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Background: The Global Anticoagulant Registry in the FIELD–Atrial Fibrillation (GARFIELD-AF) is an ongoing prospective noninterventional registry, which is providing important information on the baseline characteristics, treatment patterns, and 1-year outcomes in patients with newly diagnosed non-valvular atrial fibrillation (NVAF). This report describes data from Indian patients recruited in this registry. Methods and results: A total of 52,014 patients with newly diagnosed AF were enrolled globally; of these, 1388 patients were recruited from 26 sites within India (2012–2016). In India, the mean age was 65.8 years at diagnosis of NVAF. Hypertension was the most prevalent risk factor for AF, present in 68.5% of patients from India and in 76.3% of patients globally (P

Despite extensive research, the pathogenesis of antiphospholipid syndrome (APS) remains obscure in many aspects. However, it is widely accepted that thrombosis is the result of a hypercoagulable state caused by antibodies directed against β2-glycoprotein I (β2-GPI), a protein whose physiological role is unknown. Although underestimated, platelets may be involved in APS and its thrombotic manifestations, especially arterial, in several ways. Thrombocytopenia is the most relevant non-criteria manifestation of APS, possibly caused by direct binding of anti-β2-GPI antibodies or anti-β2-GPI–β2-GPI complexes. On the other hand, platelets may have a key role in APS-related thrombosis due to the presence of multiple receptors that can interact with anti-β2-GPI antibodies (especially apolipoprotein E receptor 2’ (apoER2’) and glycoprotein Ibα (GPIbα)) with consequent release of different procoagulant mediators such as thromboxane B2, platelet factor 4 (PF4), and platelet factor 4 variant (CXCL4L1). The aim of this review is to put together evidence on the possible role of platelets in APS and to stimulate further research on the issue.

Diagnosis of antiphosholipid syndrome (APS) is based on laboratory detection of antiphospholipid (aPL) antibodies in patients with documented thrombosis or in women with pregnancy morbidity. Recently, both clinical and laboratory criteria were revised on the basis of an international consensus conference held in Sydney (1). The previous international consensus statement of one clinical and one laboratory criterion to diagnose APS was maintained (2) but time-lapse between the previous thromboembolism and laboratory diagnosis should not exceed 5 years. Moreover, laboratory tests should not be performed in the 12 weeks following the event to avoid any interference of the acute phase of the disease. Thus, laboratory evaluation of venous thromboembolism (VTE) should not be requested during the hospital stay as tests may be false-positive with no influence on the treatment regimen...

Some previous observations suggest that a low platelet count is associated with an increased risk of adverse outcomes in patients with acute coronary syndromes (ACS). However, most of the data come from post-hoc analyses of randomized controlled trials and from studies including thrombocytopenia developed during hospital stay. Our aim was to assess the impact of low platelet count at admission on cardiovascular outcomes and treatment approach in patients hospitalized for ACS in a current real-life setting in Italy. Patients admitted to Italian coronary care units for ACS were enrolled in the START-ANTIPLATELET registry. Baseline clinical characteristics and treatment at discharge were recorded. Patients were followed-up at 6 months, 1 year and yearly thereafter. Low platelet count was defined as a count at admission < 150 > 100 k/µl or < 100 k/µL. Among 1894 enrolled patients, 157 (8.3%) had a platelet count < 150 > 100 k/µl and 30 (1.6%) < 100 k/µl. The median follow-up was 12.3 months (0.4-50.1). patients with low platelets were older (72 ± 10.4 vs 66 ± 12.4 years, p = 0.006), more frequently males (82.9 vs 72.1%, p = 0.001), hypertensive (90.0% vs 70.4%, p = 0.03), with non-valvular atrial fibrillation (NVAF) (17.1 vs 8.6%, p = 0.02), and peripheral arterial disease (11.5 vs 6.2% p = 0.01) and/or had a previous myocardial infarction (40 vs 18.7%, p = 0.008) and/or a PCI (14.6 vs 7.8%, p = 0.001) than patients with normal platelets. A slightly, but significantly, lower percentage of thrombocytopenic patients were treated with primary PCI (78.1 vs 84.4%, p = 0.04) and they were more frequently discharged on aspirin plus clopidogrel rather than aspirin plus newer P2Y 12 antagonists (51.9 vs 65.4%, p = 0.01). MACE-free survival was significantly shorter in thrombocytopenic patients compared to patients with normal platelets (< 150 > 100 k/µl: 37.6 vs 41.8 months, p = 0.002; HR = 2.7, 95% CIs 1.4-5.2; < 100 k/µl: 31.7 vs 41.8 months, p = 0.01; HR = 6.5, 95% CIs 1.5-29.1). At multivariate analysis, low platelet count, age at enrollment, low glomerular filtration rate, low ejection fraction, a previous ischemic stroke and NVAF were independent predictors of MACE. A low platelet count at admission identifies a subgroup of ACS patients with a significantly increased risk of MACE and these patients should be managed with special care to prevent excess adverse outcomes., (© 2024. The Author(s).)

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.

