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1.
Research and Practice in Thrombosis and Haemostasis Conference ; 6(Supplement 1), 2022.
Article in English | EMBASE | ID: covidwho-2128181

ABSTRACT

Background: To curb the threat of COVID-19, vaccines of different forms and shape have been developed and assessed for their efficacy in the last one and a half year. Amongst those Inactivated viral vaccines developed in China, Sinopharm and Sinovac are the most frequently employed vaccines in Pakistan. It has been established that natural infection and certain forms of SARS-CoV- 2 vaccine alters the clinical picture of blood. Aim(s): In this study we have compared the levels of three inflammatory biomarkers namely PAI-1, D-Dimer and HAI-IgG in the sera collected from SARS-CoV- 2 Vaccinated and unvaccinated Subjects. Method(s): Briefly, 80 individuals, each as a cohort of SARS-CoV- 2 vaccinated and unvaccinated were recruited with written consent after ethical approval for the study. From each subject 2 ml blood was drawn and plasma was separated to assess inflammatory biomarkers like PAI-1, D-Dimer and HIA IgG by ELISA. Additionally, platelets count were also monitored using automated counter. Result(s): Our data show difference in the level of PAI-1, D-Dimer and HIA-IgG between SARS-CoV- 2 Vaccinated and unvaccinated subjects. However, the difference was found statistically in significant. Nevertheless, segregating the data based on the nature of vaccination, age and gender of the subjects shows interesting pattern that could be insightful in relation to the clinical outcome of the vaccine efficacy. Conclusion(s): The findings in this regard could well be of clinical value, especially when the data is stratified with reference to different variables. Therefore, large scale studies are warranted with same, and few additional biomarkers would be of more resolving in relation to the host response against SARS-CoV- 2 vaccination.

2.
Research and Practice in Thrombosis and Haemostasis Conference ; 6(Supplement 1), 2022.
Article in English | EMBASE | ID: covidwho-2128178

ABSTRACT

Background: The advance pathology of SARS-CoV- 2 infection entails engagement of blood related ailment including thrombosis as secondary clinical manifestation. SARS-CoV- 2- Human protein-protein interactome has been explored. Dysregulation of the several proteins and mutations in the genes have been linked with the incidence and progression of thrombosis. Aim(s): Aim of the investigation is to develop and functionally analyze a combine molecular network of SARS-CoV- 2- Human and Thrombosis to delineate candidate molecule that could later be used for the prognosis and therapeutic intervention. Method(s): Briefly, two separate system networks were developed, one for over 500 humans protein that have shown to interact with the viral genome and 26 different proteins encoded by SARS-CoV- 2 genome. The second network is based on the genes tagged for being aberrated genetically and/or in terms of expression in thrombosis. Both networks were combined as a singular entity after removing the redundant repetition and orphans' nodes and edges by selective enrichment. The network then be dissected in different modules primarily based on the promiscuity of the nodes. Complete network and each module were assessed for in betweenness and shortest path length of edges. Result(s): The data shown over 700 genes could be coalesced as a single network providing a molecular interplay that may underpin SARS-CoV- 2 associated thrombosis. Over 16 modules were observed in the network with important candidate genes of thrombosis have been identified as hub due to the inter modular abridging potential. Identification of hub genes was further substantiated with the pathlength distance, lack of orphan edges and partner protein promiscuity. Biological functions and KEGG analysis of the holistic network and modular compartment further strengthen the predicted candidate gene status as central to the disease biology. Conclusion(s): Candidate genes identified in the study could later be used as markers for prognosis of the pathology of COVID-19 for thrombosis and/or developing therapeutic intervention.

