Evaluation of the relationship between TAFI level and prognosis in COVID-19 patients.

OBJECTIVE: Serum thrombin-activated fibrinolysis inhibitor (TAFI) levels were measured in coronavirus disease 2019 (COVID-19) patients requiring intensive care, clinical hospitalization, and outpatient follow-up. The relationships between serum TAFI levels and prognosis were determined. PATIENTS AND METHODS: Ninety patients who had positive COVID-19 PCR test results were randomly selected and included in the study. Subgroups were formed according to the clinical characteristics of the patients as follows: mild, moderate, and severe. Venous blood samples were taken from all patients, and serum C-reactive protein (CRP), lactate dehydrogenase (LDH), fibrinogen, D-dimer, ferritin, and TAFI levels were measured. The results were evaluated by comparing each group. RESULTS: The one-way ANOVA test to determine differences between subgroups resulted in p-values lower than 0.05 for all biochemical analytes (CRP, LDH, fibrinogen, D-dimer, ferritin, and TAFI). Regarding serum TAFI levels, there were significant differences in the severe group (853.04 ± 338.58 ng/mL) compared to the mild group (548.33 ± 264.17 ng/mL). ROC curve analysis to predict mortality revealed that TAFI levels were able to detect 85% of deaths. In addition, ROC analysis revealed that serum TAFI levels could detect 86% of intubated cases. CONCLUSIONS: The disease progression is more severe in patients with high TAFI levels, and high TAFI levels are associated with mortality and intubation rates. Further studies are needed to determine serum TAFI levels as a biomarker of prognosis in COVID-19 patients.

Significance of 1,25-Dihydroxyvitamin D3 on Overall Mortality in Peritoneal Dialysis Patients with COVID-19.

In previous publications, we pointed out the importance of mannosylation of fibrinogen for the development of cardiovascular complications and fucosylation as a predictor of peritoneal membrane dysfunction in patients on peritoneal dialysis (PD). After a follow-up period of 30 months from the onset of the COVID-19 pandemic, we evaluated the significance of 1,25-dihydroxyvitamin D3 (calcitriol) therapy, primary disease, biochemical and hematologic analyzes, and previously performed glycan analysis by lectin-based microarray as predictors of mortality in this patient group. After univariate Cox regression analysis, diabetes mellitus (DM) and calcitriol therapy were found to be potential predictors of mortality. Additional multivariate Cox regression analysis confirmed that only DM was a predictor of mortality. Nevertheless, the use of calcitriol in therapy significantly reduced mortality in this patient group, as shown by the Kaplan-Meier survival curve. The presence of DM as a concomitant disease proved to be a strong predictor of fatal outcome in PD patients infected with SARS-CoV-2. This is the first study to indicate the importance and beneficial effect of calcitriol therapy on survival in PD patients with COVID-19 infection. In addition, this study points to the possibility that adverse thrombogenic events observed in PD patients during the pandemic may be caused by aberrant fibrinogen glycosylation.

γ' fibrinogen levels as a biomarker of COVID-19 respiratory disease severity.

Coronavirus disease 2019 (COVID-19) is characterized by a pro-inflammatory state associated with organ failure, thrombosis, and death. We investigated a novel inflammatory biomarker, γ' fibrinogen (GPF), in 103 hospitalized patients with COVID-19 and 19 healthy controls. We found significant associations between GPF levels and the severity of COVID-19 as judged by blood oxygen saturation (SpO2). The mean level of GPF in the patients with COVID-19 was significantly higher than in controls (69.8 (95 % CI 64.8-74.8) mg/dL compared with 36.9 (95 % CI 31.4-42.4) mg/dL, p < 0.0001), whereas C-reactive protein (CRP), lactate dehydrogenase (LDH), and total fibrinogen levels were not significantly different between groups. Mean GPF levels were significantly highest in patients with severe COVID-19 (SpO2 ≤ 93 %, GPF 75.2 (95 % CI 68.7-81.8) mg/dL), compared to mild/moderate COVID-19 (SpO2 > 93 %, GPF 62.5 (95 % CI 55.0-70.0) mg/dL, p = 0.01, AUC of 0.68, 95 % CI 0.57-0.78; Youden's index cutpoint 62.9 mg/dL, sensitivity 0.64, specificity 0.63). In contrast, CRP, interleukin-6, ferritin, LDH, D-dimers, and total fibrinogen had weaker associations with COVID-19 disease severity (all ROC curves with lower AUCs). Thus, GPF may be a useful inflammatory marker of COVID-19 respiratory disease severity.

Multicolored MIS-C, a single-centre cohort study.

