Large-scale seroepidemiology identifies a nephro-vascular syndrome associated with autoimmune reactivity to tau

The microtubule-associated protein tau is involved in several neurodegenerative diseases and is currently being investigated as a plasma biomarker for the detection and monitoring of Alzheimer's disease and as an immunotherapeutical target in clinical trials. We assessed plasma anti-tau IgG reactivity in 40'098 unselected patients visiting a university hospital and healthy blood donors. We found that 4.97% patients and 1.58% healthy donors had natural anti-tau antibody titers >1.8 log10(EC50). In a multivariate model, female sex (P<0.001), age (P<0.001), cystitis (RR 1.59, 95%CI 1.14-2.16, P=0.004), other urinary disorders (RR 1.23, 95%CI 1.03-1.45, P=0.018), chronic kidney disease (RR 1.20, 95%CI 1.01-1.41, P=0.033), arterial embolism and thrombosis (RR 1.56, 95%CI 1.02-2.25, P=0.026) and atherosclerosis (RR 1.35, 95%CI 1.09-1.1.66, P=0.004) were independent predictors of anti-tau autoantibodies. We therefore conclude that anti-tau autoimmunity is associated with a systemic syndrome that includes vascular, kidney and urinary disorders. The expression of tau in these extraneural tissues suggests a potential role of autoimmunity in this syndrome.

The Correlation between Lower Extremity Fracture and Subsequent Arterial Embolism and Thrombosis—A National Population Cohort Study

The hazard of subsequent arterial embolism and thrombosis (SAET) in patients with lower leg fractures is not yet well demonstrated. The purpose of this study is to determine the correlation between lower leg fracture and SAET in Taiwan. A total of 134,844 patients with lower leg fractures (ICD-9-CM: 823) and chronological diagnosis as SAET (ICD-9-CM: 444.22) was matched (1:1) to the non-fracture cohort according to their propensity score (data coming from the National Health Insurance database between January 2000 to December 2012). Patients were matched by age, gender, and comorbidities. The incidence of SAET and correlation between SAET development and lower leg fracture was statistically analyzed, and subgroup analysis categorized by characteristics and comorbidities was conducted as well. The cumulative incidence of SAET was calculated by Kaplan–Meier analysis. Kaplan–Meier analysis plot showed that, by the end of the ten-year follow-up period, the cumulative incidence of SAET was significantly higher for the lower leg fracture cohort than for the non-fracture cohort (log-rank test: p < 0.001). The lower leg fracture, male, elder age (45–64-year-old; ≥65-year-old), hypertension, diabetes mellitus, and gout were significantly associated with lower extremity SAET risk compared with the matched group. There was an inseparable correlation between the lower leg fracture group and the risks of SAET; subgroup analysis by gender (male, female), age (age < 40 years, age 40–64 years, and age > 65 years) and comorbidities (hypertension, diabetes mellitus, and gout) show compatible results as well. Patients with lower leg fracture have a significantly increased risk of SAET since then two years after the fracture. The hazard of SAET was significantly higher in patients with lower leg fracture than in the non-fracture cohort, and the high incidence was found since then two years after fracture. Further studies are warranted.

Signal detection of drospirenone-containing oral contraceptives: a disproportionality analysis using the Korea Adverse Event Reporting System Database, 2008–2017

ObjectivesTo detect the signals for drospirenone-containing oral contraceptives (DCOCs) and describe the reporting pattern of adverse events (AEs) caused by DCOCs compared with levonorgestrel/desogestrel/gestodene-containing (second/third generation) oral contraceptives.DesignA descriptive analysis of claims data.SettingThe Korea Institute of Drug Safety & Risk Management-Korea Adverse Event Reporting System Database from 1 February 2008 to 31 December 2017.Outcome measuresSignals for DCOCs were identified using three data mining indices. The characteristics, death cases, and the annual pattern of AE reports were compared between DCOCs and second/third generation oral contraceptives.ResultsOf the 242 DCOC-related AEs, 54 signals were detected and 10 were identified as new signals that were not included in Korea, US and UK label. The newly detected signals include deep vein thrombophlebitis and frequent urination. Serious AEs were more likely to be reported with DCOCs (7.85%) than with second/third generation oral contraceptives (2.92%). Five deaths after use of DCOCs were reported with vascular AEs, such as pulmonary embolism and thrombosis, whereas one death after use of second/third generation oral contraceptives was reported with the cardiac arrest.ConclusionsWe identified 10 new signals related to DCOCs that were not included in the current label. Additionally, we found higher reports of the deaths and vascular AEs associated with DCOCs than with second/third generation oral contraceptives, which warrants careful monitoring to ensure the safe use of DCOCs.

