Persistent clotting protein pathology in Long COVID/Post-Acute Sequelae of COVID-19 (PASC) is accompanied by increased levels of antiplasmin

[SNT Gatchaman]

Authors: Pretorius et al
Published: 23 August 2021
DOI: 10.1186/s12933-021-01359-7
Full Text: Cardiovascular Diabetology (open access PDF)

Background: Severe acute respiratory syndrome coronavirus 2 (SARS-Cov-2)-induced infection, the cause of coronavirus disease 2019 (COVID-19), is characterized by acute clinical pathologies, including various coagulopathies that may be accompanied by hypercoagulation and platelet hyperactivation.

Recently, a new COVID-19 phenotype has been noted in patients after they have ostensibly recovered from acute COVID-19 symptoms. This new syndrome is commonly termed Long COVID/Post-Acute Sequelae of COVID-19 (PASC). Here we refer to it as Long COVID/PASC. Lingering symptoms persist for as much as 6 months (or longer) after acute infection, where COVID-19 survivors complain of recurring fatigue or muscle weakness, being out of breath, sleep difficulties, and anxiety or depression.

Given that blood clots can block microcapillaries and thereby inhibit oxygen exchange, we here investigate if the lingering symptoms that individuals with Long COVID/PASC manifest might be due to the presence of persistent circulating plasma microclots that are resistant to fibrinolysis.

Methods: We use techniques including proteomics and fluorescence microscopy to study plasma samples from healthy individuals, individuals with Type 2 Diabetes Mellitus (T2DM), with acute COVID-19, and those with Long COVID/PASC symptoms.

Results: We show that plasma samples from Long COVID/PASC still contain large anomalous (amyloid) deposits (microclots). We also show that these microclots in both acute COVID-19 and Long COVID/PASC plasma samples are resistant to fibrinolysis (compared to plasma from controls and T2DM), even after trypsinisation.

After a second trypsinization, the persistent pellet deposits (microclots) were solubilized. We detected various inflammatory molecules that are substantially increased in both the supernatant and trapped in the solubilized pellet deposits of acute COVID-19 and Long COVID/PASC, versus the equivalent volume of fully digested fluid of the control samples and T2DM.

Of particular interest was a substantial increase in α(2)-antiplasmin (α2AP), various fibrinogen chains, as well as Serum Amyloid A (SAA) that were trapped in the solubilized fibrinolytic-resistant pellet deposits.

 

[GlassCannonLife]

Very cool! I wish they had included an ME/CFS group though

 

[SNT Gatchaman]

The original Long COVID micro-clot paper. Relevant to discussions here and here. Also this thread.

 

[Pyrrhus]

Figure 1 from the paper:

 

[Pyrrhus]

Another paper by same author, published around the same time:

SARS-CoV-2 spike protein S1 induces fibrin(ogen) resistant to fibrinolysis: implications for microclot formation in COVID-19 (Grobbelaar et al., 2021)
https://dx.doi.org/10.1042/BSR20210611
Abstract:

Severe acute respiratory syndrome coronavirus 2 (SARS-Cov-2)-induced infection, the cause of coronavirus disease 2019 (COVID-19), is characterized by unprecedented clinical pathologies. One of the most important pathologies, is hypercoagulation and microclots in the lungs of patients.

Here we study the effect of isolated SARS-CoV-2 spike protein S1 subunit as potential inflammagen sui generis. Using scanning electron and fluorescence microscopy as well as mass spectrometry, we investigate the potential of this inflammagen to interact with platelets and fibrin(ogen) directly to cause blood hypercoagulation.

Using platelet-poor plasma (PPP), we show that spike protein may interfere with blood flow. Mass spectrometry also showed that when spike protein S1 is added to healthy PPP, it results in structural changes to β and γ fibrin(ogen), complement 3, and prothrombin. These proteins were substantially resistant to trypsinization, in the presence of spike protein S1.