BACKGROUND: The aim of this study was to investigate the clinical and laboratory parameters that can predict the severity of Multisystem Inflammatory Syndrome in Children (MIS-C) at admission. METHODS: We conducted a single-center, partly retrospective, partly prospective, observational cohort study between November 1, 2020 and December 31, 2021, which included patients aged from 1 month to 19 years, meeting the diagnostic criteria of MIS-C. We categorized the patients into three subgroups based on clinical and laboratory markers and assessed the predictive value of these factors in terms of ICU administration and cardiac abnormalities. RESULTS: 53 patients were classified in the following subgroups: Kawasaki-like disease (group 1) (47.2%, n = 25), shock with or without acute cardiac dysfunction (group 2) (32%, n = 17), fever and inflammation (group 3) (20.8%, n = 11). Subgroup analysis revealed that patients with shock and KD at initial presentation had significantly more severe manifestation of MIS-C requiring intensive care unit (ICU) treatment. Of the initial laboratory values, only CRP showed a significant difference between the 3 clinical groups, being lower in group 3. 52.6% of patients were admitted to the ICU. The median length of ICU stay was 3 days (range 3-20). ICU admission was more likely in patients with shortness of breath, renal failure (AKI) and patients with significantly increased concentrations of ferritin, D-dimer, INR and significantly milder increase concentration of fibrinogen. We found that fibrinogen and ferritin levels are independent risk factors for ICU admission. Cardiac abnormalities were found in 56.6% of total (30/53), with the following findings: decreased left ventricular function (32%), coronary abnormality (11.3%), pericardial effusion (17%), arrhythmia (32.1%) and mitral regurgitation (26.6%). Diarrhea and conjunctivitis at the initial presentation with significantly elevated CRP, Pro-BNP and blood pH concentrations were found to be a potential predisposing factor for decreased cardiac function while Pro-BNP and pH were independent risk factors for MIS-C. Regardless of the initial symptoms of MIS-C, the outcome was generally favorable. CONCLUSIONS: Clinical characteristics and baseline laboratory values ​​may help identify patients at increased risk for severe disease outcome, such as need for intensive care, presence of shock and decreased cardiac function. TRIAL REGISTRATION: Participation consent was not reqired and ethical considerations were unnecessary, since we did not perform any extra interventions, only the necessary and usual therapeutic and diagnostic methods were used.

[Clinical features of severe acute respiratory syndrome coronavirus 2 Omicron variant infection in children: an analysis of 201 cases]. / 201ä¾‹å„¿ç«¥æ–°åž‹å† çŠ¶ç— æ¯’Omicronå˜å¼‚æ ªæ„ŸæŸ“çš„ä¸´åºŠç‰¹å¾åˆ†æž.

OBJECTIVES: To study the clinical features of children with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron variant infection. METHODS: A retrospective analysis was performed on the medical data of 201 children with coronavirus disease 2019 (COVID-19) who were hospitalized and diagnosed with SARS-CoV-2 Omicron variant infection in Quanzhou First Hospital from March 14 to April 7, 2022. Among the 201 children, there were 34 children with asymptomatic infection and 167 with symptomatic infection. The two groups were compared in terms of clinical features, results of experimental examinations, and outcome. RESULTS: Of all the 201 children, 161 (80.1%) had a history of exposure to COVID-19 patients and 132 (65.7%) had a history of COVID-19 vaccination. Among the 167 children with symptomatic infections, 151 had mild COVID-19 and 16 had common COVID-19, with no severe infection or death. Among the 101 children who underwent chest CT examination, 16 had ground glass changes and 20 had nodular or linear opacities. The mean time to nucleic acid clearance was (14±4) days for the 201 children with Omicron variant infection, and the symptomatic infection group had a significantly longer time than the asymptomatic infection group [(15±4) days vs (11±4) days, P<0.05]. The group vaccinated with one or two doses of COVID-19 vaccine had a significantly higher positive rate of IgG than the group without vaccination (P<0.05). The proportions of children with increased blood lymphocyte count in the symptomatic infection group was significantly lower than that in the asymptomatic infection group (P<0.05). Compared with the asymptomatic infection group, the symptomatic infection group had significantly higher proportions of children with increased interleukin-6, increased fibrinogen, and increased D-dimer (P<0.05). CONCLUSIONS: Most of the children with Omicron variant infection have clinical symptoms, which are generally mild. The children with symptomatic infection are often accompanied by decreased or normal blood lymphocyte count and increased levels of interleukin-6, fibrinogen, and D-dimer, with a relatively long time to nucleic acid clearance. Some of them had ground glass changes on chest CT.

