Microclots, as defined by amyloid-fibrinogen aggregates, predict risks of disseminated intravascular coagulation and mortality

Blood Advances, Journal Year: 2024, Volume and Issue: 8(10), P. 2499 - 2508

Published: March 20, 2024

Microclots have been associated with various conditions, including postacute sequelae of severe acute respiratory syndrome coronavirus 2 infection. They postulated to be amyloid-fibrin(ogen) aggregates, but their role as a prognostic biomarker remains unclear. To examine possible clinical utility, blood samples were collected for the first 96 hours from critically ill patients (n = 104) admitted intensive care unit (ICU). Detection was by staining platelet-poor plasma thioflavin T and visualized fluorescent microscopy. Image J software trained identify quantify microclots, which detected in 44 (42.3%) on ICU admission not remaining 60 (57.7%) or 20 healthy controls (0.0%). primary diagnosis sepsis (microclots present sepsis, 23/44 [52.3%] vs microclots absent 19/60 [31.7%]; P .044). Multicolor immunofluorescence demonstrated that consisted amyloid-fibrinogen supported proteomic analysis. Patients either high number larger-sized had higher likelihood developing disseminated intravascular coagulation (odds ratio [OR], 51.4; 95% confidence interval [CI], 6.3-6721.1; < .001) an increased probability 28-day mortality (OR, 5.3; CI, 2.0-15.6; .001). This study concludes defined are potentially useful identifying predicting adverse coagulopathic outcomes.

Language: Английский

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Possible Role of Fibrinaloid Microclots in Postural Orthostatic Tachycardia Syndrome (POTS): Focus on Long COVID

Journal of Personalized Medicine, Journal Year: 2024, Volume and Issue: 14(2), P. 170 - 170

Published: Jan. 31, 2024

Postural orthostatic tachycardia syndrome (POTS) is a common accompaniment of variety chronic, inflammatory diseases, including long COVID, as are small, insoluble, 'fibrinaloid' microclots. We here develop the argument, with accompanying evidence, that fibrinaloid microclots, through their ability to block flow blood microcapillaries and thus cause tissue hypoxia, not simply correlated but in fact, by preceding it, may be chief intermediary POTS, which body's exaggerated 'physiological' response hypoxia. Similar reasoning accounts for symptoms bundled under term 'fatigue'. Amyloids known membrane disruptors, when targets nerve membranes, this can explain neurotoxicity hence autonomic nervous system dysfunction contributes POTS. Taken together view, we indicate microclots serve link POTS fatigue COVID manner at once both mechanistic explanatory. This has clear implications treatment such diseases.

Language: Английский

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Automated microscopic measurement of fibrinaloid microclots and their degradation by nattokinase, the main natto protease

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: April 7, 2024

Abstract Nattokinase, from the Japanese fermented food natto, is a protease with fibrinolytic activity that can thus degrade conventional blood clots. In some cases, however, including in Long COVID, fibrinogen polymerise into an anomalous amyloid form to create clots are resistant normal fibrinolysis and we refer as fibrinaloid microclots. These be detected fluorogenic stain thioflavin T. We describe automated microscopic technique for quantification of microclot formation, which also allows kinetics their formation aggregation recorded. here show recombinant nattokinase effective at degrading microclots vitro . This adds otherwise largely anecdotal evidence, review, might anticipated have value part therapeutic treatments individuals COVID related disorders involve

Language: Английский

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A Perspective on How Fibrinaloid Microclots and Platelet Pathology May be Applied in Clinical Investigations

Seminars in Thrombosis and Hemostasis, Journal Year: 2023, Volume and Issue: 50(04), P. 537 - 551

Published: Sept. 25, 2023

Abstract Microscopy imaging has enabled us to establish the presence of fibrin(ogen) amyloid (fibrinaloid) microclots in a range chronic, inflammatory diseases. Microclots may also be induced by variety purified substances, often at very low concentrations. These molecules include bacterial inflammagens, serum A, and S1 spike protein severe acute respiratory syndrome coronavirus 2. Here, we explore which properties these might used contribute differential clinical diagnoses prognoses various diseases with they associated. Such distributions their size number before after addition exogenous thrombin, spectral properties, diameter fibers are made, resistance proteolysis proteases, cross-seeding ability, concentration dependence ability bind small including fluorogenic stains. Measuring microclot parameters, together microscopy itself, along methodologies like proteomics flow cytometry, as well more conventional assays such those for cytokines, open up possibility much finer use generative methods future where personalized medicine will standard procedures all clotting pathology disease diagnoses.

