Immunothrombosis has emerged as a dominant pathological process exacerbating morbidity and mortality in acute- and long-COVID-19 infections. The hypercoagulable state is due in part to immune system dysregulation, inflammation and endothelial cell damage, as well as a reduction in defense systems. One defense mechanism in particular is glutathione (GSH), a ubiquitously found antioxidant. Evidence suggests that reduction in GSH increases viral replication, pro-inflammatory cytokine release, and thrombosis, as well as decreases macrophage-mediated fibrin removal. The collection of adverse effects as a result of GSH depletion in states like COVID-19 suggest that GSH depletion is a dominant mechanism of immunothrombosis cascade. We aim to review the current literature on the influence of GSH on COVID-19 immunothrombosis pathogenesis, as well as the beneficial effects of GSH as a novel therapeutic for acute- and long-COVID-19.

The Role of Glutathione in Prevention of COVID-19 Immunothrombosis: A Review.

Attenuated Total Reflectance-Fourier transform infrared (ATR-FTIR) spectroscopy is an emerging technology in the medical field. Blood D-dimer was initially studied as a marker of the activation of coagulation and fibrinolysis. It is mainly used as a potential diagnosis screening test for pulmonary embolism or deep vein thrombosis but was recently associated with COVID-19 severity. This study aimed to evaluate the use of ATR-FTIR spectroscopy with machine learning to classify plasma D-dimer concentrations. The plasma ATR-FTIR spectra from 100 patients were studied through principal component analysis (PCA) and two supervised approaches: genetic algorithm with linear discriminant analysis (GA-LDA) and partial least squares with linear discriminant (PLS-DA). The spectra were truncated to the fingerprint region (1800–1000 cm−1). The GA-LDA method effectively classified patients according to D-dimer cutoff (≤0.5 μg/mL and >0.5 μg/mL) with 87.5 % specificity and 100 % sensitivity on the training set, and 85.7 % specificity, and 95.6 % sensitivity on the test set. Thus, we demonstrate that ATR-FTIR spectroscopy might be an important additional tool for classifying patients according to D-dimer values. ATR-FTIR spectral analyses associated with clinical evidence can contribute to a faster and more accurate medical diagnosis, reduce patient morbidity, and save resources and demand for professionals. 

Fast screening using attenuated total reflectance- fourier transform infrared (ATR-FTIR) spectroscopy of patients based on D-dimer threshold value.

Optimal D-dimer cut-off values for diagnosing deep vein thrombosis in patients with comorbid malignancies.

Risk stratification using the plasma D-dimer level and Wells score has been proposed as a safe strategy to rule out acute lower extremity deep vein thrombosis (DVT) and limit the use of duplex ultrasound (DUS) for low-risk patients. A widely used diagnostic protocol defining the role of pretest probability and D-dimer testing in lieu of DUS has not been reported. Our aim was to define the risk of DVT in a standard population of emergency department patients who had presented with acute lower extremity symptoms and determine the role of DUS for these patients.Outpatients presenting to the emergency department with symptoms concerning for lower extremity DVT were prospectively enrolled. All the patients underwent whole leg DUS and clinical and laboratory assessments for DVT using the Wells criteria and plasma D-dimer testing. The patients were stratified into three groups according to the combination of their Wells score and plasma D-dimer level. The prevalence of DVT and the statistical performance of the combined Wells score and plasma D-dimer were compared.A total of 3087 patients were enrolled. Most of the patients had had a negative plasma D-dimer level and Wells score (n = 2290 patients). A total of 222 patients had had a positive plasma D-dimer level and Wells score. The overall prevalence of acute DVT in the present study was 7.3%. Of the 2290 patients with a negative Wells score and negative plasma D-dimer level, 4 had had a diagnosis of DVT (negative predictive value, 99.8%). In contrast, DVT was present in 181 of 222 patients (81.5%) with a positive Wells score and plasma D-dimer level (positive predictive value, 81.5%). The plasma D-dimer level also correlated with the DVT location, and the D-dimer levels were highest for the patients with proximal DVT.The combination of a negative Wells score and negative plasma D-dimer level can safely exclude the presence of DVT. Patients with a negative Wells score and negative plasma D-dimer level are unlikely to benefit from DUS. In contrast, patients with a positive D-dimer level and positive Wells score will benefit from whole leg DUS to rule out the presence of high-risk DVT. 

