Challenges in the diagnosis and management of anti-phospholipid syndrome: a case from Cameroon.
ABSTRACT: Anti-phospholipid syndrome (APLS) is a condition characterized by the presence of raised plasma levels of anti-phospholipid antibodies associated with thrombo-embolic disease and/or poor obstetrical outcomes in women. The epidemiology of APLS is unknown in most sub-Saharan African countries due to limited access to diagnosis tools. We report the case of APLS in a 29-year-old obese woman that was preceded by pre-eclampsia and fetal death. The diagnosis of APLS was made during a thrombo-embolic episode 4 years after the poor obstetrical outcome. Her management was challenging, as she had three thrombo-embolic events within 18-months despite treatment with anti-coagulant (acenocoumarol).This case highlights the need for screening for APLS after an episode of hypertensive disease in pregnancy or fetal death, and the challenges faced with the treatment, such as resistance to antivitamin K anti-coagulants and the desire for maternity.
Project description:Mitral annular calcification (MAC) has been considered a predisposition and an association of thrombo-embolic disease. Superimposed thrombus on MAC is under-appreciated as a potential cause of systemic thrombo-embolism. This report describes an elderly gentleman, who had recurrent cerebral embolism and in one of the episodes, a large mobile thrombus was detected on the ventricular surface of calcified mitral annulus. The thrombus disappeared after initiation of anti-coagulation.
Project description:Antiphospholipid antibodies (aPLs) comprise a diverse family of autoantibodies targeted against proteins with the affinity toward negatively charged phospholipids or protein-phospholipid complexes. Their clinical significance, including prothrombotic potential of anti-cardiolipin antibodies (aCLs), anti-?2-glycoprotein I antibodies (a?2-GPIs), and lupus anti-coagulant (LA), is well-established. However, the ontogeny of these pathogenic aPLs remains less clear. While transient appearance of aPLs could be induced by various environmental factors, in genetically predisposed individuals these factors may eventually lead to the development of the antiphospholipid syndrome (APS). Since the first description of APS, it has been found that a wide variety of microbial and viral agents influence aPLs production and contribute to clinical manifestations of APS. Many theories attempted to explain the pathogenic potential of different environmental factors as well as a phenomenon termed molecular mimicry between ?2-GPI molecule and infection-relevant structures. In this review, we summarize and critically assess the pathogenic and non-pathogenic formation of aPLs and its contribution to the development of APS.
Project description:Hemorrhagic events are frequent in patients on treatment with antivitamin-K oral anticoagulants due to their narrow therapeutic margin. Studies performed with acenocoumarol have shown the relationship between demographic, clinical and genotypic variants and the response to these drugs. Once the influence of these genetic and clinical factors on the dose of acenocoumarol needed to maintain a stable international normalized ratio (INR) has been demonstrated, new strategies need to be developed to predict the appropriate doses of this drug. Several pharmacogenetic algorithms have been developed for warfarin, but only three have been developed for acenocoumarol. After the development of a pharmacogenetic algorithm, the obvious next step is to demonstrate its effectiveness and utility by means of a randomized controlled trial. The aim of this study is to evaluate the effectiveness and efficiency of an acenocoumarol dosing algorithm developed by our group which includes demographic, clinical and pharmacogenetic variables (VKORC1, CYP2C9, CYP4F2 and ApoE) in patients with venous thromboembolism (VTE).This is a multicenter, single blind, randomized controlled clinical trial. The protocol has been approved by La Paz University Hospital Research Ethics Committee and by the Spanish Drug Agency. Two hundred and forty patients with VTE in which oral anticoagulant therapy is indicated will be included. Randomization (case/control 1:1) will be stratified by center. Acenocoumarol dose in the control group will be scheduled and adjusted following common clinical practice; in the experimental arm dosing will be following an individualized algorithm developed and validated by our group. Patients will be followed for three months. The main endpoints are: 1) Percentage of patients with INR within the therapeutic range on day seven after initiation of oral anticoagulant therapy; 2) Time from the start of oral anticoagulant treatment to achievement of a stable INR within the therapeutic range; 3) Number of INR determinations within the therapeutic range in the first six weeks of treatment.To date, there are no clinical trials comparing pharmacogenetic acenocoumarol dosing algorithm versus routine clinical practice in VTE. Implementation of this pharmacogenetic algorithm in the clinical practice routine could reduce side effects and improve patient safety.Eudra CT. Identifier: 2009-016643-18.