3.
Blood ; 138:3207, 2021.
Article in English | EMBASE | ID: covidwho-1736286

ABSTRACT

Background: COVID-19 has been associated with hypercoagulability, endothelial cell injury and frequent thrombotic complications resulting both from direct effects of the virus on the endothelium and from the ‘cytokine storm’ resulting from the host's immune response. Since the COVID-19 vaccines have been shown to effectively prevent symptomatic infection including hospital admissions and severe disease, the risk of COVID-19-related thrombosis should be expected to (almost) disappear in vaccinated individuals. However, some rare cases of venous thrombosis have been reported in individuals vaccinated with mRNA vaccines. Thus, there is a sharp contrast between the clinical or experimental data reported in the literature on COVID-19 and on the rare thrombotic events observed after the vaccination with these vaccines. This phenomenon raised some scepticism of even some fear about the safety of these vaccines which could compromise the adhesion of the citizens in the vaccination program. Aims: We conducted a prospective observational study, to explore the impact of vaccination with the BNT162b2 (Pfizer/BioNTech) on blood hypercoagulability and endothelial cell activation and to investigate if this is modified by the presence of active cancer. Methods: In total 229 subjects were prospectively included in the study from April to June 2021. Subjects were stratified in three predefined groups: 127 vaccinated patients with active cancer (VOnco group), 72 vaccinated health care workers (VHcw group) and 30 non vaccinated health individuals (Control group). Blood samples were obtained 2 days after the administration of the first dose of BNT162b2 vaccine and collected in Vacutainer® tubes (0.109 mol/L trisodium citrate). Platelet poor plasma (PPP) was prepared by double centrifugation at 2000 g for 20 minutes at room temperature and plasma aliquots were stored at -80°C until assayed. Samples of PPP were assessed for thrombin generation (TG) with PPP-Reagent® (Thrombogram-Thrombinoscope assay with PPP-Reagent®TF 5pM), E-selectin, D-dimers, (D-Di), Tissue Factor (TFa), procoagulant phospholipid-dependent clotting time (Procag-PPL) and von Willebrand factor (vWF), thrombomodulin (TM), tissue factor pathway inhibitor (TFPI), and platelet factor 4 (PF4). All assays were from Diagnostica Stago (France). The upper and lower normal limits (UNL and LNL) for each biomarker were calculated by the mean±2SD for the control group. Results: All vaccinated subjects showed significantly increased levels of PF4 (71% >UNL, p<0.001), D-Dimers (74% >UNL, p<0.01), vWF (60% >UNL, p<0.01), FVIII (62% >UNL, p<0.01) and shorter Procoag-PPL clotting time (96% <LNL, p<0.001), as compared to controls. Thrombin generation showed significantly higher Peak (60% >UNL, p<0.01), ETP (38% >UNL, p<0.01) and MRI (66% >UNL, p<0.01) but no differences in lag-time in vaccinated subjects as compared to the control group. Vaccinated subjects did not show any increase at the levels of TFa, TFPI, TM and E-selectin in comparison with the control group. The studied biomarkers were not significantly different between the VOnco and VHcw groups. Conclusion: The ROADMAP-COVID-19-Vaccine study shows that administration of the first dose of the BNT162b2 vaccine induced significant platelet activation documented by shorter Procoag-PPL associated with increased levels of PF4. Plasma hypercoagulability was less frequent in vaccinated individuals whereas there was no evidence of significant endothelial cells activation after vaccination. Interestingly, the presence of active cancer was not associated with an enhancement of platelet activation, hypercoagulability, or endothelial cell activation after the vaccination. Probably, the generated antibodies against the spike protein or lead to platelet activation in a FcyRIIa dependent manner that results in PF4 release. The implication of the mild inflammatory reaction triggered by the vaccination could be another possible pathway leading to platelet activation. Nevertheless, vaccination does not provoke endothelial activation even n patients with cancer. The findings of the ROADMAP-COVID-19-Vaccine study support the concept administration of mRNA based vaccines does not directly cause a systematic hypercoagulability. Disclosures: Gligorov: Roche-Genentech: Research Funding;Novartis: Research Funding;Onxeo: Research Funding;Daichi: Research Funding;MSD: Research Funding;Eisai: Research Funding;Genomic Heatlh: Research Funding;Ipsen: Research Funding;Macrogenics: Research Funding;Pfizer: Research Funding. Terpos: Novartis: Honoraria;Janssen: Consultancy, Honoraria, Research Funding;Genesis: Consultancy, Honoraria, Research Funding;Celgene: Consultancy, Honoraria, Research Funding;BMS: Honoraria;Amgen: Consultancy, Honoraria, Research Funding;Takeda: Consultancy, Honoraria, Research Funding;Sanofi: Consultancy, Honoraria, Research Funding;GSK: Honoraria, Research Funding. Dimopoulos: Amgen: Honoraria;BMS: Honoraria;Janssen: Honoraria;Beigene: Honoraria;Takeda: Honoraria.