Association of inflammatory and coagulation biomarkers with mortality in patients aged 60 years or older and hospitalized with COVID-19 / Associação entre biomarcadores inflamatórios e da coagulação com mortalidade em pacientes com 60 anos de idade ou mais hospitalizados com COVID-19

Objectives: To analyze the association of inflammatory and coagulation biomarkers with mortality in geriatric patients with COVID-19. Methods: This is a retrospective cohort study of 206 patients aged 60 years or older who were hospitalized with COVID-19 at an intensive care unit. The analyzed variables were age, sex, length of hospital stay, and inflammatory biomarkers (C-reactive protein, neutrophil-to-lymphocyte ratio, procalcitonin, fibrinogen, ferritin, and d-dimer). We constructed a receiver operating characteristic curve and analyzed the area under the curve to evaluate the accuracy of biomarkers associated with mortality in patients with COVID-19. Results: Mean age was 72 (± 8) years. There were 101 deaths (49% of the total sample), which were significantly more frequent (p = 0.006) in the older age groups and were distributed as follows: 37.50% (60 ­ 69 years old); 50% (70 ­ 79 years old); 67.50% (80 ­ 89 years old); and 75% (over 90 years old). Mortality was associated with increased serum levels of procalcitonin, neutrophil-to-lymphocyte ratio, C-reactive protein, and d-dimer, and decreased fibrinogen levels. Neutrophil-to-lymphocyte ratio occupied the largest area under the receiver operating characteristic curve (area under the curve 0.859) in this group. Conclusions: In this study, inflammatory biomarkers neutrophil-to-lymphocyte ratio, procalcitonin, C-reactive protein, and d-dimer were associated with mortality in older patients with COVID-19 hospitalized at an intensive care unit, and neutrophil-to-lymphocyte ratio presented the best accuracy.

Objetivos: Analisar associação de biomarcadores inflamatórios e da coagulação com mortalidade em pacientes geriátricos com COVID-19. Metodologia: Estudo do tipo coorte retrospectiva de 206 pacientes com 60 anos de idade ou mais internados em unidade de terapia intensiva (UTI) com COVID-19. As variáveis analisadas foram idade, sexo, tempo de permanência hospitalar e biomarcadores inflamatórios, sendo esses proteína C reativa (PCR), relação neutrófilo-linfócitos (RNL), procalcitonina, fibrinogênio, ferritina e D-dímero. Empregou-se a curva ROC, com análise da área sob a curva (ACR), para avaliar a acurácia dos biomarcadores associados à mortalidade nos pacientes com COVID-19. Resultados: A média de idade foi de 72 (± 8) anos. Ocorreram 101 óbitos (49,02% da amostra total), significativamente mais frequente (p = 0,006) nas faixas etárias mais elevadas, distribuídos por faixa etária: 37,50% (60 ­ 69 anos); 50% (70 ­ 79 anos); 67,50% (80 ­ 89 anos); e 75% (nos maiores de 90 anos). A mortalidade foi associada a aumento dos níveis séricos dos biomarcadores procalcitonina, relação neutrófiloslinfócitos (RNL), proteína C reativa (PCR) e D-dímero, bem como diminuição dos níveis de fibrinogênio. A RNL ocupou a maior área sob a curva ROC (ACR 0,859) nesse grupo. Conclusões: Neste estudo, os biomarcadores inflamatórios RNL, procalcitonina, PCR e D-dímero foram associados com mortalidade em pacientes idosos portadores de COVID-19 internados em UTI, e a RNL foi a que apresentou a melhor acurácia.

Time Course of Coagulopathy Evaluated with Rotational Thromboelastometry in Patients with Severe Coronavirus Disease 2019.

Objectives Coronavirus disease 2019 (COVID-19) reportedly causes thromboembolic complications due to coagulopathy with hypercoagulability and a hypofibrinolytic state. We evaluated the time-course of coagulopathy in patients with severe COVID-19 from admission to discharge from our intensive-care unit (ICU). Methods We conducted a retrospective study of adults with severe COVID-19 admitted to our ICU between January 20, 2021, and March 31, 2022. We obtained clinical information, laboratory data, and rotational thromboelastometry (ROTEM) parameters at admission and discharge. Results Fifteen patients were included. Fibrinogen and D-dimer values did not change significantly but were above the normal ranges at admission and discharge. Regarding ROTEM parameters, the maximum clot firmness in fibrinogen function (FIBTEM), a marker of hypercoagulability, did not change significantly but was above the normal range at admission and discharge [median (interquartile range), admission vs. discharge: 31 (25-34) mm vs. 31 (27-32) mm, p=0.589]. The maximum lysis at 60 minutes in the extrinsic coagulation pathway (EXTEM) and intrinsic coagulation pathway (INTEM), as markers of the fibrinolytic function, were both significantly lower at discharge than at admission [median (interquartile range), admission vs. discharge: EXTEM, 3 (2-4) vs. 1 (0-2), p=0.011; INTEM, 3 (1-6) vs. 1 (0-2), p=0.008]. Conclusion This study revealed a persistent hypercoagulable state at ICU discharge and a worse hypofibrinolytic state at discharge than at admission. These results may contribute to a better understanding of coagulopathies in the acute to subacute phases of severe COVID-19.

