (HRQoL) in physician-managed anticoagulated patients using vitamin K antagonists (VKAs). To describe how patients' treatment-specific knowledge, health literacy, treatment beliefs, clinical, and socio-demographic characteristics influence HRQoL in Italian physician-managed anticoagulated patients using VKAs. METHODS: Cross-sectional multicentre study with a consecutive sampling strategy, enrolling 164 long-term anticoagulated patients. Clinical and socio-demographic characteristics were collected from electronic medical records. Valid and reliable questionnaires were used to collect patients' treatment-specific knowledge, health literacy, beliefs about VKAs, physical and health perceptions. RESULTS: Obtaining and understanding health information (i.e., communicative health literacy) positively predicts both adequate mental (ORadjusted = 10.9; 95%CI = 1.99-19.10) and physical (ORadjusted = 11.54; 95%CI = 1.99-34.45) health perceptions. Conversely, the ability to perform proper health decision making (i.e., critical health literacy) was associated with lower rates of adequate mental health perception (ORadjusted = 0.13; 95%CI = 0.03-0.63). Further, age negatively predicted physical health perception (ORadjusted = 0.87; 95%CI = 0.81-0.93). CONCLUSIONS: Health literacy plays an interesting role in predicting HRQoL. The relationship between critical health literacy and mental health perception could be influenced by some psychological variables, such as distress and frustration, which could be present in patients with higher levels of critical health literacy, as they could be more inclined for self-monitoring. For this reason, future research are needed to identify the most suitable patients' profile for each OAC-management model, by longitudinally describing the predictive performance of each modifiable and non-modifiable determinant of HRQoL.

Correction to: Reversal agents for oral anticoagulant-associated major or life-threatening bleeding.

The article Reversal agents for oral anticoagulant-associated major or life-threatening bleeding, written by Marco Moia, Alessandro Squizzato was originally published electronically on the publisher's internet portal (currently SpringerLink) on 24 August 2019 without open access.

Reversal agents for oral anticoagulant-associated major or life-threatening bleeding.

Oral anticoagulants (OA) are effective drugs for treating and preventing the formation of blood clots in patients with atrial fibrillation, mechanical heart valves and venous thromboembolism but their therapeutic effect is always counterbalanced by an increased risk of bleeding. Direct oral anticoagulants (DOACs) have brought advantages in the management of many patients, with evidence of a lower risk of intracranial bleeding in comparison to vitamin K antagonists (VKAs). However, due to the increased number of anticoagulated patients worldwide, major and life threatening OA-related bleeding is also increasing, and effective reversal strategies are needed. We reviewed the reversal strategies for both VKAs and DOACs in the light of the latest evidence and recent guidelines, taking into account non-specific methods with fresh frozen plasma (FFP), prothrombin complex concentrate (PCC) or four factor PCC, as well as specific reversal antidotes that are already approved or in approval phase. Most published studies on OA reversal have drawbacks, such as lacking a control arm or data on clinically relevant outcomes, and current guidelines' recommendations are mainly based on panellists' judgment. There is an urgent need for well-designed studies in this field. In the meanwhile, to improve the correct use of available resources and patients' outcomes, we suggest a seven-element bundle for an optimal management of OA-associated major bleeding, including the implementation of fast turnaround time for laboratory tests in emergency, i.e. INR and DOAC plasma levels, and to build up a 'bleeding team' that includes experts of hemostasis, lab, trauma, emergency medicine, endoscopy, radiology, and surgery in every hospital.

Correction: Anticoagulation Knowledge Tool (AKT): Further evidence of validity in the Italian population.

[This corrects the article DOI: 10.1371/journal.pone.0201476.].

Anticoagulation Knowledge Tool (AKT): Further evidence of validity in the Italian population.