Background: Most of the carriers/patients triple-positive for antiphospholipid antibodies (lupus anticoagulant [LAC], immunoglobulin G [IgG]/immunoglobulin M [IgM] anticardiolipin, and anti-β2-glycoprotein I antibodies) are tetra-positive, being positive for antiphosphatidylserine/prothrombin (aPS/PT) antibodies. The relationship between aPS/PT titer, LAC potency, and resistance to activated protein C (aPC-R) has not been investigated., Objectives: The aim of this study was to clarify the mutual interdependence of these parameters in tetra-positive subjects., Methods: Twenty-three carriers and 30 patients with antiphospholipid syndrome, none of whom were being treated with anticoagulants, and 30 age- and sex-matched controls were studied. Detection of aPS/PT, LAC, and aPC-R in each individual was performed with established methods in our laboratory. Carriers and patients were positive for IgG or IgM aPS/PT or for both isotypes without significant difference. Since both IgG and IgM aPS/PT have anticoagulant activity, we used the sum of their titers (total aPS/PT) for the correlation studies., Results: Total aPS/PT in all individuals studied exceeded that in controls. There was no difference in total aPS/PT titers (P = .72), LAC potency (P = .56), and aPC-R (P = .82) between antiphospholipid antibody-carriers and patients with antiphospholipid syndrome. There was a significant correlation between total aPS/PT and LAC potency (r = 0.78; P < .0001) and between total aPS/PT titers and aPC-R (r = 0.80; P < .0001). LAC potency also was correlated significantly with aPC-R (r = 0.72; P < .0001)., Conclusion: This study shows that there is interdependence between aPS/PT, LAC potency, and aPC-R., Competing Interests: Declaration of competing interests V.P. received lecture fees from Werfen Group. The other authors have no competing interests to disclose., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Objective: To develop new antiphospholipid syndrome (APS) classification criteria with high specificity for use in observational studies and trials, jointly supported by the American College of Rheumatology (ACR) and EULAR., Methods: This international multidisciplinary initiative included 4 phases: 1) Phase I, criteria generation by surveys and literature review; 2) Phase II, criteria reduction by modified Delphi and nominal group technique exercises; 3) Phase III, criteria definition, further reduction with the guidance of real-world patient scenarios, and weighting via consensus-based multicriteria decision analysis, and threshold identification; and 4) Phase IV, validation using independent adjudicators' consensus as the gold standard., Results: The 2023 ACR/EULAR APS classification criteria include an entry criterion of at least one positive antiphospholipid antibody (aPL) test within 3 years of identification of an aPL-associated clinical criterion, followed by additive weighted criteria (score range 1-7 points each) clustered into 6 clinical domains (macrovascular venous thromboembolism, macrovascular arterial thrombosis, microvascular, obstetric, cardiac valve, and hematologic) and 2 laboratory domains (lupus anticoagulant functional coagulation assays, and solid-phase enzyme-linked immunosorbent assays for IgG/IgM anticardiolipin and/or IgG/IgM anti-β 2 -glycoprotein I antibodies). Patients accumulating at least 3 points each from the clinical and laboratory domains are classified as having APS. In the validation cohort, the new APS criteria versus the 2006 revised Sapporo classification criteria had a specificity of 99% versus 86%, and a sensitivity of 84% versus 99%., Conclusion: These new ACR/EULAR APS classification criteria were developed using rigorous methodology with multidisciplinary international input. Hierarchically clustered, weighted, and risk-stratified criteria reflect the current thinking about APS, providing high specificity and a strong foundation for future APS research., (© 2023 American College of Rheumatology.)

Background: Age and frailty are associated with underuse of anticoagulation in elderly patients with atrial fibrillation (AF)., Objectives: This study aimed at assessing major clinical outcomes in very elderly patients with AF treated with recommended dose edoxaban and look for a possible relation with frailty measured by a validated score., Methods: This prospective multicenter cohort study enrolled consecutive very elderly (age ≥80 years) anticoagulation-naïve patients starting recommended doses of edoxaban. Upon entry into the study, patients were categorized into nonfrail, prefrail and frail with the SHARE-FI (Survey of Health, Ageing, and Retirement in Europe-Frailty Index) score. The primary outcome was a composite incidence of stroke/systemic embolism, major bleeding, clinically relevant nonmajor bleeding, and death between frail and fitter patients over 2 years follow-up. Secondary outcomes were frailty-related incidence of the individual components part of the composite outcome., Results: Of the 180 screened patients, 176 were enrolled in the study. Of these, 58 (32.9%) were frail, 35 (19.8%) prefrail, and 83 (47.2%) nonfrail. The composite outcome occurred in 49 patients (18.9% per patient-year). No difference in the primary endpoint between frail and fitter patients (incidence rate ratio: 1.2; 95% CI: 0.6-2.2) was observed. On multivariable analysis, anemia was significantly related to the primary outcome (HR: 3.6; 95% CI: 1.8-7.3; P  < 0.001), while frailty was not (frail vs nonfrail HR: 0.9; 95% CI: 0.5-1.8). No difference across frailty categories of the individual components of composite events was observed, except for death., Conclusions: Anticoagulation with recommended dose edoxaban is feasible in very elderly patients with AF even if frail. (ESCAPE [Edoxaban and Frailty in Senior Individuals]; NCT03524924)., Competing Interests: Nonconditional support from Daiichi Sankyo Italy was received. The authors have reported that they have no relationships relevant to the contents of this paper to disclose., (© 2023 The Authors.)

Objective: This study aimed to elucidate the presence, antigen specificities, and potential clinical associations of anti-neutrophil extracellular trap (anti-NET) antibodies in a multinational cohort of antiphospholipid (aPL) antibody-positive patients who did not have lupus., Methods: Anti-NET IgG/IgM levels were measured in serum samples from 389 aPL-positive patients; 308 patients met the classification criteria for antiphospholipid syndrome. Multivariate logistic regression with best variable model selection was used to determine clinical associations. For a subset of the patients (n = 214), we profiled autoantibodies using an autoantigen microarray platform., Results: We found elevated levels of anti-NET IgG and/or IgM in 45% of the aPL-positive patients. High anti-NET antibody levels are associated with more circulating myeloperoxidase (MPO)-DNA complexes, which are a biomarker of NETs. When considering clinical manifestations, positive anti-NET IgG was associated with lesions affecting the white matter of the brain, even after adjusting for demographic variables and aPL profiles. Anti-NET IgM tracked with complement consumption after controlling for aPL profiles; furthermore, patient serum samples containing high levels of anti-NET IgM efficiently deposited complement C3d on NETs. As determined by autoantigen microarray, positive testing for anti-NET IgG was significantly associated with several autoantibodies, including those recognizing citrullinated histones, heparan sulfate proteoglycan, laminin, MPO-DNA complexes, and nucleosomes. Anti-NET IgM positivity was associated with autoantibodies targeting single-stranded DNA, double-stranded DNA, and proliferating cell nuclear antigen., Conclusion: These data reveal high levels of anti-NET antibodies in 45% of aPL-positive patients, where they potentially activate the complement cascade. While anti-NET IgM may especially recognize DNA in NETs, anti-NET IgG species appear to be more likely to target NET-associated protein antigens., (© 2023 The Authors. Arthritis & Rheumatology published by Wiley Periodicals LLC on behalf of American College of Rheumatology.)