Colitis as the Main Presentation of COVID-19: A Case Report.

The main symptoms of coronavirus disease (COVID-19) are fever, cough, tiredness, and loss of smell and taste. Gastrointestinal symptoms are less common. A 38-year-old female patient, previously healthy, presented with a history of hematochezia up to 8 times per day, followed by abdominal cramps, urgency, and chills for two days. She did not have any respiratory symptoms and was previously vaccinated for COVID-19. She was afebrile, with normal vital signs. Blood samples showed normal complete blood count and increased C-reactive protein (CRP), fibrinogen, and D-dimer levels (66 mg/L, 4.1 g/L, and 2302 µ/L FEU, respectively). Stool samples for stool culture, C. difficile, and viral examination came back negative. On day 3, she reported a mild cough, fever and loss of smell and taste. Nasopharyngeal swab for SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) PCR test came back positive. On day 6, the patient still had hematochezia accompanied by abdominal cramps, but fever and respiratory symptoms withdrew. CRP, fibrinogen, and D-dimers were still elevated, as well as liver enzyme levels. Sigmoidoscopy was performed with biopsies taken from sigmoid and rectum for histology and PCR SARS-CoV-2 testing. CT angiography showed no signs of thrombosis in mesenteric veins or arteries. PCR test for SARS-CoV-2 virus from rectal biopsy sample was positive. Patient was treated with methylprednisolone iv for two days and peroral prednisone afterwards, with mesalamine, metronidazole and enoxaparin. Sigmoidoscopy was repeated after two weeks showing only mild hyperemia. At that time, the patient had normal stool, normal CRP, liver enzyme, fibrinogen, and D-dimer levels, and normocytic anemia (hemoglobin level of 103 g/L). We wanted to show that severe gastrointestinal symptoms, such as hemorrhagic colitis, can be the main presentation of COVID-19, even in young patients with no prior comorbidities. In such a case, PCR test in biopsy samples can be performed to prove SARS-CoV-2 infection of bowel mucosa.

Characteristics of Products of Fibrinogen Origin in the Presence of Anti- SARS-CoV-2 IgG in the Bloodstream.

BACKGROUND: The hemostasis system has been extensively investigated in patients in the acute phase of coronavirus disease 2019 (COVID-19). In contrast, the post-COVID syndrome is a poorly known entity, and there is a lack of information on the mechanisms underlying the hemostasis abnormalities in the post-COVID period. AIM: To analyze the potential changes in the parameters of the hemostasis system in the post- COVID period in the plasma of donors with different titers of anti-SARS-CoV-2 IgG. METHODS: The plasma from 160 donors who had recovered from COVID infection was used in the study. Based on the results of the Abbott SARS-CoV-2 IgG serological assay, all donors were divided into several groups: 5 ± 3 (n = 20); 55 ± 5 (n = 20); 65 ± 5 (n = 20); 75 ± 5 (n = 20); 85 ± 5 (n = 20); 95 ± 5 (n = 20); 125 ± 5 (n = 20); 175 ± 5 (n = 20) Index (S/C). A total of 20 healthy individuals without anti-SARS-CoV-2 IgG constituted the control group. Key laboratory parameters, such as fibrinogen concentrations, soluble fibrin monomer complex (SFMCs), and Ddimer, were investigated. In addition, the qualitative composition of the fraction of SFMCs was analyzed. RESULTS: The slight increase in the concentration of fibrinogen, SFMCs, and D-dimers in some donor groups have been found, which could cause the development of hemostasis disorders. In the fraction of SFMCs, the increase in the number of protein fragments with a molecular weight of less than 250 kDa and an increase in the level of proteins with a molecular weight of more than 270 kDa was revealed. CONCLUSION: The obtained results indicated the relationship between the changes in the parameters of the hemostasis system and the titers of anti-SARS-CoV-2 IgG in donors in the post-COVID period. It can be assumed that donors with higher titers of anti-SARS-CoV-2 IgG (>55 ± 5 Index (S/C)) are more prone to hemostasis abnormalities in the post-COVID period since a pronounced imbalance in the levels of SFMCs and D-dimer characterizes them. The appearance of protein fragments of different molecular weights in the fraction of SFMC points to uncontrolled activation of biochemical processes involving molecules of fibrinogenic origin. Additional studies are required to elucidate the role of anti-SARS-CoV-2 IgG in the post-COVID period.

Multiplatform analyses reveal distinct drivers of systemic pathogenesis in adult versus pediatric severe acute COVID-19.