ROLE OF PROPHYLACTIC ANTI COAGULANTS AND ANTI PLATELETS TO REDUCE THE INCIDENCE OF THROMBOSIS, STROKE, MYOCARDIAL INFARCTION IN ASYMPTOMATIC PATIENTS OF COVID19

BACKGROUND: As we are in the middle of the second year of the COVID19 Pandemic,we are observing an increased incidence of conditions like Cerebrovascular Accidents, Ischemic Heart Disease, Myocardial Infarction, Deep Vein Thrombosis,Pulmonary Embolism,and Thrombosis of Other Vessels. MATERIALS AND METHODS: Literature Review and Analysis of Coagulation Profiles of Patients in the past 1 year treated by the author was done. RESULTS AND CONCLUSIONS: 1. COVID19 is not just an infectious disease, but also an Immune Disease. The Immune Part can also happen in Asymptomatic Patients and those who got the vaccine. 2. Most of the disease processes in the body start after the virus has been cleared from the throat. The vigil against complications must not stop when the Throat Swab becomes negative or even when the patient is discharged but must continue for months till all the disease processes stop. 3.It is recommended that: a.Initial Evaluation with PT, aPTT, INR is done for: I.Those suffering from COVID 19 who have not undergone D Dimer evaluation ii.Those recovering from COVID 19. iii.Those likely to have had COVID 19 (based on the symptoms),but the infection was not documented. iv.Those likely to have had asymptomatic COVID 19 (contacts of COVID19 infected patients) v.Those planning to take Vaccines for COVID19. b.An Abnormal Value in PT,aPTT,INR may be managed with appropriate Drugs like Aspirin,Clopidogrel,Dipyridamole, Ticlopidine, Rivaroxaban, Dabigatran, Apixaban, Edoxaban, Heparin, Low Molecular Weight Heparin, Warfarin, and other drugs. c. Serial Evaluation of PT, aPTT, INR be done after 1 month, 3 months, 6 months (and even at more frequent intervals if indicated) and the drugs are added or removed,the dosage of the drugs is increased or reduced based on the results. d.Standard Indication of IVC Filter may be followed. 4.It is the knowledge of the pathogenesis of Thrombosis that is crucial in the prevention and management of Stroke, Heart Attack, Deep Vein Thrombosis, and Pulmonary Embolism rather than fancy gadgets, expensive tests, and exotic drugs.

Renal ischemic adverse drug events related to tranexamic acid in women of child-bearing age: an analysis of pharmacovigilance data

Purpose In response to a large trial, the World Health Organization broadened their recommendation on tranexamic acid to be used for post-partum hemorrhage. A 2013 French periodic safety update report warned of an abnormally high rate of renal cortical necrosis associated with tranexamic acid and other drugs for severe post-partum hemorrhage. We aimed to identify the reporting incidence of adverse thrombo-embolic events among women in child-bearing age who received tranexamic acid, with a focus on renal vascular and ischemic conditions. Methods We analyzed individual case safety reports (ICSRs) on renal vascular and ischemic conditions, pulmonary thrombotic and embolic conditions, and peripheral embolism and thrombosis from the database of the World Health Organization – Uppsala Monitoring Centre (WHO-UMC). ICSRs were restricted to reports including tranexamic acid as a suspected drug, sex reported as female, and reported age between 18 and 44 years. Reporting odds ratios (RORs) and 95% confidence intervals (95% CIs) were calculated by comparing ICSRs on tranexamic acid to all other drugs in VigiBase. Results Within 2245 included ICSRs on tranexamic acid, we identified 29 reports of adverse renal vascular and ischemic conditions, 42 reports of pulmonary thrombotic and embolic conditions, and 41 reports of peripheral embolism and thrombosis. RORs were statistically significant by 32.6-fold (32.62, 95% CI: 22.50–47.29), 2.5-fold (2.52, 95% CI: 1.85–3.42), and 2.7-fold (2.67, 95% CI: 1.96–3.64), respectively, when compared to any other drug within VigiBase. Conclusion Tranexamic acid might bear an increased risk for renal ischemic adverse drug events in women of child-bearing age.