Several antiphospholipid antibody (aPL) profiles ("triple" and lupus anticoagulant [LA] positivity) are associated with a higher risk for clinical manifestations of antiphospholipid syndrome (APS). Further risk is correlated with higher levels of anticardiolipin antibody (aCL) and anti-β 2 glycoprotein-I antibody (aβ 2 GPI), and with aPL persistence. Given that the 3 aPL tests detect partially overlapping sets of antibodies, the primary goal of this study was to characterize the associations among aPL tests using AntiPhospholipid Syndrome Alliance for Clinical Trials and InternatiOnal Networking (APS ACTION) core laboratory data. The APS ACTION Registry includes annually followed adult patients with positive aPL based on the Revised Sapporo Classification Criteria. We analyzed baseline and prospective core laboratory data of the registry for associations among aPL tests using the Spearman rank correlation with Bonferroni-adjusted significance level for multiple comparisons. An aPL Load was calculated based on 6 tests (aCL IgG/IgM/IgA and aβ 2 GPI IgG/IgM/IgA); a receiver operating characteristic curve was used to evaluate the diagnostic performance of the aPL Load in predicting LA positivity. In 351 patients simultaneously tested for LA, aCL, and aβ 2 GPI, the frequency of moderate-to-high (≥40 U) titers of aCL and aβ 2 GPI IgG/IgM/IgA was higher in patients who were positive for LA vs those who were negative. An aPL Load was calculated for each patient to assess the overall aPL burden. For every 1-point increase in the aPL Load, the possibility of a positive LA test increased by 32% (odds ratio, 1.32; 95% CI, 1.2-1.5; P < .001). Based on core laboratory data from a large international registry, most aPL enzyme-linked immunosorbent assay ≥40 U and a high calculated aPL Load combining 6 aPL enzyme-linked immunosorbent assays were predictive of a positive LA. These data suggest that the combined quantitative burden of aPL may provide a mechanistic explanation of a positive LA., (Copyright © 2023 United States & Canadian Academy of Pathology. Published by Elsevier Inc. All rights reserved.)

Objective: The present study was undertaken to longitudinally evaluate titers of antibodies against β 2 -glycoprotein I (anti-β 2 GPI) and domain 1 (anti-D1), to identify predictors of variations in anti-β 2 GPI and anti-D1 titers, and to clarify whether antibody titer fluctuations predict thrombosis in a large international cohort of patients who were persistently positive for antiphospholipid antibodies (aPL) in the APS ACTION Registry., Methods: Patients with available blood samples from at least 4 time points (at baseline [year 1] and at years 2-4 of follow-up) were included. Detection of anti-β 2 GPI and anti-D1 IgG antibodies was performed using chemiluminescence (BIO-FLASH; INOVA Diagnostics)., Results: Among 230 patients in the study cohort, anti-D1 and anti-β 2 GPI titers decreased significantly over time (P < 0.0001 and P = 0.010, respectively). After adjustment for age, sex, and number of positive aPL tests, we found that the fluctuations in anti-D1 and anti-β 2 GPI titer levels were associated with treatment with hydroxychloroquine (HCQ) at each time point. Treatment with HCQ, but not immunosuppressive agents, was associated with 1.3-fold and 1.4-fold decreases in anti-D1 and anti-β 2 GPI titers, respectively. Incident vascular events were associated with 1.9-fold and 2.1-fold increases in anti-D1 and anti-β 2 GPI titers, respectively. Anti-D1 and anti-β 2 GPI titers at the time of thrombosis were lower compared to titers at other time points. A 1.6-fold decrease in anti-D1 titers and a 2-fold decrease in anti-β 2 GPI titers conferred odds ratios for incident thrombosis of 6.0 (95% confidence interval [95% CI] 0.62-59.3) and 9.4 (95% CI 1.1-80.2), respectively., Conclusion: Treatment with HCQ and incident vascular events in aPL-positive patients predicted significant anti-D1 and anti-β 2 GPI titer fluctuations over time. Both anti-D1 and anti-β 2 GPI titers decreased around the time of thrombosis, with potential clinical relevance., (© 2023 The Authors. Arthritis & Rheumatology published by Wiley Periodicals LLC on behalf of American College of Rheumatology.)

Introduction: Variable D-dimer trends during hospitalization reportedly result in distinct in-hospital mortality. In this multinational case series from the first and second waves, we show the universality of such D-dimer trends., Methods: We reviewed 405 patients with COVID-19 during the first wave admitted to three institutions in the United States, Italy, and Colombia, and 111 patients admitted to the U.S. site during the second wave and 55 patients during the third wave. D-dimer was serially followed during hospitalization., Results: During the first wave, 66 (15%) patients had a persistently-low pattern, 33 (8%) had early-peaking, 70 (16%) had mid-peaking, 94 (22%) had fluctuating, 30 (7%) had late-peaking, and 112 (26%) had a persistently-high pattern. During the second and third waves, similar patterns were observed. D-dimer patterns were significantly different in terms of in-hospital mortality similarly in all waves. Patterns were then classified into low-risk patterns (persistently-low and early-peaking), where no deaths were observed in both waves, high-risk patterns (mid-peaking and fluctuating), and malignant patterns (late-peaking and persistently-high). Overall, D-dimer trends were associated with an increased risk for in-hospital mortality in the first wave (overall: HR: 1.73) and stayed the same during the second (HR: 1.67, p < 0.001) and the third (HR: 4.4, p = 0.001) waves., Conclusion: D-dimer behavior during COVID-19 hospitalization yielded universal categories with distinct mortality risks that persisted throughout all studied waves of infection. Monitoring D-dimer behavior may be useful in the management of these patients., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Ronderos Botero, Omar, Pengo, Haider, Latif, Parati, Pengo, Cañas Arboleda, Díaz, Villaquirán-Torres, Contreras and Chilimuri.)