Here we suggest that, in part, the presence of spike protein in circulation may contribute to the hypercoagulation in COVID-19 positive patients and may cause substantial impairment of fibrinolysis. Such lytic impairment may result in the persistent large microclots we have noted here and previously in plasma samples of COVID-19 patients. This observation may have important clinical relevance in the treatment of hypercoagulability in COVID-19 patients.

(spacing added for readability)

 

[Pyrrhus]

This is not directly related, but it bears mentioning that a portion of the spike protein has been suggested to be a "superantigen". A "superantigen" is a substance that "over-activates" T cells.

Again not necessarily relevant to this conversation. (Unless somehow it is...)

Superantigenic character of an insert unique to SARS-CoV-2 spike supported by skewed TCR repertoire in patients with hyperinflammation (Cheng et al., 2020)
https://doi.org/10.1073/pnas.2010722117
Excerpt:

A hyperinflammatory syndrome reminiscent of toxic shock syndrome (TSS) is observed in severe COVID-19 patients, including children with Multisystem Inflammatory Syndrome in Children (MIS-C). TSS is typically caused by pathogenic superantigens stimulating excessive activation of the adaptive immune system. We show that SARS-CoV-2 spike contains sequence and structure motifs highly similar to those of a bacterial superantigen and may directly bind T cell receptors. We further report a skewed T cell receptor repertoire in COVID-19 patients with severe hyperinflammation, in support of such a superantigenic effect. Notably, the superantigen-like motif is not present in other SARS family coronaviruses, which may explain the unique potential for SARS-CoV-2 to cause both MIS-C and the cytokine storm observed in adult COVID-19.

 

[SWAlexander]

The "adaptive immune system" seams to be the real problem for LC. In my opinion the T-cells are not recognizing the intruder (bacteria/virus/) and over reacting by producing more T-cells/superantigen. If this is the case, there is no known mechanism to shut them off. Hyperinflammation will continue until the spleen becomes exhausted and shots down. The question is , is this the reason why some people die from LC?

 

[Treeman]

The "adaptive immune system" seams to be the real problem for LC. In my opinion the T-cells are not recognizing the intruder (bacteria/virus/) and over reacting by producing more T-cells/superantigen.

Interesting. If the system didn't recognize the intruder, why would it continue to make more T cells etc? Do you mean it recognises the intruder, but fails to successfully control it? Thanks.

 

[SWAlexander]

Interesting. If the system didn't recognize the intruder, why would it continue to make more T cells etc? Do you mean it recognises the intruder, but fails to successfully control it? Thanks.

Not recognizing as a specific danger.
Yes, the defense mechanism can sense danger and produce T-cells but don´t know how to counter react specifically.
Example Tetanus. After contracting Clostridium tetani (Tetanus) the body reacts with muscle weakness (and more symptoms) and cannot defend itself. This is the reason we need to be Tetanus vaccinated. Only then the defense mechanism can recognizance and counter-react against the intruder.

 

[Pyrrhus]

New(er) preprint from Pretorius:

Combined triple treatment of fibrin amyloid microclots and platelet pathology in individuals with Long COVID/ Post-Acute Sequelae of COVID-19 (PASC) can resolve their persistent symptoms (Pretorius et al., 2021 preprint)
https://forums.phoenixrising.me/thr...ng-covid-and-at-least-some-cases-of-me.86537/

 

[SNT Gatchaman]

During the 3rd Long Covid Coalition Congress: Thrombosis and Coagulation (YouTube), there was a presentation by Martin Kräter. He is a post-doc at the Max Planck Institute for the Study of Light and works on microfluidics and high-throughput single-cell deformability analysis.

This congress was a 3 hr plus session, with presentations of varying quality, so please jump directly to Martin's talk at 27:00 which runs for 25 mins. At 41:25 he shows something which they think is a real structure, and are assessing to see if it could represent a microclot.

 

[LindyGirl]

I know sufferers of Long COVID who can't function without https://progressivelabs.com/product/natto-nsk-mega/

This is the only Nattokinase that works for them.