Health Rising by Cort Johnson
Health Rising by Cort Johnson
The Complement Connection in Long COVID: Microclots, Herpesviruses and More - Could it Explain Much?

Thanks to Geoff for providing a narration of this blog


Complement Cascade

The complement cascade – it starts with an antigen (foreign substance) and ends with the membrane attack complex that drills a hole in the invader.

The “complement” system doesn’t at first glance sound like much. Its name reflects the fact that, in part, it “complements” the immune system; i.e. it triggers immune cells to attack pathogens and clean up damaged cells. It also, though, torpedoes bacteria by drilling a hole into them, causing them to spill their guts.

All in all, the rather unimpressive named complement system plays a major role in the innate, or early, immune response – which is responsible for a great deal of inflammation in the body. A breakdown in the complement system can produce many problems including inflammation, or an inability to fight off pathogens.

Indeed, dysregulated complement systems have been found to play a role in many diseases including lupus, rheumatoid arthritis, asthma, multiple sclerosis, vasculitis, ischemia-reperfusion injury, and others. Overactivated complement systems can cause tissue damage while underactivated ones can leave one susceptible to infections.

The complement system consists of about 50 proteins and protein fragments that get activated when they bump into signs of infection and/or damage. One arm of the complement system gets activated when it comes across antigen-antibody complexes (when an antibody binds to a toxin or foreign substance – classical pathway); another when the proteins meet up with sugars produced by bacteria (lectin pathway); or when a cell come across microbes (alternative pathway).

Once activated, complement factors trigger the production of cytokines, which then trigger immune cells to attack pathogens, clear the body of damaged cells, and produce inflammation.

Complement system

The complement system – which sits at the base of the innate immune response – is complex! (Image of classical complement pathways by Architha-Srinivasan CC-3, Wikimedia Commons)

Health Rising by Cort Johnson
Health Rising by Cort Johnson
The Complement Connection in Long COVID: Microclots, Herpesviruses and More - Could it Explain Much?


Instead of directly killing pathogens for cleaning up broken down cells, the complement triggers immune cells to do that.  It’s no small player, though. A critical part of the early or innate immune response, the complement system plays an important role in inflammation, and has been found dysregulated in many autoimmune and other diseases.

The 152-person study did an open-ended analysis of a large number of proteins (<7,000). A pathway analysis found the complement pathway was highly activated in the long-COVID patients.

Next, a machine learning (AI-type analysis) plucked out proteins associated with the complement system in the long-COVID patients.

  • An upregulation of early complement factors and the downregulation of the later complement factors suggested that the system was producing inflammation and not effectively fighting off pathogens.
  • Speaking of pathogens, elevated levels of both anti-CMV and anti-EBV IgG titers in long-COVID patients at 6 months suggested that a herpesvirus reactivation could be driving the complement system activation.
  • Not only that, elevated coagulation factors suggested that microclots could either be driving the complement system activation, or might be driven by it.
  • Plus, some evidence suggested that monocytes – a key part of the complement cascade – were also dysregulated. Monocytes have shown up big time in some recent ME/CFS studies.
  • All in all, the study produced a nice package – complement activation associated with herpesvirus activation, coagulation, and monocytes – each of which have been found in ME/CFS.
  • Since this study was published, two other studies have highlighted the complement system in long COVID.
  • While the complement system has never been a major focus in ME/CFS, several studies have found evidence of complement dysregulation, including one which found complement abnormalities after exercise.
  • Complement dysregulation plays a major role in many diseases, and a variety of drugs have been produced to battle it. The authors of the various articles proposed almost a dozen drugs that could be piloted in long COVID and ultimately, possibly ME/CFS.

Some of the complement pathways are really complex. Check out what happens in the classical complement pathway:

C1q binds directly to the surface of the pathogen. Such binding leads to conformational changes in the C1q molecule, which leads to the activation of two C1r molecules. C1r is a serine protease. They then cleave C1s (another serine protease). The C1r2s2 component now splits C4 and then C2, producing C4a, C4b, C2a, and C2b (historically, the larger fragment of C2 was called C2a but is now referred to as C2b). C4b and C2b bind to form the classical pathway C3-convertase (C4b2b complex), which promotes cleavage of C3 into C3a and C3b. C3b later joins with C4b2b to make C5 convertase (C4b2b3b complex).

It’s no wonder the finding brought an, “Oh no! Not the complement cascade”, from Eric Topol as he mused on the recent complement findings in long COVID.

While each of the three pathways are initiated in different ways, they all end up cleaving complement factor 5 (C5) into C5b when then binds to C6, C7, C8, and C9, to form the terminal complement complex (or TCC; C5b-9). This complex bores holes into the membranes covering pathogens, causing the internal components of the pathogen to leak out and die.