INTRODUCTION: Oral Anticoagulation therapy (OAC) is highly effective in the management of thromboembolic disorders. An adequate level of knowledge is important for self-management and optimizing clinical outcomes. The Anticoagulation Knowledge Tool (AKT) was developed to assess OAC knowledge and caters for both patients prescribed direct oral anticoagulants or vitamin K antagonist (VKA). However, evidence regarding its psychometric proprieties, validity and reliability are unavailable in non-English speaking settings. For this reason, the aim of this study is to provide further evidence of validity for AKT and also developing an Italian AKT version (I-AKT) supported by evidence of validity and reliability. METHODS: A multiphase study was conducted which included the following: cultural and linguistic validity; i.e. content validity; construct validity; reliability assessment. The Construct validity was performed using the contrasted group approach using three groups comprised of health care providers, patients and the general public. Furthermore, Exploratory Structural Equation Modelling (ESEM) was performed to confirm the mono-dimensional structure of the items in the AKT. RESULTS: In construct validity phase 334 participants were enrolled. One-way ANOVA and post hoc analysis test demonstrated significant differences between the means knowledge scores of the three groups: 30.42±3.04 vs 23.45± 4.57 vs14.32±6.07 (Statistic F = 266.83; p < .001). ESEM analysis demonstrates the I-AKT mono-dimensionally structure with an explained variance of 56.42%. The scale also showed both good internal consistency reliability (Cronbach's α = 0.896) and test-retest reliability (r = 0.855). CONCLUSION: This study developed and validated I-AKT with supporting evidence for validity and reliability. The study also confirms the mono-dimensional of the items in the AKT. This suggest that the instrument can be useful in non-English setting for knowledge assessment and in potentially developing patient education materials.

How and when to measure anticoagulant effects of direct oral anticoagulants? Practical issues.

Direct oral anticoagulants (DOACs) do not require dose adjustment based on laboratory testing. However, it might be necessary to measure their plasma concentrations in the following specific situations: 1) before thrombolytic therapy in patients with stroke; 2) before surgery or invasive procedure; 3) in case of adverse events (thrombosis or hemorrhage); 4) when immediate reversal of anticoagulation is needed; 5) in patients with extreme body weight; 6) when administering additional drugs potentially interfering with DOACs; and 7) when overdosage is suspected regardless of concomitant bleeding. Basic coagulation tests, such as prothrombin and activated partial thromboplastin time, should not be used as standalone tests to assess the levels of anticoagulation as they are not specific for DOACs and their results are dependent on the type of reagent used for testing. Plasma DOAC concentrations should be assessed by dedicated tests: dilute thrombin time or ecarin tests (for dabigatran) or anti-factor Xa assays (for anti-factor Xa inhibitors). Dedicated tests should be calibrated against their respective plasma calibrators at certified DOAC concentrations and results should be expressed as ng/ml. Caution should be exerted when interpreting the results of the most common hemostatic parameters such as antithrombin, proteins C and S, lupus anticoagulant, or individual coagulation factors, as they may be strongly affected by the presence of a DOAC. Whenever possible, these parameters should be measured 4 to 5 days after discontinuation of DOAC anticoagulation.

The vexed question of whether or not to measure levels of direct oral anticoagulants before surgery or invasive procedures.

Direct oral anticoagulants (DOAC) possess high bioavailability, and their anticoagulant effect is more predictable than that of vitamin K antagonists, hence they do not require routine dose adjustment based on laboratory testing. However, there are circumstances when laboratory testing may be useful, including patients who need to undergo surgery or invasive procedures. Most guidelines state that patients on DOAC may safely undergo surgery/invasive procedures by stopping anticoagulation for a few days before intervention without testing if renal function is within normal limits. This review article discusses the pros and cons of measuring (or not measuring) DOAC levels before surgery/invasive procedures by a multidisciplinary team of experts with different background, including the thrombosis laboratory, clinical thrombosis, internal medicine, cardiology and nephrology. The conclusion is that measuring DOAC with dedicated tests before surgical or invasive procedures is important for patient safety. It provides the best and most direct evidence to rule in (or to rule out) clinically relevant concentrations of residual drugs. Regulatory agencies should urgently approve their use in clinical practice. Hospital administrators should make them available, and clinical laboratories should set up the relative methods and make them available to clinicians.

Harmful and Beneficial Effects of Anticoagulants in Patients With Cirrhosis and Portal Vein Thrombosis.

