ABSTRACT
Background: Optimal secondary prevention antithrombotic therapy for patients with antiphospholipid syndrome (APS)-associated ischemic stroke, transient ischemic attack, or other ischemic brain injury is undefined. The standard of care, warfarin or other vitamin K antagonists at standard or high intensity (international normalized ratio (INR) target range 2.0-3.0/3.0-4.0, respectively), has well-recognized limitations. Direct oral anticoagulants have several advantages over warfarin, and the potential role of high-dose direct oral anticoagulants vs high-intensity warfarin in this setting merits investigation. Objectives: The Rivaroxaban for Stroke patients with APS trial (RISAPS) seeks to determine whether high-dose rivaroxaban could represent a safe and effective alternative to high-intensity warfarin in adult patients with APS and previous ischemic stroke, transient ischemic attack, or other ischemic brain manifestations. Methods: This phase IIb prospective, randomized, controlled, noninferiority, open-label, proof-of-principle trial compares rivaroxaban 15 mg twice daily vs warfarin, target INR range 3.0-4.0. The sample size target is 40 participants. Triple antiphospholipid antibody-positive patients are excluded. The primary efficacy outcome is the rate of change in brain white matter hyperintensity volume on magnetic resonance imaging, a surrogate marker of presumed ischemic damage, between baseline and 24 months follow-up. Secondary outcomes include additional neuroradiological and clinical measures of efficacy and safety. Exploratory outcomes include high-dose rivaroxaban pharmacokinetic modeling. Conclusion: Should RISAPS demonstrate noninferior efficacy and safety of high-dose rivaroxaban in this APS subgroup, it could justify larger prospective randomized controlled trials.
ABSTRACT
The association between Medically Assisted Reproduction (MAR) and thromboembolic complications has been reported widely in multiple published studies. Although venous thromboembolism (VTE) is not thought to be a common complication of MAR, it is associated with high morbidity and is often preventable. Since VTE usually occurs after completion of MAR treatment and is often managed outside of the treating fertility unit, these complications are likely to be underreported and there may be limited awareness of the risks among clinicians. As we continue to see a rise in the total number of MAR treatment cycles, particularly in women over 40 years of age, along with a steady increase in the number of fertility preservation cycles for both medical and social indications, it is likely that we will see an increase in absolute numbers of VTE complications. Currently, there is a lack of management guidance and reporting of VTE events associated with assisted conception treatment. The aim of this guidance is to provide clinicians with information on VTE risk factors, guidance on assessing VTE risk and the best practice recommendations on risk reducing strategies for individuals at risk of VTE undergoing ovarian stimulation and embryo transfer cycles.
Subject(s)
Reproductive Techniques, Assisted , Venous Thromboembolism , Female , Humans , Risk Factors , United Kingdom , Venous Thromboembolism/prevention & control , Societies, Medical/standardsABSTRACT
Antiphospholipid syndrome (APS) is a prothrombotic autoimmune disease with heterogeneous clinicopathological manifestations and is a well-established cause of acute ischemic stroke (AIS) and transient ischemic attack (TIA), particularly in younger patients. There is growing recognition of a wider spectrum of APS-associated cerebrovascular lesions, including white matter hyperintensities, cortical atrophy, and infarcts, which may have clinically important neurocognitive sequalae. Diagnosis of APS-associated AIS/TIA requires expert review of clinical and laboratory information. Management poses challenges, given the potential for substantial morbidity and recurrent thrombosis, additional risk conferred by conventional cardiovascular risk factors, and limited evidence base regarding optimal antithrombotic therapy for secondary prevention. In this review, we summarize key features of APS-associated cerebrovascular disorders, with focus on clinical and laboratory aspects of diagnostic evaluation. The current status of prognostic markers is considered. We review the evidence base for antithrombotic treatment in APS-associated stroke and discuss uncertainties, including the optimal intensity of anticoagulation and efficacy of direct oral anticoagulants. Clinical practice recommendations are provided, covering antithrombotic treatment, supportive management, and options for anticoagulant-refractory cases, and we highlight the benefits of adopting a considered, multidisciplinary team approach.
