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Objectives: APS-associated heart valve disease (HVD) is well described. Nonetheless, limited data exist on clinical parameters associated with the course of primary APS (pAPS) patients with HVD. The goal of this study was to assess clinical features and related outcomes in patients with APS-associated HVD., Methods: In this multicentre retrospective study, we identified 33 pAPS patients with HVD (pAPS-HVD group) and compared their clinical course with 128 pAPS patients with normal heart valves on echocardiography (pAPS-control group)., Results: pAPS-HVD patients had more cerebrovascular events (56.3% vs 25%, P = 0.005) and livedo reticularis (24.2% vs 7.8%, P = 0.013) than pAPS-controls. Furthermore, catastrophic-APS (CAPS) (12.1% vs 2.4%, P = 0.034), recurrent thrombosis (33.3% vs 4.7%, P < 0.001) and need for advanced therapy (i.e. IVIG, plasmapheresis or rituximab) were more frequent in pAPS-HVD patients. Anti-β2-glycoprotein 1 IgG (84.8% vs 63.2%, P = 0.034), anti-cardiolipin IgG (90.9% vs 64.8%, P = 0.005) and triple positive aPL (75.8% vs 56.5%, P = 0.047) were commoner in pAPS-HVD patients vs pAPS-controls. Ten of the 33 patients with pAPS-HVD underwent valve surgery, which was associated with male gender, smoking, arterial limb ischaemia and livedo reticularis., Conclusion: pAPS-HVD patients had a more severe APS clinical course including CAPS and thrombotic events as well as a specific serology, namely IgG isotype aPL antibodies and triple positivity. Our data suggest that pAPS-HVD represents a high-risk subgroup of APS patients., (© The Author(s) 2023. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: We aimed to examine the efficiency of fixed daily dose enoxaparin (40 mg) thromboprophylaxis strategy for patients undergoing inpatient rehabilitation., Methods: This was an observational, prospective, cohort study that included 63 hospitalized patients undergoing rehabilitative treatment following sub-acute ischemic stroke (SAIS) or spinal cord injury (SCI), with an indication for thromboprophylaxis. Anti-Xa level measured three hours post-drug administration (following three consecutive days of enoxaparin treatment or more) was utilised to assess in vivo enoxaparin activity. An anti-Xa level between 0.2-0.5 U/ml was considered evidence of effective antithrombotic activity., Results: We found sub-prophylactic levels of anti-Xa (<0.2 U/ml) in 19% (12/63). Results were within the recommended prophylactic range (0.2-0.5 U/ml) in 73% (46/63) and were supra-prophylactic (>0.5 U/ml) in 7.9% (5/63) of patients. Anti-Xa levels were found to inversely correlate with patients' weight and renal function as defined by creatinine clearance (CrCl) (p<0.05)., Conclusions: Our study confirmed that a one-size-fits-all approach for venous thromboembolism (VTE) prophylaxis may be inadequate for rehabilitation patient populations. The efficacy of fixed-dose enoxaparin prophylaxis is limited and may be influenced by renal function and weight. This study suggests that anti-Xa studies and prophylactic enoxaparin dose adjustments should be considered in certain patients, such as those who are underweight, overweight and or have suboptimal renal function., Trial Registration: No. NCT103593291, registered August 2018., (© 2024. The Author(s).)

Multiple myeloma (MM) is associated with an increased risk of venous and arterial thrombosis. Pathophysiologic mechanisms include patient, disease and treatment related factors. Risk assessment models have been developed to determine whichpatients are at highest thrombotic risk and pursuant to this, risk adapted thrombosis prophylaxis has been suggested. Areas in which further basic and clinical research is imperative include the molecular and cellular mechanisms of thrombosis in myeloma, the inclusion of relevant biomarkers in risk assessment scores and controlled clinical trials of VTE prophylaxis and treatment using direct oral anticoagulants.