Clinical features and prognosis of acute myocardial infarction due to coronary artery embolism

Background Coronary artery embolism (CE) is one of the important causes of acute coronary syndrome (ACS). The feature of CE is that angiographic evidence of coronary artery embolism and thrombosis without atherosclerotic components. However, the prevalence of CE remains unknown because of the diffifulty to diagnose in the acute settings. A recent retrospective analysis suggested that up to 3% of ACS cases may result from CE. Purpose The aim of this study was to elucidate the prevalence, clinical features and long-term outcomes including all-cause and cardiac death. Methods We analysed the consecutive 2695 patients with first AMI performed coronary intervention between January 2004 and July 2017. CE was diagnosed by clinical histories and angiographic findings. We retrospectively evaluated the clinical and lesion characteristics and outcomes including all-cause and cardiac death. Results The prevalence of CE was 2.0% (n=55; CE group and n=2640; non-CE group), including 8 (15%) patients with multivessel CE. The CE group had higher average age (70.8±14.9 vs. 68.4±12.6, p&lt;0.01), prevalence of female (54% vs. 27%, p&lt;0.01), lower prevalence of smoking (34% vs. 62%, p&lt;0.01). The common causes with CE were atrial fibrillation (47%), and malignant tumor (9%), and cardiomyopathy (5%), and patent foramen ovale (4%). Only 20% of patients with CE were treated with anti-coagulant therapy. The rate of distal infarction site (defined as #4, #8, #14–15) was significantly higher in CE group than non-CE group (54.0% vs. 4.9%, p&lt;0.01). During median follow-up of 53.6 [32.6–77.3] months, CE and thromboembolism recurred in 5 patients (CE: 1 patient, stroke 4 patients). The 4-year incidence of all-cause death was significantly higher in the CE group, but cardiac death was not significantly different between the groups (28.8% vs. 14.8%, p=0.03; 12.8% vs. 5.1%, p=0.11). Conclusion Compared with non-CE group, the prevalence of distal infarction site was significantly higher in the CE group, and the incidence of cardiac death is not significantly different. Funding Acknowledgement Type of funding source: None

Self-regulated hirudin delivery for anticoagulant therapy

Pathological coagulation, a disorder of blood clotting regulation, induces a number of cardiovascular diseases. A safe and efficient system for the delivery of anticoagulants to mimic the physiological negative feedback mechanism by responding to the coagulation signal changes holds the promise and potential for anticoagulant therapy. Here, we exploit a “closed-loop” controlled release strategy for the delivery of recombinant hirudin, an anticoagulant agent that uses a self-regulated nanoscale polymeric gel. The cross-linked nanogel network increases the stability and bioavailability of hirudin and reduces its clearance in vivo. Equipped with the clot-targeted ligand, the engineered nanogels promote the accumulation of hirudin in the fibrous clots and adaptively release the encapsulated hirudin upon the thrombin variation during the pathological proceeding of thrombus for potentiating anticoagulant activity and alleviating adverse effects. We show that this formulation efficiently prevents and inhibits the clot formation on the mouse models of pulmonary embolism and thrombosis.

Venous thromboembolism in patients with COVID-19 (SARS-CoV-2 infection) – a position paper of the German Society of Angiology (DGA)

Summary: As observed in other infections with a systemic inflammatory response, severe COVID-19 is associated with hypercoagulability and a prothrombotic state. Currently, there is growing evidence that pulmonary embolism and thrombosis contribute to adverse outcomes and increased mortality in critically ill patients with COVID-19. The optimal thromboprophylactic regimen for patients with COVID-19 is not known. Whereas pharmacologic thromboprophylaxis is generally recommended for all hospitalized COVID-19 patients, adequate dosing of anticoagulants remains a controversial issue. Therefore, we summarize current evidence from the available literature and, on behalf of the German Society of Angiology (DGA), we aim to provide advice to establish an improved and more uniform strategy for thromboprophylaxis in patients with COVID-19.