Subject(s)
Antiphospholipid Syndrome , Ischemic Attack, Transient , Ischemic Stroke , Stroke , Humans , Antiphospholipid Syndrome/complications , Antiphospholipid Syndrome/diagnosis , Antiphospholipid Syndrome/drug therapy , Stroke/drug therapy , Ischemic Stroke/drug therapy , Fibrinolytic Agents/therapeutic use , Ischemic Attack, Transient/complications , Antibodies, Antiphospholipid/therapeutic use , Anticoagulants/adverse effectsABSTRACT
OBJECTIVES: To determine whether early damage and its kinetics measured by the Damage Index for Antiphospholipid Syndrome (DIAPS) predicts mortality. METHODS: We carried out a single-centre retrospective analysis of thrombotic APS patients (2006 Sydney criteria), using the DIAPS for damage assessment. Early damage was considered to be at six months after disease onset; early damage increase (delta-DIAPS) was deemed to be at least a one-point rise in DIAPS within the first five years of illness. Groups were compared using appropriate statistical tests. Survival was analysed by the Kaplan-Meier method. Cox regression analysis was performed to investigate predictors of mortality. RESULTS: A total of 197 patients (71.1% female; 65.9% primary APS; 72.4% Caucasian) were followed for up to 43 years (median 10). Damage developed in 143 (73.6%) patients. Twenty-three patients (12%) died. Secondary APS (HR 3.07, 95%CI 1.32-7.12, p=0.009), male sex (HR 3.14, 95%CI 1.35-7.33, p=0.008) and age at APS onset ≥40 years (HR 5.34, 95%CI 1.96-14.53, p=0.001) were risk factors for death. Early damage (n=69, 35.0%) was not associated with death (p=0.231). Having a first arterial event was associated with early damage (p<0.001), but not with delta-DIAPS (p=0.539) nor with the risk of death (p=0.151). Delta-DIAPS (n=53/181, 29.3%) predicted mortality (HR 5.40, 95%CI 2.33-12.52, p<0.001), even after adjusting individually for APS category (secondary), sex (male), early damage and age at APS onset (≥40 years) (all p<0.005). CONCLUSIONS: Evolving damage in the first five years of illness, but not early damage, predicted mortality regardless of the nature of the first thrombotic event, sex, APS category and age.
Subject(s)
Antiphospholipid Syndrome , Thrombosis , Humans , Male , Female , Adult , Antiphospholipid Syndrome/complications , Antiphospholipid Syndrome/diagnosis , Retrospective Studies , Thrombosis/complications , Regression AnalysisABSTRACT
Limited evidence exists to guide the management of recurrent thrombosis occurring despite therapeutic anticoagulation in patients with thrombotic antiphospholipid syndrome (APS). In this case series, fondaparinux, with or without an antiplatelet agent, provided an effective and safe option in three patients with thrombotic APS, all two triple and one single positive for antiphospholipid antibodies, who had recurrent venous and/or arterial thromboembolism. Rituximab was also used in all patients. Recurrent events occurred despite therapeutic anticoagulation, including at high-intensity, with warfarin and subsequent low-molecular-weight heparin. There were no major bleeding events. Adjunctive therapies used for thrombosis included catheter-directed thrombolysis and rituximab.
