A central role for amyloid fibrin microclots in long COVID/PASC: origins and therapeutic implications

Abstract

Post-acute sequelae of COVID (PASC), usually referred to as ‘Long COVID’ (a phenotype of COVID-19), is a relatively frequent consequence of SARS-CoV-2 infection, in which symptoms such as breathlessness, fatigue, ‘brain fog’, tissue damage, inflammation, and coagulopathies (dysfunctions of the blood coagulation system) persist long after the initial infection. It bears similarities to other post-viral syndromes, and to myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). Many regulatory health bodies still do not recognize this syndrome as a separate disease entity, and refer to it under the broad terminology of ‘COVID’, although its demographics are quite different from those of acute COVID-19. A few years ago, we discovered that fibrinogen in blood can clot into an anomalous ‘amyloid’ form of fibrin that (like other β-rich amyloids and prions) is relatively resistant to proteolysis (fibrinolysis). The result, as is strongly manifested in platelet-poor plasma (PPP) of individuals with Long COVID, is extensive fibrin amyloid microclots that can persist, can entrap other proteins, and that may lead to the production of various autoantibodies. These microclots are more-or-less easily measured in PPP with the stain thioflavin T and a simple fluorescence microscope. Although the symptoms of Long COVID are multifarious, we here argue that the ability of these fibrin amyloid microclots (fibrinaloids) to block up capillaries, and thus to limit the passage of red blood cells and hence O2 exchange, can actually underpin the majority of these symptoms. Consistent with this, in a preliminary report, it has been shown that suitable and closely monitored ‘triple’ anticoagulant therapy that leads to the removal of the microclots also removes the other symptoms. Fibrin amyloid microclots represent a novel and potentially important target for both the understanding and treatment of Long COVID and related disorders.

Vitamin B12 and D deficiency as cofactors of COVID-19 vaccine-induced chronic neurological adverse reactions: Two cases and a hypothesis

“…However, without fluorescence and with suboptimal equipment these tests were difficult to interpret and thus inconclusive. We want to raise awareness that some (Kell et al, 2022) have hypothesised that microclots could skew blood results to incorrectly come back "normal", for example by entrapment of inflammatory proteins. The slight abnormalities shown as white matter hyperintensities in HAC's MRI scan may be indicative of vascular damage and/or neurodegeneration (i.e.…”

The occurrence of hyperactivated platelets and fibrinaloid microclots in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS)

“…Furthermore, these fibrinaloid microclots are amyloid in nature (as inferred by ThT staining), and as such have been shown to resist degradation via fibrinolytic means (Grobbelaar et al, 2021, Kell and Pretorius, 2017. These amyloid microclots may contribute to poor blood circulation and perfusion, possibly by blocking microcapillaries (Kell et al, 2022), and impairing oxygen and nutrient delivery to various tissues. This provides a ready explanation for the fatigue and other symptoms experienced by individuals with ME/CFS.…”

“…When solubilized in the laboratory via a second trypsinization step, it was shown that they contain inflammatory molecules and clotting factors including α(2)antiplasmin (α2AP), various fibrinogen chains, and serum amyloid A (SAA). This pathology may lead to significant endothelial inflammation, (temporary) capillary blockage and hypoxia (Kell et al, 2022).…”

COVID-19 2022 update: transition of the pandemic to the endemic phase

“…These micro-clots seem to show resistance to the body’s fibrinolytic processes in patients suffering from post-acute (long) COVID-19. Preliminary results demonstrated the efficacy in reducing the symptoms of long COVID-19 patients through the administration of antiplatelet or anticoagulant therapy [ 77 ].…”