Defining the Role of Risk Stratification and Duplex Ultrasound in the Diagnosis of Acute Lower Extremity Deep Vein Thrombosis.

Introduction Post-thrombotic syndrome (PTS) is a frequent chronic complication of deep venous thrombosis (DVT). Biomarkers are potentially valuable clinical tools for handling PTS. The purpose of this review was to examine which biomarkers are associated with the development of PTS in adults with lower extremity DVT. Methods We performed a systematic review of all English language prospective studies of biomarkers and PTS published in PubMed and EMBASE. Studies were included if diagnosing DVT by diagnostic imaging and assessing PTS by clinical scales, for example, the Villalta scale. Biomarkers of thrombophilia and pathological clot properties were not assessed. Data was reported qualitatively. Results 15 prospective studies were included. Studies varied widely in study design and methods of data analysis. Forty-six different biomarkers were examined, with seven being measured in two or more studies. The most frequently studied biomarkers were D-dimer, CRP, and IL-6. Associations between PTS and D-dimer were predominantly significant, while results on CRP and IL-6 were inconsistent. ICAM-1 was consistently associated with PTS in all studies and at all timepoints. IL-10 was significantly related to PTS development in the largest study and at all time points. Adiponectin, tPA, HRG and TAFI, MMP-1 and -8, and TIMP-1 and -2 were significantly associated with PTS in single studies. Conclusion (1) Further research on biomarkers and PTS is clearly warranted. (2) Significant differences in study designs made it difficult to draw reliable conclusions regarding individual biomarkers. We suggest the implementation of a standardized framework for the study of biomarkers and PTS, to make comparison of future studies more feasible. (3) D-dimer, ICAM-1, IL-10, MMP-1 and 8, TIMP-1, TIMP-2, and adiponectin are clinical biomarkers of particular interest to include in future studies of PTS. Large scale systemic quantitative proteomic analyses of DVT patients could help identify novel biomarkers of interest in PTS-patients.

Biomarkers and the post-thrombotic syndrome: A systematic review of biomarkers associated with the occurrence of the post-thrombotic syndrome after lower extremity deep venous thrombosis

Objective Plasma D-dimer levels >5000 ng/mL are encountered in a number of conditions other than venous thromboembolism (VTE). Recent studies have used plasma D-dimer levels as a prognostic indicator for coronavirus disease 2019 (COVID-19) infection. The implications of abnormal levels are less clear for patients diagnosed with COVID-19 with a baseline elevation in plasma D-dimer levels. In the present study, we reviewed the occurrence of plasma D-dimer levels >5000 ng/mL and investigated the clinical significance of this finding before the onset of the COVID-19 pandemic. Methods Inpatient records for a 4-year period were screened for laboratory results of plasma D-dimer levels >5000 ng/mL. The patient data were reviewed for the clinical identifiers commonly associated with elevated plasma D-dimer levels, including VTE, cancer, sepsis, pneumonia, other infection, bleeding, and trauma. The patients were then categorized into groups stratified by the plasma D-dimer level to allow for comparisons between the various clinical diagnoses. Results A total of 671 patients were included in the present study. VTE was the most common diagnosis for patients with a plasma D-dimer level >5000 ng/mL, followed by cancer and pneumonia. Multiple clinical diagnoses were present in 61% of the patients. No clear cause for the ultra-high plasma D-dimer level could be identified in 11.3% of the patients. Among the patients lacking a clinical diagnosis at discharge, mortality was 24% in the 5000- to 10,000-ng/mL group, 28.6% in the 10,000- to 15,000-ng/mL group, and 75% in the >15,000-ng/mL group. Conclusions VTE, cancer, and pneumonia were frequently present when ultra-high plasma D-dimer levels were encountered, and mortality was high when the levels were >15,000 ng/mL. The results from our study from a pre–COVID-19 patient population suggest that ultra-high plasma D-dimer levels indicate the presence of severe underlying disease. This should be considered when using the plasma D-dimer level as a screening tool or prognostic indicator for COVID-19 infection.

The clinical significance of ultra-high D-dimer levels.

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The clinical significance of ultra-high D-dimer levels.