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Thrombotic Antiphospholipid Syndrome (APS) is a condition affecting young individuals in whom a thromboembolic event occurs in the presence of circulating antiphospholipid antibodies (aPL). An extensive body of literature has covered the most common clinical presentation of the syndrome, venous thromboembolism. Arterial thrombosis in APS, a lesser clinical expression, is less studied. This review will concentrate on the body of literature concerning pathogenesis, clinical presentation and management of arterial thrombosis in APS., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

In the last decade, direct oral anticoagulants (DOACs) have entered the clinical practice of different specialists for the prevention of cardioembolic stroke in patients with non-valvular atrial fibrillation (NVAF) and the prevention and treatment of venous thromboembolism (VTE). Owing to the persistent uncertainties about the use of DOACs in daily clinical scenarios not fully explored in the clinical trials, we conducted a national Delphi consensus regarding issues deemed interesting by the Italian Atherosclerosis, Thrombosis and Vascular Biology (ATBV) Study Group in relation to: (i) elderly and/or frail patients; (ii) chronic kidney disease; (iii) drug-drug interactions; (iv) lower doses and safety; (v) criteria for choosing individual drugs and compliance; (vi) VTE in the cancer patient. Eighty-four Italian clinicians (cardiologists, internists, geriatricians, neurologists and hematologists) expressed their level of agreement on each statement using a 5-point Likert scale (1: very much in disagreement, 2: disagreement, 3: partial agreement, 4: agreement, 5: very much in agreement). In particular, 1-2 selections were considered as disagreement, while 3-5 selections were considered as agreement. A ≥66% agreement between the participants for each statement was considered consensus. In general, a broad and general awareness and sharing of the methods of use of DOACs emerged from our initiative, and in particular their preferential indication in the elderly population and in frail patients or with renal insufficiency or oncological, always following the prescription indications and dose reduction criteria. The importance of being aware of drug-drug interactions has also been underlined in a concordant way, as well as simplicity of treatment in the multi-treated patient. In view of the persistent, albeit limited (12%), absence of consensus on some issues, with regard to the frail patient, drug-food interactions and availability of antidote, the acquisition of further evidence and a persistent educational effort are nonetheless indicated.

Background: Coronavirus disease 2019 (COVID-19) global pandemic has strikingly high mortality rate with hypercoagulability state being part of the imputed mechanisms. We aimed to compare the rates of in hospital mortality in propensity score matched cohorts of COVID-19 patients in chronic anticoagulation versus those that were not., Methods: In this population-based study in the Veneto Region, we retrospectively reviewed all patients aged 65 years or older, with a laboratory-confirmed COVID-19 diagnosis. We compared, after propensity score matching, those who received chronic anticoagulation for atrial fibrillation with those who did not., Results: Overall, 4697 COVID-19 patients fulfilled inclusion criteria, and the propensity score matching yielded 559 patients per arm. All-cause mortality rate ratio was significantly higher among non-anticoagulated patients (32.2% vs 26.5%, p = 0.036). On time to event analysis, all-cause mortality was found lower among anticoagulated patients, although the estimate was not statistically significant. (HR 0.81, 95%CI 0.65-1.01, p = 0.054)., Conclusion: Among elderly patients with COVID-19, those on chronic oral anticoagulant treatment for atrial fibrillation seem to be at lower risk of all-cause mortality compared to their propensity score matched non-anticoagulated counterpart. This finding needs to be confirmed in further studies., Competing Interests: Declaration of Competing Interest None., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Objective: The APS ACTION Registry studies long-term outcomes in persistently antiphospholipid antibody (aPL)-positive patients. Our primary objective was to determine whether clinically meaningful aPL profiles at baseline remain stable over time. Our secondary objectives were to determine (1) whether baseline characteristics differ between patients with stable and unstable aPL profiles, and (2) predictors of unstable aPL profiles over time., Methods: A clinically meaningful aPL profile was defined as positive lupus anticoagulant (LAC) test and/or anticardiolipin (aCL)/anti-β 2 glycoprotein-I (anti-β 2 -GPI) IgG/M ≥ 40 U. Stable aPL profile was defined as a clinically meaningful aPL profile in at least two-thirds of follow-up measurements. Generalized linear mixed models with logit link were used for primary objective analysis., Results: Of 472 patients with clinically meaningful aPL profile at baseline (median follow-up 5.1 yrs), 366/472 (78%) patients had stable aPL profiles over time, 54 (11%) unstable, and 52 (11%) inconclusive. Time did not significantly affect odds of maintaining a clinically meaningful aPL profile at follow-up in univariate ( P = 0.906) and multivariable analysis ( P = 0.790). Baseline triple aPL positivity decreased (OR 0.25, 95% CI 0.10-0.64, P = 0.004) and isolated LAC test positivity increased (OR 3.3, 95% CI 1.53-7.13, P = 0.002) the odds of an unstable aPL profile over time., Conclusion: Approximately 80% of our international cohort patients with clinically meaningful aPL profiles at baseline remain stable at a median follow-up of 5 years; triple aPL-positivity increase the odds of a stable aPL profile. These results will guide future validation studies of stored blood samples through APS ACTION Core Laboratories., (Copyright © 2021 by the Journal of Rheumatology.)

Background: Peripheral arterial disease (PAD) was reported to increase the risk of new cardiovascular events in patients with acute coronary syndromes (ACS). However, most of the evidence comes from randomized clinical trials. We aimed to assess the impact of PAD on cardiovascular outcome and treatment decisions in ACS patients in a current real-life setting., Methods: START-ANTIPLATELET is a multicenter registry enrolling ACS patient. Baseline clinical characteristics and treatment at discharge were recorded and follow-up was repeated at 6-months and 1-year. PAD was defined as intermittent claudication and/or previous revascularization., Results: Among 1442 patients enrolled, 103 (7.1%) had PAD. PAD patients were older (71.8 ± 10.6vs66.2 ± 12.6 yrs., p < 0.0001), more frequently hypertensive (90.3vs68.6%, p< 0.0001), hypercholesterolemic (66vs52%, p= 0.037), diabetic (51.5vs24%, p= 0.0001), obese (28.2vs19.3%, p= 0.029) and with previous TIA (7.8vs2.8%, p= 0.005) or stroke (11.7vs3.1%, p< 0.0001). Clinical presentation and acute treatment were similar in non-PAD and PAD patients, but the latter were discharged significantly less frequently on dual antiplatelet therapy (DAPT) (68.9vs85%, p= 0.005). After a median follow-up time of 11.1 months, major cardio/cerebrovascular event-free survival [MACCE, including cardiovascular death, MI, TIA and stroke, target-vessel revascularization (TVR) and major arterial ischemic events] was significantly shorter (9.0vs11.2 months, p= 0.02; HR 3.2, 2.4-8.4) in PAD patients and net adverse cardiovascular events (NACE = MACCE plus major hemorrhages) were significantly more frequent (19.1%vs10.5%, p = 0.049)., Conclusions: PAD identifies a subgroup of ACS patients at significantly increased cardiovascular risk, but these patients tend to be undertreated. Patients admitted for ACS should be screened for PAD and optimal medical therapy at discharge should be implemented., Competing Interests: Declaration of Competing Interest G. Patti declares to be speaker, consultant, member of advisory board for Amgen, Sanofi, Bayer, Bohering-Ingelheim, BMS-Pfizer, Daiichi Sanyo, Astra Zeneca, Sigma-Tau, Malesci, PIAM and MDS. All the other authors declare no conflict of interest., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Optimal dual antiplatelet therapy (DAPT) strategy in high-bleeding risk (HBR) patients presenting with acute coronary syndrome remains debated. We sought to investigate the use of clopidogrel versus ticagrelor in HBR patients with acute coronary syndrome and their impact on ischemic and bleeding events at 1 year. In the START-ANTIPLATELET registry (NCT02219984), consecutive patients with ≥ 1 HBR criteria were stratified by DAPT type in clopidogrel versus ticagrelor groups. The primary endpoint was net adverse clinical endpoints (NACE), defined as a composite of all-cause death, myocardial infarction, stroke, and major bleeding. Of 1209 patients with 1-year follow-up, 553 were defined at HBR, of whom 383 were considered eligible for the study as on DAPT with clopidogrel (174 or 45.4%) or ticagrelor (209 or 54.6%). Clopidogrel was more often administered in patients at increased ischemic and bleeding risk, while ticagrelor in those undergoing percutaneous coronary intervention. Mean DAPT duration was longer in the ticagrelor group. At 1 year, after multivariate adjustment, no difference in NACEs was observed between patients on clopidogrel versus ticagrelor (19% vs. 11%, adjusted hazard ratio 1.27 [95% CI 0.71-2.27], p = 0.429). Age, number of HBR criteria, and mean DAPT duration were independent predictors of NACEs. In a real-world registry of patients with acute coronary syndrome, 45% were at HBR and frequently treated with clopidogrel. After adjustment for potential confounders, the duration of DAPT, but not DAPT type (stratified by clopidogrel vs. ticagrelor), was associated with the risk of ischemic and bleeding events at 1 year.