Subject(s)
Antiphospholipid Syndrome , Lupus Erythematosus, Systemic , Thrombosis , Antibodies, Antiphospholipid/therapeutic use , Anticoagulants/therapeutic use , Antiphospholipid Syndrome/complications , Antiphospholipid Syndrome/drug therapy , Fondaparinux/therapeutic use , Heparin, Low-Molecular-Weight/therapeutic use , Humans , Lupus Erythematosus, Systemic/drug therapy , Platelet Aggregation Inhibitors/adverse effects , Rituximab/therapeutic use , Thrombosis/chemically induced , Thrombosis/etiology , Warfarin/therapeutic useABSTRACT
INTRODUCTION: Pharmacological prophylaxis of venous thromboembolism (VTE) requires nuanced decision-making to balance the risk of VTE against haemorrhage. This problem is compounded in neurosurgical patients, in whom postoperative intracranial haemorrhage (ICH) may be catastrophic, compared to non-neuraxial bleeding in other types of surgery. Current major guidelines recommend caution when using pharmacological prophylaxis in elective cranial surgery, but incorporate low-quality evidence and lack precise guidance on timing and duration of anticoagulation. METHODS: We aimed to answer the following questions for patients undergoing elective cranial surgery: (1) when is the optimal time to initiate postoperative anticoagulation, and (2) how long should postoperative anticoagulation be continued for? In this systematic review, we screened randomised and non-randomised studies reporting original data on pharmacological VTE prophylaxis in elective cranial surgery. Outcomes of interest were VTE and ICH. RESULTS: Three retrospective, single-centre observational studies met eligibility criteria, with a total of 923 participants. Meta-analysis was not performed due to a high risk of bias across all studies. Through narrative synthesis, we found that patients who developed VTE were significantly more likely to receive their first postoperative dose at a later time (mean: 144 vs. 29 h, p = .04). Shorter courses of anticoagulation (<7 days) were associated with significantly lower ICH rates (p = .03) compared to longer courses (>21 days). CONCLUSION: The limited evidence favours earlier initiation and shorter courses of thromboprophylactic anticoagulation. These findings are specific to patients undergoing surgery for meningioma or glioma and may not apply to other populations. Randomised controlled trials or robustly designed observational studies are necessary to establish a clearer evidence base.
Subject(s)
Venous Thromboembolism , Anticoagulants/therapeutic use , Elective Surgical Procedures/adverse effects , Hemorrhage/drug therapy , Humans , Retrospective Studies , Venous Thromboembolism/prevention & controlSubject(s)
Multiple Myeloma , Venous Thromboembolism , Anticoagulants/therapeutic use , Humans , Multiple Myeloma/complications , Multiple Myeloma/drug therapy , Prospective Studies , Pyrazoles , Pyridones/adverse effects , Venous Thromboembolism/drug therapy , Venous Thromboembolism/prevention & controlABSTRACT
Coagulation dysfunction and thrombosis are major complications in patients with coronavirus disease 2019 (COVID-19). Patients on oral anticoagulants (OAC) prior to diagnosis of COVID-19 may therefore have better outcomes. In this multicentre observational study of 5 883 patients (≥18 years) admitted to 26 UK hospitals between 1 April 2020 and 31 July 2020, overall mortality was 29·2%. Incidences of thrombosis, major bleeding (MB) and multiorgan failure (MOF) were 5·4%, 1·7% and 3·3% respectively. The presence of thrombosis, MB, or MOF was associated with a 1·8, 4·5 or 5·9-fold increased risk of dying, respectively. Of the 5 883 patients studied, 83·6% (n = 4 920) were not on OAC and 16·4% (n = 963) were taking OAC at the time of admission. There was no difference in mortality between patients on OAC vs no OAC prior to admission when compared in an adjusted multivariate analysis [hazard ratio (HR) 1·05, 95% confidence interval (CI) 0·93-1·19; P = 0·15] or in an adjusted propensity score analysis (HR 0·92 95% CI 0·58-1·450; P = 0·18). In multivariate and adjusted propensity score analyses, the only significant association of no anticoagulation prior to diagnosis of COVID-19 was admission to the Intensive-Care Unit (ICU) (HR 1·98, 95% CI 1·37-2·85). Thrombosis, MB, and MOF were associated with higher mortality. Our results indicate that patients may have benefit from prior OAC use, especially reduced admission to ICU, without any increase in bleeding.