Project description:AIMS:To compare demographic characteristics, clinical presentation, and outcomes of patients with and without concomitant cardiac disease, hospitalized for COVID-19 in Brescia, Lombardy, Italy. METHODS AND RESULTS:The study population includes 99 consecutive patients with COVID-19 pneumonia admitted to our hospital between 4 March and 25 March 2020. Fifty-three patients with a history of cardiac disease were compared with 46 without cardiac disease. Among cardiac patients, 40% had a history of heart failure, 36% had atrial fibrillation, and 30% had coronary artery disease. Mean age was 67 ± 12 years, and 80 (81%) patients were males. No differences were found between cardiac and non-cardiac patients except for higher values of serum creatinine, N-terminal probrain natriuretic peptide, and high sensitivity troponin T in cardiac patients. During hospitalization, 26% patients died, 15% developed thrombo-embolic events, 19% had acute respiratory distress syndrome, and 6% had septic shock. Mortality was higher in patients with cardiac disease compared with the others (36% vs. 15%, log-rank P = 0.019; relative risk 2.35; 95% confidence interval 1.08-5.09). The rate of thrombo-embolic events and septic shock during the hospitalization was also higher in cardiac patients (23% vs. 6% and 11% vs. 0%, respectively). CONCLUSIONS:Hospitalized patients with concomitant cardiac disease and COVID-19 have an extremely poor prognosis compared with subjects without a history of cardiac disease, with higher mortality, thrombo-embolic events, and septic shock rates.
Project description:Atrial fibrillation (AF) is the most common arrhythmic disorder world-wide, accounting for 15 % of all strokes. Management of stroke risk in AF is complicated by intolerance of anti-coagulation (AC) therapy and difficulty maintaining therapeutic range in patients treated with warfarin. The left atrial appendage (LAA) is a source of thrombus in AFrelated thrombo-embolic events and surgical LAA exclusion (LAAO) is commonly performed during cardiac surgery in AF patients. Surgical approaches are limited by a high incidence of incomplete closure with a potential for consequent thrombo-embolic events as well as the morbidity of an open-heart procedure. More recently, percutaneous approaches to LAAO have been developed. The LARIAT device is an epicardial LAA exclusion system that enables percutaneous suture ligation of the LAA via combined, pericardial and trans-septal access. The device has 510k Federal Drug Administration (FDA) clearance for soft-tissue ligation and has been studied in canine models in pre-clinical studies as well as published series of clinical experience with LARIAT LAAO. The history, patient selection, procedural technique and complications of LARIAT LAAO are reviewed here. Additionally, insights and procedural improvements that have been elucidated from clinical series and outcomes from the collective experience are discussed. The LARIAT's epicardial approach to LAA ligation is unique compared with other percutaneous LAA exclusion devices, however more data regarding device safety and efficacy is needed for the LARIAT to emerge as an established therapy for stroke prevention in AF.