How to prevent recurrences after a first venous thromboembolic (VTE) event in elderly patients is still an open issue, especially because of the high bleeding risk of anticoagulation in these patients. The placebo-controlled "Jason" study aims at assessing the efficacy and safety for secondary VTE prevention in elderly patients of oral Sulodexide (Vessel ® ) administration, a mixture of glycosaminoglycans (Alfasigma, Bologna, Italy) which proved effective against recurrences in a general population (SURVET study) without major bleeding (MB) complications. 1450 patients, aged ≥ 75 years, after at least 3 months of anticoagulation treatment for a first VTE episode, are double-blind randomized to receive for 12 months either sulodexide 500 lipasemic units (LSUs) twice daily, or sulodexide 250 LSU twice daily + indistinguishable placebo, or indistinguishable placebo. Primary outcomes for efficacy are the composite of death for VTE and recurrent VTE, and occurrence of MB for safety. Secondary outcomes include stroke, cardiovascular death and other thromboembolic events, and MB + clinically relevant non-MB. The first patient is scheduled to be randomized in May 2020. The study protocol has been approved by AIFA (Agenzia Italiana del Farmaco) and the Ethics Committee of the coordinating center. Written informed consent will be obtained from all patients prior to study participation. Jason study is an investigator-initiated trial, promoted by "Arianna Anticoagulazione" Foundation, Bologna, Italy, and supported by Alfasigma, Bologna, Italy. Study findings will be disseminated to participant centers, at research conferences and in peer-reviewed journals. Trial registration numbers NCT04257487; EudraCT (2019-000570-33).

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.)

Background: Screening strategies to diagnose previously undetected atrial fibrillation (AF), especially silent AF (SAF), in at-risk populations may help reduce the number of strokes. We prospectively assessed the incidence rate of AF, including SAF, using an automated AF-detection capable sphygmomanometer in the General Practitioner (GP) setting., Methods: This was a population-based prospective study of unselected general population of ≥65 years without prior AF. Participating GPs were requested, in the period February 2018-April 2019, to record all AF diagnoses including those derived from the AF-detection capable sphygmomanometer and confirmed by 12‑lead ECG or ECG Holter in asymptomatic patients., Results: Overall, 14,987 patients assisted by 76 GPs accumulated 16,838 patient-years of follow up. The incidence rate of AF was 2.25% patient-years (95%CI 2.03-2.48). AF was more frequently detected in male, older, overweight, and patients with prior stroke, congestive heart failure, and chronic kidney disease. One in four patients had device-detected SAF (0.56% patient-years, 95%CI 0.46-0.69). Age, overweight, and the number of annual visits, were independent predictors of both SAF and AF. In addition, congestive heart failure, mitral valve disease were independent predictors of AF. Due to the interaction between blood pressure and age the risk of AF increased exponentially after 75 years of age in patients with higher systolic blood pressure values., Conclusion: We found a higher than previously reported incidence rate of AF possibly by capturing SAF. Our simple protocol might be feasible in large-scale screening for AF and SAF in routine GP care., (Copyright © 2020 Elsevier B.V. All rights reserved.)

In patients with coronavirus disease 2019 (COVID-19), the prevalence of pre-existing cardiovascular diseases is elevated. Moreover, various features, also including pro-thrombotic status, further predispose these patients to increased risk of ischemic cardiovascular events. Thus, the identification of optimal antithrombotic strategies in terms of the risk-benefit ratio and outcome improvement in this setting is crucial. However, debated issues on antithrombotic therapies in patients with COVID-19 are multiple and relevant. In this article, we provide ten questions and answers on risk stratification and antiplatelet/anticoagulant treatments in patients at risk of/with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection based on the scientific evidence gathered during the pandemic.

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.)

Anti phosphatidylserine/prothrombin antibodies (aPS/PT) are currently not included in the laboratory work-up of antiphospholipid symdrome (APS). However, several studies indicate that aPS/PT confer additional risk for thromboembolic events when added to classical antiphospholipid (aPL) antibody panel. We aimed to study thrombin generation (TG), a test that describes hyper or hypo-coagulability, in a cohort of antiphospholipid antibody (aPL) carriers with or without aPS/PT. As oral anticoagulants interfere with TG, we performed the study in carriers of aPL antibodies not on oral anticoagulants treatment. TG in tissue factor-triggered platelet-poor plasma and its inhibition by thrombomodulin was measured with a calibrated automated thrombogram method. Data are expressed as minutes (Interquartile Range). Of 55 aPL carriers, 37 were positive and 18 were negative for aPS/PT. Lag Time 5.4 min (4.1; 7.3) vs 3.4 min (3.0;4.5) is significant longer (p < 0.0001) and time to peak 9.6 min (8.1;11) vs 7.7 min (6.8;8.8) is significantly delayed (p = 0.0011) in aPS/PT positive as compared to aPS/PT negative carriers. Endogenous Thrombin Potential (ETP), peak thrombin formation and the velocity index are lower in aPS/PT positive carriers but did not reach statistical significance. Inhibition of ETP by thrombomodulin was significantly lower (protein C resistance) in aPS/PT positive vs aPS/PT negative group (22.8%±11.5 vs 34.9%±20.4, p = 0.01). In conclusion, aPS/PT positive carriers show an anticoagulant effect in TG while they exert a procoagulant effect in response to thrombomodulin-activated protein C., Competing Interests: Declaration of Competing Interest Senior Author (V.P.) received lecture fees from Werfen Group., (Copyright © 2020 Elsevier B.V. All rights reserved.)

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.)