Data are needed on direct oral anticoagulants (DOACs) for the treatment of venous thromboembolism (VTE) in hematological malignancies (HM). Retrospective studies to date lacked a control group and did not focus on patients with VTE. Out aim was to assess the incidence of VTE recurrence and bleeding in HM patients treated with low molecular weight heparin (LMWH) or DOACs for acute VTE. This is a retrospective cohort study including patients with active HM and newly-diagnosed VTE, indexed on the first day of anticoagulation and followed for 12 months. The outcome was a composite of recurrent VTE, major bleeding or clinically relevant non-major bleeding. Cumulative incidence [95% confidence interval (CI)] was calculated for each anticoagulation group (LMWH, DOAC) and hazard ratios (HR) were calculated using cox-proportional hazards model, with death as a competing risk. 143 HM patients treated with LMWH (96) or DOACs (47) for acute VTE were included. The most common HM types were lymphoma in 83 (58%) and plasma cell dyscrasia in 32 (22.3%). The 12-month cumulative incidence of the composite outcome was 24.2% (95% CI 15.9-33.5%; n = 22) in the LMWH group and 18.5% (8.5-31.5%; n = 8) in the DOAC group (HR 1.51 [0.695-3.297]). Two recurrent VTE occurred (both in the DOAC group while off-treatment). Nine (9.4%) LMWH-treated patients had major bleeding compared to 1 (2.1%) DOAC-treated patient (HR 4.85 [0.64-36.56]). This study generates the hypothesis that DOACs may be a safe and effective alternative to LMWH for VTE in patients with HM types represented in the study., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Objective: Antiphospholipid syndrome (APS) is an acquired coagulopathy associated with the presence of antiphospholipid antibodies. Whether ethnicity modulates APS clinical course is not known. The aim of our study was to assess the interplay of ethnicity and APS in Israel., Methods: We retrospectively evaluated the ethnic distribution of APS patients from 3 medical centers in Israel compared to the general population. Ethnic groups were defined according to the Israeli Bureau of Statistics as Ashkenazi (European), former Union of Soviet Socialist Republics (USSR), North African, Asian (West Asia, Greece, and Turkey), Israeli Arab individuals, and others., Results: Our cohort included 382 patients. The prevalence of Ashkenazi and Asian ethnicities was more pronounced (33% versus 12.8% and 15.4% versus 7.7%, respectively; P < 0.001), while Israeli Arabs were less represented (5.2% versus 31.1%; P < 0.001) relative to their part in the general population. Arab patients were younger at presentation (mean ± SD 28 ± 10 years versus 34 ± 13 years; P < 0.001) and were more likely to present with venous thrombosis (50% versus 35%; P = 0.037) and to suffer from venous thrombotic recurrence (45% versus 16%; P < 0.001) compared to other ethnicities. Mortality was higher among patients of Asian ethnic origin (8.8% versus 1.1%; P = 0.005); intriguingly, this group experienced cardiovascular risk factors more often (i.e., dyslipidemia and hypertension)., Conclusion: Ethnicity may affect the prevalence and/or natural course of APS, which is less prevalent and differs clinically in Israeli Arab patients, while mortality was linked with Asian ethnicity., (© 2021 American College of Rheumatology.)

Introduction: Primary obstetric antiphospholipid syndrome (OAPS) is defined by specific morbidities and/or losses of pregnancy in the presence of persistent antiphospholipid antibodies (aPL). This variant of APS is usually treated during pregnancy and the post-partum period. Data on occurrence of thrombotic event during long term follow-up of OAPS patients is limited. Methods: A multi-centre retrospectively cohort of female patients with primary APS (pAPS) was assembled during 2004-2019. Patients were grouped according to disease presentation as pure OAPS or thrombotic APS (tAPS) for those presenting with thrombosis. Clinical and serological data were compared between groups. Results: Of 219 pAPS female patients 67 (30.6%) were diagnosed with OAPS and 152 (69.4%) with tAPS. During >10 years of follow-up 24/67 (35.8%) OAPS and 71/152 (50%) tAPS suffered a new thrombotic event ( p = 0.06 ) , while obstetric morbidity was more likely in the OAPS group (31.3 vs. 10.5%, p < 0.001) respectively. Among patients with OAPS at presentation heart valve disease and the presence of ANA were related to thrombosis following diagnosis (25 vs. 4.7%, p = 0.02; and 45.8 vs. 20.8%, p = 0.04 respectively). Conclusion: Thrombotic event following diagnosis were common among female patients with pAPS regardless of disease presentation. Heart valve disease and ANA positivity may be risk factors for thrombosis during follow-up of patients presenting with pure OAPS., 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 © 2022 Niznik, Rapoport, Avnery, Lubetsky, Shavit, Ellis and Agmon-Levin.)