BACKGROUND & AIMS: Vitamin K antagonists (VKAs) promote recanalization of portal vein thrombosis (PVT) in patients with cirrhosis. However, the benefit of PVT recanalization might be offset by major and minor bleeding associated with use of anticoagulants. We evaluated harmful and beneficial effects of VKA in patients with PVT and cirrhosis. METHODS: We performed a retrospective study of 63 consecutive patients with cirrhosis given anticoagulants for the first detection of non-neoplastic PVT from 2003 to 2015 in Italy. We collected data on bleeding events in these patients and compared them with those from patients without cirrhosis with venous thromboembolism (VTE) (n = 160) for up to 4 years. Time in the therapeutic range, based on the international normalized ratio, was used to determine the quality of anticoagulation. We also collected data from 139 patients with cirrhosis who did not receive VKAs (controls), to analyze portal hypertension-related events. We performed survival analyses to determine the effects of VKA in patients with PVT vs controls. RESULTS: The group with VTE and the group with PVT were comparable in age, sex, and time in the therapeutic range, but patients with VTE received VKAs for a longer time period (31.1 ± 16.9 mo vs 23.3 ± 16.2 mo; P = .002). The incidence of major or minor bleeding was higher in patients with PVT than patients with VTE (major, 24% vs 7%; P = .012; minor, 29% vs 19%; P = .024). Patients with PVT had a higher rate of major bleeding from the upper-gastrointestinal tract than patients with VTE (P = .019), but there were no significant differences in other types of major bleeding (P = .376). Patients with PVT and controls had the same rate of upper-gastrointestinal bleeding. Complete recanalization in patients with PVT receiving VKA (n = 31) was independently associated with increased portal hypertension-related event-free and transplantation-free survival times. CONCLUSIONS: In a retrospective analysis of 63 patients with cirrhosis given anticoagulants for PVT, we found VKA use to increase risk of minor bleeding, compared with patients without cirrhosis given VKA. However, this risk is offset by the ability of VKA to increase portal hypertension-related, event-free, and transplantation-free survival of patients with PVT recanalization. Portal hypertension, rather than anticoagulants, could account for the difference in risk of major bleeding between patients with PVT vs patients with VTE.

Position Paper on laboratory testing for patients on direct oral anticoagulants. A Consensus Document from the SISET, FCSA, SIBioC and SIPMeL.

Although direct oral anticoagulants (DOAC) do not require dose-adjustment on the basis of laboratory test results, the measurement of their anticoagulant effect is useful in special situations. This position paper issued by the Italian Scientific Societies that are mainly involved in the management of patients on DOAC is aimed at providing guidance to care-givers on which tests should be used and the situations in which testing is useful. The guidance is based on the data from the literature so far available and/or on consensus among experts.

Vitamin K antagonist therapy: changes in the treated populations and in management results in Italian anticoagulation clinics compared with those recorded 20 years ago.

Vitamin K antagonists (VKA) are the most widely used anticoagulants in the world. An appropriate management of treated patients is crucial for their efficacy and safety. The prospective, observational, multicenter, inception-cohort FCSA-START Register, a branch of START Register (NCT02219984) included VKA-treated patients managed by centers of Italian Federation of anticoagulation clinics (AC). Baseline patient characteristics and data during treatment were analyzed and compared with those of ISCOAT study, performed by the Federation and published in 1996/7. 5707 naïve patients [53% males, mean age 73.0 years (28.1% >80 years)], 61.6% treated for atrial fibrillation (AF), and 28.0% for venous thromboembolism were included. During the 8906 patient-years (pt-yrs) of observation, 123 patients had major bleeding (MB) (1.38% pt-yrs; fatal: 0.11% pt-yrs), while non-major clinically relevant bleeds were 144 (1.62% pt-yrs). Bleeding was more frequent in elderly (≥70 years; p = 0.04), and during initial 3-month therapy (p = 0.02). Bleeding rate was 2.5% pt-yrs for temporally related INR results <3.0, increasing to 12.5% for INR ≥ 4.5. Thrombotic events were 47 (0.53% pt-yrs; 4 fatal 0.04% pt-yrs). Compared with ISCOAT-1996/7 results, patients older than 80 y are increased from 8 to 28% (p < 0.01), and those treated for AF are increased from 17 to 61%. The quality of anticoagulation control and incidence of MB are not different. However, thrombotic complications fell drastically from 3.5 to 0.53% pt-yrs (p < 0.01), with lower mortality (p = 0.01). VKA-treated patients monitored in Italian AC have good clinical results, with low bleeding and thrombotic complications rates. Important changes in the treated population and improvement in thrombotic complications are detected compared with the ISCOAT-1996/7 study.

Coagulation parameters in patients with cirrhosis and portal vein thrombosis treated sequentially with low molecular weight heparin and vitamin K antagonists.