Objective: This study aimed to use cluster analysis (CA) to identify different clinical phenotypes among antiphospholipid antibodies (aPL)-positive patients., Methods: The Alliance for Clinical Trials and International Networking (APS ACTION) Registry includes persistently positive aPL of any isotype based on the Sydney antiphospholipid syndrome (APS) classification criteria. We performed CA on the baseline characteristics collected retrospectively at the time of the registry entry of the first 500 patients included in the registry. A total of 30 clinical data points were included in the primary CA to cover the broad spectrum of aPL-positive patients., Results: A total of 497 patients from international centres were analysed, resulting in three main exclusive clusters: (a) female patients with no other autoimmune diseases but with venous thromboembolism (VTE) and triple-aPL positivity; (b) female patients with systemic lupus erythematosus, VTE, aPL nephropathy, thrombocytopaenia, haemolytic anaemia and a positive lupus anticoagulant test; and (c) older men with arterial thrombosis, heart valve disease, livedo, skin ulcers, neurological manifestations and cardiovascular disease (CVD) risk factors., Conclusions: Based on our hierarchical cluster analysis, we identified different clinical phenotypes of aPL-positive patients discriminated by aPL profile, lupus or CVD risk factors. Our results, while supporting the heterogeneity of aPL-positive patients, also provide a foundation to understand disease mechanisms, create new approaches for APS classification and ultimately develop new management approaches.

Background: Intracranial hemorrhage (ICH) is associated with severe prognosis and recurrent risk. This impacts on the decision to resume anticoagulation in atrial fibrillation (AF) or venous thromboembolism (VTE) patients. Purpose of our study is to evaluate the incidence rate of recurrent ICH in patients with AF or VTE resuming anticoagulation after a first ICH episode., Methods: We report data of two cohorts of AF or VTE after a first ICH. The Vitamin K antagonist (VKA) cohort (166 patients) derives from CHIRONE Study, the direct oral anticoagulant (DOAC) cohort (178 patients) derives from START2-Register RESULTS: The clinical characteristics of the two cohort are similar with the exception of more prevalence of history of previous stroke/TIA in DOAC patients with respect to VKA (p = 0.02) and serum creatinine levels>1.5 mg/dL in VKA patients with respect to DOAC(p = 0.0001). The index ICH was spontaneous in 66.4% and in 33.7% among DOAC and VKAs cohort respectively (p = 0.0001). During follow-up, 14 recurrent ICH were recorded; 9 (rate 2.5 × 100 patient-years) in VKA and 5 (rate 1.3 × 100 patient-years) in DOAC (Relative Risk 1.9; 95% CI 0.6-7.4; p = 0.2). The univariate logistic regression analysis showed that patients with recurrent ICH were more frequently males, hypertensive, with a history of previous Stroke/TIA and older than patients without recurrence. VKA patients showed a higher risk of recurrence with respect to DOAC patients (OR 1.9;95% CI 0.7-6.7)., Conclusions: A trend toward fewer ICH recurrences was detected among DOACs patients in comparison to the previously reported rate of patients on warfarin., Competing Interests: Declaration of Competing Interest None declared, (Copyright © 2020 The Author(s). Published by Elsevier B.V. All rights reserved.)

Antithrombotic treatment in patients with atrial fibrillation undergoing percutaneous coronary intervention is still debated. We conducted a meta-analysis of recent randomized controlled trials to evaluate the benefit of different antithrombotic strategies. Data were analyzed between May and September 2019. Efficacy outcomes were trial-defined major adverse cardiovascular events (MACE); its individual components; stent thrombosis. Safety outcomes were trial-defined primary bleeding outcome; TIMI and ISTH major bleeding; clinically relevant non-major bleeding; intracranial hemorrhage. Differences in outcomes among groups were expressed as pooled odds ratio (OR) and corresponding 95% confidence interval (CI). Four randomized studies were included (10,969 patients). The mean age ranged from 69 to 72 years, prevalence of acute coronary syndrome (ACS) varied from 48 to 62%. Comparing dual antithrombotic therapy (DAT) with a direct oral anticoagulant (DOAC) versus triple antithrombotic therapy (TAT) with vitamin K antagonist (VKA), OR for trial-defined MACE and primary bleeding outcome were 1.03 (95% CI, 0.86-1.24) and 0.59 (95% CI, 0.41-0.86), respectively. There was a 68% lower risk of intracranial hemorrhage and a non-statistically significant higher risk of stent thrombosis with DAT. DAT was as effective and safer than TAT in patients with stable coronary artery disease, while a trend towards increased ischemic events was seen in ACS patients. DAT with a DOAC showed similar efficacy and less bleeding than TAT with a VKA. However, increased stent thrombosis with DAT may be present, and TAT should be considered in patients at high ischemic risk, such as ACS patients.

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.)

Competing Interests: Declaration of Competing Interest Advisory Board and Lecture fees: Bayer HealthCare, Daiichi-Sankyo, Werfen Group.

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.

Given the high prevalence of preexisting cardiovascular diseases and the increased incidence of adverse cardiovascular events in patients hospitalized for SARS-CoV-2 infection, the identification of optimal antithrombotic approaches in terms of risk/benefit ratio and outcome improvement appears crucial in this setting. In the present position paper we collected current evidence from the literature to provide practical recommendations on the management of antithrombotic therapies (antiplatelet and anticoagulant) in various clinical contexts prevalent during the SARS-CoV-2 outbreak: in-home management of oral anticoagulant therapy; interactions between drugs used in the SARS-CoV-2 infection and antithrombotic agents; in-hospital management of antithrombotic therapies; diagnosis, risk stratification and treatment of in-hospital thrombotic complications.

Aims: To compare mortality between anticoagulated atrial fibrillation patients and general population and among anticoagulation specific categories [direct oral anticoagulants (DOACs) vs. vitamin K antagonists(VKA)]., Methods: This was a population-based study including all residents in the Veneto Region aged 18 years or older. Administrative claims from July 2013 to September 2017 were used to identify anticoagulation-naïve atrial fibrillation patients. Propensity score matching was employed to compare patients on new and old anticoagulants., Results: Overall, 17 225 patients on direct anticoagulants were 1 : 1 matched to patients on VKA (49% males, median age 77 years). Mortality was higher with respect to the general population by 22 and 39% among patients on direct anticoagulants and VKA, respectively. Mortality from intracranial hemorrhage in the direct anticoagulant group was similar to that in the general population [standardized mortality ratio: 1.06, 95% confidence intervals (CI) 0.76-1.48], whereas it almost doubled in VKA group (1.92, 95% CI 1.49-2.46). When directly compared with the VKA cohort, the risk of death from intracranial hemorrhage halved with DOACs (hazard ratio 0.56, 95% CI 0.37-0.84)., Conclusion: The mortality rate of anticoagulated atrial fibrillation patients is increased with respect to the general population, particularly among patients treated with VKAs. The mortality rate for intracranial bleeding with DOACs is similar to that observed in the general population.

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.)

Male patients, especially the young, are at a higher risk of recurrent venous thromboembolism (RVTE) than females. Recent scientific reports show the use of D-dimer does not help predict RVTE risk in males. In the present report, we reviewed the data obtained in the DULCIS study (main report published in Blood 2014), focusing on D-dimer results recorded in non-elderly patients of both genders included in the study, and their relationship with RVTE events occurring during follow-up. Using specifically designed cutoff values for positive/negative interpretation, serial D-dimer measurements (performed during warfarin treatment and up to 3 months after discontinuation of anticoagulation) in 475 patients (males 57.3%) aged ≤ 65 years were obtained. D-dimer resulted positive in 46.3% and 30.5% of males and females, respectively (p = 0.001). Following management procedure, anticoagulation was stopped in 53.7% of males and 69.5% of females, who had persistently negative D-dimer results. The rate of subsequent recurrent events was 1.7% (95% CI 0.5-4.5%) and 0.4% (95% CI 0-2.5%) patient-years in males and females, respectively, with upper limits of confidence intervals always below the level of risk considered acceptable by international scientific societies for stopping anticoagulation (< 5%). In conclusion, using sensitive quantitative assays with specifically designed cutoff values and serial measurements during and after discontinuation of anticoagulation, D-dimer testing is useful to predict the risk of RVTE and is of help in deciding the duration of anticoagulation in both male and female adult patients aged up to 65 years.