Subject(s)
Anticoagulants/therapeutic use , COVID-19/complications , Thrombosis/complications , Thrombosis/drug therapy , Administration, Oral , Adult , Aged , Aged, 80 and over , Anticoagulants/adverse effects , COVID-19/diagnosis , COVID-19/epidemiology , COVID-19/therapy , Female , Hemorrhage/chemically induced , Hospitalization , Humans , Intensive Care Units , Male , Middle Aged , SARS-CoV-2/isolation & purification , Severity of Illness Index , Thrombosis/epidemiology , United Kingdom/epidemiologyABSTRACT
Antiphospholipid syndrome (APS) and myeloproliferative neoplasms (MPN) are associated with an increased risk of thrombosis. The optimal management of patients with coexistent APS and MPN has not been defined. A single centre and systematic literature review of patients with coexistent APS and MPN was performed. Cases were divided into two groups based on whether they met international consensus criteria for APS. Of the 12 studies identified, eight were excluded (leaving five of a total 54 patients), as although antiphospholipid antibodies (aPL) were documented, the diagnosis of APS was not conclusively demonstrated. Another ten patients with definite APS were identified at our centre. Fifteen patients (ten females, five males) were therefore included in this analysis (eleven definite APS and four highly likely), median age 44 (range: 13-71) years. Nine had polycythaemia vera and six, essential thrombocythaemia. Thirteen of the 15 patients (86.7%) had thrombotic APS (seven with initial venous events and six arterial) and two (13.3%) had obstetric APS. Nine patients were single-positive, and six double-positive for aPL. None were triple aPL-positive. Four patients at our centre had recurrent thrombotic/obstetric events, including while on anticoagulation/antiplatelet treatment.
Subject(s)
Antiphospholipid Syndrome , Polycythemia Vera , Thrombocytosis , Thrombosis , Adolescent , Adult , Aged , Antibodies, Antiphospholipid , Antiphospholipid Syndrome/complications , Antiphospholipid Syndrome/diagnosis , Antiphospholipid Syndrome/drug therapy , Cohort Studies , Female , Humans , Male , Middle Aged , Polycythemia Vera/complications , Polycythemia Vera/diagnosis , Pregnancy , Recurrence , Thrombocytosis/complications , Thrombocytosis/diagnosis , Thrombosis/etiology , Young AdultABSTRACT
The impact of COVID-19 infection on pregnant women remains relatively unknown but the physiological changes of pregnancy and hypercoagulability of COVID-19 may further increase thrombotic risk. In this retrospective multicentre observational study, we report clinical characteristics and outcomes in 36 pregnant women requiring hospitalisation for COVID-19 compared to a propensity-matched cohort of non-pregnant women. Pregnant women had a lower haemoglobin and higher lymphocyte counts but no differences in other haematological or biochemical parameters on admission compared to non-pregnant women. There was no significant difference in the duration of hospitalisation; median two days (1-77) for pregnant versus eight days (1-49) for non-pregnant women. A higher proportion of non-pregnant women required mechanical ventilation [11/36 (31%) vs 3/36 (8%), P = 0·03] and received thromboprophylaxis with low-molecular-weight heparin (LMWH) within 24 h of admission [25/36 (69%) vs 15 /36(42%), P = 0·03] compared to pregnant women. One pregnant woman required extracorporeal membrane oxygenation. The rate of thrombosis was similar in both groups (one in each group). No women developed major bleeding or died. Data suggest that although non-pregnant women had a severe clinical course, overall outcomes were not different between women with or without pregnancy. The use of thromboprophylaxis was inconsistent, demonstrating a need for establishing evidence-based guidance for COVID-19 during pregnancy.