4.
European Heart Journal ; 42(SUPPL 1):2473, 2021.
Article in English | EMBASE | ID: covidwho-1554277

ABSTRACT

Introduction: Severe acute respiratory syndrome coronavirus 2 (SARSCoV- 2) has resulted in a pandemic which has infected more than 128 million people and led to over 2.8 million deaths worldwide. Although the introduction of efficacious vaccines has led to overall declines in the incidence of SARS-CoV-2 infection, there has been a recent increase in infections once more due to the appearance of mutant strains with higher virulence. It therefore remains vital to identify predictors of poor outcomes in this patient population. Purpose: The objective of our study was to identify predictors of prolonged hospitalization, intensive care unit (ICU) admission, intubation, and death in patients infected with SARS-CoV-2. Methods: We conducted a retrospective analysis of all patients hospitalized with SARS-CoV-2 at our health system that includes one tertiary care center and two community hospitals located in the Chicago metropolitan area. The main outcome was a composite endpoint of hospitalization >28 days, ICU admission, intubation, and death. Explanatory variables associated with the primary outcome in the bivariate analysis (p<0.05) were included in the multivariable logistic regression model. Statistical analysis was performed using IBM SPSS 25.0. Results: Between March 1, 2020 and May 31, 2020, 1029 patients hospitalized with SARS-CoV-2 were included in our analysis. Of these patients, 379 met the composite endpoint. Baseline demographics are described in Table 1. Of note, our cohort consisted of a predominantly minority patient population including 47% Hispanic, 17% African American, 16% Caucasian, and 16% other. In bivariate analysis, age, hypertension, tobacco and alcohol abuse, obesity, coronary artery disease, arrhythmias, valvular heart disease, dyslipidemia, hypertension, stroke, diabetes, documented thrombosis, troponin, CRP, ESR, ferritin, LDH, BNP, D-dimer >5x the upper limit of normal, lactate, and right ventricular outflow tract velocity time integral <9.5 were significant. After multivariable adjustment, explanatory variables associated with the composite endpoint included troponin (OR 2.36;95% CI 1.08-5.17, p 0.03), D-dimer (OR 1.5;95% CI 1.23-1.98, p<0.01, lactate (OR 1.58;95% CI 1.28-1.95, p<0.01), and documented thrombosis (OR 3.56;95% CI 1.30-8.70, p<.05). Race was not a predictor of poor outcomes in the bivariate or multivariate analysis (Table 2). Conclusions: In a large urban cohort with a predominantly minority population, we identified several clinical predictors of poor outcomes. Of note, race was not a predictor of the primary endpoint in this study. While recent literature has demonstrated worse outcomes among racial minorities infected with SARS-CoV-2, our data suggests these variations are related to social determinants of health rather than biologic causes. (Figure Presented).