Background: Antiphospholipid syndrome (APS) is an acquired hypercoagulable condition associated with antiphospholipid antibody (aPL) presence. Data on re-thrombosis following APS-diagnosis are limited., Methods: This is a retrospective analysis of new thrombotic events among primary APS (pAPS) patients followed for up to 15 years in three medical centers in Israel., Results: Among 312 primary-APS patients, 143 (46%) had new thrombotic event classified to three patterns: (1) Arterial- associated with heart valve disease (OR 7.24, 95% C.I. 2.26-24.6), hypertension (OR 3, 95% C.I. 1.44-6.25), elevated anti-B2-GPI IgM (OR 1.04, 95% C.I. 0.996-1.08), arterial thrombosis at presentation (OR 1.74 95% C.I. 0.992-3.26), and older age (41 vs. 34 years, p < 0.001). (2) Venous- linked with venous thrombosis at presentation (OR 12.9, 95% C.I. 5.27-31.6, p < 0.001), heart valve disease (OR 9.81 95% C.I. 1.82-52.9, p = 0.018), aGAPSS (OR 1.15 95% C.I. 1.02-1.29), and younger age (31 vs. 36.5 years, p = 0.001); and (3) Combined pattern -associated with heart valve disease (OR 40.5 95% C.I. 7.7-212) and pulmonary embolism (OR 7.47 95% C.I. 1.96-28.5). A 4th variant "the Breakthrough pattern" defined by re-thrombosis despite prophylactic therapy was observed in 100/143 (70%) patients and linked with heart valve disease (OR 8. 95% C.I. 2.43-26.3), venous thrombosis at presentation (OR 2.61 95% C.I. 1.47-4.66), leg ulcers (OR 12.2, 95% C.I. 1.4-107), hypertension (OR 1.99, 95% C.I. 0.92-4.34), and higher aGAPSS (OR 1.08, 95% C.I. 0.99-1.18)., Conclusion: In this real-life observation, re-thrombosis was common among pAPS patients including in those recommended to receive prophylactic therapy. Different patterns of recurrence were identified and linked with presenting symptoms, specific serological markers, APS manifestations, and comorbidities. Studies that will address interventions to prevent recurrences of APS-related events are needed., 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 © 2022 Niznik, Rapoport, Avnery, Lubetsky, Haj Yahia, Ellis and Agmon-Levin.)

Venous thromboembolism comprising deep venous thrombosis and pulmonary embolus is common. Patients with venous thromboembolism may present to a variety of health care providers, and while a significant proportion of patients begin treatment in the hospital, ambulatory management of both deep venous thrombosis and pulmonary embolus is feasible and becoming more common. Initial anticoagulant management, investigation of venous thromboembolism etiology, and decisions about extended anticoagulation require coordinated care by physicians from multiple specialties. Comprehensive management of venous thromboembolism requires coordinated care from the time of presentation in order to expedite diagnosis, initiate timely anticoagulant treatment, determine the need for extended anticoagulation based on risk of bleeding and recurrent thrombosis, and advise on thromboprophylaxis during future high-risk periods for venous thromboembolism. In this review we use case scenarios to provide an operational framework, based on current evidence-based recommendations, for informed decision-making about a number of clinical practice issues that are frequently encountered in the management of venous thromboembolism patients., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: Patients with venous thromboembolism (VTE) secondary to transient risk factors may develop VTE recurrences after discontinuing anticoagulation. Identifying at-risk patients could help to guide the duration of therapy., Methods: We used the RIETE database to assess the prognostic value of d-dimer testing after discontinuing anticoagulation to identify patients at increased risk for recurrences. Transient risk factors were classified as major (postoperative) or minor (pregnancy, oestrogen use, immobilization or recent travel)., Results: In December 2018, 1655 VTE patients with transient risk factors (major 460, minor 1195) underwent d-dimer measurements after discontinuing anticoagulation. Amongst patients with major risk factors, the recurrence rate was 5.74 (95% CI: 3.19-9.57) events per 100 patient-years in those with raised d-dimer levels and 2.68 (95% CI: 1.45-4.56) in those with normal levels. Amongst patients with minor risk factors, the rates were 7.79 (95% CI: 5.71-10.4) and 3.34 (95% CI: 2.39-4.53), respectively. Patients with major risk factors and raised d-dimer levels (n = 171) had a nonsignificantly higher rate of recurrences (hazard ratio [HR]: 2.14; 95% CI: 0.96-4.79) than those with normal levels. Patients with minor risk factors and raised d-dimer levels (n = 382) had a higher rate of recurrences (HR: 2.34; 95% CI: 1.51-3.63) than those with normal levels. On multivariate analysis, raised d-dimers (HR: 1.74; 95% CI: 1.09-2.77) were associated with an increased risk for recurrences in patients with minor risk factors, not in those with major risk factors., Conclusions: Patients with raised d-dimer levels after discontinuing anticoagulant therapy for VTE provoked by a minor transient risk factor were at an increased risk for recurrences., (© 2019 The Association for the Publication of the Journal of Internal Medicine.)