Introduction: To measure direct factor Xa inhibitor (apixaban, edoxaban, rivaroxaban) concentrations, dedicated chromogenic anti-Xa assays are recommended as suitable methods to provide rapid drug quantification. Moreover, the high-performance liquid chromatography with ultraviolet detection (HPLC-UV) is reported as a reliable quantitative technique. We investigated seven anti-Xa assays and an HPLC-UV method for measurement of apixaban and rivaroxaban levels in patients enrolled in the START-Register., Methods: A total of 127 apixaban and 124 rivaroxaban samples were tested by HPLC-UV and the following anti-Xa assays: Biophen DiXaI and Heparin LRT (Hyphen BioMed), Berichrom and Innovance Heparin (Siemens), STA-Liquid Anti-Xa (Stago Diagnostics), Technochrom anti-Xa (Technoclone), and HemosIL Liquid Anti-Xa (Werfen). Each method was performed in one of the participating laboratories: Bologna, Cremona, Florence, and Padua., Results: Our data confirmed the overestimation of apixaban and rivaroxaban levels by the antithrombin-supplemented anti-Xa method (Berichrom). Performances and reproducibility of the six anti-Xa assays not supplemented with antithrombin and the HPLC-UV method were good, with limits of quantification from 8-39 ng/mL (apixaban) and 15-33 ng/mL (rivaroxaban). The six chromogenic methods showed good concordances with the quantitative HPLC-UV [bias: -26.9-22.3 ng/mL (apixaban), -11.3-18.7 ng/mL (rivaroxaban)]. Higher bias and wider range between limits of agreement were observed at higher concentrations [<100 ng/mL: bias -21.3-4.1 ng/mL (apixaban) and -6.2-3.8 ng/mL (rivaroxaban); >200 ng/mL: bias -42.2-36.8 ng/mL (apixaban) and -20.1-68.9 ng/mL (rivaroxaban)]., Conclusion: Overall, the anti-Xa assays not supplemented with antithrombin and the HPLC-UV method proved to be suitable for apixaban and rivaroxaban quantification., (© 2020 John Wiley & Sons Ltd.)

Lupus anticoagulant is a misnomer as it is commonly associated with thromboembolic events. In few cases, the name retains its literal meaning when it characterizes patients with a bleeding disorder. We describe a patient with lupus anticoagulant, hypoprothrombinemia, and major bleeding (lupus anticoagulant/hypoprothrombinemia syndrome). Immunological studies revealed a huge amount of circulating monoclonal immunoglobulin M lambda (IgMλ) antiphosphatidylserine/prothrombin antibodies (14,400 U/mL). Affinity purified monoclonal antibodies (440 U/mL) prolonged the coagulation time of normal plasma by 12.2 seconds (diluted Russell viper venom time) and 25.5 seconds (silica clotting time). The original patient's plasma mixed 1:1 with normal plasma showed a marked prolongation of coagulation times (lupus cofactor) from a ratio of 2.94 to 5.23 in diluted Russel viper venom time and from 2.30 to 3.00 using the silica clotting time. Human prothrombin added to original patient's plasma caused a marked prolongation of coagulation times in diluted Russell viper venom test thus unequivocally explaining the lupus cofactor phenomenon. In conclusion, we have shown that lupus anticoagulant/hypoprothrombinemia syndrome is attributable to monoclonal IgMλ antibodies directed to phosphatidylserine/prothrombin and that prothrombin is the protein responsible for the observed lupus cofactor phenomenon., Competing Interests: Conflicts of Interest None declared.

Optimal medical therapy (OMT) at discharge is recommended after acute coronary syndrome (ACS). Few studies report the impact of OMT on long-term clinical outcome in a real-world scenario. We evaluated the impact of discharge OMT on top of dual-antiplatelet therapy (DAPT) on clinical outcome in the real-world ACS population of the Survey on anTicoagulated pAtients RegisTer ANTIPLATELET registry. The primary end point was major adverse cardiac and cerebrovascular event (MACCE), a composite of death, myocardial infarction, stroke, or target vessel revascularization. The co-primary end point was net adverse cardiac and cerebrovascular event (NACE), based on MACCE plus major bleeding. Consecutive patients with ACS with 1-year follow-up were enrolled. They were evaluated at discharge for the use of a β-blocker, angiotensin-converting enzyme inhibitor/angiotensin II receptor blockers and statins. Optimal medical therapy was defined as the use of ≥2 of 3 medications. At multivariate analysis, both MACCE and NACE were significantly higher in non-OMT patients than in OMT patients (MACCE 18 [19] vs 59 [9], hazard ratio [HR] = 0.44 [0.26-0.75], P = .002, NACE 19 [20] vs 67 [10], HR = 0.47 [0.28-0.79], P = .004). In this real-world scenario, OMT at discharge on top of DAPT seems associated with a better clinical outcome compared with patients discharged on non-OMT.

Platelet activation and decrease in platelet count characterize the development of the most feared form of antiphospholipid syndrome (APS), i.e. catastrophic APS (CAPS). We aimed to assess if immuno-affinity purified anti-β2-glycoprotein I (aβ2GPI) antibodies enhance platelet activation inducing a significant flow obstruction in a platelet function analyzer (PFA). Affinity purified aβ2GPI antibodies were obtained from 13 triple positive patients with a strong lupus anticoagulant (LA) and high titers of IgG anticardiolipin antibodies (aCL) and IgG aβ2GPI. Platelet activation stimulated by adenosine diphosphate (ADP) in the presence or absence of aβ2GPI was measured by the expression of P-selectin on platelet surface using flow cytometry. P-selectin expression remained close to baseline when normal whole blood was incubated with aβ2GPI alone. When stimulated using aβ2GPI combined with ADP, P-selectin expression (28.42 ± 5.15% vs. 20.98 ± 3.94%, p  = 0.0076) was significantly higher than ADP alone. Closure time of normal whole blood passed through the PFA was significantly shorter using affinity purified aβ2GPI than control IgG both in Col/ADP (160.1 ± 62.1 s vs. 218.6 ± 43.8 s; p  = 0.021) and Col/EPI cartridges (149.5 ± 26.7 s vs. 186.9 ± 45.5 s; p  = 0.030). Thus, platelet activation is enhanced by aβ2GPI antibodies with a consequent premature closure in a PFA, possibly resembling that in microcirculation in patients with CAPS.

Background: Variability remains a challenge in lupus anticoagulant (LA) testing., Objective: To validate LA test performance between Antiphospholipid Syndrome Alliance for Clinical Trials and International Networking (APS ACTION) Core laboratories and examine agreement in LA status between Core and local/hospital laboratories contributing patients to this prospective registry., Methods: Five Core laboratories used the same reagents, analyzer type, protocols, and characterized samples for LA validation. Non-anticoagulated registry samples were retested at the corresponding regional Core laboratories and anticoagulated samples at a single Core laboratory. Categorical agreement and discrepancies in LA status between Core and local/hospital laboratories were analyzed., Results: Clotting times for the reference/characterized plasmas used for normalized ratios were similar between Core laboratories (CV <4%); precision and agreement for LA positive/negative plasma were similar (all CV ≤5%) in the four laboratories that completed both parts of the validation exercise; 418 registry samples underwent LA testing. Agreement for LA positive/negative status between Core and local/hospital laboratories was observed in 87% (115/132) non-anticoagulated and 77% (183/237) anticoagulated samples. However, 28.7% (120/418) of samples showed discordance between the Core and local/hospital laboratories or equivocal LA results. Some of the results of the local/hospital laboratories might have been unreliable in 24.7% (41/166) and 23% (58/252) of the total non-anticoagulated and anticoagulated samples, respectively. Equivocal results by the Core laboratory might have also contributed to discordance., Conclusions: Laboratories can achieve good agreement in LA performance by use of the same reagents, analyzer type, and protocols. The standardized Core laboratory results underpin accurate interpretation of APS ACTION clinical data., (© 2019 International Society on Thrombosis and Haemostasis.)