Background: The efficacy and safety of direct oral anticoagulants (DOACs) for patients with thrombotic antiphospholipid syndrome remain controversial., Objectives: The authors performed a systematic review and meta-analysis of randomized controlled trials that compared DOACs with vitamin K antagonists (VKAs)., Methods: We searched PubMed, EMBASE, and Cochrane Central Register of Controlled Trials through April 9, 2022. The 2 main efficacy outcomes were a composite of arterial thrombotic events and venous thromboembolic events (VTEs). The main safety outcome was major bleeding. Random effects models with inverse variance were used., Results: Our search retrieved 253 studies. Four open-label randomized controlled trials involving 472 patients were included (mean control-arm time-in-therapeutic-range 60%). All had proper random sequence generation and adequate allocation concealment. Overall, the use of DOACs compared with VKAs was associated with increased odds of subsequent arterial thrombotic events (OR: 5.43; 95% CI: 1.87-15.75; P < 0.001, I 2  = 0%), especially stroke, and the composite of arterial thrombotic events or VTE (OR: 4.46; 95% CI: 1.12-17.84; P = 0.03, I 2  = 0%). The odds of subsequent VTE (OR: 1.20; 95% CI: 0.31-4.55; P = 0.79, I 2  = 0%), or major bleeding (OR: 1.02; 95% CI: 0.42-2.47; P = 0.97; I 2  = 0%) were not significantly different between the 2 groups. Most findings were consistent within subgroups., Conclusions: Patients with thrombotic antiphospholipid syndrome randomized to DOACs compared with VKAs appear to have increased risk for arterial thrombosis. No significant differences were observed between patients randomized to DOACs vs VKAs in the risk of subsequent VTE or major bleeding., Competing Interests: Funding Support and Author Disclosures Dr Piazza has received research support from Bristol Myers Squibb/Pfizer Alliance, Bayer, Janssen, Alexion, Amgen, and Boston Scientific Corporation; and has received consulting fees from Bristol Myers Squibb/Pfizer Alliance, Boston Scientific Corporation, Janssen, Namsa, Prairie Education and Research Cooperative, Boston Clinical Research Institute, and Amgen. Dr Jiménez has received research support from Daiichi-Sankyo and Sanofi; and has received consulting fees from Bristol Myers Squibb/Pfizer Alliance, Daiichi-Sankyo, Leo Pharma, Rovi, and Sanofi. Dr Monreal has received research support from Sanofi, Leo, and Rovi; and has received consulting fees from Sanofi. Dr Pengo has received lecture fees from Werfen Group. Dr Cortes-Hernandez has received institutional research funding from Bayer Hispania to conduct the APS RCT. Dr Connors has received research funding to her institution from CSL Behring; has received consulting fees from Abbott; has received honoraria for lectures from Bristol Myers Squibb, Roche, and Sanofi; and has participated on the advisory board of Abbott, Alnylam, Anthos, Bristol Myers Squibb, Sanofi, and Takeda, outside of the submitted work. Dr Kanthi is an inventor on a pending patent application by the University of Michigan on the use of biogases in vascular disease (US202201670756A1); and is supported by the National Heart, Lung, and Blood Institute Intramural Research Program and the Lasker Foundation. Dr Krumholz has received (within the last 3 years) expenses and/or personal fees from UnitedHealth, Element Science, Aetna, Reality Labs, Tesseract/4Catalyst, F-Prime, the Siegfried and Jensen Law Firm, the Arnold and Porter Law Firm, and the Martin/Baughman Law Firm; is a cofounder of Refactor Health, an enterprise health care artificial intelligence–augmented data management company, and HugoHealth, a personal health information platform; and is associated with contracts through Yale University from Johnson and Johnson. Dr Middeldorp has received grants and personal fees from Daiichi-Sankyo; has received grants and personal fees from Bayer, Pfizer, and Boehringer Ingelheim; and has received personal fees from Portola/Alexion, Abbvie, Bristol Myers Squibb Pfizer, Norgine, and Viatris, all paid to her institution. Dr Falanga has received honoraria/consulting fees from Stago, Sanofi, Daiichi-Sankyo, Leo Pharma, and Pfizer. Dr Goldhaber has received research support from Bayer, Bristol Myers Squibb, Boston Scientific BTG EKOS, Janssen, National Heart, Lung, and Blood Institute, and Pfizer; and has received consulting fees from Agile, Bayer, and Pfizer. Dr Bikdeli is a consulting expert, on behalf of the plaintiff, for litigation related to 2 specific brand models of IVC filters; and is supported by the Scott Schoen and Nancy Adams IGNITE Award from the Mary Horrigan Connors Center for Women's Health and Gender Biology at Brigham and Women's Hospital and a Career Development Award from the American Heart Association and VIVA Physicians (#938814). All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2023 American College of Cardiology Foundation. All rights reserved.)

