Previous studies have shown that patients with chronic lymphocytic leukemia (CLL) and coronavirus disease 2019 (COVID-19) have high mortality rates. Infection with the Omicron variant has been ...described as a milder disease course in the general population. However, the outcome for immunocompromised patients has not previously been reported. In a cohort of patients with CLL tested for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) at hospital test sites in the time periods before and after dominance of the Omicron variant, rates of hospitalizations and intensive care unit admissions declined significantly, whereas 30-day mortality remained as high as 23% in the period with dominance of the Omicron sublineage BA.2 variant. However, for a larger population-based cohort of patients with CLL (including the hospital cohort), 30-day mortality was 2%. Thus, patients with CLL with close hospital contacts and, in particular, those >70 years of age with 1 or more comorbidities should be considered for closer monitoring and preemptive antiviral therapy upon a positive SARS-CoV-2 test.
•In the era of the Omicron variant of COVID-19, lower fatality rates in CLL are seen along with milder disease in the background population.•Patients with CLL who have hospital contact and test positive for SARS-CoV-2 should still be considered for preemptive therapy.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
There is emerging evidence that early trauma-induced coagulopathy (TIC) is mechanistically linked to disruption of the vascular endothelium and its glycocalyx, assessed by thrombomodulin and syndecan ...1, respectively. This study evaluated if degradation of the endothelial glycocalyx and ensuing release of its heparin-like substances induce autoheparinization and thereby contributes to TIC.
Prospective observational study of 77 trauma patients admitted to a Level I trauma center having blood sampled at admission. Data on demography, hematology, Injury Severity Score, transfusion requirements, 30-day mortality, and thrombelastography (TEG, concurrent kaolin-activated/kaolin-heparinase-activated) were recorded. Retrospective analysis of plasma/serum for biomarkers reflecting endothelial glycocalyx and cell damage (syndecan 1, thrombomodulin), tissue injury (histone-complexed DNA fragments), sympathoadrenal activation (adrenaline, noradrenaline), coagulation activation/anticoagulation (prothrombin fragment 1+2, fibrinogen, von Willebrand factor, factor XIII, antithrombin, protein C, activated protein C, tissue factor pathway inhibitor), fibrinolysis (tissue-type plasminogen activator, plasminogen activator inhibitor 1) and inflammation (interleukin 6, terminal complement complex). Stratification of patients was according to the degree of TEG-measured heparinization.
Four patients (5.2%) displayed evidence of high-degree autoheparinization, and these patients had higher Injury Severity Score (median interquartile range, 31 26-37 vs. 17 10-26), increased glucose (median, 13.6 vs. 8.0 mmol/L), and lower hemoglobin level (median, 5.8 vs. 8.4 mmol/L) and received more transfusions during the first 1 hour (median, 5 vs. 0) and 24 hours (median, 10 vs. 0) (all p < 0.05). Importantly, patients with autoheparinization had fourfold higher syndecan 1 levels (median interquartile range, 116 ng/mL 78-140 ng/mL vs. 31 ng/mL 18-49 ng/mL), and they had higher international normalized ratio (median, 1.4 vs. 1.1), thrombomodulin (median, 4.1 vs. 1.7 ng/mL) and interleukin 6 (median, 129 vs. 71 pg/mL) but lower protein C (85% vs. 109%) (all p < 0.05), indicating profound endothelial damage, coagulopathy and inflammation.
Five percent of the patients with trauma in the present study had evidence of acute endogenous coagulopathy with autoheparinization by TEG, which appeared mechanistically linked to endothelial glycocalyx degradation. Acute endogenous autoheparinization may contribute to TIC.
Prognostic study, level III.
Sympathoadrenal activation and endothelial damage are hallmarks of acute critical illness. This study investigated their association and predictive value in patients resuscitated from out-of-hospital ...cardiac arrest (OHCA).
Post-hoc analysis of patients included at a single site in The Targeted Temperature Management at 33 degrees versus 36 degrees after Cardiac Arrest (TTM) trial. The main study reported similar outcomes with targeting 33 versus 36 degrees. TTM main study ClinicalTrials.gov: NCT01020916. One hundred sixty three patients resuscitated from OHCA were included at a single site ICU. Blood was sampled a median 135 min (Inter Quartile Range (IQR) 103-169) after OHCA. Plasma catecholamines (adrenaline, noradrenaline) and serum endothelial biomarkers (syndecan-1, thrombomodulin, sE-selectin, sVE-cadherin) were measured at admission (immediately after randomization). We had access to data on demography, medical history, characteristics of the OHCA, patients and 180-day outcome.