Objective: Although direct oral anticoagulants (DOAC) are the recommended antithrombotic therapy for patients with non-valvular atrial fibrillation (NVAF), anticoagulation in patients with NVAF is still inadequate. The effect of withholding DOAC therapy on patient survival is unknown. Therefore, our objective was to compare all-cause mortality rates between DOAC-treated patients with NVAF and similar patients receiving no anticoagulation., Methods: We performed a retrospective cohort study analysing Clalit Health Services' extensive electronic database, regarding all newly diagnosed, anticoagulant-naïve patients with NVAF who were eligible for DOAC therapy from 1 January 2011 to 31 December 2016. Patients who received DOAC therapy were matched by propensity scoring to patients receiving no anticoagulation. The primary outcome was all-cause mortality. Final patient follow-up date was 15 May 2017., Results: 18 901 eligible patients were identified. 8298 received treatment with a DOAC and 10 603 received no anticoagulation therapy. Of those, 5657 patients who received DOAC therapy were matched with 5657 patients who did not receive any anticoagulant. Death occurred in 715 patients in the DOAC-treated group (7.6% per year) and in 2075 patients in the non-anticoagulated patient group (11.1% per year). DOAC therapy was associated with significantly lower risk for all-cause mortality (HR=0.69, 95% CI 0.63 to 0.75, p<0.001). The benefit of DOAC therapy was demonstrated across all subgroups analysed., Conclusions: In this cohort of newly diagnosed patients with NVAF, DOAC therapy was associated with a significantly lower risk of death compared with no oral anticoagulation. Our findings provide further evidence for the importance of providing DOAC anticoagulation in patients with NVAF., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2019. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Direct oral anticoagulants (DOACs) reduce the risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation but may result in serious bleeding complications. Off-label dose-reduced use of DOACs to mitigate bleeding is common in routine clinical practice although data about its consequences on patient outcomes are limited. Therefore, our objective was to evaluate the effectiveness and safety of off-label dose-reduced vs per-label standard-dose DOAC treatment., Methods: The study cohort included newly diagnosed patients with nonvalvular atrial fibrillation that had initiated DOAC therapy between 2011 and 2017 in Clalit Health Services (Tel Aviv, Israel). Effectiveness was defined as the composite outcome of all-cause mortality, stroke, or myocardial infarction. The safety outcome was defined as bleeding events requiring hospitalization. Patients were followed until March 30, 2018 or until occurrence of an outcome event. Hazard ratios (HR) were adjusted for 21 variables, including comorbidities, concomitant medications, and socioeconomic factors, using multivariate regression., Results: A total of 8425 patients met the study criteria; 5140 (61%) patients were treated with DOACs at per-label dosing and 3285 (39%) patients were treated with off-label dose-reduced DOAC. Off-label dose-reduced treatment was associated with a higher rate of the composite effectiveness outcome: adjusted HR 1.57 (95% confidence interval, 1.34-1.83; P < .001) and a higher rate of bleeding: adjusted HR 1.63 (95% confidence interval, 1.14-2.34; P = .008)., Conclusions: Almost 4 of 10 patients were treated with off-label dose-reduced DOAC, which was associated with reduced effectiveness without a safety benefit. Compliance with per-label dosage may significantly improve outcomes of this population., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Introduction: The direct oral anticoagulants (DOACs) are a class of drugs used for the prevention of stroke and systemic embolism in patients with non-valvular atrial fibrillation and for prevention and treatment of venous thrombo-embolism. They are as effective and are safer than the vitamin K antagonists that were the oral drugs previously used for this purpose. The DOACs are convenient to use because of their fixed dose-response relationship which makes routine monitoring of drug levels unnecessary. Further, they have no food interactions and relatively few drug interactions. A number of practical considerations related to the routine clinical use of the DOACs have become apparent. These include choosing the appropriate drug and importantly dose-based on patient characteristics, managing the use of DOACs peri-operatively and the appropriate management of the acutely bleeding DOAC-treated patient. Recent controlled and observational studies provide guidance for dealing with these clinical situations thus enhancing the efficacy and safety of DOAC treatment in routine clinical practice.