D-dimer assay is used to stratify patients with unprovoked venous thromboembolism (VTE) for the risk of recurrence. However, this approach was never evaluated since direct oral anticoagulants are available. With this multicenter, prospective cohort study, we aimed to assess the value of an algorithm incorporating serial D-dimer testing and administration of reduced-dose apixaban (2.5 mg twice daily) only to patients with a positive test. A total of 732 outpatients aged 18 to 74 years, anticoagulated for ≥12 months after a first unprovoked VTE, were included. Patients underwent D-dimer testing with commercial assays and preestablished cutoffs. If the baseline D-dimer during anticoagulation was negative, anticoagulation was stopped and testing repeated after 15, 30, and 60 days. Patients with serially negative results (286 [39.1%]) were left without anticoagulation. At the first positive result, the remaining 446 patients (60.9%) were given apixaban for 18 months. All patients underwent follow-up planned for 18 months. The study was interrupted after a planned interim analysis for the high rate of primary outcomes (7.3%; 95% confidence interval [CI], 4.5-11.2), including symptomatic proximal deep vein thrombosis (DVT) or pulmonary embolism (PE) recurrence, death for VTE, and major bleeding occurring in patients off anticoagulation vs that in those receiving apixaban (1.1%; 95% CI, 0.4-2.6; adjusted hazard ratio [HR], 8.2; 95% CI, 3.2-25.3). In conclusion, in patients anticoagulated for ≥1 year after a first unprovoked VTE, the decision to further extend anticoagulation should not be based on D-dimer testing. The results confirmed the high efficacy and safety of reduced-dose apixaban against recurrences. This trial was registered at www.clinicaltrials.gov as #NCT03678506., (© 2022 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Objectives: Patients with APS and triple-positive for aPL are at high risk of recurrent events. As COVID-19 and COVID-19 vaccination may induce thrombotic complications, the objective of the study was to assess the course of COVID-19 and adverse events after vaccination in these patients., Methods: This is a nationwide multicentre survey conducted in nine APS referral centres by means of a questionnaire. Included patients are thrombotic APS with triple-positive aPL confirmed 12 weeks apart. Reference specialist physicians used a four-graded scale of severity for COVID-19 [from 0 (asymptomatic) to 3 (hospitalization in intensive care unit)] and a six-graded scale for adverse reactions to vaccination [from 0 (transient local injection site sign/symptoms) to 5 (potentially life-threatening reactions)]. Outcomes were considered within a 30-day period., Results: Out of 161 patients interviewed, 18 (11%) had COVID-19. All of them fully recovered without any progression to severe disease nor thromboembolic event. A total of 146 patients received the first (92%) and 129 (80%) the second dose of vaccine; side effects were minimal and, in most cases (83% after the first and 68% after the second vaccination) limited to a sore arm. Fifteen patients (9%) were unvaccinated. Most of them raised doubts on the need for vaccination, complained of poor safety and in general were reluctant about COVID-19 vaccination., Conclusion: Patients with triple-positive thrombotic APS did not suffer from severe COVID-19 outcomes. Importantly, COVID-19 vaccination was well tolerated. These data may reassure patients and physicians and contribute to reducing hesitancy in unvaccinated patients., (© The Author(s) 2022. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Objectives: To describe the outcomes of pregnancies in antiphospholipid antibody (aPL)-positive patients since the inception of the AntiPhospholipid Syndrome Alliance for Clinical Trials and InternatiOnal Networking Registry., Methods: We identified persistently aPL-positive patients recorded as 'pregnant' during prospective follow-up, and defined 'aPL-related outcome' as a composite of: (1) Preterm live delivery (PTLD) at or before 37th week due to pre-eclampsia (PEC), eclampsia, small-for-gestational age (SGA) and/or placental insufficiency (PI); or (2) Otherwise unexplained fetal death after the 10th week of gestation. The primary objective was to describe the characteristics of patients with and without aPL-related composite outcomes based on their first observed pregnancies following registry recruitment., Results: Of the 55 first pregnancies observed after registry recruitment among nulliparous and multiparous participants, 15 (27%) resulted in early pregnancy loss <10 weeks gestation. Of the remaining 40 pregnancies: (1) 26 (65%) resulted in term live delivery (TLD), 4 (10%) in PTLD between 34.0 weeks and 36.6 weeks, 5 (12.5%) in PTLD before 34th week, and 5 (12.5%) in fetal death (two associated with genetic anomalies); and (2) The aPL-related composite outcome occurred in 9 (23%). One of 26 (4%) pregnancies with TLD, 3/4 (75%) with PTLD between 34.0 weeks and 36.6 weeks, and 3/5 (60%) with PTLD before 34th week were complicated with PEC, SGA and/or PI. Fifty of 55 (91%) pregnancies were in lupus anticoagulant positive subjects, as well as all pregnancies with aPL-related composite outcome., Conclusion: In our multicentre, international, aPL-positive cohort, of 55 first pregnancies observed prospectively, 15 (27%) were complicated by early pregnancy loss. Of the remaining 40 pregnancies, composite pregnancy morbidity was observed in 9 (23%) pregnancies., Competing Interests: Competing interests: MAP is the chair for the Belimumab Pregnancy Registry, supported by GSK. DWB is the co-principal investigator of The TNF-alpha Blockade with Certolizumab to Prevent Pregnancy Complications in High-Risk Patients with APS, supported by a grant from the NIH/NIAMS R21AR21069189-03S1. DWB is the principal investigator of The Certolizumab to Prevent Pregnancy Complications in High-Risk Patients with APS or SLE, supported by UCB Pharma Inc., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Available evidence on left atrial (LA) thrombus dissolution in patients with atrial fibrillation (AF) largely refers to the use of vitamin K antagonist oral anticoagulants (VKAs), showing >50% thrombus resolution over a 4-week to 12-month treatment period. Available data on non-vitamin K antagonist anticoagulants (NOACs) in this setting are limited and derive from isolated case reports or observational small-sized investigations with dabigatran, rivaroxaban or apixaban. The aim of this study was to investigate the extent of thrombus resolution with edoxaban therapy in patients with AF and LA thrombosis. We conducted a prospective, observational, open-label pilot study in seven Italian institutions. We included a total of 25 patients with non-valvular AF and LA (or left atrial appendage (LAA)) thrombosis, documented by transesophageal echocardiography (TEE). All patients received edoxaban OD treatment (n = 23 on 60 mg daily; n = 2 on 30 mg daily) and underwent TEE examination after 4 weeks. The primary endpoint was the percentage of patients with complete thrombus resolution by TEE imaging at 4 weeks. The mean age of the study population was 68.3 ± 10.8 years with a female population of 16%. AF was permanent in all cases, with a mean arrhythmia duration of 4.3 ± 1.7 years. CHA2DS2-VASc and HAS-BLED scores were 3.2 ± 1.5 and 1.9 ± 1.1, respectively. We were able to demonstrate a complete thrombus resolution in 14 patients (56%) at 4 weeks. In patients with residual atrial thrombosis (n = 11), we observed a 15.4 ± 14.9% reduction in the thrombus area from baseline. As compared with patients without thrombus dissolution, those with thrombus resolution had a numerically lower-indexed LA diameter (27.9 ± 9.3 vs 34.8 ± 16.1 mm/m2), a smaller maximum thrombus area at baseline (45.5 ± 44.6 vs 63.9 ± 43.5 mm2), a higher left ventricular ejection fraction (47.4 ± 21.0% vs 38.4 ± 20.6%) and higher maximum LAA flow velocities (26.3 ± 15.2 vs 19.3 ± 10.0 cm/s). Figures on the percentage of thrombus resolution in this study are comparable to those reported in the literature for the other OACs. We conclude that, in patients with AF, the use of edoxaban is associated with a >50% resolution of atrial thrombus at 4 weeks, similar to studies using VKAs and the other NOACs (ClinicalTrials.gov identifier number: NCT034899395).

Objective: To describe the baseline characteristics of patients with positivity for antiphospholipid antibodies (aPLs) who were enrolled in an international registry, the Antiphospholipid Syndrome (APS) Alliance for Clinical Trials and International Networking (APS ACTION) clinical database and repository, overall and by clinical and laboratory subtypes., Methods: The APS ACTION registry includes adults who persistently had positivity for aPLs. We evaluated baseline sociodemographic and aPL-related (APS classification criteria and "non-criteria") characteristics of patients overall and in subgroups (aPL-positive without APS, APS overall, thrombotic APS only, obstetric APS only, and both thrombotic APS/obstetric APS). We assessed baseline characteristics of patients tested for the presence of three aPLs (lupus anticoagulant [LAC] test, anticardiolipin antibody [aCL], and anti-β 2 -glycoprotein I [anti-β 2 GPI]) antibodies by aPL profiles (LAC only, single, double, and triple aPL positivity)., Results: The 804 aPL-positive patients assessed in the present study had a mean age of 45 ± 13 years, were 74% female, and 68% White; additionally, 36% had other systemic autoimmune diseases. Of these 804 aPL-positive patients, 80% were classified as having APS (with 55% having thrombotic APS, 9% obstetric APS, and 15% thrombotic APS/obstetric APS). In the overall cohort, 71% had vascular thrombosis, 50% with a history of pregnancy had obstetric morbidity, and 56% had experienced at least one non-criteria manifestation. Among those with three aPLs tested (n = 660), 42% were triple aPL-positive. While single-, double-, and triple aPL-positive subgroups had similar frequencies of vascular, obstetric, and non-criteria events, these events were lowest in the single aPL subgroup, which consisted of aCLs or anti-β 2 GPI only., Conclusion: Our study demonstrates the heterogeneity of aPL-related clinical manifestations and laboratory profiles in a multicenter international cohort. Within single aPL positivity, LAC may be a major contributor to clinical events. Future prospective analyses, using standardized core laboratory aPL tests, will help clarify aPL risk profiles and improve risk stratification., (© 2020, American College of Rheumatology.)