Adrenaline and noradrenaline correlated positively with syndecan-1 and thrombomodulin i.e., biomarkers reflecting endothelial damage (both p<0.05). Overall 180-day mortality was 35%. By Cox analyses, plasma adrenaline, serum sE-selectin, reflecting endothelial cell activation, and thrombomodulin levels predicted mortality. However, thrombomodulin was the only biomarker independently associated with mortality after adjusting for gender, age, rhythm (shockable vs. non-shockable), OHCA to return of spontaneous circulation (ROSC) time, shock at admission and ST elevation myocardial infarction (30-day Hazards Ratio 1.71 (IQR 1.05-2.77), p=0.031 and 180-day Hazards Ratio 1.65 (IQR 1.03-2.65), p=0.037 for 2-fold higher thrombomodulin levels).
Circulating catecholamines and endothelial damage were intercorrelated and predicted increased mortality. Interventions aiming at protecting and/or restoring the endothelium may be beneficial in OHCA patients.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Introduction of vaccines against COVID-19 has provided the most promising chance to control the world-wide COVID-19 pandemic. However, the adenovirus-vector based Oxford/AstraZeneca ChAdOx1 (AZ) and ...Johnson & Johnson Ad26.CoV2.S COVID-19 vaccines have been linked with serious thromboembolic events combined with thrombocytopenia, denominated Vaccine-induced Immune Thrombocytopenia and Thrombosis (VITT). The pathogenesis of COVID-19 VITT remain incompletely understood; especially the initial events that trigger platelet activation, platelet factor (PF)4 release, complex formation and PF4 antibody production are puzzling. This is a prospective study investigating the impact of different COVID-19 vaccines on inflammation (CRP, TNF-α, IL-1β, IL-6, IL-8, IL-10), vascular endothelial activation (syndecan-1, thrombomodulin, E-selectin, ICAM-1, ICAM-3, VCAM-1), platelet activation (P-selectin, TGF-β, sCD40L) and aggregation (Multiplate
impedance aggregometry), whole blood coagulation (ROTEM
), thrombin generation and PF4 antibodies to reveal potential differences between AZ and mRNA vaccines in individuals without VITT. The study included 80 (55 AZ and 55 mRNA) vaccinated individuals and 55 non-vaccinated age- and gender matched healthy controls. The main findings where that both vaccines enhanced inflammation and platelet activation, though AZ vaccination induced a more pronounced increase in several inflammatory and platelet activation markers compared to mRNA vaccination and that post-vaccination thrombin generation was higher following AZ vaccination compared to mRNA vaccination. No difference in neither the PF4 antibody level nor the proportion of individuals with positive PF4 antibodies were observed between the vaccine groups. This is the first study to report enhanced inflammation, platelet activation and thrombin generation following AZ vaccination compared to mRNA vaccination in a head-to-head comparison. We speculate that specific components of the AZ adenovirus vector may serve as initial trigger(s) of (hyper)inflammation, platelet activation and thrombin generation, potentially lowering the threshold for a cascade of events that both trigger complications related to excessive inflammation, platelet and coagulation activation as observed in epidemiological studies and promote development of VITT when combined with high-titer functionally active PF4 antibodies.
