Untargeted metabolomics of COVID-19 patient serum reveals potential prognostic markers of both severity and outcome

Metabolomics, Journal Year: 2021, Volume and Issue: 18(1)

Published: Dec. 20, 2021

Abstract Introduction The diagnosis of COVID-19 is normally based on the qualitative detection viral nucleic acid sequences. Properties host response are not measured but key in determining outcome. Although metabolic profiles well suited to capture state, most metabolomics studies either underpowered, measure only a restricted subset metabolites, compare infected individuals against uninfected control cohorts that suitably matched, or do provide compact predictive model. Objectives Here we well-powered, untargeted assessment 120 patient samples acquired at hospital admission. study aims predict patient’s infection severity (i.e., mild severe) and potential outcome discharged deceased). Methods High resolution UHPLC-MS/MS analysis was performed serum using both positive negative ionization modes. A 20 intermediary metabolites were selected univariate statistical significance multiple predictor Bayesian logistic regression model created. Results predictors for their relevant biological function include deoxycytidine ureidopropionate (indirectly reflecting load), kynurenine (reflecting inflammatory response), short chain acylcarnitines (energy metabolism) among others. Currently, this approach predicts with Monte Carlo cross validated area under ROC curve 0.792 (SD 0.09) 0.793 0.08), respectively. blind validation an additional 90 patients predicted AUC 0.83 (CI 0.74–0.91) 0.76 0.67–0.86). Conclusion Prognostic tests markers discussed paper could allow improvement planning treatment.

Language: Английский

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Erythrocyte, Platelet, Serum Ferritin, and P-Selectin Pathophysiology Implicated in Severe Hypercoagulation and Vascular Complications in COVID-19

International Journal of Molecular Sciences, Journal Year: 2020, Volume and Issue: 21(21), P. 8234 - 8234

Published: Nov. 3, 2020

Progressive respiratory failure is seen as a major cause of death in severe acute syndrome coronavirus 2 (SARS-Cov-2)-induced infection. Relatively little known about the associated morphologic and molecular changes circulation these patients. In particular, platelet erythrocyte pathology might result vascular issues, manifestations may include thrombotic complications. These pathologies be both extrapulmonary intrapulmonary central to failure. Previously, we reported presence amyloid microclots patients with disease 2019 (COVID-19). Here, investigate related circulating biomarkers, including C-reactive protein (CRP), serum ferritin, P-selectin. biomarkers are well-known interact with, to, platelets erythrocytes. We also study structure erythrocytes using fluorescence microscopy (using markers PAC-1 CD62PE) scanning electron microscopy. Thromboelastography viscometry were used coagulation parameters plasma viscosity. conclude that structural found erythrocytes, together spontaneously formed microclots, observed during COVID-19 progression, microangiopathy, diffuse intravascular coagulation, large-vessel thrombosis, well ground-glass opacities lungs. Consequently, this clinical snapshot strongly suggests it true considering such should form an essential part treatment regime.

Language: Английский

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The potential role of ischaemia–reperfusion injury in chronic, relapsing diseases such as rheumatoid arthritis, Long COVID, and ME/CFS: evidence, mechanisms, and therapeutic implications

Biochemical Journal, Journal Year: 2022, Volume and Issue: 479(16), P. 1653 - 1708

Published: Aug. 31, 2022

Ischaemia-reperfusion (I-R) injury, initiated via bursts of reactive oxygen species produced during the reoxygenation phase following hypoxia, is well known in a variety acute circumstances. We argue here that I-R injury also underpins elements pathology chronic, inflammatory diseases, including rheumatoid arthritis, ME/CFS and, our chief focus and most proximally, Long COVID. Ischaemia may be fibrin amyloid microclot blockage capillaries, for instance as exercise started; reperfusion necessary corollary when it finishes. rehearse mechanistic evidence these occurrences here, terms their manifestation oxidative stress, hyperinflammation, mast cell activation, production marker metabolites related activities. Such microclot-based phenomena can explain both breathlessness/fatigue post-exertional malaise observed conditions, many other observables. The recognition processes implies, mechanistically, therapeutic benefit potentially to had from antioxidants, anti-inflammatories, iron chelators, suitable, safe fibrinolytics, and/or anti-clotting agents. review considerable existing consistent with this, biochemical mechanisms involved.

Language: Английский

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Relative Hypercoagulopathy of the SARS-CoV-2 Beta and Delta Variants when Compared to the Less Severe Omicron Variants Is Related to TEG Parameters, the Extent of Fibrin Amyloid Microclots, and the Severity of Clinical Illness

Seminars in Thrombosis and Hemostasis, Journal Year: 2022, Volume and Issue: 48(07), P. 858 - 868

Published: Sept. 29, 2022

Earlier variants of SARS-CoV-2 have been associated with hypercoagulability and an extensive formation fibrin amyloid microclots, which are considered to contribute the pathology coronavirus 2019 disease (COVID-19). The newer omicron appear be far more transmissible, but less virulent, even when taking immunity acquired from previous infections or vaccination into account. We here show that while clotting parameters significantly raised over those healthy, matched controls, they levels lower than seen severe such as beta delta. also observed individuals infected manifested microclot in platelet-poor plasma compared harboring virulent variants. measurement effects between different acts a kind "internal control" demonstrates relationship extent coagulopathies virulence variant interest. This adds evidence microclots may play important role reflecting severity symptoms COVID-19.