5.
European Heart Journal ; 42(SUPPL 1):2492, 2021.
Article in English | EMBASE | ID: covidwho-1554276

ABSTRACT

Introduction: While the global dissemination of vaccines targeting the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has resulted in a decline in the incidence of infections, the case fatality rates have remained relative stable. A major objective of managing hospitalized patients with documented or suspected COVID-19 infection is the rapid identification of features associated with severe illness using readily available laboratory tests and clinical tools. The sequential organ failure assessment (SOFA) score is a validated tool to facilitate the identification of patients at risk of dying from sepsis. Purpose: The aim of this study was to assess the discriminatory accuracy of the SOFA score in predicting clinical decompensation in patients hospitalized with COVID-19 infection. Methods:We conducted a retrospective analysis at a three-hospital health system, comprised of one tertiary and two community hospitals, located in the Chicago metropolitan area. All patients had positive SARS-CoV-2 testing and were hospitalized for COVID-19 infection. The primary outcome was clinical decompensation, defined as the composite endpoint of death, ICU admission, or need for intubation. We utilized the most abnormal laboratory values observed during the admission to calculate the SOFA score. Receiver Operating Curves (ROC) were then constructed to determine the sensitivity and specificity of SOFA scores. Results: Between March 1st and May 31st 2020, 1029 patients were included in our analysis with 367 patients meeting the study endpoint. The median SOFA score was 2.0 IQR (Q1, Q3 1,4) for the entire cohort. Patients who had in-hospital mortality had a median SOFA score of 4.0 (Q1,Q3 3,7). In patients that met the primary composite endpoint, the median SOFA score was 3.0, IQR (Q1, Q3 2,6). The ROC was 0.776 (95% CI 0.746-0.806, p<0.01). Conclusion: The SOFA score demonstrates strong discriminatory accuracy for prediction of clinical decompensation in patients presenting with COVID-19 at our urban hospital system. (Figure Presented).

6.
Research and Practice in Thrombosis and Haemostasis ; 5(SUPPL 2), 2021.
Article in English | EMBASE | ID: covidwho-1509073

ABSTRACT

Background : Administration of a standard-dose thromboprophylaxis in all hospitalized Coronavirus disease (COVID-19) patients is recommended. However, despite thromboprophylaxis, frequent thrombotic complications are diagnosed. Rotational thromboelastometry (ROTEM) is a method to access hypercoagulable state in whole blood from these patients. Aims : To analyze ROTEM parameters during the entire clinical COVID-19 stages including mild, moderate and critical phases and to assess the extent of hypercoagulablity by profiling ROTEM patterns. Methods : We evaluated coagulation abnormalities via traditional tests and ROTEM profile in a group of 94 patients with confirmed SARS-CoV-2 infection with different severity of pneumonia (34 moderate, 25 severe, 35 critical). Shorter than normal clotting time (CT) and higher than normal maximum clot firmness (MCF) in extrinsic rotational thromboelastometry (EXTEM) and fibrinogen rotational thromboelastometry (FIBTEM), shorter than normal EXTEM clot formation time (CFT), and higher than normal α-angle were identified as markers of hypercoagulable state. Results : At least one hypercoagulable ROTEM parameter had 62 (66%) patients. Increment in the number of patients with ≥ 2 hypercoagulable parameters, higher EXTEM ( P = .0001), FIBTEM MCF ( P = 0.0001) and maximum lysis decrement ( P = 0.002) with increment in disease severity was observed ( P = 0.0001). Significant positive correlations between IL6 and CT EXTEM ( P = 0.003), MCF EXTEM ( P = 0.033), MCF FIBTEM ( P = 0.01), and negative with ML EXTEM ( P = 0.006) were seen. Conclusions : These findings confirm that a hypercoagulable ROTEM profile characterized by clot formation acceleration, high clot strength, and reduced fibrinolysis was more frequent in advanced disease groups and patients with elevated IL6. These results underscore the need for different thromboprophylactic approaches for different severity groups.