Introduction Postoperative complications affect up to 15% of surgical patients constituting a major part of the overall disease burden in a modern healthcare system. While several surgical risk ...calculators have been developed, none have so far been shown to decrease the associated mortality and morbidity. Combining deep neural networks and genomics with the already established clinical predictors may hold promise for improvement. Methods The UK Biobank was utilized to build linear and deep learning models for the prediction of surgery relevant outcomes. An initial GWAS for the relevant outcomes was initially conducted to select the Single Nucleotide Polymorphisms for inclusion in the models. Model performance was assessed with Receiver Operator Characteristics of the Area Under the Curve and optimum precision and recall. Feature importance was assessed with SHapley Additive exPlanations. Results Models were generated for atrial fibrillation, venous thromboembolism and pneumonia as genetics only, clinical features only and a combined model. For venous thromboembolism, the ROC-AUCs were 60.1% 59.6%-60.4%, 63.4% 63.2%-63.4% and 66.6% 66.2%-66.9% for the linear models and 51.5% 49.4%-53.4%, 63.2% 61.2%-65.0% and 62.6% 60.7%-64.5% for the deep learning SNP, clinical and combined models, respectively. For atrial fibrillation, the ROC-AUCs were 60.3% 60.0%-60.4%, 78.7% 78.7%-78.7% and 80.0% 79.9%-80.0% for the linear models and 59.4% 58.2%-60.9%, 78.8% 77.8%-79.8% and 79.8% 78.8%-80.9% for the deep learning SNP, clinical and combined models, respectively. For pneumonia, the ROC-AUCs were 50.1% 49.6%-50.6%, 69.2% 69.1%-69.2% and 68.4% 68.0%-68.5% for the linear models and 51.0% 49.7%-52.4%, 69.7% .5%-70.8% and 69.7% 68.6%-70.8% for the deep learning SNP, clinical and combined models, respectively. Conclusion In this report we presented linear and deep learning predictive models for surgery relevant outcomes. Overall, predictability was similar between linear and deep learning models and inclusion of genetics seemed to improve accuracy.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
To investigate the association between markers of acute endothelial glycocalyx degradation, inflammation, coagulopathy, and mortality after trauma.
Hyperinflammation and acute coagulopathy of trauma ...predict increased mortality. High catecholamine levels can directly damage the endothelium and may be associated with enhanced endothelial glycocalyx degradation, evidenced by high circulating syndecan-1.
Prospective cohort study of trauma patients admitted to a Level 1 Trauma Centre in 2003 to 2005. Seventy-five patients were selected blindly post hoc from 3 predefined injury severity score (ISS) groups (<16, 16-27, >27). In all patients, we measured 17 markers of glycocalyx degradation, inflammation, tissue and endothelial damage, natural anticoagulation, and fibrinolysis (syndecan-1, IL-6, IL-10, histone-complexed DNA fragments, high-mobility group box 1 (HMGB1), thrombomodulin, von Willebrand factor, intercellular adhesion molecule-1, E-selectin, protein C, tissue factor pathway inhibitor (TFPI), antithrombin, D-dimer, tissue-type plasminogen activator (tPA), urokinase-type plasminogen activator (uPA), soluble uPA receptor, and plasminogen activator inhibitor-1), hematology, coagulation, catecholamines, and assessed 30-day mortality. Variables were compared in patients stratified according to syndecan-1 median.
Patients with high circulating syndecan-1 had higher catecholamines, IL-6, IL-10, histone-complexed DNA fragments, HMGB1, thrombomodulin, D-dimer, tPA, uPA (all P < 0.05), and 3-fold increased mortality (42% vs. 14%, P = 0.006) despite comparable ISS (P = 0.351). Only in patients with high glycocalyx degradation was higher ISS correlated with higher adrenaline, IL-6, histone-complexed DNA fragments, HMGB1, thrombomodulin, and APTT, lower protein C (all P < 0.05), unchanged TFPI and blunted D-dimer response (P < 0.001) because D-dimer was profoundly increased even at low ISS. After adjusting for age and ISS, syndecan-1 was an independent predictor of mortality (OR: 1.01 95%CI, 1.00-1.02; P = 0.043).
In trauma patients, high circulating syndecan-1, a marker of endothelial glycocalyx degradation, is associated with inflammation, coagulopathy and increased mortality.
The endothelial glycocalyx layer (EGL) is a key regulator of vascular permeability, cell adhesion, and inflammation. The EGL is primarily composed of syndecan-1, hyaluronic acid (HA), heparan sulfate ...(HS) and chondroitin sulfate (CS). While many studies have observed increased shedding of syndecan-1 during hemorrhagic shock, little is known about the shedding of other EGL components, and their effects on altered permeability and coagulation. We characterized shedding of all four primary components of the EGL, as well as the plasma's effect on permeability and thrombin generation in a cohort of trauma patients.
Plasma samples were collected from 5 healthy consented volunteers and 22 severely injured trauma patients upon admission to the emergency department. ELISA assays were performed to quantify shed HA, HS, CS and syndecan-1 in plasma. A colloid osmometer and Electric Cell-substrate Impedance Sensing (ECIS) system were used to measure plasma colloid osmotic pressure (COP) and cell permeability, respectively. Thrombin generation was measured using a calibrated automated thrombogram (CAT). Initial vital signs, routine laboratory values, and injury severity scores (ISS) were recorded. Non-parametric statistical tests were used to compare differences between groups.
