It was a small study, but small studies done in the right hands and pursued vigorously enough can make a real difference. Plus, there’s nothing like really digging into the brain – and this took actual digging – to learn what the SARS-CoV-2 virus is doing to this most obscure and difficult-to-access organ.

leaky blood vessels long COVID

Nath’s findings suggested to him that leaky blood vessels may be sparking inflammation in the brains of long-COVID patients.

In a sense, the senior author of this study, Avindra Nath, has been here before. A year and a half ago, in Feb. 2021, Nath produced one of the first – and still the most interesting – brain findings in COVID. The “Microvascular Injury in the Brains of Patients with Covid-19” study highlighted a theme – small blood vessel damage – that has only grown over time. Nath’s early study found widespread punctate hyperintensities – similar to what was found in ME/CFS decades ago – and small blood vessel damage and leakage across the brain.

Proteins such as fibrinogen, C1q, IgG, and IgM – which should only be found in the blood – had leaked into the brain – triggering, no doubt, an immune reaction. The study findings suggested that damage to the blood-brain barrier that protects the brain had occurred.

Avindra Nath on “A Neurologic Crisis” Plus Leaky Brains in Long COVID, ME/CFS and Fibromyalgia?

A recent survey of the long-COVID literature found no less than 15 studies addressing blood vessel and blood clotting issues in COVID. None of them have addressed blood vessel problems in the brain, however.

In “Neurovascular injury with complement activation and inflammation in COVID-19“, Nath was back with a more detailed autopsy study that tells us much more about what this virus can do. The virus really displayed its potentially lethal character in this study: all the participants in this study died quite quickly after getting infected and, while they did experience respiratory symptoms, the virus did its deadly work in their brains. While the participants in the study died, Nath has, in interviews, stated that he believes their findings may well inform what’s happening with long COVID.

The study dug deep into the endothelial cells lining the blood vessels. Immune complexes produced by antibodies found on the endothelial cells indicated that an immune attack had occurred. IgG and IgM antibodies and platelet aggregates (i.e. small blood clots) were associated with proteins (C1q, C4d, and C5b-9) produced by the classical pathway of the complement branch of the immune system. Activation of the classical pathway occurs in many autoimmune and inflammatory disorders.

Complement Proteins

Staining shows high levels of different complement proteins in the COVID-19 patients (below) vs the controls (above).

Increased levels of an adhesion receptor on the surfaces of those cells suggested the damaged cells were attracting activated platelets to them. They produced a clotting cascade that damaged the endothelial cells, causing them to leak. (Gene expression data indicated that a coagulation cascade had begun and that a clotting event had occurred.) Increased levels of the von Willebrand factor, which is associated with damage to the endothelial cells lining the blood vessels, further cemented the fact that blood vessel damage had occurred.

The authors noted that COVID-19 lung studies have found similarly “strange” blood vessel findings including “unique vascular features consisting of endothelial damage, micro thrombosis (micro blood clots) and intussusception angiogenesis (‘splitting blood vessels’)”.

The all-important antigen – the molecule found on the endothelial cells – which had prompted the immune system to attack them remains unknown, but the authors suggested it could either come from the spike protein of the coronavirus or to the ACE-2 receptor the virus uses to penetrate the cells. Given the abnormal ACE-2 findings in chronic fatigue syndrome (ME/CFS), the latter would probably be more useful for people with ME/CFS.

An inflammatory response primarily involving the macrophages in the spaces surrounding the blood vessels reflected an attempt to repair the damage produced by the leaky blood vessels. With that, you have an ongoing inflammatory process taking place in the brain.

Widespread neuron loss and damage in the brainstem area, in particular, were found. While the study did not find evidence of infection there, they noted that “Involvement of the brainstem could have dire consequences since many vital functions are controlled by this region.” and that “five patients in our study died suddenly, most while sleeping”. The brainstem, of course, is of major interest in ME/CFS.

The Model

Nath endothelial cells long COVID

Nath’s model of endothelial cell damage in long COVID.