Background: DOACs are characterized by a higher incidence of gastrointestinal bleeding and this may be different among males and females. Female patients were underrepresented in the DOAC pivotal trials. We aimed to assess real-world differences in gastrointestinal bleeding with oral anticoagulants (DOACs and VKAs) among males and females with atrial fibrillation. Methods: We performed a population-based retrospective analysis on linked administrative claims. Atrial fibrillation patients of 65 years and above were considered. Bleeding risk factors were assessed through HASBED and previous history of gastrointestinal disease. A time-to-event analysis compared gastrointestinal bleeding between males and females. Results: The overall cohort consisted of 15338 (55% female) DOAC and 44542 (50% female) VKA users. Most of the patients showed HASBED ≥2. Incidence rate of GI bleeding was higher in females as compared to males among DOAC users (0.90% vs 0.59%), and significant gender difference in GI bleeding was found, after adjustment, in the Cox regression analysis (HR 1.48, 95%CI 1.02-2.16). In the VKA group, no significant difference among genders was found in the time-to-event analysis. Conclusions: Our data suggest that female patients treated with DOACs have a higher risk of GI bleeding versus male patients; this difference is not observed in VKA patients.

Background: Venous thromboembolism (VTE) is a frequent and serious disease that requires immediate and long-term anticoagulant treatment, which is inevitably associated with a risk of bleeding complications. Some studies, though not all, reported a higher risk of bleeding in female patients treated with either old anticoagulants [vitamin k antagonists (VKAs)] or recent anticoagulants [direct oral anticoagulants (DOACs)]. Furthermore, analyses of clinical trials reported an abnormal vaginal bleeding in women of reproductive age treated with DOACs. This study aimed at comparing the risk of bleeding in an inception cohort of VTE women and men included in a prospective observational registry., Methods: Baseline characteristics and bleeding events occurring during anticoagulation in patients of both sexes, included in the START-Register after a first VTE, were analyzed., Results: In all, 1298 women were compared with 1290 men. Women were older and more often had renal diseases; their index events were often provoked (often by hormonal contraception and pregnancy), and more frequently presented as isolated pulmonary embolism (PE). The rate of bleeding was similar in women (2.9% patient-years) and men (2.1% patient-years), though it was higher when uterine bleeds were included (3.5% patient-years, p = 0.0141). More bleeds occurred in VKA- than DOAC-treated patients (6.4% versus 2.6%, respectively; p = 0.0013). At multivariate analysis, age ⩾ 75 years was associated with higher prevalence of bleeds., Conclusion: The occurrence of bleeding was not different between women and men during anticoagulation after VTE. Only after inclusion of vaginal/uterine bleeds, the rate of bleeding was higher in women. The incidence of bleeding was higher in women treated with VKAs., Plain Language Summary: The risk of bleeding in women anticoagulated for deep vein thrombosis or pulmonary embolism is not higher than that in men, except for vaginal bleeding: Background:: The occurrence of a venous thromboembolic event (VTE, including deep vein thrombosis and pulmonary embolism) necessarily requires a period of at least 3-6 months of treatment with anticoagulant drugs [either vitamin k antagonists (VKA) or, more recently, direct oral anticoagulants (DOACs)]. Anticoagulation therapy, however, is associated with a risk of bleeding that is influenced by several factors. Sex is one of these factors as some authors have hypothesized that women are at higher risk than men. Furthermore, some studies have recently found more vaginal bleeding in VTE women treated with a DOAC compared with those who received VKAs. Methods:: The present study aimed to compare the frequency of bleeds occurring in women and in men who were treated with DOACs or VKAs for a first VTE event and followed in real-life conditions. Since the beginning of their anticoagulant treatment, the patients were included in a prospective, multicenter, observational registry (the START-Register), and bleeding events were recorded. Results:: A total of 1298 women were compared with 1290 men. Women were older and more often were affected by renal diseases; their VTE events were often associated with risk factors (especially hormonal contraception and pregnancy) and presented as isolated pulmonary embolism. The rate of all bleeding events (including major, non-major but clinically relevant, and minor bleeds) was higher in women (3.5% patient-years) than in men (2.1% patient-years, p = 0.0141); however, the difference was no longer statistically significant after exclusion of uterine bleeds (2.9% patient years). More bleeding occurred in women receiving VKA as anticoagulant drug compared with those treated with a DOAC (6.4% versus 2.6%, respectively; p = 0.0013). At multivariate analysis, age ⩾ 75 years was associated with higher prevalence of bleeds. Conclusion:: In conclusion, we found that in real-life conditions, the rate of bleeding events occurring during anticoagulation after a VTE episode is not higher in women than in men. Only after inclusion of vaginal bleeds, the rate of bleeding was higher in women. More bleeds (including vaginal bleeding) occurred in women treated with VKA than DOACs., Competing Interests: Conflict of interest statement: The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s), 2021.)

Background: Antiphospholipid syndrome (APS) is characterized by episodes of thrombosis, obstetric morbidity or both, associated with persistently positive antiphospholipid antibodies (aPL). Studying the profile of a rare disease in an admixed population is important as it can provide new insights for understanding an autoimmune disease. In this sense of miscegenation, Brazil is characterized by one of the most heterogeneous populations in the world, which is the result of five centuries of interethnic crosses of people from three continents. The objective of this study was to compare the clinical and laboratory characteristics of Brazilian vs. non-Brazilian primary antiphospholipid syndrome (PAPS) patients., Methods: We classified PAPS patients into 2 groups: Brazilian PAPS patients (BPAPS) and PAPS patients from other countries (non-BPAPS). They were compared regarding demographic characteristics, criteria and non-criteria APS manifestations, antiphospholipid antibody (aPL) profile, and the adjusted Global Antiphospholipid Syndrome Score (aGAPSS)., Results: We included 415 PAPS patients (88 [21%] BPAPS and 327 [79%] non-BPAPS). Brazilian patients were significantly younger, more frequently female, sedentary, obese, non-white, and had a higher frequency of livedo (25% vs. 10%, p < 0.001), cognitive dysfunction (21% vs. 8%, p = 0.001) and seizures (16% vs. 7%, p = 0.007), and a lower frequency of thrombocytopenia (9% vs. 18%, p = 0.037). Additionally, they were more frequently positive for lupus anticoagulant (87.5% vs. 74.6%, p = 0.01), and less frequently positive to anticardiolipin (46.6% vs. 73.7%, p < 0.001) and anti-ß2-glycoprotein-I (13.6% vs. 62.7%, p < 0.001) antibodies. Triple aPL positivity was also less frequent (8% vs. 41.6%, p < 0.001) in Brazilian patients. Median aGAPSS was lower in the Brazilian group (8 vs. 10, p < 0.0001). In the multivariate analysis, BPAPS patients still presented more frequently with livedo, cognitive dysfunction and sedentary lifestyle, and less frequently with thrombocytopenia and triple positivity to aPL. They were also less often white., Conclusions: Our study suggests a specific profile of PAPS in Brazil with higher frequency of selected non-criteria manifestations and lupus anticoagulant positivity. Lupus anticoagulant (not triple positivity) was the major aPL predictor of a classification criteria event., (© 2021. The Author(s).)