Anticoagulation is often used in superior vena cava syndrome (SVCS) associated with cancer (i.e malignant SVCS), even without thrombosis, but its effect on outcomes has not been reported. We aimed to determine factors and outcomes associated with thrombosis and anticoagulation in malignant SVCS. Patients with malignant SVCS diagnosed on computerized tomography (CT) were retrospectively included, indexed at diagnosis and followed for 6 months using medical records. The cohort included 183 patients with malignant SVCS of which 153 (84%) were symptomatic. Thirty of the 127 patients (24%) with a reviewable baseline CT had thrombosis of the SVC or tributaries at diagnosis. Patients with baseline thrombosis more often had symptomatic SVCS (p < 0.01). 70% (21/30) of patients with thrombosis and 52% (49/97) of those without thrombosis at baseline received anticoagulation, most often at therapeutic doses. Thrombosis occurred in 5/39 patients with anticoagulation (13%) compared to 2/18 (11%) of those without, during follow-up (p = 0.85). Anticoagulation was associated with a reduction in risk of SVC stent placement during follow-up that did not reach statistical significance (HR 0.47, 95% CI 0.2-1.13, p = 0.09). Major bleeding occurred in 7 (4%) patients, six of whom received anticoagulation (four therapeutic and two intermediate dose). Neither thrombosis nor anticoagulation affected survival. Anticoagulation is commonly used as primary prevention but its benefit remains to be proven. The role of reduced-dose anticoagulation in non-thrombotic malignant SVCS should be prospectively assessed.

Background: Complications of deep vein thrombosis (DVT) are related to adequacy of initial anticoagulant therapy. In this study, we analyze consecutive patients with lower-limb proximal DVT and compare the characteristics, treatment, and clinical outcomes of patients receiving entirely ambulatory treatment versus those hospitalized for initial treatment., Methods: This was a retrospective study of consecutive patients with a first proximal lower-limb DVT during a 2-year period. Patients were followed for 90 days. Major end points were all-cause mortality, bleeding requiring hospitalization, and recurrent venous thromboembolism (VTE). Events were determined for patients who were hospitalized versus those treated on an entirely ambulatory basis., Results: A total of 236 patients were included in the study. Of these, 147 patients were hospitalized and 89 patients received ambulatory treatment. There were 20 fatalities-18 in-hospital and 2 in-ambulatory patients ( P = .008). By multivariable Cox regression analysis, the presence of active cancer (hazard ratio [HR] = 5.44; confidence interval [CI]: 2.16-13.7; P = .001), age (HR = 1.06; CI: 1.02-1.1; P = .001), and hospitalization (HR = 5.73; CI: 1.33-24.69; P = .019) were associated with death. Eight hospitalized and 2 ambulatory patients required readmission because of bleeding. Age was the only variable associated with bleeding (HR = 1.10; CI: 1.03-1.18; P = .004). There were no recurrent VTE events., Conclusion: In this study of routine management of proximal DVT, we demonstrate that patients suitable for ambulatory care are adequately identified by physicians and may be treated with equal safety and efficacy to hospitalized patients.

Imatinib, which has revolutionized chronic myeloid leukemia (CML) treatment, was suggested to improve lipid profile. Statins, a dyslipidemia drug, were reported to potentiate imatinib's antileukemic effect. However, analysis of imatinib combined with statins is lacking. We have retrospectively analyzed the normalization period of bcr-abl, blood counts, and lipids in 40 CML patients, 19 of which co-treated with statins, during short (<12 months) and prolonged (>12 months) imatinib treatment. Prior statins treatment did not hinder nor sensitized imatinib's anti-leukemic and lipid-lowering effects. CML cells (K562) treated with 1μM imatinib (24-96 h) were further assessed for the expression of central lipid-related genes by real-time PCR. HMGCoAR, LDL-R, and apobec1 expressions were significantly increased while CETP declined after 48-96 h. To conclude, imatinib produces an independent favorable lipid profile, which is not hindered by statins and is partly mediated via transcription regulation of genes involved in the clearance of plasma lipids.