The Study

This Swiss study, “Persistent complement dysregulation with signs of thromboinflammation in active Long Covid“, made waves when published earlier this year for several reasons. For one, it was pretty comprehensive, and for another, it suggested that complement problems in long COVID may be associated with two other big issues – coagulation and herpesvirus activation.

The 152-person study did an open-ended analysis of a large number of proteins (<7,000); i.e. it statistically assessed all the proteins it found to see what insights would emerge.

The pathway analysis examined all the biological pathways found in the proteins that were differently expressed in the long-COVID patients. Think of it a large overview of what got tweaked biologically in them.

Filling two of the top three spots (“complement cascade,” “regulation of complement cascade,” and “immune system”), complement pathways dominated the protein findings.

The fact that the complement dysregulation showed up during the initial infection in the long-COVID patients (but not the recovered patients) suggested that problems with the complement system may lay the groundwork for long COVID.

An analysis of the proteins themselves found that complement c7 was significantly decreased at 6 months in the long-COVID patients. Next, a machine learning (AI-type analysis) concluded that proteins associated with the complement system were the most dysregulated six and 12 months after infection in long COVID.

Membrane attack factors - complement

High levels of earlier complement factors plus low levels of membrane attack factors indicated the complement system was off. (Image by Д.Ильин,-CC0,-via-Wikimedia-Commons)

Reduced levels of the soluble complexes (C5b-7, C5b-8, and C5b-9) that are associated with the later “terminal complement complex (TCC)” were found. The later terminal complex consists of complement factors that get deposited onto pathogens in order to kill them. At the same time, the long-COVID patients exhibited an increase in early TCC factors (C5bC6).

The upregulation of early complement factors and the downregulation of the later complement factors suggested that something had gone awry. The authors assessed protein clusters associated with complement factor c7 in an attempt to figure out where the breakdown occurred. (C7 is the factor that allows the C5b-7 complex to integrate into cell membranes of pathogens.)

High levels of the C5bC6 complex that preceded it indicated that the complement system was likely hyperactivated, causing inflammation. Indeed, the increased levels of two different complement factors (C2, Ba) suggested that two of the three arms of the complement system had been overactivated in the long-COVID patients.

Herpesvirus Reactivation (again)

The researchers uncovered two possible reasons why: elevated levels of both anti-CMV and anti-EBV IgG titers in the long-COVID patients at 6 months could be triggering the complement system activation.

Coagulation (again)

The complement and coagulation systems are closely linked. Because complement can also be activated directly via a coagulation factor called thrombin, a coagulation cascade could also explain the complement activity.

blood clots

The findings suggested that complement activation could be producing blood clots, or vice versa!

indeed, elevated pro-coagulation factors (vWF and TSP-1) and decreased anti-coagulation factors (ADAMTS13, PAF-AH, and ApoA1) indicated that a “thromboinflammatory” response was present; i.e., a coagulation-activated inflammatory response was present in the long-COVID patients. Evidence of a “hemolytic process” in which red blood cells are being destroyed also showed up.

The authors noted that complement activity has been associated with the microclots found in long COVID before, and complement deposition has been found on the endothelial cells lining the blood vessels and platelets in autopsies of long-COVID patients.

Monocytes (Again)

Monocytes showed up big time in a recent ME/CFS gene expression study. In fact, that study suggested they might be ground zero for the immune problems in ME/CFS. That’s an interesting finding given that monocytes play a crucial and multifaceted role in the complement system.

The long-COVID study, interestingly, found that the monocytes showed “distinct transcriptomic changes”; i.e. distinct changes in gene expression – as did the ME/CFS study.

Filling the Gaps?

This study’s ability to potentially bring together important factors (complement activation, herpesvirus activation, coagulation triggered inflammation, monocyte dysregulation) that could combine to produce the chronic disease state we know as long COVID was impressive. Plus, it may also have resulted in a diagnostic signature as well.

One of the co-authors, Dr. Felicity Liew, stated, “It is unusual to find evidence of ongoing complement activation several months after acute infection has resolved, suggesting that long COVID symptoms are a result of active inflammation.”

Reviewing the study, Dr. Russo agreed that the activation of complement in long COVID could be producing the microclots found, which could cause “premature cardiac events, dementia, respiratory failure, and renal failure” as well as the fatigue that people with long COVID struggle with.

The authors proposed using antivirals to target coronavirus and herpesvirus infections and other drugs (anakinra, JAK inhibitors) to target the overactive complement system in long COVID “… and possibly other postinfection syndromes.

Complimenting the Complement Findings

Since the paper was published, two more studies have highlighted complement activation in long COVID.

British Study

Just last week, a British study,Large-scale phenotyping of patients with long COVID post-hospitalization reveals mechanistic subtypes of disease“, involving dozens of researchers, found evidence of complement activation in formerly hospitalized COVID-19 patients who had come down with long COVID.