The protective effect of obesity on mortality in acute coronary syndromes (ACS) patients remains debated. We aimed at evaluating the impact of obesity on ischemic and bleeding events as possible explanations to the obesity paradox in ACS patients. For the purpose of this substudy, patients enrolled in the START-ANTIPLATELET registry were stratified according to body mass index (BMI) into 3 groups: normal, BMI <25 kg/m 2 ; overweight, BMI: 25 to 29.9 kg/m 2 ; obese, BMI ≥30 kg/m 2 . The primary end point was net adverse clinical end points (NACE), defined as a composite of all-cause death, myocardial infarction, stroke, and major bleeding. In n = 1,209 patients, n = 410 (33.9%) were normal, n = 538 (44.5%) were overweight and n = 261 (21.6%) were obese. Compared to the normal weight group, obese and overweight patients had a higher prevalence of cardiovascular risk factors but were younger, with a better left ventricular ejection fraction and lower PRECISE-DAPT score. At 1-year follow-up net adverse clinical endpoints was more frequently observed in normal than in overweight and obese patients (15.1%, 8.6%, and9.6%, respectively; p = 0.004), driven by a significantly higher rate of all-cause death (6.3%, 2.6%, and 3.8%, respectively; p = 0.008), whereas no significant differences were noted in terms of myocardial infarction, stroke, and major bleeding. When correcting for confounding variables, BMI loses its power in independently predicting outcomes, failing to confirm the obesity paradox in a real-world ACS population. In conclusion, our study conflicts the obesity paradox in real-world ACS population, and suggest that the reduced rate of adverse events and mortality in obese patients may be explained by relevant differences in the clinical risk profile and medications rather than BMI per se., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Objectives: To assess whether patients with antiphospholipid syndrome (APS) and history of recurrent thrombosis have higher levels of adjusted Global AntiphosPholipid Syndrome Score (aGAPSS) when compared to patients without recurrent thrombosis., Methods: In this cross-sectional study of antiphospholipid antibody (aPL)-positive patients, we identified APS patients with a history of documented thrombosis from the AntiPhospholipid Syndrome Alliance For Clinical Trials and InternatiOnal Networking (APS ACTION) Clinical Database and Repository ("Registry"). Data on aPL-related medical history and cardiovascular risk factors were retrospectively collected. The aGAPSS was calculated at Registry entry by adding the points corresponding to the risk factors: three for hyperlipidemia, one for arterial hypertension, five for positive anticardiolipin antibodies, four for positive anti-β 2 glycoprotein-I antibodies and four for positive lupus anticoagulant test., Results: The analysis included 379 APS patients who presented with arterial and/or venous thrombosis. Overall, significantly higher aGAPSS were seen in patients with recurrent thrombosis (arterial or venous) compared to those without recurrence (7.8 ± 3.3 vs. 6 ± 3.9, p<0.05). When analyzed based on the site of the recurrence, patients with recurrent arterial, but not venous, thrombosis had higher aGAPSS (8.1 ± SD 2.9 vs. 6 ± 3.9; p<0.05)., Conclusions: Based on analysis of our international large-scale Registry of aPL-positive patients, the aGAPSS might help risk stratifying patients based on the likelihood of developing recurrent thrombosis in APS., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Secondary thromboprophylaxis with low molecular heparin or vitamin K antagonists (VKAs) is recommended in patients with definite antiphospholipid syndrome (APS). Direct oral anticoagulant (DOACs) have been approved in different prothrombotic conditions and have numerous advantages compared to VKAs. Whether DOACs can be used for secondary prophylaxis in APS is an open question. Data from the TRAPS randomized controlled Trial, meta-analysis and case reports indicate that we should not treat patients with triple positive APS and/or arterial thrombi with routine doses of DOACS. On the other hand, data from the literature including, case series, meta- analysis and the RAPS trial indicate that there are low risk patients, such as patients who suffered from a venous but not an arterial thromboembolism and are LAC negative who may benefit from the treatment with DOACs. Prospective trials addressing these low risk patients are needed in order to consider DOAC treatment in such patients., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Background: Patients with acute pulmonary embolism (PE) often have leg deep vein thrombosis (DVT); sometimes, however, a DVT is not detected (isolated PE, I-PE). We aimed at assessing the proportion of patients with I-PE, and their characteristics and clinical evolution compared to those with DVT with/without PE (DVT/PE)., Methods: Among 3573 patients included in the START2-Register for a venous thromboembolic event, 2880 (80.6%) had DVT/PE, the remaining I-PE (19.4%)., Results: Patients with I-PE were older [(≥75 years, OR 1.4 (95%CI 1.13-1.69)], and more frequently females [OR 1.4 (1.19-1.67)]. Young females (aged ≤ 50 years) with an index event occurring during hormonal contraception (HC), were more prevalent in I-PE [OR 1.96 (1.26-3.03)]. At multivariate analysis, age > 75 years, female sex, heart failure, cancer and use of HC were risk factors significantly associated with I-PE, whereas thrombophilic alterations were associated with DVT/PE. During a follow-up of 4504 years (during anticoagulation), the rate of bleeding events was 1.1% patient/years and 1.0% patient/years in I-PE and DVT/PE, respectively. Venous thromboembolic events were equally prevalent in DVT/PE or I-PE (1.94% vs 0.86%, ns), whereas arterial complications were more prevalent in the latter group (1.01% vs 0.28%, p = 0.008)., Conclusion: I-PE and DVT/PE have important differences. Older age, female sex, heart failure and cancer, were risk factors for I-PE; thrombophilic alterations were associated with DVT/PE. HC use was more frequent in the I-PE group. The prevalence of arterial complications was higher in patients with I-PE. Further studies, specifically designed on this issue, are warranted., (Copyright © 2019 The Authors. Published by Elsevier B.V. All rights reserved.)

The objective was to develop evidence-based recommendations for the management of antiphospholipid syndrome (APS) in adults. Based on evidence from a systematic literature review and expert opinion, overarching principles and recommendations were formulated and voted. High-risk antiphospholipid antibody (aPL) profile is associated with greater risk for thrombotic and obstetric APS. Risk modification includes screening for and management of cardiovascular and venous thrombosis risk factors, patient education about treatment adherence, and lifestyle counselling. Low-dose aspirin (LDA) is recommended for asymptomatic aPL carriers, patients with systemic lupus erythematosus without prior thrombotic or obstetric APS, and non-pregnant women with a history of obstetric APS only, all with high-risk aPL profiles. Patients with APS and first unprovoked venous thrombosis should receive long-term treatment with vitamin K antagonists (VKA) with a target international normalised ratio (INR) of 2-3. In patients with APS with first arterial thrombosis, treatment with VKA with INR 2-3 or INR 3-4 is recommended, considering the individual's bleeding/thrombosis risk. Rivaroxaban should not be used in patients with APS with triple aPL positivity. For patients with recurrent arterial or venous thrombosis despite adequate treatment, addition of LDA, increase of INR target to 3-4 or switch to low molecular weight heparin may be considered. In women with prior obstetric APS, combination treatment with LDA and prophylactic dosage heparin during pregnancy is recommended. In patients with recurrent pregnancy complications, increase of heparin to therapeutic dose, addition of hydroxychloroquine or addition of low-dose prednisolone in the first trimester may be considered. These recommendations aim to guide treatment in adults with APS. High-quality evidence is limited, indicating a need for more research., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2019. No commercial re-use. See rights and permissions. Published by BMJ.)