7.
HemaSphere ; 5(SUPPL 2):641-642, 2021.
Article in English | EMBASE | ID: covidwho-1393455

ABSTRACT

Background: Thrombosis is frequently diagnosed in patients with Coronavirus disease (COVID - 19), despite the use of a standard-dose thromboprophylaxis in all hospitalized. Since conventional coagulation tests (CCTs) reflect only limited parts of the coagulation system and are insufficient to assess hypercoagulability, rotational thromboelastometry (ROTEM) could be more effective in identifying hypercoagulable pattern and patient in high-risk of thrombosis. Aims: 1. To analyze ROTEM parameters across the entire clinical COVID-19 pneumonia spectrum, from moderate to critical. 2. To determine the incidence of hypercoagulable ROTEM patterns and improve risk stratification. Methods: We evaluated coagulation abnormalities via CCTs and ROTEM in a group of 94 patients with confirmed SARS-CoV-2 infection and different severity of pneumonia (34 moderate, 25 severe, 35 critical). Shorter than normal clotting time (CT) and higher than normal maximum clot firmness (MCF) in both extrinsic pathway (EXTEM) and fibrinogen pathway (FIBTEM), as well as shorter than normal EXTEM clot formation time (CFT) and higher than normal α-angle were classified as markers of hypercoagulable state. Results: At least one hypercoagulable ROTEM parameter had 62 (66%) patients. Increment in the number of patients with ≥ 2 hypercoagulable parameters, higher EXTEM MCF (P = 0.0001), higher FIBTEM MCF (P = 0.0001) and decrement in maximum lysis (P = 0.002) were observedwith increment in disease severity (P = 0.0001). Significant positive correlations between interleukine - 6 (IL6) and CT EXTEM (P = 0.003), MCF EXTEM (P = 0.033), MCF FIBTEM (P = 0.01) as well as negative with ML EXTEM (P = 0.006) were seen. Contrary to hypercoagulable ROTEM pattern which was not predictive for death, hypocoagulability represented by prolonged EXTEM CT (P = 0.0001) and CFT (P = 0.0001), smaller α angle (P = 0.014) and a prolonged FIBTEM CT (P = .0001) was a predictor. Summary/Conclusion: Our findings confirmed that a hypercoagulable ROTEM pattern characterized by clot formation acceleration, high clot strength, and reduced fibrinolysis was more frequent in advanced disease groups and patients with high IL6. These results support the need for different thromboprophylaxis approaches for different severity groups.

8.
Blood ; 136:6, 2020.
Article in English | EMBASE | ID: covidwho-1348337

ABSTRACT

Introduction: Currently, there is a shortage of porcine heparin due to several factors such as limited availability of porcine mucosa, supply chain issues, and increased usage due to COVID-19. This has warranted the development of heparin from alternate sources such as bovine and ovine mucosa which is abundantly available for this purpose. On a mass basis, commercially available porcine heparins exhibit a similar potency (200 units/mg) to their ovine counterpart (190 units/mg) and a higher potency in contrast to their bovine counterpart (130-150 units/mg). Therefore, at gravimetric levels, the porcine heparins exhibit stronger biochemical and pharmacological effects in various laboratory assays in comparison to bovine heparin and similar effects in comparison to ovine heparins. Since heparin is standardized in biologic units and cross referenced against USP or EP Standard, it is hypothesized that potency equated porcine, ovine, and bovine heparin will exhibit similar biologic activities in laboratory assays carried out in the in vitro setting. The purpose of this study is to compare the biologic properties of the porcine, ovine, and bovine heparin at USP potency equated levels in standardized laboratory assays. Materials and Methods: Active pharmaceutical ingredients (API) of porcine mucosal heparin (200 units/mg) of U.S. origin was commercially obtained from Medefil Inc. (Glendale Heights, IL). Ovine heparin was obtained from Ronnsi Pharmaceutical (Jiangsu, China). Bovine heparin (140 units/mg) was obtained from Kin Master Pharmaceuticals (Posso Fundo, Brazil). All heparins were diluted at a concentration of 100 units/mL in saline. The anticoagulant effect of all heparins were evaluated using the whole blood clotting assays such as the ACT and thromboelastographic methods. Heparins were diluted in citrated human plasma yielding a final concentration range of 0-1 unit/mL. Clot based assays such as aPTT, TT, and prothrombinase induced clotting time (PiCT) were measured. Thrombin generation inhibition assay was carried out using a kinetic assay (CAT system, Diagnositca Stago, Paris, France). Protamine and heparinase neutralization profiles of these agents were also investigated in the plasma-based systems. These assays were then repeated at gravimetric dosages at final concentrations of 0-10 ug/mL. The results collected from these trials were then mathematically converted to units and compared to the results collected from the potency adjusted trials. All results were tabulated and compared, and applicable statistical methods were applied. Results: The USP potency adjusted heparin exhibited comparable anticoagulant effects in both the ACT and TEG assays. At equigravimetric levels porcine and ovine heparins produced comparable anticoagulant effects and bovine heparin produced weaker anticoagulant effect in both assays. In the citrated plasma supplementation studies, all drugs produced similar anticoagulant effects at potency adjusted dosages. In the chromogenic anti-Xa and anti-IIa assays, the behaviors of the agents were also comparable. In the thrombin generation assays, in terms of peak thrombin generation, area under the curve, and lag time, the porcine, ovine, and bovine heparins showed comparable effects. The protamine neutralization profiles of the porcine, ovine, and bovine heparin exhibited variable assay dependent results. Potency adjusted bovine heparin required higher amount of protamine for the complete neutralization of the biologic effects in comparison to the porcine heparin. At gravimetric concentrations, bovine heparins exhibited lower potencies than both the porcine and ovine heparins, which produced similar results. Summary and Conclusion: These results show that at potency adjusted concentrations, the porcine, ovine, and bovine heparin exhibit comparable biochemical and anticoagulant responses in the plasma-based systems. Therefore, the hypothesis that potency equated porcine, ovine, and bovine heparins exhibit comparable biochemical and anticoagulant activities is validated. Thus, the proposed ap roach to standardize heparins against a common standard in a biologic assay such as the USP method is valid. Furthermore, these results warrant regulatory considerations to fast track the review process for the re-introduction of bovine heparin and approval of bovine heparin as a biosimilar anticoagulant to porcine heparin. Disclosures: No relevant conflicts of interest to declare.