Language: Английский

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Multimodal Molecular Imaging Reveals Tissue-Based T Cell Activation and Viral RNA Persistence for Up to 2 Years Following COVID-19

medRxiv (Cold Spring Harbor Laboratory), Journal Year: 2023, Volume and Issue: unknown

Published: July 31, 2023

ABSTRACT The etiologic mechanisms of post-acute medical morbidities and unexplained symptoms (Long COVID) following SARS-CoV-2 infection are incompletely understood. There is growing evidence that viral persistence immune dysregulation may play a major role. We performed whole-body positron emission tomography (PET) imaging in cohort 24 participants at time points ranging from 27 to 910 days acute using novel radiopharmaceutical agent, [ 18 F]F-AraG, highly selective tracer allows for anatomical quantitation activated T lymphocytes. Tracer uptake the COVID group, which included those with without Long symptoms, was significantly higher compared pre-pandemic controls many regions, including brain stem, spinal cord, bone marrow, nasopharyngeal hilar lymphoid tissue, cardiopulmonary tissues, gut wall. Although cell activation tended be imaged closer illness, increased up 2.5 years infection. observed cord wall associated presence symptoms. In addition, lung tissue persistent pulmonary Notably, these tissues also individuals COVID. Given high F]F-AraG detected gut, we obtained colorectal situ hybridization RNA immunohistochemical studies subset identified cellular rectosigmoid lamina propria all participants, 158 676 initial COVID-19 suggesting could long-term immunological perturbations.

Language: Английский

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Cardiovascular and haematological pathology in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS): A role for viruses

Blood Reviews, Journal Year: 2023, Volume and Issue: 60, P. 101075 - 101075

Published: March 20, 2023

ME/CFS is a debilitating chronic condition that often develops after viral or bacterial infection. Insight from the study of Long COVID/Post Acute Sequelae COVID-19 (PASC), post-viral syndrome associated with SARS-CoV-2 infection, might prove to be useful for understanding pathophysiological mechanisms ME/CFS. Disease presentation similar between two conditions, and subset COVID patients meet diagnostic criteria Since characterized by significant vascular pathology – including endothelial dysfunction, coagulopathy, dysregulation question whether not same biological abnormalities are significance in arises. Cardiac have while now been documented cohorts, recent studies demonstrating major deficits cerebral blood flow, hence dysregulation. A growing body research accompanied platelet hyperactivation, anomalous clotting, procoagulant phenotype, dysfunction. Endothelial damage dysregulated clotting can impair substance exchange tissues, result hypoperfusion, which may contribute manifestation certain symptoms. Here we review literature summarize cardiovascular haematological findings condition, and, this context, briefly discuss potential role previously-implicated pathogens. Overall, cardiac present within cohorts. While atherosclerotic heart disease significantly ME/CFS, suboptimal function defined reduced output, impaired are, these do appear influenced deconditioning. Rather, dysfunction (autonomic) nervous system. Plenty recently published hyperactivity as well processes. It particular importance determine what extent symptom severity, if systems targeted therapeutic purposes. Viral reservoirs herpesviruses exist most likely directly indirectly. This highlights studying functioning, vasculature, coagulation system

Language: Английский

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The Proteome Content of Blood Clots Observed Under Different Conditions: Successful Role in Predicting Clot Amyloid(ogenicity)

Molecules, Journal Year: 2025, Volume and Issue: 30(3), P. 668 - 668

Published: Feb. 3, 2025

A recent analysis compared the proteome of (i) blood clots seen in two diseases—sepsis and long COVID—when was known to have clotted into an amyloid microclot form (as judged by staining with fluorogenic stain thioflavin T) (ii) that those non-amyloid considered formed normally. Such fibrinaloid microclots are also relatively resistant fibrinolysis. The proteins contained differed markedly both from soluble typical plasma normal clots, between diseases studied (an acute syndrome sepsis ITU a chronic disease represented Long COVID). Many were low concentration effectively accumulated fibres, whereas many other abundant excluded. found associated tended be themselves amyloidogenic. We here ask inverse question. This is: can clot tell us whether particular observed uniquely (or highly over-represented) relative thus fact nature? answer is affirmative variety major coagulopathies, viz., venous thromboembolism, pulmonary embolism, deep vein thrombosis, various cardiac issues, ischaemic stroke. Galectin-3-binding protein thrombospondin-1 seem especially widely amyloid-type latter has indeed been shown incorporated growing fibrin fibres. These may consequently provide useful biomarkers mechanistic basis.