Autoantibodies targeting prothrombin (aPT) can be found in antiphospholipid syndrome (APS) patients. However, their detection has proven difficult to standardize. Here, we developed a new ELISA assay to improve the identification of aPT and compared its performance with currently available anti-phosphatidylserine/prothrombin antibodies (aPS/PT) and autoantibodies targeting prothrombin bound to the plastic plate (aPT-A) assays using a cohort of 27 APS patients at high risk of thrombosis. We generated a novel prothrombin variant, ProTS525A-Biot, carrying an artificial tag at the C-terminus suitable for site-specific biotinylation and added the mutation S525A to improve stability. ProTS525A-Biot was immobilized to neutravidin-coated plates at the desired density and with a defined orientation, i.e., pointing the N-terminal fragment-1 toward the solvent. Antibodies against ProTS525A-Biot (aPT-Bio) were found in 24 out of 27 triple-positive APS patients (88%). When compared to aPS/PT and aPT-A, aPT-Bio showed an excellent linear correlation with aPS/PT (R 2 = 0.85) but not with aPT-A (R 2 = 0.40). Since aPS/PT but not aPT-A are an emerging biomarker of thrombosis in APS, this method may find utility for detecting pathogenic aPT in APS but also other prothrombotic conditions such as COVID-19., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The handling editor declared a past co-authorship with one of the authors NP and declared a shared committee with the author VP., (Copyright © 2021 Chinnaraj, Pengo and Pozzi.)

Over the years, several devices have been created (and the development of many others is currently in progress) to be in permanent contact with blood: mechanical circulatory supports represent an example thereof. The hemocompatibility of these devices largely depends on the chemical composition of blood-contacting components. In the present work, an innovative material (hybrid membrane) is proposed to fabricate the inner surfaces of a pulsatile ventricular chamber: it has been obtained by coupling a synthetic polymer (e.g., commercial polycarbonate urethane) with decellularized porcine pericardium. The hemocompatibility of the innovative material has been preliminarily assessed by measuring its capacity to promote thrombin generation and induce platelet activation. Our results demonstrated the blood compatibility of the proposed hybrid membrane., (© 2021. The Author(s).)

Objective: Most high-risk thrombotic antiphospholipid syndrome (APS) patients test positive for anti-β2-glycoprotein I (aβ2GPI) and anti-phosphatidylserine/prothrombin (aPS/PT) antibodies. Information on the influence of these antibodies on thrombin generation and activated protein C resistance (aPCr) is still sparse and contradictory., Methods: Plasma of 16 patients poured into a β2GPI affinity column allowed the perfect separation of aβ2GPI and aPS/PT antibodies. aPS/PT antibodies were further purified through a prothrombin affinity column. Obtained material was spiked into normal pooled plasma (NPP) and tested in the thrombin generation assay in the absence or presence of aPC., Results: aPS/PT antibodies showed a marked anticoagulant effect. Affinity purified aPS/PT and aβ2GPI antibodies from five patients were compared. aPS/PT antibodies showed significantly prolonged lag time and time to peak (5.0 minutes [interquartile range (IQR)3.5-6.1] versus 2.7 minutes [IQR2.2-3.5], P = .03 and 8.7 minutes [IQR6.7-10.3] versus 5.7 minutes [IQR4.5-6.2], P = .05, respectively) and significantly lower peak and velocity index (143 nmol/L [IQR131-163] versus 171 nmol/L [IQR157-182], P = .03 and 35 nmol/L/min [IQR32-59] versus 72 nmol/L/min [IQR54-77], P = .03, respectively). When aPC was added to the system, aPCr was significantly increased compared to controls for both aβ2GPI and aPS/PT antibodies. However, it was significantly stronger using aPS/PT antibodies. Median inhibition of endogenous thrombin potential was 22% (IQR16-33) with aPS/PT compared to 52% (IQR46-56) with aβ2GPI antibodies (P = .002)., Conclusions: Aβ2GPI antibodies show a mild anticoagulant and moderate procoagulant effect in thrombin generation and moderate aPC resistance. Conversely, aPS/PT antibodies show a strong anticoagulant effect and a strong aPCr., (© 2020 International Society on Thrombosis and Haemostasis.)

Background: Trial of Rivaroxaban in AntiPhospholipid Syndrome was a prospective randomized, open-label, noninferiority study conducted in 14 centers in Italy. Rivaroxaban was compared with warfarin for the prevention of thromboembolic events, major bleeding, and vascular death in high-risk, triple-positive patients with antiphospholipid syndrome., Objective: The aim of this paper is to report the events during the 2-year follow-up after the study closure., Methods: On January 28, 2018, the trial was prematurely stopped by adjudication and safety committee for an excess of events in the rivaroxaban group. Randomized patients were advised on trial results and those randomized to rivaroxaban were solicited to switch to warfarin. All 14 participating centers were asked and accepted to follow their patients for clinical events. This report describes the rate of events that occurred between January 28, 2018, and January 28, 2020., Results: Of 120 randomized patients, 115 were available for follow-up. Outcome events were two in six (33.3%) patients who remained on direct oral anticoagulants (DOACs) and six in 109 (5.7%) patients on warfarin (hazard ratio [HR] 6.9; 95% confidence interval [CI] 1.4-34.5, P = .018). The two patients on DOACs (one taking dabigatran and one taking rivaroxaban) suffered from thromboembolic events, whereas of the six patients with composite outcomes on warfarin, three had thromboembolic events (HR for thrombosis 13.3; 95% CI 2.2-79.9, P = .005)., Conclusion: These data further support the use of warfarin in high-risk patients with antiphospholipid syndrome., (© 2020 International Society on Thrombosis and Haemostasis.)