BACKGROUND/AIMS: Information on coagulation for cirrhotics on anticoagulants is scanty. We investigated plasma from 23 cirrhotics treated with low-molecular-weight-heparin (LMWH) followed by vitamin K antagonists (VKA). METHODS: On days 1-4 patients received full-dose LMWH. On day-5 VKA was started and LMWH was terminated when INR therapeutic-interval was reached. Blood was collected at peak and trough during LMWH, LMWH+VKA and VKA. Non-cirrhotics on VKA were included as controls. RESULTS: Anti-factor Xa increased from baseline-to-peak during LMWH. During LMWH+VKA was high and reverted to zero during VKA. INR was slightly high at baseline, trough or peak during LMWH and increased to 2.2 during LMWH+VKA or VKA. Mean VKA weekly-doses for cirrhotics and controls were 28.5mg and 28.6mg. Protein C decreased upon VKA, but not to the expected extent. Endogenous-thrombin-potential (ETP) decreased from baseline (1436nMmin) to trough (1258nMmin) and peak (700nMmin) during LMWH and was further reduced during LMWH+VKA (395nMmin). CONCLUSIONS: Target-INR for cirrhotics can be reached by VKA dosages similar to those for non-cirrhotics. ETP reduction parallels the effect of LMWH and/or VKA. Whether these parameters represent the antithrombotic action elicited by these drugs remains to be determined by clinical-trials and laboratory-measurements. ETP, being a global-test reflecting both pro- and anti-coagulants targeted by antithrombotic drugs, seems the candidate for these trials.

Thrombophilic risk of individuals with rare compound factor V Leiden and prothrombin G20210A polymorphisms: an international case series of 100 individuals.

The risk of thrombosis in individuals with rare compound thrombophilias, homozygous factor V Leiden (FVL) plus heterozygous prothrombin G20210A (PTM), homozygous PTM plus heterozygous FVL, and homozygous FVL plus homozygous PTM, is unknown. We identified, worldwide, individuals with these compound thrombophilias, predominantly through mailing members of the International Society on Thrombosis and Haemostasis. Physicians were sent a clinical questionnaire. Confirmatory copies of the genetic results were obtained. One hundred individuals were enrolled; 58% were female. Seventy-one individuals had a venous thrombosis (includes superficial and deep vein thrombosis, and pulmonary embolism), 4 had an arterial thrombosis and 6 had both. Nineteen individuals had never had a thrombotic event. Thrombosis-free survival curves demonstrated that 50% of individuals had experienced a thrombotic event by 35 yrs of age, while 50% had a first venous thromboembolic event (VTE; includes all venous thrombosis except superficial thrombosis) by 41 yrs of age; 38.2% of first VTEs were unprovoked. 37% of patients had at least one VTE recurrence. Seventy percent of first pregnancies carried to term and not treated with anticoagulation were thrombosis-free. In conclusion, patients with these rare compound thrombophilias are not exceedingly thrombogenic, even though they have a substantial risk for VTE.

Patient preferences and willingness to pay for different options of anticoagulant therapy.

New anticoagulant drugs alternative to vitamin K antagonists are currently under clinical evaluation. Patient's preferences should be considered in the development of new therapeutic strategies. Our study aim was to elicit patient preferences, and estimate their willingness to pay for the different treatment options. A Discrete Choice Experiment was administered to patients consecutively attending an anticoagulation clinic, either on stable oral anticoagulant therapy, or during their first visit at the time of starting therapy. Six treatment characteristics were analysed: route and number of medication administrations, frequency of monitoring, risk of some minor bleeding, the amount of attention required for drug/food interactions, requirement for dose adjustment, and out-of-pocket treatment cost. Relationships between patient's preferences and their characteristics were analysed. 255 patients participated (55 % men, with a mean age 64 years; 35.7 % on stable therapy). A statistically significant importance was attributed to all but two characteristics (the amount of attention required for interaction with other drugs/food and for dose adjustment.) Monthly patient willingness to pay was 79 for tablets versus injections; 41 for once-daily versus twice-daily tablets, 25 for drugs without risk of minor bleeding events and 20 for once-monthly versus twice-monthly monitoring. Patients on stable therapy considered more important the amount of attention required for drug/food interactions than did the starters. Younger or working patients considered the reduction of monitoring frequency more important than did the older or not working patients (retired, housewives). This study elicited preferences from patients on oral anticoagulant therapy with a simple and well established method, which allows to obtain information warranted for planning optimal healthcare.