Subject(s)
COVID-19/blood , Thrombosis/drug therapy , Adult , Female , Hospitalization , Humans , Middle Aged , Pregnancy , Pregnant Women , Retrospective Studies , United Kingdom , Young AdultABSTRACT
Thrombotic antiphospholipid syndrome (APS) is characterised by venous, arterial and/or small vessel thrombosis in the context of persistently positive antiphospholipid antibodies (aPL). The diagnosis and management of thrombotic APS continues to prove challenging for clinicians. We provide a practical guide to the diagnosis of APS including who to test for aPL and which tests to do. We also consider clinical practice points on the management of venous, arterial and small vessel thrombosis, in the context of first and recurrent thrombotic events. Non-criteria manifestations of APS are reviewed. An approach to recurrent thrombosis and anticoagulant-refractory APS is discussed, with options including increasing the anticoagulation intensity of vitamin K antagonists, switching to low-molecular-weight-heparin, the use of fondaparinux and/or the addition of antiplatelet treatment. Adjunctive options such as vitamin D, hydroxychloroquine and statins are also addressed.
Subject(s)
Antiphospholipid Syndrome , Thrombosis , Antibodies, Antiphospholipid , Anticoagulants/therapeutic use , Antiphospholipid Syndrome/diagnosis , Antiphospholipid Syndrome/drug therapy , Blood Coagulation , Humans , Thrombosis/diagnosis , Thrombosis/drug therapyABSTRACT
Lifelong anticoagulation with warfarin or alternative vitamin K antagonist is the standard anticoagulant treatment for thrombotic antiphospholipid syndrome. Anticoagulant-refractory thrombotic antiphospholipid syndrome can be broadly defined as breakthrough thrombosis while on standard oral anticoagulation treatment and its management is a major challenge given the serious nature of the thrombotic disease observed, which has become refractory to oral anticoagulation. The factors (genetic and cellular) that cause anticoagulant-refractory thrombotic antiphospholipid syndrome are now better understood. However, efforts to use this greater understanding have not yet transformed the capacity to treat it successfully in many patients. In this Viewpoint, we review the factors that are likely to be contributing to the cause of this syndrome and consider how they might be modified or inhibited. We also discuss management, including general strategies to minimise thrombotic risk, intensification of anticoagulation, addition of an antiplatelet agent, adjunctive treatment for thrombosis, immunomodulatory therapy, complement inhibition, vascular options, and future potential therapeutic targets.
Subject(s)
Anticoagulants/pharmacology , Antiphospholipid Syndrome/therapy , Drug Resistance/drug effects , Fibrinolytic Agents/therapeutic use , Platelet Aggregation Inhibitors/therapeutic use , Thrombolytic Therapy , Thrombosis/prevention & control , Antiphospholipid Syndrome/pathology , Humans , Thrombosis/pathologyABSTRACT
Arterial and venous thromboses occur in patients with POEMS (polyneuropathy, organomegaly, endocrinopathy, M-protein level, and skin changes) syndrome at a previously reported rate of 20%. We reviewed the University College London Hospitals (UCLH) POEMS Registry to determine the rate of venous thromboembolism (VTE), arterial events, and risk factors. This registry, established in 1999 and comprising 103 patients at the time of this study, is the largest single-center cohort in Europe. Of the 83 assessable patients, median age at presentation was 52 years (range, 31-84). Twenty-five patients experienced clinically apparent arterial or venous events, and 2 had concurrent arterial and venous thromboses. Eleven patients had VTEs, including deep vein thrombosis (DVT; 3 of 11), pulmonary embolism (4 of 11), and peripherally inserted central catheter-associated DVT, which occurred during autologous stem cell transplantation (3 of 11). Sixteen patients experienced arterial events: stroke (7 of 16), peripheral arterial occlusion (5 of 16), myocardial infarction (3 of 16), and microvascular disease (1 of 16), with no discernible relationship with thrombocytosis or polycythemia. Thirty percent of POEMS patients have arterial and venous thromboses, higher than previously reported. There were more arterial than venous events, and most occurred during active disease, before the start of chemotherapy, indicating the need for a preemptive approach to thromboprophylaxis.