Antiphospholipid syndrome (APS) is an acquired thrombophilia with an uncertain role in the development of chronic thromboembolic pulmonary hypertension (CTEPH). We aimed to assess the association of APS with the clinical phenotype of CTEPH. We retrospectively reviewed data of CTEPH patients referred to our center. Clinical, angiographic, and hemodynamic data were available for all patients. APS was diagnosed in the presence of one or more positive antiphospholipid (aPL) tests confirmed more than 12 weeks apart. Data were compared between APS-positive and APS-negative patients. From May 2013 to December 2018, 297 patients with CTEPH were enrolled. Twenty-three (7.7%) were positive for laboratory tests exploring aPL antibodies. Among them, 17 patients (74%) had a triple positive aPL profile. When compared with the APS-negative group, APS patients were significantly younger (30.0 ± 11.1 vs. 55.6 ± 12.9 years, p  < 0.0001), had more frequently a history of pulmonary embolism (95.6% vs. 65.7%, p  = 0.003), and had more frequently associated autoimmune disease (43.5% vs. 2.9%, p  < 0.0001). In APS-positive patients, pulmonary artery lesions were more proximal and hemodynamic profiles were less compromised. Our results show that patients with APS are a unique group of CTEPH patients with well-defined clinic and hemodynamic characteristics., Competing Interests: None declared., (Georg Thieme Verlag KG Stuttgart · New York.)

Objective: Antiphospholipid antibodies (aPL) are risk factors for thrombosis and adverse pregnancy outcomes (APO). The management of the so called "aPL carriers" (subjects with aPL positivity without the clinical criteria manifestations of APS) is still undefined. This study aims at retrospectively evaluating the outcomes and the factors associated with APO and maternal complications in 62 pregnant aPL carriers. Methods: Medical records of pregnant women regularly attending the Pregnancy Clinic of 3 Rheumatology centers from January 1994 to December 2015 were retrospectively evaluated. Patients with concomitant autoimmune diseases or other causes of pregnancy complications were excluded. Results: An aPL-related event was recorded in 8 out of 62 patients (12.9%) during pregnancy: 2 thrombosis and 6 APO. At univariate analysis, factors associated with pregnancy complications were acquired risk factors (p:0.008), non-criteria aPL manifestations (p:0.024), lupus-like manifestations (p:0.013), and triple positive aPL profile (p:0.001). At multivariate analysis, only the association with a triple aPL profile was confirmed (p:0.01, OR 21.3, CI 95% 1.84-247). Patients with triple aPL positivity had a higher rate of pregnancy complications, despite they were more frequently receiving combined treatment of low dose aspirin (LDA) and low molecular weight heparin (LMWH) at prophylactic dose. Conclusion: This study highlights the importance of risk stratification in pregnant aPL carriers, in terms of both immunologic and non-immunologic features. Combination treatment with LDA and LMWH did not prevent APO in some cases, especially in carriers of triple aPL positivity. Triple positive aPL carriers may deserve additional therapeutic strategies during pregnancy.

Background: Anticoagulation therapy is central for the management of stroke in patients with non-valvular atrial fibrillation (NVAF). Persistence with oral anticoagulation is essential to prevent thromboembolic complications., Methods: We performed a population-based retrospective cohort study in the Veneto Region (north-eastern Italy, about 5 million inhabitants) using the regional health system databases. Naïve patients initiating direct oral anticoagulants (DOACs) for stroke prevention in NVAF from July 2013 to September 2017 were included in the study. Patients were identified using Anatomical Therapeutic Chemical (ATC) codes, excluding other indications for anticoagulation therapy using ICD-9CM codes. Treatment persistence was defined as the time from initiation to discontinuation of the therapy, including any therapeutic switching among DOACs. Baseline characteristics and comorbidities associated to the persistence of therapy with DOACs were explored by means of Kaplan-Meier curves and assessed through Cox regression., Results: Naïve patients initiating direct oral anticoagulants for stroke prevention in NVAF identified in a 4.25-year period are 17,920. After one year, the persistence to the DOACs is 72.9%. Approximately 9.8% of the discontinuations are due to switch to vitamin k antagonists (VKAs). On multivariate analysis, factors negatively affecting persistence were female gender, age <65 years, renal disease and history of bleeding. On the other hand, persistence was better in patients with hypertension, previous cerebral ischemic events, and previous acute myocardial infarction., Conclusion: In this study of real world data, one out four naive patients stopped treatment with DOACs within 12 months. Some characteristics may identify patients with poor persistence., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Background: Balloon pulmonary angioplasty (BPA) is a percutaneous treatment option for patients affected by chronic thromboembolic pulmonary hypertension (CTEPH) and either judged inoperable or with persistent symptoms after pulmonary endoarteriectomy. Current data regarding BPA are sparse and results vary according to local center experience. A systematic review of the literature was performed to better understand the effectiveness and safety of BPA in the treatment of CTEPH., Methods and results: PubMed and EMBASE were searched for studies reporting BPA results in patients with CTEPH. Differences in clinical and hemodynamic parameters before and after the procedure were analyzed. Weighted mean proportion and 95% confidence intervals (CIs) of adverse events were calculated. In total, 14 studies were included (725 patients). BPA was associated with a reduction in mean pulmonary artery pressure (from 43 to 32.5 mmHg), reduction in pulmonary vascular resistance (from 9.94 to 5.06 Woods units), increase in cardiac index (from 2.35 to 2.62 L/min/m 2 ), and improvement of 6-minute walking distance (from 345 to 442 m). Periprocedural mortality occurred in 2.1% of patients (95% CoI 0.8-4.1) while reperfusion and pulmonary vessel injuries occurred in 9.3% (95% CoI 3.1-18.4) and 2.3% (95% CoI 0.9-4.5) of total BPA sessions, respectively., Conclusions: Our systematic review suggested that BPA for CTEPH patients was an effective and relatively safe treatment option.

Background: Despite great advances with the introduction of ticagrelor and prasugrel in the treatment of acute coronary syndromes (ACS), the risk of thrombosis and bleeding remains significant and affects the choice of clinicians in the treatment of the single patient. Large registries are effective tools to explore patterns of drug administration and adherence to guideline recommendations in real-world clinical practice., Methods: START- antiplatelet is a prospective, observational registry carried out by seven Italian cardiology institutions on patients admitted for ACS aimed to document the real world treatment of ACS patients, adding also data on 12-month follow-up. We present data on the first 1050 patients who have completed 1-year follow-up on a total of 1537 patients. Primary end-points were: 1) MACCE (Major Adverse Cardiovascular and Cerebrovascular Events) including all-cause and cardiovascular mortality, non fatal MI, urgent revascularization, TIA and ischemic stroke; 2) Major and minor bleeding according to TIMI, GUSTO and ISTH classifications., Results: The dual antiplatelet treatment most prescribed was aspirin plus ticagrelor (47.9%) and aspirin plus clopidogrel (32.1%). At a mean follow-up was 335±131 days, both ticagrelor and prasugrel are associated with a statistically significant reduced total and cardiovascular mortality. Both prasugrel and ticagrelor do not show a significant increased incidence of major and minor bleedings with respect to clopidogrel. Patients with monotherapy had significantly higher incidence of both ischemic stroke and major bleedings., Discussion: The analysis of the register has documented that both ticagrelor and prasugrel are associated with a statistically significant reduced total and cardiovascular mortality but both do not show a significant increased incidence of major and minor bleedings with respect to clopidogrel., Competing Interests: The authors have declared that no competing interests exist.