10.
medrxiv; 2020.
Preprint in English | medRxiv | ID: ppzbmed-10.1101.2020.09.28.20201475

ABSTRACT

The COVID-19 pandemic has spread rapidly throughout the world. In the UK, the initial peak was in April 2020; in the county of Norfolk (UK) and surrounding areas, which has a stable, low-density population, over 3,200 cases were reported between March and August 2020. As part of the activities of the national COVID-19 Genomics Consortium (COG-UK) we undertook whole genome sequencing of the SARS-CoV-2 genomes present in positive clinical samples from the Norfolk region. These samples were collected by four major hospitals, multiple minor hospitals, care facilities and community organisations within Norfolk and surrounding areas. We combined clinical metadata with the sequencing data from regional SARS-CoV-2 genomes to understand the origins, genetic variation, transmission and expansion (spread) of the virus within the region and provide context nationally. Data were fed back into the national effort for pandemic management, whilst simultaneously being used to assist local outbreak analyses. Overall, 1,565 positive samples (172 per 100,000 population) from 1,376 cases were evaluated; for 140 cases between two and six samples were available providing longitudinal data. This represented 42.6% of all positive samples identified by hospital testing in the region and encompassed those with clinical need, and health and care workers and their families. 1,035 cases had genome sequences of sufficient quality to provide phylogenetic lineages. These genomes belonged to 26 distinct global lineages, indicating that there were multiple separate introductions into the region. Furthermore, 100 genetically-distinct UK lineages were detected demonstrating local evolution, at a rate of ~2 SNPs per month, and multiple co-occurring lineages as the pandemic progressed. Our analysis: identified a sublineage associated with 6 care facilities; found no evidence of reinfection in longitudinal samples; ruled out a nosocomial outbreak; identified 16 lineages in key workers which were not in patients indicating infection control measures were effective; found the D614G spike protein mutation which is linked to increased transmissibility dominates the samples and rapidly confirmed relatedness of cases in an outbreak at a food processing facility. The large-scale genome sequencing of SARS-CoV-2-positive samples has provided valuable additional data for public health epidemiology in the Norfolk region, and will continue to help identify and untangle hidden transmission chains as the pandemic evolves.

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