Subject(s)
Hematopoietic Stem Cell Transplantation , POEMS Syndrome , Venous Thromboembolism , Anticoagulants , Humans , London , POEMS Syndrome/complications , POEMS Syndrome/epidemiology , Registries , Transplantation, Autologous , United Kingdom , Universities , Venous Thromboembolism/epidemiology , Venous Thromboembolism/etiologyABSTRACT
Routine thromboprophylaxis (TP) in newly-diagnosed multiple myeloma (NDMM) patients comprises either aspirin for standard risk patients or low molecular weight heparin for high risk patients. Studies using DOACs in cancer patients include few with myeloma. The aim of this feasibility clinical trial was to establish the foundations for creating a multicentre trial and identify any safety concerns with apixaban. Patient perspectives were sought. NDMM patients were stratified according to VTE risk and randomised to either standard TP or apixaban 2.5 mg BD and reviewed every 3 weeks throughout their chemotherapy. Two focus groups were carried out on 2 occasions at King's College Hospital and Guy's Hospital, London. Each lasted an hour, were recorded, transcribed and themes explored using NVivo 11. Ten patients were recruited, 2 considered high risk and received apixaban and 8 standard risk; 4 randomised to aspirin and 4 to apixaban. Five patients and 2 carers participated in the focus groups. There were no major bleeding or VTE events. Patients were not aware of the thrombotic risk associated with cancer. There is a lack of both written and verbal information on this topic. Myeloma patients were happy to be included in more than one trial simultaneously. Our study provides information on the difficulties facing physicians and patients on obtaining evidence of the safety of DOACs in the context of myeloma. Despite patients being happy to co-recruit into thromboprophylaxis trials along with chemotherapy trials this is not current practice.EudraCT Number: 2015-002668-18.
Subject(s)
Multiple Myeloma/complications , Randomized Controlled Trials as Topic , Venous Thromboembolism/prevention & control , Aged , Aspirin/therapeutic use , Clinical Trial Protocols as Topic , Feasibility Studies , Female , Focus Groups , Heparin, Low-Molecular-Weight/therapeutic use , Humans , Male , Middle Aged , Pyrazoles/therapeutic use , Pyridones/therapeutic use , Risk Assessment , Venous Thromboembolism/etiologySubject(s)
Cryoglobulinemia/diagnosis , Aged , Antibodies, Monoclonal, Murine-Derived/administration & dosage , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Blood Specimen Collection/methods , Cladribine/administration & dosage , Combined Modality Therapy , Cryoglobulinemia/etiology , Humans , Male , Plasmapheresis , Rituximab , Waldenstrom Macroglobulinemia/complications , Waldenstrom Macroglobulinemia/diagnosis , Waldenstrom Macroglobulinemia/drug therapyABSTRACT
BACKGROUND AND OBJECTIVES: Multidisciplinary care (MDC) is known to improve the management of chronic diseases. In this study, we investigated whether MDC improves outcomes in patients with advanced chronic kidney disease. DESIGN, SETTING, PARTICIPANTS AND MEASUREMENTS: In this retrospective case-control study we have compared the outcomes at the point of starting dialysis and beyond between a cohort of MDC patients (n = 171) and a cohort of nephrology patients (n = 194). The groups were well-matched demographically and were seen in the clinic for at least 3 months before starting dialysis. Dialysis access, blood pressure, haemoglobin, various biochemical parameters, hospital admissions, and survival were compared between the 2 groups. RESULTS: In the MDC group, 68.4% started dialysis with permanent access compared with 58.8% in the nephrologist group (p = 0.04). The mean haemoglobin in the MDC group was 10.28 +/- 1.86 versus 9.81 +/- 1.76 g/dl in the nephrology group (p = 0.02). There was no difference between the groups in terms of blood pressure control or serum calcium, phosphate, or albumin levels. There were fewer hospital admissions in the MDC cohort (1.42 vs. 2.52 admissions per patient per year, p = 0.005). Kaplan-Meier survival analysis showed that patient survival was significantly better in the MDC group (p = 0.033). CONCLUSIONS: This study demonstrates that patients attending a multidisciplinary clinic are better prepared for dialysis treatment, have fewer hospital admissions after start of dialysis, and have a higher patient survival compared to those attending a traditional nephrology clinic.