We observed increased shedding of all four proteins in trauma patient plasma compared to healthy controls: 31.7 vs. 21.2 U/L of CS, 175.8 vs. 121.9 ng/ml of HS, 946.7 vs. 618.6 ng/ml of HA and 245.8 vs. 31.6 ng/ml of syndecan-1 (all p<0.05). Patients with low plasma COP (≤16 mmHg) had significantly increased syndecan-1 and HA compared to those with normal COP, which corresponded to increased cell permeability via ECIS. CS and HS did not vary between COP groups. Lastly, patients with low COP displayed reduced peak thrombin generation of less than 250 nM on average (p<0.05).
Glycocalyx components were shed more in trauma patients compared to healthy controls in this cohort. However, only syndecan-1 and HA shedding were significantly higher in patients with reduced plasma COP. Thrombin generation was impaired in patients with low plasma COP. These data suggest that low plasma COP correlates well to glycocalyx degradation and thrombin loss following trauma, which consequently affect permeability and coagulation.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
We report a genome-wide association study of venous thromboembolism (VTE) incorporating 81,190 cases and 1,419,671 controls sampled from six cohorts. We identify 93 risk loci, of which 62 are ...previously unreported. Many of the identified risk loci are at genes encoding proteins with functions converging on the coagulation cascade or platelet function. A VTE polygenic risk score (PRS) enabled effective identification of both high- and low-risk individuals. Individuals within the top 0.1% of PRS distribution had a VTE risk similar to homozygous or compound heterozygous carriers of the variants G20210A (c.*97 G > A) in F2 and p.R534Q in F5. We also document that F2 and F5 mutation carriers in the bottom 10% of the PRS distribution had a risk similar to that of the general population. We further show that PRS improved individual risk prediction beyond that of genetic and clinical risk factors. We investigated the extent to which venous and arterial thrombosis share clinical risk factors using Mendelian randomization, finding that some risk factors for arterial thrombosis were directionally concordant with VTE risk (for example, body mass index and smoking) whereas others were discordant (for example, systolic blood pressure and triglyceride levels).
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GEOZS, IJS, IMTLJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBMB, UL, UM, UPUK, ZAGLJ
Abstract Background Endothelial glycocalyx breakdown elicits syndecan-1 shedding, and traumatic endotheliopathy (EoT). We hypothesized that a cutoff syndecan-1 level can identify patients with ...endothelial dysfunction who would have poorer outcomes. Study Design Prospective observational study; trauma patients with the highest level of activation admitted during July 2011-September 2013 were eligible. We recorded demographics, injury type/severity (ISS), physiology and outcome data, and quantified syndecan-1 and soluble thrombomodulin from plasma with ELISAs. With receiver operating characteristic curve (ROC) analysis, we defined EoT+ as the syndecan-1 cutoff level that maximized the sum of sensitivity and specificity (Youden index) in predicting 24-hour in-hospital mortality. We stratified by this cutoff, and compared both groups. Factors associated with 30-day in-hospital mortality were assessed with multivariable logistic regression (adjusted odds ratios (ORs) and 95% confidence intervals (CIs) reported). Results From ROC analysis (area under the curve=0.71, 95%CI 0.58-0.84), we defined EoT+ as syndecan-1 level ≥ 40 ng/ml (sensitivity= 0.62, specificity= 0.73). Of the 410 patients evaluated, 34% (n=138) were EoT+ patients, who presented with higher ISS ( p <0.001) and blunt trauma frequency ( p =0.016) than EoT- patients. While EoT+ patients had lower systolic blood pressure (median 119 vs. 128 mmHg; p <0.001), base excess and hemoglobin were similar between groups. The proportion of transfused (EoT+ 71.7% vs. EoT- 36.4%; p<0.001), and deceased EoT+ patients (EoT+ 24.6% vs. EoT- 12.1%; p <0.001) was higher. EoT+ was significantly associated with 30-day in-hospital mortality (adjusted OR 2.23, 95%CI 1.22-4.04). Conclusions A syndecan-1 level ≥40 ng/ml identified patients with significantly worse outcomes, despite similar admission physiology to those without the condition.
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