Essentials Currently, DOACs are given at fixed doses and do not require laboratory monitoring. Direct oral anticoagulant-specific measurements were performed at trough and peak. Patients who developed bleeding events showed higher DOAC plasma levels at peak. This study suggests the need of a more accurate DOAC dose assessment., Background: Direct oral anticoagulants (DOACs) are administered at fixed dose. The aim of the study was to evaluate the relationship between DOAC C-trough or C-peak plasma levels and bleeding complications in patients with non-valvular atrial fibrillation (NVAF)., Methods: Five hundred sixty five consecutive naive NVAF patients were enrolled. The DOAC measurements at C-trough and at C-peak (available in 411 patients) were performed at steady state, within the first month of treatment. Major bleeding (MB), clinically relevant non-major bleeding (CRNMB), and minor bleeding (MinB), occurring during 1 year of follow-up after blood sampling, were recorded. For each DOAC, interval of C-trough and C-peak levels was subdivided into four equal classes and results were attributed to these classes; the median values of results were also calculated., Results: Two hundred eight patients were on apixaban, 185 on dabigatran, and 172 on rivaroxaban. For 1-[qqqdeletezzz] year follow up for all patients, we observed: 19 MB (3.36%), 6 CRNMB (1.06%), and 47 MinB (8.31%). The prevalence of bleeding patients with anticoagulant levels in the upper classes of C-peak activity (II + III + IV) was higher than that in the lowest class. Normalized results of C-peak levels were higher in patients with bleeding than in those without bleeding., Conclusions: Bleeding complications during DOAC treatment were more frequent among atrial fibrillation (AF) patients with higher C-peak anticoagulant levels. In addition to a previous study that showed an increased risk of thrombotic complications in the patients with low C-trough levels, this study seems to indicate that patients with NVAF on DOACs would need a more accurate definition of their optimal therapeutic window., (© 2019 The Authors. Journal of Thrombosis and Haemostasis published by Wiley Periodicals, Inc. on behalf of International Society on Thrombosis and Haemostasis.)

Anti-phosphatidylserine/prothrombin (aPS/PT) antibodies are often detected in patients with antiphospholipid syndrome (APS), but how aPS/PT engage prothrombin at the molecular level remains unknown. Here, the antigenic determinants of immunoglobulin G aPS/PT were investigated in 24 triple-positive APS patients at high risk of thrombosis by using prothrombin mutants biochemically trapped in closed and open conformations, and relevant fragments spanning the entire length of prothrombin. Two novel unexpected findings emerged from these studies. First, we discovered that some aPS/PT are unique among other anti-prothrombin antibodies insofar as they efficiently recognize prothrombin in solution after a conformational change requiring exposure of fragment-1 to the solvent. Second, we identified and characterized 2 previously unknown subpopulations of aPS/PT, namely type I and type II, which engage fragment-1 of prothrombin at different epitopes and with different mechanisms. Type I target a discontinuous density-dependent epitope, whereas type II engage the C-terminal portion of the Gla-domain, which remains available for binding even when prothrombin is bound to the phospholipids. Based on these findings, APS patients positive for aPS/PT were classified into 2 groups, group A and group B, according to their autoantibody profile. Group A contains mostly type I antibodies whereas group B contains both type I and type II antibodies. In conclusion, this study offers a first encouraging step toward unveiling the heterogeneity of anti-prothrombin antibodies in correlation with thrombosis, shedding new light on the mechanisms of antigen-autoantibody recognition in APS., (© 2019 by The American Society of Hematology.)

The cytochrome P450 (CYP)4F2 gene is known to influence mean coumarin dose. The aim of the present study was to undertake a meta-analysis at the individual patients level to capture the possible effect of ethnicity, gene-gene interaction, or other drugs on the association and to verify if inclusion of CYP4F2*3 variant into dosing algorithms improves the prediction of mean coumarin dose. We asked the authors of our previous meta-analysis (30 articles) and of 38 new articles retrieved by a systematic review to send us individual patients' data. The final collection consists of 15,754 patients split into a derivation and validation cohort. The CYP4F2*3 polymorphism was consistently associated with an increase in mean coumarin dose (+9% (95% confidence interval (CI) 7-10%), with a higher effect in women, in patients taking acenocoumarol, and in white patients. The inclusion of the CYP4F2*3 in dosing algorithms slightly improved the prediction of stable coumarin dose. New pharmacogenetic equations potentially useful for clinical practice were derived., (© 2018 The Authors Clinical Pharmacology & Therapeutics © 2018 American Society for Clinical Pharmacology and Therapeutics.)

How thrombophilia may contribute to the development of chronic thromboembolic pulmonary hypertension (CTEPH) is unknown. We searched on PubMed and EMBASE (until 15 April 2018), studies on CTEPH reporting data on inherited or acquired thrombophilia. Starting from 367 articles mentioning the search terms, 347 were excluded mainly as duplicate articles or articles not in English. After reading the full text of remaining articles, ten were excluded for being reviews, editorials, letters or case reports, and two were further removed from the analysis because of the potential selection bias. All the eight considered studies provided the proportion of patients positive for antiphospholipid (aPL) antibodies. The crude rate of aPL in CTPEH patients is 11.8% (95% CI 10.09-13.8%). The meta-analysis considering the weighted mean proportion and 95% confidence intervals (CIs) yields a rate of aPL antibody-positive profile of 12.06% (95% CI 8.12-16.65%) among the patients with CTEPH in the random effects model (I 2 76.33%; 95% CI 52.75-88.14%, p = 0.0001). The sensibility analysis confirms the result. No predictors of heterogeneity are found in a meta-regression analysis. Our results suggest that aPL antibodies are frequently associated with CTEPH underlining the need to test for aPL antibodies in young patients with "idiopathic" and "provoked" PE caused by mild provoking risk factors.