Language: Английский

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Metabolic Influences Modulating Erythrocyte Deformability and Eryptosis

Metabolites, Journal Year: 2021, Volume and Issue: 12(1), P. 4 - 4

Published: Dec. 21, 2021

Many factors in the surrounding environment have been reported to influence erythrocyte deformability. It is likely that some influences represent reversible changes rigidity may be involved physiological regulation, while others early stages of eryptosis, i.e., red cell self-programmed death. For example, rigidification during exercise probably a mechanism, alterations blood cells (RBCs) observed pathological conditions (inflammation, type 2 diabetes, and sickle-cell disease) are more lead eryptosis. The splenic clearance rigid erythrocytes major regulator RBC physicochemical characteristics (thermal injury, pH, osmolality, oxidative stress, plasma protein profile) also play role. However, there many other deformability In this comprehensive review, we discuss various elements circulating molecules might RBCs modify their deformability: purinergic signaling, gasotransmitters such as nitric oxide (NO), divalent cations (magnesium, zinc, Fe2+), lactate, ketone bodies, lipids, several hormones. Meal composition (caloric carbohydrate intake) modifies Therefore, appears under factors. This suggests homeostatic regulatory loops adapt order cope with need for oxygen or fuel delivery tissues. Furthermore, appear irreversibly damage cells, resulting destruction removal from blood. These two categories modifications should thus differentiated.

Language: Английский

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TEG®, Microclot and Platelet Mapping for Guiding Early Management of Severe COVID-19 Coagulopathy

Journal of Clinical Medicine, Journal Year: 2021, Volume and Issue: 10(22), P. 5381 - 5381

Published: Nov. 18, 2021

An important component of severe COVID-19 disease is virus-induced endothelilitis. This leads to disruption normal endothelial function, initiating a state failing clotting physiology. Massively increased levels von Willebrand Factor (VWF) lead overwhelming platelet activation, as well activation the enzymatic (intrinsic) pathway. In addition, there an impaired fibrinolysis, caused by, amongst others, alpha-(2) antiplasmin. The end result hypercoagulation (proven by thromboelastography® (TEG®)) and reduced inevitably leading difficult-to-overcome hypercoagulated physiological state. Platelets in circulation also plays significant role clot formation, but they themselves may drive when are overactivated due interactions their receptors with endothelium, immune cells or circulating inflammatory molecules. From literature it clear that platelets severely ill patients has been markedly underestimated even ignored. We here highlight value early management coagulopathy guided TEG®, microclot mapping. argue failure clinical trials, where efficacy prophylactic versus therapeutic clexane (low molecular weight heparin (LMWH)) were not always successful, which be because was taken into account during planning trial. conclude that, alteration clotting, outcome any trial evaluating single anticoagulant, including thrombolytic, would negative. Here we suggest use degree dysfunction presence microclots circulation, together might used guideline for severity. A multi-pronged approach, TEG® mapping, required maintain physiology disease.

Language: Английский

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Treatment of Long COVID symptoms with triple anticoagulant therapy

Research Square (Research Square), Journal Year: 2023, Volume and Issue: unknown

Published: March 21, 2023

Abstract Background: Fibrin(ogen) amyloid microclots and platelet hyperactivation are key pathological findings in patients with acute COVID-19 infection also those Long COVID/Post-Acute Sequelae of (PASC). These pathologies may represent a suitable target for pharmacological treatment COVID. Methods: Here we report on the symptoms displayed by cohort 91 South African COVID at baseline after clinician-initiated anticoagulant regime was completed. For laboratory analysis, provided blood sample before treatment. Fibrinaloid microclot presence studied adding thioflavin T to poor plasma (PPP), whilst using two markers- PAC1 CD62P (P-selectin). The included dual antiplatelet therapy (DAPT- Clopidogrel 75mg + Aspirin 75mg) once day, direct oral (DOAC- Apixaban) 5mg twice day. A proton pump inhibitor (PPI) pantoprazole 40 mg/day prescribed gastric protection. Each treated cases reported their main symptoms, whether resolved following or not. Results: In our most participants did not any comorbidities infection. Hypertension dyslipidaemia were commonest underlying illnesses, commonly fatigue, cognitive dysfunction, shortness breath, joint muscle pains. Following completion treatment, each different majority patients. This reflected where decrease severity fibrin microclotting degree pathology noted. No serious adverse bleeding events reported. Conclusions: Fibrin microclots, hyperactivation/ aggregation, widespread endothelialitis inhibit transport oxygen capillary/cellular level. provides ready explanation By normalizing failed clotting physiology reversal endothelialitis, triple represents promising option that appears be highly efficacious, warrants controlled clinical studies. We caution such must only followed under expert medical supervision view risk bleeding.

Language: Английский

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