Objective: The proportion and characteristics of Italian patients affected by venous thromboembolism (VTE) treated with direct oral anticoagulants (DOACs) or vitamin K antagonists (VKAs), and complications occurring during follow-up., Design: A prospective cohort of 2728 VTE patients included in the Survey on anticoagulaTed pAtients RegisTer (START2-Register) from January 2014 to June 2018 was investigated. Characteristics of patients, type of treatment and complications occurring during 2962 years of follow-up were analysed., Setting: About 60 Italian anticoagulation and thrombosis centres participated in the observational START2-Register PARTICIPANTS: 2728 adult patients with VTE of a lower limb and/or pulmonary embolism (PE), with a follow-up after the initial phase treatment., Interventions: Patients could receive DOACs or VKAs; both prescribed by the National and Regional Health Systems for patients with VTE., Outcomes Measures: Efficacy: rate of VTE recurrence (all thrombotic complications were also recorded)., Safety: the rate of major and clinically relevant non-major bleeding events., Results: Almost 80% of patients were treated with DOACs. The prevalence of symptomatic PE and impaired renal function was higher in patients receiving VKAs. Duration of anticoagulation was >180 days in approximately 70% of patients. Bleeding events were similar in both treatment groups. The overall eventuality of recurrence was significantly higher in DOAC cohorts versus VKA cohorts (HR 2.15 (1.14-4.06), p=0.018); the difference was almost completely due to recurrences occurring during extended treatment (2.73% DOAC vs 0.49% VKA, p<0.0001). All-cause mortality was higher in VKA-treated (5.9%) than in DOAC-treated patients (2.6%, p<0.001)., Conclusion: Italian centres treat most patients with VTE with DOACs and prefer VKA for those with more serious clinical conditions. Recurrences were significantly more frequent in DOAC-treated patients due to increased incidence after 180 days of treatment, probably due to reduced adherence to treatment. These results underline the importance of structured surveillance of DOAC-treated patients with VTE to strengthen treatment adherence during extended therapy., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

This guidance focuses on methodological aspects of lupus anticoagulant (LA) testing, as well as interpretation of results for clinicians. The main changes in how to test for LA compared with the International Society on Thrombosis and Haemostasis Scientific and Standardization Committee 2009 guidelines, in the preanalytical phase are more detailed recommendations on how to handle testing in anticoagulated patients, and the timing of testing. Also, routine coagulation tests are advised to obtain more information on the coagulation background of the patient, and when necessary, anti-Xa activity measurement for heparins or specific assays for direct oral anticoagulants should be performed. The three-step procedure with two test systems (diluted Russell's viper venom time and activated partial thromboplastin time [aPTT]) is essentially not changed. Silica remains the preferable activator in the aPTT assays, but ellagic acid is not excluded. We advise simultaneous performance of the mixing and confirmatory step, in each sample with a prolonged screening test. The confirmatory step can also be performed on a mixture of patient plasma and normal pooled plasma. Cutoff values should be established in-house on at least 120 normals, with transference of the manufacturer's cutoffs as an alternative. Reporting of results has not been changed, although more attention is focused on what clinicians should know. Patient selection for LA testing has been expanded., (© 2020 International Society on Thrombosis and Haemostasis.)

Clarity and guidance is required with regard to the use of direct oral anticoagulants in antiphospholipid syndrome (APS) patients, within the confines of the recent European Medicines Agency recommendations, discrepant recommendations in other international guidelines and the limited evidence base. To address this, the Lupus Anticoagulant/Antiphospholipid Antibodies Scientific and Standardization Committee (SSC) chair and co-chairs together with SSC Control of Anticoagulation members propose guidance for healthcare professionals to help them manage APS patients. Uncertainty in this field will be addressed. This guidance will also serve as a call and focus for research., (© 2020 International Society on Thrombosis and Haemostasis.)

β 2 -Glycoprotein I (β 2 GPI) is an abundant plasma protein displaying phospholipid-binding properties. Because it binds phospholipids, it is a target of antiphospholipid antibodies (aPLs) in antiphospholipid syndrome (APS), a life-threatening autoimmune thrombotic disease. Indeed, aPLs prefer membrane-bound β 2 GPI to that in solution. β 2 GPI exists in two almost equally populated redox states: oxidized, in which all the disulfide bonds are formed, and reduced, in which one or more disulfide bonds are broken. Furthermore, β 2 GPI can adopt multiple conformations ( i.e. J-elongated, S-twisted, and O-circular). While strong evidence indicates that the J-form is the structure bound to aPLs, which conformation exists and predominates in solution remains controversial, and so is the conformational pathway leading to the bound state. Here, we report that human recombinant β 2 GPI purified under native conditions is oxidized. Moreover, under physiological pH and salt concentrations, this oxidized form adopts a J-elongated, flexible conformation, not circular or twisted, in which the N-terminal domain I (DI) and the C-terminal domain V (DV) are exposed to the solvent. Consistent with this model, binding kinetics and mutagenesis experiments revealed that in solution the J-form interacts with negatively charged liposomes and with MBB2, a monoclonal anti-DI antibody that recapitulates most of the features of pathogenic aPLs. We conclude that the preferential binding of aPLs to phospholipid-bound β 2 GPI arises from the ability of its preexisting J-form to accumulate on the membranes, thereby offering an ideal environment for aPL binding. We propose that targeting the J-form of β 2 GPI provides a strategy to block pathogenic aPLs in APS., Competing Interests: Conflict of interest—The authors declare that they have no conflicts of interest with the contents of this article.

Background: The concurrent presence of lupus anticoagulant, anticardiolipin, and anti β2-glycoprotein I antibodies (triple positive profile) identifies patients at high risk of thromboembolic events. These patients are also positive for anti-phosphatidyl-serine/prothrombin antibodies (tetra-positive profile)., Objective: Understand which antibody among anti-β2-glycoprotein I and anti-phosphatidyl-serine/prothrombin is responsible for lupus anticoagulant activity., Patients/methods: Affinity purified anti-β2-glycoprotein I antibodies from plasma of 14 tetra-positive patients spiked into normal pooled plasma were tested., Results and Conclusions: Anti-β2-glycoprotein I antibodies did not prolong the diluted Russell viper venom time and silica clotting time (median ratio 0.98, interquartile ratio [IQR] 0.9-1.06; and 1.0, IQR 0.91-1.03, respectively). Anticoagulant activity remained in the flow-through that was deprived of anti-β2 glycoprotein I antibodies (median ratio 1.88, IQR 1.58-2.77; and 1.75, IQR 1.17-2.9, respectively). This material was loaded on size-exclusion chromatography Sephacryl S-300 column and showed that anticoagulant activity and anti-phosphatidyl-serine/prothrombin antibodies coeluted in the same fractions. Besides, the flow through was poured into a prothrombin affinity column. Protein yield in three patients ranged from 54 to 91 μg/mL and showed strong positivity in phosphatidyl-serine/prothrombin ELISA. The affinity purified material prolonged the coagulation time of normal pooled plasma: the diluted Russell viper venom ratio in the three patients was 2.09, 1.21, and 1.35; that of silica clotting time was 2.05, 1.5, and 2.13. In conclusion, under the assay conditions used, anticoagulant activity in tetra-positive antiphospholipid syndrome patients may largely be attributable to anti-phosphatidyl-serine/prothrombin antibodies., (© 2020 International Society on Thrombosis and Haemostasis.)