The Gist

  • Over a year ago, Avindra Nath published the results of a small autopsy study which suggested that small blood vessel leaks in the brains of people with COVID-19 were causing inflammation in the brain. 
  • In an attempt to figure out how that happened, his most recent study took a closer look at the endothelial cells lining the blood vessels of the brain. 
  • Since that time, over a dozen studies have looked at blood vessel functioning in long COVID, and small blood vessel functioning has become a topic of great interest in long COVID and ME/CFS. 
  • Nath’s most recent study found that immune complexes associated with IgM and IgG antibodies were found on the endothelial cells lining the blood vessels. They indicated that the immune system had attacked the endothelial cells. These cells are responsible for opening/closing the blood vessels and play an important immune role. 
  • Nath was unable to determine what had attracted the immune system to these cells but posited that  either the spike protein of the coronavirus, or damage to the ACE-II receptor that the virus uses to enter the cells, could be responsible. (Note that a couple of studies suggest damage to the ACE-II receptor has occurred in ME/CFS and POTS). 
  • The damage to the endothelial cells caused them to activate and produce more immune factors – including drawing platelets to the area and initiating a clotting cascade. 
  • The small blood clots that formed appear to have burst the tight junctions of the endothelial cells lining the blood vessels – spilling proteins into the perivascular spaces surrounding the blood vessels. 
  • Those proteins, and the immune response they elicited in the microglial cells, then produced an ongoing inflammatory state. 
  • The lack of lung involvement and the high degree of brain involvement seen in these patients – most of whom died without ever stepping into a hospital – led Nath to posit that if these patients had survived, they probably would have ended up with long COVID. 
  • A similar process may be occurring in ME/CFS. Thirty years ago, an ME/CFS study found widespread levels of “punctate hyperintensities” in ME/CFS patients that are believed to reflect small blood vessel dysfunction. Seven years ago, James Baraniuk’s cerebral spinal fluid proteome study pointed to the deposition of amyloidic proteins in endothelial cells, weakened brain blood vessel walls, and leakage into the brain. 
  • Nath suggested that treatment to tamp down the immune system activation could be helpful in long COVID and has begun a 40-person IVIG trial in long COVID. 
  • This is a hot field! More blogs on small blood vessel functioning in long COVID and ME/CFS are coming up. 

The authors proposed the following happened: The virus triggers – in a way they don’t know yet – the complement pathway to form immune antibody complexes that target and activate the endothelial cells. The activated endothelial cells then express pro-inflammatory and clotting factors which caused clots to form. The damaged endothelial cells allowed proteins to leak out into the spaces surrounding the blood vessels.

The unwanted proteins then attract monocytes – which turn into macrophages – which then engulf the proteins in an attempt to clean up the area. Some proteins, though, made their way to the immune cells in the brain – the glial cells – as well as to the neurons they surround and support. Sensing an invader, the glial cells pounce on the proteins, but in doing so, damage the neurons – causing the macrophages to clean them up as well.

The patches of leaky brain blood vessels scattered across the brain, but apparently focused more in the hindbrain area where the brainstem resides produce an ongoing inflammatory response in the brain and nerve damage. The symptoms each person experiences depends on which part of the brain the blood vessel leakage occurs.

Long-COVID Connection?

The participants in this study had died, but the lack of lung involvement and the massive hit their brains took cried out long COVID to Nath. If these patients had survived, Nath felt they probably would have become long-COVID patients, stating “It is quite possible that this same immune response persists in long COVID patients, resulting in neuronal injury.”

Noting that immune-modulating therapies might help turn off the immune activation that may be causing so much trouble, Nath stated, “these findings have very important therapeutic implications.” Nath has begun a 40-person long-COVID IVIG/corticosteroid study.

ME/CFS Connection?

This model is all the more interesting because it appears to fit what some past ME/CFS studies have found. Baraniuk’s 2005 cerebrospinal proteome study found evidence of amyloid (misfolded protein) deposition in the blood vessels and a weakening of the blood vessel walls in the brain. Baraniuk speculated that localized bleeding caused by amyloid deposition into the blood vessels might be occurring throughout ME/CFS patients’ brains.

Back in 1992, a large study co-authored by Dr. Peterson, Dr. Cheney, Dr. Komaroff, and Dr. Paul Gallo, found widespread punctate hyperintensities in the brains of people with ME/CFS. The authors stated that these punctate hyperintensities corresponded to the perivascular spaces surrounding the cerebrospinal fluid and suggested that a similar process had occurred: leakage had ignited an inflammatory response in the brain that damaged the neurons. As with Nath’s findings, the location of the hyperintensities varied by patient. Punctate hyperintensities are now believed to be caused by microvascular disease; i.e. damage to the small blood vessels in the brain – exactly what Nath has found.

Hot Research Area

With over a dozen endothelial cell, blood vessel, and clotting studies popping up in long COVID, and similar studies popping up in ME/CFS, the blood vessels and the blood itself have become areas of intense interest. More on that is coming up soon.





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