Project description:BACKGROUND AND PURPOSE:In order to assess the association of microparticles derived from activated platelets (PMP) or endothelial cells (EMP) with risk markers for recurrent embolic events in patients with symptomatic carotid artery disease, we studied the associations between PMP/EMP and three risk markers: plaque haemorrhage (PH), micro-embolic signals and cerebral diffusion abnormalities. METHODS:Patients with recently symptomatic high-grade carotid artery stenosis (60-99%, 42 patients, 31 men; mean age 75 ± 8 years) and 30 healthy volunteers (HV, 11 men; mean age 56 ± 12 years) were prospectively recruited. Patients were characterised by carotid magnetic resonance imaging (presence of PH [MRI PH]), brain diffusion MRI (cerebral ischaemia [DWI+]) and transcranial Doppler ultrasound (micro-embolic signals [MES+]). PMP and EMP were classified by flow cytometry and expressed as log-transformed counts per microlitre. RESULTS:MES+ patients (n = 18) had elevated PMP (MES+ 9.61 ± 0.57) compared to HV (8.80 ± 0.73; p < 0.0001) and to MES- patients (8.55 ± 0.85; p < 0.0001). Stroke patients had elevated PMP (9.49 ± 0.64) and EMP (6.13 ± 1.0) compared to non-stroke patients (PMP 8.81 ± 0.73, p = 0.026, EMP 5.52 ± 0.65, p = 0.011) and HV (PMP 8.80 ± 0.73, p = 0.007, and EMP 5.44 ± 0.47, p = 0.006). DWI+ patients (n = 16) showed elevated PMP (DWI+ 9.53 ± 0.64; vs. HV, p = 0.002) and EMP (DWI+ 5.91 ± 0.99 vs. HV 5.44 ± 0.47; p = 0.037). Only PMP but not EMP were higher in DWI+ versus DWI- patients (8.67 ± 0.90; p = 0.002). No association was found between PMP and EMP with MRI PH. CONCLUSIONS:PMP and EMP were associated with stroke and recent cerebrovascular events (DWI+) but only PMP were also associated with ongoing (MES+) thrombo-embolic activity suggesting a differential biomarker potential for EMP to index cerebral ischaemia while PMP may predict on-going thrombo-embolic activity.
Project description:Abstract Background Coronavirus disease 2019 (COVID-19) is a rapidly spreading pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). It is a multisystemic disease associated with micro- and macrovascular thrombo-embolic complications, including intracardiac thrombosis, which has not been previously reported in the literature. Case summary We report a case of a 68-year-old woman with COVID-19 admitted to our intensive care unit with acute respiratory distress, undifferentiated shock, hyperkalaemia, acute kidney injury, and coagulopathy. She received crystalloid infusion, broad-spectrum antibiotics, hydroxychloroquine, insulin–dextrose, calcium gluconate, sodium bicarbonate, and i.v. vasopressors. Continuous renal replacement therapy (CRRT) was started for refractory hyperkalaemia and metabolic acidosis. Transthoracic echocardiogram obtained for concern of pulmonary embolism found bi-atrial thrombosis with normal bi-ventricular dimensions and function. Systemic anticoagulation was provided, but this was stopped soon afterwards due to worsening coagulopathy and bleeding. Despite intensive measures and supportive therapy, the patient developed worsening hypoxia, refractory shock, and multiorgan failure. After discussion of goals of care with her family, a decision was made to initiate hospice care. The patient died within 72 h of hospital admission. Discussion Infection with SARS-CoV-2 is a multisystemic disease that primarily affects the lungs, but also predisposes to rare thrombo-embolic phenomena such as intracardiac thrombosis.
Project description:<h4>Background</h4>Severe coronavirus-induced disease 2019 (COVID-19) leads to acute respiratory distress syndrome with an increased risk of venous thrombo-embolic events. To a much lesser extent, arterial thrombo-embolic events have also been reported in this setting.<h4>Case summary</h4>Here, we describe four different cases of COVID-19 infection with ischaemic arterial events, such as a myocardial infarction with high thrombus load, ischaemic stroke on spontaneous thrombosis of the aortic valve, floating thrombus with mesenteric, splenic and renal infarction, and acute limb ischaemia.<h4>Discussion</h4>Cardiovascular risk factors such as hypertension, obesity, and diabetes are comorbidities most frequently found in patients with a severe COVID-19 infection and are associated with a higher death rate. Our goal is to provide an overview of the clinical spectrum of ischaemic arterial events that may either reveal or complicate COVID-19. Several suspected pathophysiological mechanisms could explain the association between cardiovascular events and COVID-19 (role of systemic inflammatory response syndrome, endothelial dysfunction, activation of coagulation cascade leading to a hypercoagulability state, virus-induced secondary antiphospholipid syndrome). We need additional studies of larger size, to estimate the incidence of these arterial events and to assess the efficacy of anticoagulation therapy.
