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

Abstract

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

Editorial Compilation—XV

“…This issue begins with several manuscripts still focused on COVID-19 (coronavirus disease 2019) or its potential aftermath, a condition colloquially called “long-COVID,” and otherwise known as “post-acute sequelae of COVID-19 (PASC).” 1 2 3 Long-COVID represents a heterogeneous clinical syndrome characterized by a pathologic continuum of signs, symptoms, and also laboratory/radiologic abnormalities that may persist for a long time after recovering from an acute SARS-CoV-2 (severe acute respiratory syndrome-coronavirus disease 2) infection. Among the various components of this post-viral condition, the risk of venous thromboembolism (VTE) in patients hospitalized for COVID-19 remains considerably higher after discharge, especially in the earlier period (i.e., within the first 6–12 months), in older individuals, in men, in patients with longer hospital stays and more aggressive clinical management (e.g., mechanical ventilation and/or intensive care), when thromboprophylaxis is not used, and in those with a persistent pro-thrombotic state.…”

“…Next, Pretorius and Kell provide an extensive Commentary on the topic of microclots, as potentially seen in both acute COVID-19 and in long-COVID. 2 Microscopy imaging has enabled health workers to appreciate the presence of fibrin(ogen) amyloid (“fibrinaloid”) microclots in a range of chronic, inflammatory diseases. Microclots may also be induced by a variety of purified substances, often at very low concentrations.…”

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

“…implying that these microclots are on the aetiological pathway of the disease, and they can explain many symptoms [183], including fatigue [184], post-exertional symptom exacerbation [185], autoantibody generation [107] and Postural Orthostatic Tachycardia Syndrome (POTS) [186]. Fibrin amyloid microclots also occur during sepsis [187], while amyloid deposits are also observed in the skeletal muscles of those with Long COVID [188].…”

“…More recently, we have established the prevalence of these fibrinaloid microclots in post-viral diseases such as Long COVID [106,175-178] (and see [179]) and ME/CFS (myalgic encephalopathy/chronic fatigue syndrome) [180,181]. The lower amyloidogenicity of omicron versus earlier variants of SARS-CoV-2 is also reflected in its lower virulence [182], implying that these microclots are on the aetiological pathway of the disease, and they can explain many symptoms [183], including fatigue [184], post-exertional symptom exacerbation [185], autoantibody generation [107] and Postural Orthostatic Tachycardia Syndrome (POTS) [186]. Fibrin amyloid microclots also occur during sepsis [187], while amyloid deposits are also observed in the skeletal muscles of those with Long COVID [188].…”

Fibrinaloid Microclots and Atrial Fibrillation

“…• Sepsis (we ignore subtypes [289,290]) likely involves microclots [291], which can be induced experimentally in the presence of cell-surface components of infectious agents such as bacterial lipopolysaccharide [40][41][42]292] or lipoteichoic acid [41], or the spike protein of SARS-CoV-2 [43,44,293].…”