Aim: To analyse the clinical features, laboratory data and foetal-maternal outcomes, and follow them up on a cohort of 1000 women with obstetric antiphospholipid syndrome (OAPS)., Methods: The European Registry of OAPS became a registry within the framework of the European Forum on Antiphospholipid Antibody projects and was placed on a website in June 2010. Thirty hospitals throughout Europe have collaborated to carry out this registry. Cases with obstetric complaints related to antiphospholipid antibodies (aPL) who tested positive for aPL at least twice were included prospectively and retrospectively. The seven-year survey results are reported., Results: 1000 women with 3553 episodes were included of which 2553 were historical and 1000 were latest episodes. All cases fulfilled the Sydney classification criteria. According to the laboratory categories, 292 (29.2%) were in category I, 357 (35.7%) in IIa, 224 (22.4%) in IIb and 127 (12.7%) in IIc. Miscarriages were the most prevalent clinical manifestation in 386 cases (38.6%). Moreover, the presence of early preeclampsia (PE) and early foetal growth restriction (FGR) appeared in 181 (18.1%) and 161 (16.1%), respectively. In this series, 448 (44.8%) women received the recommended OAPS treatment. Patients with recommended treatment had a good live-birth rate (85%), but worse results (72.4%) were obtained in patients with any treatment (low-dose aspirin (LDA) or low-molecular-weight heparin (LMWH) not on recommended schedule, while patients with no treatment showed a poor birth rate (49.6%)., Conclusion: In this series, recurrent miscarriage is the most frequent poor outcome. To avoid false-negative diagnoses, all laboratory category subsets were needed. OAPS cases have very good foetal-maternal outcomes when treated. Results suggest that we were able to improve our clinical practice to offer better treatment and outcomes to OAPS patients., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Objective: To evaluate the subsequent rate of thrombosis among women with obstetric antiphospholipid syndrome (Ob-APS) in a multicentre database of antiphospholipid antibody (aPL)-positive patients, and the clinical utility of the adjusted Global Antiphospholipid Syndrome Score (aGAPSS), a validated tool to assess the likelihood of developing new thrombosis, in this group of patients., Design: Retrospective study., Setting: The Antiphospholipid Syndrome Alliance for Clinical Trials and International Networking Clinical Database and Repository., Population: Women with Ob-APS., Methods: Comparison of clinical and laboratory characteristics and measurement of aGAPSS in women with Ob-APS, with or without thrombosis, after initial pregnancy morbidity (PM)., Main Outcome Measures: Risk factors for thrombosis and aGAPSS., Results: Of 550 patients, 126 had Ob-APS; 74/126 (59%) presented with thrombosis, and 47 (63%) of these women developed thrombosis after initial PM, in a mean time of 7.6 ± 8.2 years (4.9/100 patient years). Younger age at diagnosis of Ob-APS, additional cardiovascular risk factors, superficial vein thrombosis, heart valve disease, and multiple aPL positivity increased the risk of first thrombosis after PM. Women with thrombosis after PM had a higher aGAPSS compared with women with Ob-APS alone [median 11.5 (4-16) versus 9 (4-13); P = 0.0089]., Conclusion: Based on a retrospective analysis of our multicentre aPL database, 63% of women with Ob-APS developed thrombosis after initial obstetric morbidity; additional thrombosis risk factors, selected clinical manifestations, and high-risk aPL profile increased the risk. Women with subsequent thrombosis after Ob-APS had a higher aGAPSS at entry to the registry. We believe that aGAPSS is a valid tool to improve risk stratification in aPL-positive women., Tweetable Abstract: More than 60% of women with obstetric antiphospholipid syndrome had thrombosis after initial pregnancy morbidity., (© 2018 Royal College of Obstetricians and Gynaecologists.)

We investigated whether gender influences antiplatelet treatment in patients with acute coronary syndrome (ACS). The primary end point was major adverse cardiac and cerebrovascular events (MACCEs), a composite of death, myocardial infarction (MI), stroke, or target vessel revascularization. The coprimary end point was net adverse cardiac and cerebrovascular events (NACEs), based on MACCE plus major bleeding. From January 2014 to December 2016, 840 consecutive patients with ACS who completed 1-year follow-up were enrolled, 625 (74%) males and 215 (26%) females. Percutaneous coronary interventions (PCI) and drug-eluting stents (DES) were more often used in males (PCI: 532 [87%] vs 168 [80%], P = .02 and DES 474 [76%] vs 143 [66%], P = .01). Males were more often treated with dual antiplatelet therapy (DAPT; 94% vs 88%, P = .01). In DAPT, ticagrelor was the most prevalent strategy, regardless of gender (47% vs 49%, P = .68); clopidogrel was preferred in women (42% vs 33%, P = .04); and prasugrel was preferred in men (11% vs 17%, P = .04). At multivariate analysis, MACCE and NACE were similar between genders. Therefore, although P 2 Y 12 inhibitor choice in DAPT might be influenced by gender, a DAPT choice, tailored by balancing the ischemic/bleeding risk, has a similar clinical outcome irrespective of gender.

Background: The APS ACTION International Clinical Database and Repository includes a secure web-based data capture system storing patient information including demographics, antiphospholipid antibodies (aPL)-related medical history, and aPL tests. Despite efforts at harmonization, inter-assay variability remains a problem in aPL testing. As a clinical repository open to researchers, ensuring comparability between assays and consistency in results between APS ACTION laboratories is essential to the validity of studies emerging from this network., Objective: To assess the level of agreement between an aPL-registry inclusion and core laboratory (core lab) anticardiolipin antibody (aCL) and anti-β 2 -glycoprotein-I antibody (aβ 2 GPI) ELISA testing results., Methods: Patients are recruited from 25 international centers based on positive aPL tests at inclusion. All samples are retested at the corresponding national APS ACTION core lab to confirm aPL positivity based on standard validated protocols. We analysed the categorical agreement, degree of linear association, and correlation between inclusion (local laboratory) and core lab aPL tests. Samples were included in this study only if results of aPL testing with ELISA at baseline were available., Results: 497 registry samples underwent confirmatory aPL tests. Categorical agreement between the inclusion and core lab values, as expressed by Cohen's kappa coefficients, ranged between 0.61 and 0.80 (as substantial agreement). The correlation between quantitative results in the aCL and aβ 2 GPI was better for IgM and IgA compared to IgG (Spearman rho 0.789 and 0.666 vs. 0.600 for aCL and rho 0.892 and 0.744 vs. 0.432 for aβ 2 GPI)., Conclusions: The results of inclusion for aCL and aβ 2 GPI tests used for recruitment into the registry were in agreement to the results obtained by the APS ACTION core laboratories; aCL and aβ 2 GPI results showed very good categorical agreement. This agreement increased when considering high titer (>40 units) samples. APS ACTION is a reliable and useful research resource for APS., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Introduction: Patients admitted with acute medical conditions are at prolonged risk for venous thrombosis. The efficacy and safety, and the appropriate duration of thromboprophylaxis have not been clearly determined. In recent years, direct coagulation factor inhibitors have been successfully tested for the prevention and treatment of arterial and venous thromboembolism. Betrixaban is a novel direct inhibitor of factor Xa with a noteworthy pharmacological feature: limited renal clearance. Areas covered: This review focuses on the pharmacological profile of Betrixaban, including its clinical efficacy and safety. It also covers the results of the pivotal APEX trial assessing the safety and efficacy of betrixaban for extended thromboprophylaxis in patients with acute medical conditions. Expert opinion: The role of extended thromboprophylaxis in acutely ill medical patients is subject to debate. The beneficial results in terms of VTE prevention were offset by the relevant increase in major bleeding. Betrixaban is the only direct oral anticoagulant to have shown a favorable risk-benefit profile in this setting especially in patients at higher risk for thrombosis.

Diabetes mellitus is an important risk factor for a first cardiovascular event and for worse outcomes after a cardiovascular event has occurred. This situation might be caused, at least in part, by the prothrombotic status observed in patients with diabetes. Therefore, contemporary antithrombotic strategies, including more potent agents or drug combinations, might provide greater clinical benefit in patients with diabetes than in those without diabetes. In this Consensus Statement, our Working Group explores the mechanisms of platelet and coagulation activity, the current debate on antiplatelet therapy in primary cardiovascular disease prevention, and the benefit of various antithrombotic approaches in secondary prevention of cardiovascular disease in patients with diabetes. While acknowledging that current data are often derived from underpowered, observational studies or subgroup analyses of larger trials, we propose antithrombotic strategies for patients with diabetes in various cardiovascular settings (primary prevention, stable coronary artery disease, acute coronary syndromes, ischaemic stroke and transient ischaemic attack, peripheral artery disease, atrial fibrillation, and venous thromboembolism). Finally, we summarize the improvements in cardiovascular outcomes observed with the latest glucose-lowering drugs, and on the basis of the available evidence, we expand and integrate current guideline recommendations on antithrombotic strategies in patients with diabetes for both primary and secondary prevention of cardiovascular disease.