The pathogenesis of multi-organ dysfunction associated with severe acute SARS-CoV-2 infection remains poorly understood. Endothelial damage and microvascular thrombosis have been identified as drivers of COVID-19 severity, yet the mechanisms underlying these processes remain elusive. Here we show alterations in fluid shear stress-responsive pathways in critically ill COVID-19 adults as compared to non-COVID critically ill adults using a multiomics approach. Mechanistic in-vitro studies, using microvasculature-on-chip devices, reveal that plasma from critically ill COVID-19 adults induces fibrinogen-dependent red blood cell aggregation that mechanically damages the microvascular glycocalyx. This mechanism appears unique to COVID-19, as plasma from non-COVID sepsis patients demonstrates greater red blood cell membrane stiffness but induces less significant alterations in overall blood rheology. Multiomics analyses in pediatric patients with acute COVID-19 or the post-infectious multi-inflammatory syndrome in children (MIS-C) demonstrate little overlap in plasma cytokine and metabolite changes compared to adult COVID-19 patients. Instead, pediatric acute COVID-19 and MIS-C patients show alterations strongly associated with cytokine upregulation. These findings link high fibrinogen and red blood cell aggregation with endotheliopathy in adult COVID-19 patients and highlight differences in the key mediators of pathogenesis between adult and pediatric populations.

Exercise modulation in inflammation and metabolic hormonal disorders of COVID-19 to decrease risk factors in coronary heart disease.

OBJECTIVES: Sedentary life style separated during COVID-19 pandemic. Patients with cardiovascular diseases (CVD) are vulnerable with sedentary life style. Therefore, the aim of this study was to investigate the effect of 8 weeks of combined and high intensity interval training (HIIT) on C Reactive protein, galectin-3, leptin, fibrinogen and insulin resistance index in coronary heart disease after COVID-19. METHODS: Thirty-six cardiovascular patients (55.14 ± 1.4 years, 78.6 ± 5.1 kg) were divided into three groups of combined exercise (n=13), HIIT (n=12) and control group (n=11). Combined exercise consisted of aerobic (4 weeks) and aerobic + HIIT exercise (4 weeks), three sessions per weeks. The protocol of the HIIT group included performing high intensity interval training, three sessions per weeks for 8 weeks. Blood samples were taken 24 h before the first training session and 48 h after the last training. C Reactive protein (CRP), galectin-3, leptin, fibrinogen measured with ELISA kit. RESULTS: CRP, galectin-3 and fibrinogen decreased significantly after 8 weeks of combined training and HIIT (compare to pre-test). Also, insulin resistance index after 8 weeks of combined exercise showed a significant decrease compare to pre-test (p<0.05). After 8 weeks, CRP, galectin-3 and insulin resistance significantly decreased compare to control group (p<0.05). CONCLUSIONS: In the patient with CVD, combined exercise training may be more effective than HIIT in reducing metabolic and heart risk factors after an epidemic such as COVID-19. However, change of leptin need to more studies.

Cerebral venous thrombosis after ChAdOx1 nCoV-19 vaccination: a systematic review.

OBJECTIVE: To perform a systematic review of case reports or case series regarding thrombosis with thrombocytopenia syndrome (TTS) and cerebral venous thrombosis (CVT) related to ChAdOx1 nCoV-19 vaccination to address the clinical features, laboratory findings, treatment modalities, and prognosis related with CVT. SUBJECTS AND METHODS: We included 64 TTS patients from 19 articles, 6 case series and 13 case reports, in which thrombosis occurred after the first dose of ChAdOx1 nCoV-19 vaccination published up to 30 June 2021 in Embase, ePubs, Medline/PubMed, Scopus, and Web of Science databases. RESULTS: Of the 64 TTS patients, 38 (59.3%) had CVT. Patients with CVT were younger (median 36.5 vs. 52.5 years, p<0.001), had lower fibrinogen levels (130 vs. 245 mg/dL, p=0.008), had more frequent history of intracerebral hemorrhage (ICH), and had higher mortality rate (48.6% vs. 19.2%, p=0.020) than that of patients without CVT. In multivariable analysis, the possibility of presence of CVT was higher in younger age groups [odd ratio (OR): 0.91, 95% confidence interval (CI): (0.86-0.97, p<0.001)] and those with accompanying intracerebral hemorrhage (ICH) (OR: 13.60, 95% CI (1.28-144.12, p=0.045). CONCLUSIONS: Our study demonstrated that CVT related to ChAdOx1 nCoV-19 vaccination was associated with younger age, low levels of fibrinogen, presence of ICH and more frequent mortality compared to those of non-CVT. If TTS occurs after ChAdOx1 nCoV-19 vaccination, the presence of CVT in patients with young age or ICH should be considered.

The effect of hereditary thrombotic factors and comorbidities on the severity of COVID-19 disease.