Language: Английский

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Fibrinaloid Microclots and Atrial Fibrillation

Biomedicines, Journal Year: 2024, Volume and Issue: 12(4), P. 891 - 891

Published: April 17, 2024

Atrial fibrillation (AF) is a comorbidity of variety other chronic, inflammatory diseases for which fibrinaloid microclots are known accompaniment (and in some cases, cause, with mechanistic basis). Clots are, course, well-known consequence atrial fibrillation. We here ask the question whether seen plasma or serum may fact also be cause (or contributor to) development AF. consider ‘risk factors’ AF, and particular, exogenous stimuli such as infection air pollution by particulates, both to The external accompaniments bacterial (lipopolysaccharide lipoteichoic acids) viral (SARS-CoV-2 spike protein) infections stimulate when added vitro, microclots, amyloid proteins, can cytotoxic, inducing hypoxia/reperfusion means. Strokes thromboembolisms common consequences Consequently, taking systems approach, we review considerable evidence detail, leads us suggest that it likely well have an aetiological role This has significant therapeutic implications.

Language: Английский

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Circulating microclots are structurally associated with Neutrophil Extracellular Traps and their amounts are strongly elevated in long COVID patients

Research Square (Research Square), Journal Year: 2024, Volume and Issue: unknown

Published: July 3, 2024

BACKGROUND: The persistence of vasculo-thrombotic complications has been put forward as a possible contributing factor in the long COVID (LC) syndrome. OBJECTIVES: Given recently reported separate demonstration association LC with elevated levels fibrin amyloid microclots (FAM) and those neutrophil extracellular traps (NETs), markers that are linked to thromboinflammation, this study considers FAM NETs. RESULTS: results show NETs quantitatively structurally associated size number patients LC. These showed strong diagnostic performance, both independently when combined. CONCLUSIONS: Our revealed may be component circulating FAM, We suggest higher formation promotes stabilization circulation, leading deleterious effects which contribute causally

Language: Английский

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A protet-based model that can account for energy coupling in oxidative and photosynthetic phosphorylation

Biochimica et Biophysica Acta (BBA) - Bioenergetics, Journal Year: 2024, Volume and Issue: 1865(4), P. 149504 - 149504

Published: Aug. 15, 2024

Two-stage (e.g. light-dark) phosphorylation experiments showed that there is a stored 'high-energy' intermediate linking electron transport and phosphorylation. Large, artificial electrochemical proton gradients (protonmotive forces or pmfs) can also drive phosphorylation, fact seen as strongly supportive of the chemiosmotic coupling hypothesis pmf intermediate. However, in such an experimental threshold (pmf >170 mV, equivalent to ΔpH ∼2.8) below which no observed, 220 mV are required recreate vivo rates. This leads correct question, then whether those values generated by large enough. Even lower ones for any (leave alone explain rates) [1, 2], measured directly with microelectrodes via use membrane-permeant ions and/or acids/bases (which always transporter substrates [3], so all measurements artefactual). The single case seemed enough (220 mV) now admitted be diffusion potential artefact [4]. Many other observables (inadequate bulk H

Language: Английский

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Long COVID – a critical disruption of cholinergic neurotransmission?