Project description:Background and Purpose- Cellular Fn-EDA (fibronectin containing extra domain A) is expressed in activated endothelial cells and elevated in circulation in patients with cardiovascular diseases. Although global deficiency of Fn-EDA in mice improves stroke outcome, the specific contribution of plasma versus endothelium Fn-EDA in stroke outcome is currently unknown. We investigated the role of plasma versus endothelial Fn-EDA in stroke exacerbation in the comorbid condition of hyperlipidemia. Methods- We generated novel plasma Fn-EDA-/- ( Fn-EDA fl/fl Alb Cre) and endothelial Fn-EDA-/- ( Fn-EDA fl/fl Tie2 Cre) strains on hyperlipidemic apolipoprotein E-deficient ( ApoE-/-) background. By following the Stroke Therapy Academic Industry Roundtable guidelines, we evaluated stroke outcome in male and female mice. Susceptibility to ischemia/reperfusion injury was evaluated in 2 different models of stroke: intraluminal monofilament and embolic model on days 1, 3, and 7. Quantitative assessment of stroke outcome was evaluated by measuring infarct volume (by magnetic resonance imaging), cerebral blood flow (by laser speckle imaging), neurological and sensory-motor outcome, and postischemic thrombo-inflammation (platelet thrombi, fibrin, neutrophil, phospho-NF?B [nuclear factor ?B], TNF? [tumor necrosis factor ?], and IL1? [interleukin 1?]). Results- Stroke outcome was comparable in ApoE-/- Fn-EDA fl/fl Tie2 Cre and control ApoE-/- Fn-EDA fl/fl mice suggesting endothelial Fn-EDA does not contribute to stroke. ApoE-/- Fn-EDA fl/fl Alb Cre mice exhibited significantly smaller infarcts and improved neurological and sensory-motor outcome at days 1, 3, and 7 in monofilament and embolic models of stroke. Improved stroke outcome was concomitant with enhanced survival, and decreased postischemic thrombo-inflammatory response ( P<0.05 versus ApoE-/- Fn-EDA fl/fl). No sex-based differences were observed. Laser speckle imaging revealed significantly improved regional cerebral blood flow at 1 hour in ApoE-/- Fn-EDA fl/fl Alb Cre mice suggesting plasma Fn-EDA promotes postischemic secondary thrombosis. Coinfusion of anti-Fn-EDA antibody with r-tPA (recombinant tissue-type plasminogen activator) in ApoE-/- mice, 1 hour after embolization, improved stroke outcome with enhanced survival, and improved neurological outcome ( P<0.05 versus r-tPA). Conclusions- Genetic evidence suggests that plasma Fn-EDA exacerbates stroke outcome by promoting postischemic thrombo-inflammation. Interventions targeting plasma Fn-EDA may reduce brain damage after reperfusion.
Project description:Antiphospholipid syndrome (APS) is defined by clinical manifestations that include thrombosis and/or fetal loss or pregnancy morbidity in patients with antiphospholipid antibodies (aPL). Antiphospholipid antibodies are among the most common causes of acquired thrombophilia, but unlike most of the genetic thrombophilias are associated with both venous and arterial thrombosis. Despite an abundance of clinical and basic research on aPL, a unified mechanism that explains their prothrombotic activity has not been defined; this may reflect the heterogeneity of aPL and/or the fact that they may influence multiple pro- and/or antithrombotic pathways. Antiphospholipid antibodies are directed primarily toward phospholipid binding proteins rather than phospholipid per se, with the most common antigenic target being ?2-glycoprotein 1 (?2GPI) although antibodies against other targets such as prothrombin are well described. Laboratory diagnosis of aPL depends upon the detection of a lupus anticoagulant (LA), which prolongs phospholipid-dependent anticoagulation tests, and/or anticardiolipin and anti-?2-glycoprotein 1 antibodies. Indefinite anticoagulation remains the mainstay of therapy for thrombotic APS, although new strategies that may improve outcomes are emerging. Preliminary reports suggest caution in the use of direct oral anticoagulants in patients with APS-associated thrombosis. Based on somewhat limited evidence, aspirin and low molecular weight heparin are recommended for obstetrical APS. There remains a pressing need for better understanding of the pathogenesis of APS in humans, for identification of clinical and laboratory parameters that define patients at greatest risk for APS-related events, and for targeted treatment of this common yet enigmatic disorder.