OBJECTIVE: Coronavirus disease 2019 (COVID-19) has rapidly spread worldwide and presents critical challenges for public health. Due to its chronic and systemic course, COVID-19 is currently accepted as a multi-systemic infectious disease. Here we explore the possible association between disease course and hereditary thrombotic factors and comorbidities. PATIENTS AND METHODS: The patients admitted to the COVID-19 center in the Istanbul Faculty of Medicine were recruited for the study. The patients were classified according to the clinical course, severe vs. mild. Five polymorphic loci were analyzed by multiplex PCR: Factor V Leiden (FVL), FII G20210A, Beta-fibrinogen G-455A, and methylenetetrahydrofolate reductase (MTHFR) C677T and A1298C. RESULTS: FII G20210A and Beta-fibrinogen G-455A genotypes were significantly higher in the study group compared to the literature. Wildtype genotype (GG) in Factor V Leiden locus was significantly associated with low D-Dimer levels (p =0.013). The GA genotype increased the D-Dimer levels 2.55-times compared to the GG genotype (p =0.003). Moreover, the Beta-fibrinogen G-455G genotype was significantly higher in the LDH>250 group (p =0.046). CONCLUSIONS: The presence of solid tumors in patients with COVID-19 was related to the severity of the disease course. No evidence of a correlation between the severity of the disease and all five thrombotic mutations was found, whereas the FII G20210A and Beta-fibrinogen G-455A mutations were significantly high compared to previously reported Turkish population data and global carrier rates. This finding will need to be verified by further studies with larger samples since it may reflect a likelihood of having the COVID-19 disease. The high carrier frequency of FVL mutation was more likely present in the D-dimer high group generating an increase in the D-dimer levels 2.55-times compared to the wildtype.

Inference from longitudinal laboratory tests characterizes temporal evolution of COVID-19-associated coagulopathy (CAC).

Temporal inference from laboratory testing results and triangulation with clinical outcomes extracted from unstructured electronic health record (EHR) provider notes is integral to advancing precision medicine. Here, we studied 246 SARS-CoV-2 PCR-positive (COVIDpos) patients and propensity-matched 2460 SARS-CoV-2 PCR-negative (COVIDneg) patients subjected to around 700,000 lab tests cumulatively across 194 assays. Compared to COVIDneg patients at the time of diagnostic testing, COVIDpos patients tended to have higher plasma fibrinogen levels and lower platelet counts. However, as the infection evolves, COVIDpos patients distinctively show declining fibrinogen, increasing platelet counts, and lower white blood cell counts. Augmented curation of EHRs suggests that only a minority of COVIDpos patients develop thromboembolism, and rarely, disseminated intravascular coagulopathy (DIC), with patients generally not displaying platelet reductions typical of consumptive coagulopathies. These temporal trends provide fine-grained resolution into COVID-19 associated coagulopathy (CAC) and set the stage for personalizing thromboprophylaxis.

A novel interaction between extracellular vimentin and fibrinogen in fibrin formation.

INTRODUCTION: Thrombosis is frequently manifested in critically ill patients with systemic inflammation, including sepsis and COVID-19. The coagulopathy in systemic inflammation is often associated with increased levels of fibrinogen and D-dimer. Because elevated levels of vimentin have been detected in sepsis, we sought to investigate the relationship between vimentin and the increased fibrin formation potential observed in these patients. MATERIALS AND METHODS: This hypothesis was examined by using recombinant human vimentin, anti-vimentin antibodies, plasma derived from healthy and critically ill patients, confocal microscopy, co-immunoprecipitation assays, and size exclusion chromatography. RESULTS: The level of vimentin in plasma derived from critically ill subjects with systemic inflammation was on average two-fold higher than that of healthy volunteers. We determined that vimentin directly interacts with fibrinogen and enhances fibrin formation. Anti-vimentin antibody effectively blocked fibrin formation ex vivo and caused changes in the fibrin structure in plasma. Additionally, confocal imaging demonstrated plasma vimentin enmeshed in the fibrin fibrils. Size exclusion chromatography column and co-immunoprecipitation assays demonstrated a direct interaction between extracellular vimentin and fibrinogen in plasma from critically ill patients but not in healthy plasma. CONCLUSIONS: The results describe that extracellular vimentin engages fibrinogen in fibrin formation. In addition, the data suggest that elevated levels of an apparent aberrant extracellular vimentin potentiate fibrin clot formation in critically ill patients with systemic inflammation; consistent with the notion that plasma vimentin contributes to the pathogenesis of thrombosis.

COVID-19-associated pulmonary aspergillosis is associated with increased in-hospital mortality and prolonged SARS-CoV-2 viral shedding.