Bioelectronic Medicine, Journal Year: 2025, Volume and Issue: 11(1)

Published: Feb. 27, 2025

Abstract Background Following the COVID-19 pandemic, there are many chronically ill Long COVID (LC) patients with different symptoms of varying degrees severity. The pathological pathways LC remain unclear until recently and make identification path mechanisms exploration therapeutic options an urgent challenge. There is apparent relationship between impaired cholinergic neurotransmission. Methods This paper reviews current literature on effects blocked nicotinic acetylcholine receptors (nAChRs) main affected organ cell systems contrasts this unblocking alkaloid nicotine. In addition, presented that could explain previously unexplained phenomenon post-vaccination syndrome (PVS). fact not only SARS-CoV-2 but numerous other viruses can bind to nAChRs discussed under assumption post-viral diseases autoimmune (ADs) may also be due transmission. We present a case report demonstrates changes in transmission, specifically, availability α4β2 by using (-)-[ 18 F]Flubatine whole-body positron emission tomography (PET) imaging dysfunction patient along significant neurological improvement before after low-dose transcutaneous nicotine (LDTN) administration. Lastly, descriptive analysis evaluation were conducted results survey involving 231 users LDTN. Results A substantial body research has emerged offers compelling explanation for LC, suggesting it plausibly explained because nAChR function human body. ten-day course administration, no enduring neuropathological manifestations observed patient. observation was accompanied increase number free ligand binding sites (LBS) nAChRs, as determined PET imaging. shows majority (73.5%) their LC/MEF/CFS disease result Conclusions conclusion, based knowledge, LDTN appears promising safe procedure relieve expected long-term harm.

Language: Английский

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Vascular Pathogenesis in Acute and Long COVID: Current Insights and Therapeutic Outlook

Seminars in Thrombosis and Hemostasis, Journal Year: 2024, Volume and Issue: unknown

Published: Sept. 30, 2024

Abstract Long coronavirus disease 2019 (COVID-19)—a postacute consequence of severe acute respiratory syndrome 2 infection—manifests with a broad spectrum relapsing and remitting or persistent symptoms as well varied levels organ damage, which may be asymptomatic present events such heart attacks strokes recurrent infections, hinting at complex underlying pathogenic mechanisms. Central to these is vascular dysfunction rooted in thrombotic endothelialitis. We review the scientific evidence that widespread endothelial (ED) leads chronic symptomatology. briefly examine molecular pathways contributing pathology provide detailed analysis how cellular processes underpin clinical picture. Noninvasive diagnostic techniques, flow-mediated dilation peripheral arterial tonometry, are evaluated for their utility identifying ED. then explore mechanistic, cellular-targeted therapeutic interventions potential treating Overall, we emphasize critical role health managing COVID highlight need early intervention prevent long-term dysfunction.

Language: Английский

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Proteomic evidence for amyloidogenic cross-seeding in fibrinaloid microclots

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: July 17, 2024

Abstract In classical amyloidoses, amyloid fibres form through the nucleation and accretion of protein monomers, with protofibrils fibrils exhibiting a cross-β motif parallel or antiparallel β-sheets oriented perpendicular to fibre direction. These can intertwine mature fibres. Similar phenomena occur in blood from individuals circulating inflammatory molecules (also those originating viruses bacteria). presence inflammagens, pathological clotting occur, that results an anomalous termed fibrinaloid microclots. Previous proteomic analyses these microclots have shown non-fibrin(ogen) proteins, suggesting more complex mechanism than simple entrapment. We provide evidence against entrapment model, noting clot pores are too large centrifugation would removed weakly bound proteins. Instead, we explore whether co-aggregation into may involve axial (multiple proteins within same fibril), lateral (single-protein contributing fibre), both types integration. Our analysis data different diseases shows no significant overlap normal plasma proteome correlation between abundance Notably, abundant like α-2-macroglobulin, fibronectin, transthyretin absent microclots, while less such as adiponectin, periostin, von Willebrand Factor well represented. Using bioinformatic tools including AmyloGram AnuPP, found entrapped exhibit high amyloidogenic tendencies, their integration elements structures. This likely contributes microclots’ resistance proteolysis. findings underscore role cross-seeding microclot formation highlight need for further investigation structural properties implications thrombotic diseases. insights foundation developing novel diagnostic therapeutic strategies targeting disorders.

Language: Английский

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