Monocytes – which play a critical role in the complement system – showed up in 2 long COVID studies as well as recent ME/CFS studies.

The study – which also assessed plasma proteins – also found evidence of monocyte/macrophage activation and, in a nice twist, was able to link immune factors with symptoms.

One set of factors associated with cognitive problems (brain fog) suggested that neuroinflammation was the cause. Elevations of another protein also found in irritable bowel syndrome were associated with gut issues. Proinflammatory signatures dominated the cardiorespiratory, fatigue, and anxiety/depression groups. Markers of myeloid inflammation were associated with fatigue.

These factors are important because they could provide treatment approaches for these different symptoms.

The authors noted that all the mechanisms proposed for long COVID (autoimmunity, thrombosis, vascular dysfunction, SARS-CoV-2 persistence, and latent virus reactivation) potentially involve the complement system and myeloid inflammation. Myeloid inflammation involves monocytes, macrophages, dendritic cells, and other cells of the innate immune system that the complement system interacts with.

They proposed that trials of steroids, IL-1 antagonists, JAK inhibitors, naltrexone, and colchicine be done.

Welsh Study

Plus, a preprint out of the University of Wales had the enticing title, “Complement dysregulation is a predictive and therapeutically amenable feature of long COVID“.

This 243-person study, which used Elisa assays, uncovered markers of significantly increased activation in all three complement pathways (classical, alternative, terminal) in the long-COVID patients (compared to recovered COVID-19 patients).

An AUC score of .785, using four complement factors, indicated that those four factors did a “good” job of separating long-COVID patients from healthy controls.

The researchers proposed that pilot studies assessing three drugs: pegcetacoplan (targeting C3), iptacopan (targeting FB), and vemircopan (targeting FD) be undertaken in long COVID.

The Complement System in Chronic Fatigue Syndrome (ME/CFS)


Exercise-induced complementation activation in ME/CFS.

While the complement system has never been a major thrust of immune research, it has shown up several times. The interest began when a 2003 CDC study found increased levels of a complement factor called c4a in people with ME/CFS after exercise. A small CDC 2009 gene expression exercise study concluded that exercise might have altered the lectin pathway, resulting in a downregulation of protease which then boosted C4a levels and produced inflammation.

In 2015, another CDC gene expression study highlighted alterations in two complement genes that were associated with physical fatigue, body pain, and overall ME/CFS symptom scores.

In 2019, the Nijs group found that increased levels of C4a after exercise were associated in increased pain sensitivity in one measure (but not two others) in ME/CFS. Then in 2021, a different complement factor (C1q) “unexpectedly”, according to the authors, showed up in a large ME/CFS study. The study, which assessed just 4 complement factors (C1 inhibitor, C1q, C3, C4) used more or less common blood tests. ME/CFS patients with high C1q levels also had significantly increased C3 and C4 levels, and reduced C1 inhibitors.

The authors suggested that chronic activation of the classical complement pathway might result from an infection or from the clearing away of damaged cells in a large subset of patients, and proposed, interestingly enough, that coagulation be studied in this group.

Treatment Potential

Given the role complement plays in many autoimmune diseases, it’s not surprising that a variety of drugs have been approved to treat complement dysregulation. That’s potentially good news if complement should turn out to play a major role in these diseases. They include:

The authors of the long-COVID and ME/CFS studies proposed that clinical trials of the following drugs be attempted: pegcetacoplan (targeting C3), iptacopan (targeting FB), vemircopan (targeting FD) anakinra, JAK inhibitors, steroids, IL-1 antagonists, naltrexone and colchicine). (Note that a Dutch anakinra trial did not find that anakinra reduced fatigue in ME/CFS.)


More work needs to be done, but it was good to see the complement system show up big time in three recent long-COVID studies. All found evidence of complement upregulation, two found evidence of monocyte issues – a potentially important topic in long COVID and ME/CFS – and the biggest study linked complement upregulation to coagulation – a potentially very valuable tie-in. As other long-COVID and ME/CFS studies have done, these studies once again pointed fingers at the innate immune system which is responsible for much inflammation in the body.

While the ME/CFS studies found different dysregulations, the association of complement activation with exercise was intriguing, and one study pointed to possible coagulation issues in ME/CFS. A gene expression and a gene polymorphism study highlighted the complement system in ME/CFS well, and recent ME/CFS studies have highlighted monocytes – key players in the complement system.

Finally, the authors proposed a variety of drugs we haven’t made much acquaintance with before that might help return the complement system to health and reduce the inflammation they believe is driving these diseases.

Time will tell how this all turns out, but as always, it’s good to see studies pointing arrows at the same culprits.

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