Red Blood Cell Polyunsaturated Fatty Acids and Vascular Diseases: A Mendelian Randomization Study

Objectives To evaluate the causal association of omega-3 and omega-6 polyunsaturated fatty acids (PUFAs), as measured in red blood cells (RBC), with cardiovascular disease (CVD), cerebrovascular disease (CBVD), and peripheral vascular disease (PVD). Methods Applying a two-sample Mendelian Randomization approach, we first developed genetic instruments for RBC-PUFAs by utilizing summary statistics from previous genome-wide association study in the Framingham Heart Study. We then evaluated the association of these instrumental variables with CVD, CBVD, PVD, and their subtypes in the UK Biobank cohort. Results Strong evidence of causal association with at least one RBC-PUFAs was observed for the overall risk of PVD and three of its subtypes (aortic aneurysm and dissection, arterial embolism and thrombosis, and other PVDs), but only for two CVD subtypes (hypertensive heart disease, and chronic ischemic heart disease) and for two CBVD subtypes (stroke, and cerebral infarction). Based on their effects on all examined diseases, RBC-PUFAs clustered into two groups: a protective group with alpha-Linolenic acid (ALA), linoleic acid (LA), eicosadienoic acid (EDA), and dihomo-gamma-linolenic acid (DGLA); and the other risk group with docosapentaenoic acid (DPA), gamma-linolenic acid (GLA), arachidonic acid (AA), and adrenic acid (AdrA). PUFAs in the protective group are protective, while those in the risk group are risk-increasing, for all diseases with significant associations except for hypertensive heart diseases. In the metabolic pathway converting short-chain PUFAs into long-chain ones, the protective group is mapped to precursors of desaturases, while the risk group corresponds to their products. Conclusions Genetically regulated RBC-PUFAs are associated with the risk of PVD, and subtypes of PVD, CVD, and CBVD. Funding Sources University of Georgia Research Foundation.

Abstract P114: Association of Atrial Fibrillation With Incidence of Extracranial Systemic Embolic Events (SEE) in the Atherosclerosis Risk in Communities (ARIC) Study

Objectives: Embolic stroke is a major complication of atrial fibrillation (AF). Mechanisms that lead to elevated stroke risk in AF are also likely to increase risk of extracranial systemic embolic events (SEE). However, little is known about the magnitude of the association of AF with SEE, needed to fully characterize the impact of AF on cardiovascular outcomes. We evaluated the association of AF with SEE and the prediction of SEE among persons with AF in a community-based cohort. Methods: We included 14,941 participants of the ARIC study (mean age, 54 ± 6, 55% women, 74% white) without AF at baseline (1987-89) and followed through 2017. AF was identified from study electrocardiograms, hospital discharges, and death certificates. SEE was defined as the presence of hospitalization discharge codes ICD-9-CM 444.xx or ICD-10-CM I74.x (Arterial embolism and thrombosis) in any position. CHA2DS2-VASc score, a predictor of stroke risk in AF, was calculated at the time of AF diagnosis. Cox models adjusting for fixed and time-varying covariates were used to estimate associations of incident AF with SEE risk and between CHA2DS2-VASc score and SEE risk in those with incident AF. Results: Among eligible participants, 3,114 developed AF and 270 had a SEE event. Incident AF was associated with increased risk of SEE [hazard ratio (HR) = 3.6, 95% confidence interval (CI) 2.6 - 5.0], after adjusting for baseline and time-dependent covariates (Table). The association of incident AF with SEE was stronger in women (HR 5.3, 95% CI 3.3 - 8.4) than in men (HR 2.7, 95% CI 1.7 - 4.3) (p for interaction = 0.002). In participants with incident AF, we identified 59 SEE events. Higher CHA 2 DS 2 -VASc score was associated with increased SEE risk (HR per 1-point increase = 1.2, 95% CI 1.1 - 1.5). Conclusions: AF is associated with more than a tripling of the risk of SEE, with a stronger association in women than in men. CHA 2 DS 2 -VASc is associated with SEE risk in AF patients, highlighting the value of the score to predict outcomes and guide treatments in persons with AF.