BACKGROUND/PURPOSE: Coronavirus disease 2019 (COVID-19)-associated pulmonary aspergillosis (CAPA) is common in critically ill patients with COVID-19 and is associated with worse outcomes. However, reports on CAPA and its impact on treatment outcomes in Asian populations are limited. METHODS: Patients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) reverse transcription polymerase chain reaction-confirmed COVID-19 admitted to intensive care units (ICUs) were retrospectively enrolled in this observational study. The incidence rate of CAPA during ICU admission was investigated. The clinical factors associated with CAPA, including corticosteroid exposure, were analyzed. The impact of CAPA on the treatment outcomes and SARS-CoV-2 viral shedding were explored. RESULTS: A total of 72 ICU-admitted patients with COVID-19 were included in the analysis. The incidence rate of CAPA was 15.3% (11/72) in all patients and 23% (11/48) in the mechanically ventilated patients. The median time from ICU admission to CAPA diagnosis was 15 days. A lower fibrinogen level (adjusted odds ratio [aOR], 0.983; 95% confidence interval [CI], 0.967-0.999) was independently associated with CAPA. The patients with CAPA had a higher in-hospital mortality rate (55% vs. 13%, p = 0.001) and a longer SARS-CoV-2 viral shedding time (22 days vs. 16 days, p = 0.037) than those without CAPA. CONCLUSION: Lower serum fibrinogen levels was independently associated with CAPA among the ICU-admitted patients with COVID-19. The patients with CAPA had a higher in-hospital mortality rate and a longer SARS-CoV-2 viral shedding time than those without CAPA.

Increased KL-6 levels in moderate to severe COVID-19 infection.

BACKGROUND: The global coronavirus disease 2019 (COVID-19) has presented significant challenges and created concerns worldwide. Besides, patients who have experienced a SARS-CoV-2 infection could present post-viral complications that can ultimately lead to pulmonary fibrosis. Serum levels of Krebs von den Lungen 6 (KL-6), high molecular weight human MUC1 mucin, are increased in the most patients with various interstitial lung damage. Since its production is raised during epithelial damages, KL-6 could be a helpful non-invasive marker to monitor COVID-19 infection and predict post-infection sequelae. METHODS: We retrospectively evaluated KL-6 levels of 222 COVID-19 infected patients and 70 healthy control. Serum KL-6, fibrinogen, lactate dehydrogenase (LDH), platelet-lymphocytes ratio (PLR) levels and other biological parameters were analyzed. This retrospective study also characterized the relationships between serum KL-6 levels and pulmonary function variables. RESULTS: Our results showed that serum KL-6 levels in COVID-19 patients were increased compared to healthy subjects (470 U/ml vs 254 U/ml, P <0.00001). ROC curve analysis enabled us to identify that KL-6 > 453.5 U/ml was associated with COVID-19 (AUC = 0.8415, P < 0.0001). KL-6 level was positively correlated with other indicators of disease severity such as fibrinogen level (r = 0.1475, P = 0.0287), LDH level (r = 0,31, P = 0,004) and PLR level (r = 0.23, P = 0.0005). However, KL-6 levels were not correlated with pulmonary function tests (r = 0.04, P = 0.69). CONCLUSIONS: KL-6 expression was correlated with several disease severity indicators. However, the association between mortality and long-term follow-up outcomes needs further investigation. More extensive trials are required to prove that KL-6 could be a marker of disease severity in COVID-19 infection.

Extended coagulation profile of children with Long Covid: a prospective study.

Emerging data suggests that endotheliopathy changes can be associated with post covid condition (PCC) in adults. Research on the matter in children is lacking. We analyzed an extended coagulation profile including biomarkers of endothelial damage in children with PCC and compared it with a control group of children that fully recovered post- SARS-CoV-2 infection. A case-control study enrolling children below 18 years of age with previous microbiologically confirmed SARS-CoV-2 infection in a pediatric post-covid unit in Italy ≥ 8 weeks after the initial infection. Samples were taken at 8 and 12 weeks after the SARS-CoV-2 diagnosis and analyzed for coagulation profiling (fibrinogen, prothrombin time, international normalized ratio, activated partial thromboplastin time, d-dimers, factor VIII coagulant activity, plasma von Willebrand factor (VWF) antigen and VWF ristocetin cofactor (RC)). We compared coagulation profiles in samples from children identified with PCC (at least one, or three or more symptoms, which could not be explained by an alternative diagnosis, at the 8- and 12-week follow-up assessment using the pediatric Long Covid International Severe Acute Respiratory and Emerging Infection Consortium (ISARIC) survey. Seventy-five children were enrolled, 49.3% were females, the median age was 10.2 (IQR 4.9) years. Forty-six (61%) of the children had at least one persisting symptom at the eight weeks post-onset, (PCC8); 39/75 (52%) had persistent symptoms for more than 12 weeks (PCC12) and 15/75(32%) had at least three persisting symptoms (PCC ≥ 3) at 12 weeks. Children with PCC presented more frequently with abnormal D-Dimer levels above the reference range compared to children that had fully recovered at the 8-12 weeks (39.1% vs. 17.2%, p = 0.04), and 12 week follow up or more (41% vs. 17.2%, p = 0.05), and in children with three or more symptoms at 12 weeks follow up compared to those that had recovered (64.3% vs. 22.2%, p = 0.002). For the other coagulation profiles, there were abnormal values detected for VWF, FVIII, RC and Fibrinogen but no significant differences between children with PCC compared to controls. Although the majority of children in our cohort showed coagulation profile within or close to normal ranges, we found that a higher proportion of children with PCC, and specifically those with a more severe spectrum characterized with three or more persisting symptoms, had abnormal D-dimer levels compared to other children that fully recovered from an acute SARS-CoV-2 infection.

