A Possible Why For The Clotting Problem Of COVID-19 Vaccines

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There has been a small incidence of diffuse clotting, especially in atypical body sites, like the central vein draining the brain, among some AstraZeneca and J&J COVID-19 vaccine recipients. A newly released pre-print suggests a possible underlying biologic cause.

I found this a plausible study, but we should consider it speculative rather than accepted. First, the research is based on cell cultures. Second, the nuances of cell culture are frankly outside my ability to discern good from bad in technique. Third, it is not a peer-reviewed paper at this point. You can find the paper here, and you are welcome to apply belief or disbelief as you feel necessary. 

If you need a refresher on the adverse clotting events, you can find a review here. These adverse clotting events involve the two COVID-19 vaccines that are "vector-based" - hopping a ride within a specially constructed adenovirus to begin stimulating our immune response. The researchers' hypothesis is based upon the premise that the delivery method, compared with Pfizer's and Moderna's mRNA vaccines, played a role. Let us quickly describe those differences. 

Location, Location, Location

For both approved mRNA vaccines, the payload is mRNA, which codes for COVID-19’s spike protein. It is encased in a tiny fat particle, a lipid nanoparticle, that muscle cells surrounding the injection site ingest. The fatty covering is stripped away in the cytosol, the fluid within the cell, where the mRNA is transformed by the cell’s factory, the endoplasmic reticulum, into spike proteins. This viral antigen, in turn, embeds in the cell’s outer membrane, where it comes into contact with our immune system, initiating our immune response.

The delivery of the mRNA payload by the two adenovirus vector vaccines differs in one critical way. The genetic code for COVID’s spike protein is housed within an adenovirus. The adenovirus binds to and enters the cells around the injection site. Then, the adenovirus's protective layer is removed in the cytosol, just like those lipid nanoparticles protecting the "naked" mRNA. The adenoviral DNA enters the cell’s nucleus, where the spike mRNA is sliced free, replicated, and then returns to the cytosol for translation into the spike protein. 

“And exactly here lies the problem: the viral piece of DNA - deriving from an RNA virus - is not optimized to be transcribed inside of the nucleus.”

In the process of being sliced free and replicating within the cell nucleus, the spike mRNA is liable to be slightly altered. The research hypothesis was that the slight alterations resulted in a viral antigen that had lost its ability to attach and embed into the cell wall; instead, it allowed some of the mRNA to be soluble and circulate throughout the body. In the words of the researchers, 

“arbitrary splice events [taking place in the cell nucleus] that enables the secretion of a soluble Spike protein.”

Let me be clear; the vaccine did not cause anyone to be infected with COVID-19. It is just that the spike antigen was able to escape from the area around the injection site and travel to other locations in the body. 


We know that COVID-19 can cause a diffuse inflammatory response, especially in the cells lining our arteries and veins. That is believed to be due to the significant presence of ACE receptors in these lining cells, the endothelium. Soluble spike protein, inadvertently generated from the inaccurate slicing and subsequent replication of AstraZeneca’s and J&J’s vaccine, still retains the ability to attach to those endothelial cells, initiating the strong inflammatory response and the clotting disorders frequently seen in COVID-19 infections. These unintended and unwanted soluble, traveling spike proteins may be the underlying cause of the adverse clotting events. The researchers point out that the J&J vaccine has fewer sites for errors in slicing the mRNA free from the adenovirus DNA and that “this may explain the ~ 10-fold lower incidence of severe side effects with the Johnson & Johnson vaccine when compared to the AZD1222 [AstraZeneca] vaccine.”

As I mentioned initially, the clotting site in these vaccinated patients is unusual; most clots form in our legs. These vaccine-related clots are seen in large veins of our central nervous system and intestines. Arterial flow is based upon pressure provided by our contracting heart. By the time blood has passed through the capillaries and is beginning to return to the heart through the veins, there is no longer a significant blood pressure gradient between the tissue and heart, so flow should stop. The propulsive pressure or force for venous flow comes from the compression of the veins by surrounding muscles as we move, e.g., by our calf muscles (the calf-pump), and from gravity draining our head when we stand and legs when we sit or put our feet up. One-way valves in the veins keep the sluggish flow moving back towards the heart. The unusual sites of clotting associated with COVID-19 infections and the adverse response to the vaccines frequently involve veins with sluggish flow due to the absence of valves, less external compression by muscles, making gravity the prime determinant of flow.  Sluggish flow allows for greater time for circulating cells and antibodies to interact with the lining of the veins and increases the effects of our immune system's inflammatory response.

Additional considerations that might explain the susceptibility of younger patients is that their immune system is more robust in its responses. Women have a heightened immune response compared to men, and this may make them more susceptible. 

Adverse clotting events represent a vanishingly small risk for patients, especially for those at greater risk for mortality from COVID-19. But perhaps, as the authors note, the mRNA delivered by the adenovirus can be “tweaked” to make it more resistant to mistranslation and further reduce the risk. And as I said at the beginning and will not say again, this is not settled science, but it does offer a plausible explanation. 


Source: “Vaccine-Induced Covid-19 Mimicry” Syndrome: Splice reactions within the SARS-CoV-2 Spike open reading frame result in Spike protein variants that may cause thromboembolic events in patients immunized with vector-based vaccines Research Square DOI: 10.21203/rs.3.rs-558954/v1