Comparative Assessment of the Inhibitory Potential of the Herbicide Glyphosate and Its Structural Analogs on RGD-Specific Integrins Using Enzyme-Linked Immunosorbent Assays.

Transmembrane glycoprotein integrins play crucial roles in biochemical processes, and by their inhibition or activation, different signal pathways can be disrupted, leading to abnormal physiological functions. We have previously demonstrated the inhibitory effect of glyphosate herbicide's active ingredient on cell adhesion and its αvß3 integrin antagonist effect. Therefore, it appeared particularly exciting to investigate inhibition of glyphosate and its metabolites on a wider range of Arg-Gly-Asp (RGD) binding integrins, namely αvß3, α5ß1 and αllbß3. Thus, the purpose of this study was to assess how extended the inhibitory effect observed for glyphosate on the integrin αvß3 is in terms of other RGD integrins and other structurally or metabolically related derivatives of glyphosate. Five different experimental setups using enzyme-linked immunosorbent assays were applied: (i) αvß3 binding to a synthetic polymer containing RGD; (ii) αvß3 binding to its extracellular matrix (ECM) protein, vitronectin; (iii) α5ß1 binding to the above polymer containing RGD; (iv) αllbß3 binding to its ECM protein, fibrinogen and (v) αvß3 binding to the SARS-CoV-2 spike protein receptor binding domain. Total inhibition of αvß3 binding to RGD was detected for glyphosate and its main metabolite, aminomethylphosphonic acid (AMPA), as well as for acetylglycine on α5ß1 binding to RGD.

SARS-CoV-2 Spike Proteins and Cell-Cell Communication Inhibits TFPI and Induces Thrombogenic Factors in Human Lung Microvascular Endothelial Cells and Neutrophils: Implications for COVID-19 Coagulopathy Pathogenesis.

In SARS-CoV-2-infected humans, disease progression is often associated with acute respiratory distress syndrome involving severe lung injury, coagulopathy, and thrombosis of the alveolar capillaries. The pathogenesis of these pulmonary complications in COVID-19 patients has not been elucidated. Autopsy study of these patients showed SARS-CoV-2 virions in pulmonary vessels and sequestrated leukocytes infiltrates associated with endotheliopathy and microvascular thrombosis. Since SARS-CoV-2 enters and infects target cells by binding its spike (S) protein to cellular angiotensin-converting enzyme 2 (ACE2), and there is evidence that vascular endothelial cells and neutrophils express ACE2, we investigated the effect of S-proteins and cell-cell communication on primary human lung microvascular endothelial cells (HLMEC) and neutrophils expression of thrombogenic factors and the potential mechanisms. Using S-proteins of two different SARS-CoV-2 variants (Wuhan and Delta), we demonstrate that exposure of HLMEC or neutrophils to S-proteins, co-culture of HLMEC exposed to S-proteins with non-exposed neutrophils, or co-culture of neutrophils exposed to S-proteins with non-exposed HLMEC induced transcriptional upregulation of tissue factor (TF), significantly increased the expression and secretion of factor (F)-V, thrombin, and fibrinogen and inhibited tissue factor pathway inhibitor (TFPI), the primary regulator of the extrinsic pathway of blood coagulation, in both cell types. Recombinant (r)TFPI and a thiol blocker (5,5'-dithio-bis-(2-nitrobenzoic acid)) prevented S-protein-induced expression and secretion of Factor-V, thrombin, and fibrinogen. Thrombomodulin blocked S-protein-induced expression and secretion of fibrinogen but had no effect on S-protein-induced expression of Factor-V or thrombin. These results suggests that following SARS-CoV-2 contact with the pulmonary endothelium or neutrophils and endothelial-neutrophil interactions, viral S-proteins induce coagulopathy via the TF pathway and mechanisms involving functional thiol groups. These findings suggest that using rTFPI and/or thiol-based drugs could be a viable therapeutic strategy against SARS-CoV-2-induced coagulopathy and thrombosis.