Thread by @kakape

Like everything in this pandemic the science around the rare clotting disorder seen in AstraZeneca vaccinees has moved at an incredible pace. As the link has become clear, hints for a cause have emerged
Story with @GretchenVogel1 is here, thread to come:
sciencemag.org/news/2021/04/h…

@GretchenVogel1 As we explained in an earlier story, the combination of thromboses in unusual places and a low platelet count, quickly led researchers to think of HIT (heparin-induced thrombocytopenia), a rare side effect in people given the blood thinner heparin.

sciencemag.org/news/2021/03/r…

@GretchenVogel1 On Friday, reports from a group in Germany and one in Norway appeared in @NEJM. Both show that the patients have some of the hallmarks of HIT, like antibodies against platelet factor 4 and platelet activation.
nejm.org/doi/full/10.10…
nejm.org/doi/full/10.10…

@GretchenVogel1 @NEJM Quick note on the name:
Greinacher earlier suggested the name "vaccine-induced prothrombotic immune thrombocytopenia” or VIPIT for the rare disorder.
But the two papers now both call it VITT: "vaccine-induced immune thrombotic thrombocytopenia"

@GretchenVogel1 @NEJM So what’s the mechanism behind VITT and is it likely to be caused by other vaccines than the AstraZeneca one as well?
Let’s go through what scientists are thinking:

@GretchenVogel1 @NEJM One early thought was that this might be a rare reaction in people who had already had #covid19 before being vaccinated. But that’s been largely dismissed. All 5 Norwegian cases for instance appear not to have had a prior #SARSCoV2 infection.

@GretchenVogel1 @NEJM Another hypothesis: That the antibodies against spike that the vaccine induces cross-react with PF4. That would have been particularly worrying because in that case the effect we want from the vaccine (the anti-spike antibodies) would also be the problem.

@GretchenVogel1 @NEJM Greinacher and colleagues investigated this in a new paper (out as a preprint) and their results suggests this hypothesis is false too. For one, the platelet-activating antibodies isolated from #VITT patients did not react to the coronavirus spike protein.
researchsquare.com/article/rs-404…

@GretchenVogel1 @NEJM That suggests that producing antibodies against spike does not automatically run the risk of producing anti-PF4 antibodies as well.
That’s why Greinacher said on Friday, that the finding was “fantastic news for the vaccination program.”

@GretchenVogel1 @NEJM So what mechanism does Greinacher think IS at play?
Well, HIT is caused when PF4, which is small and positively charged, binds to heparin, a large, negatively charged molecule. That then makes PF4 “more visible” to our immune system.

@GretchenVogel1 @NEJM Greinacher thinks something similar could be happening with free DNA (also a negatively charged molecule) in the vaccine. There are about 50 billion viral particles in a dose of the vaccine and some of them may break apart spilling DNA, he suggests.

@GretchenVogel1 @NEJM Again, this is just a hypothesis. What is interesting though is that there is some research suggesting that extracellular DNA triggers thromboses as part of an evolved response by our body to deal with injured cells.
(See here for instance: frontiersin.org/articles/10.33…)

@GretchenVogel1 @NEJM Another possibility:
PF4 antibodies are already present in vaccinees.
We all harbor some auto-antibodies that could create problems, but they are usually kept in check through an immune mechanism called “peripheral tolerance”. Could the vaccination trigger a breakdown of that?

@GretchenVogel1 @NEJM As Gowthami Arepally told me: “When you get vaccinated, sometimes the mechanisms of peripheral tolerance get disrupted. When that happens, does that unleash any autoimmune syndromes that you are predisposed to, like HIT?”

@GretchenVogel1 @NEJM We know the AZ vaccine produces a lot of inflammation. So one hypothesis is that this strong inflammatory response breaks down peripheral tolerance in some people with PF4 antibodies leading to VITT.
Again: This is another hypothesis that scientists are testing.

@GretchenVogel1 @NEJM There are other hypotheses, too, of course. Pinpointing the mechanism at work here is important to figure out what can be done to reduce the risk and what other vaccines may carry the same risk.

@GretchenVogel1 @NEJM If inflammation is crucial, an easy fix may be to halve the dose of the vaccine, Greinacher told us.
People that accidentally got a half-dose of the vaccine did experience fewer side effects. “Part of the problem might be that they just overdose” the vaccine, says Greinacher.

@GretchenVogel1 @NEJM Of course, we don’t know any of this for sure.
As @Cox_A_R told me, having fewer common side effects does not necessarily mean rare side effects are fewer too: “We can’t automatically assume effects on more common side effects map to these extremely rare reactions."

@GretchenVogel1 @NEJM @Cox_A_R One piece of the puzzle that will become clearer soon is whether we will see the same side effect in other vaccines, particularly the other adenovirus vector ones, like those from J&J and CanSino and Russia’s Sputnik V vaccine.
That will give us important information too.

@GretchenVogel1 @NEJM @Cox_A_R Already, EMA is investigating four cases of similar clotting seen in U.S. patients who received the J&J vaccine.
We should not jump to conclusions, this may be a coincidence, but as Greinacher says: “It’s at least very suspicious.”

@GretchenVogel1 @NEJM @Cox_A_R I’ll write a separate thread about the risk-benefit calculations here later today or tomorrow.
For now just a very general reminder that these clotting disorders are extremely rare events and in most places for most people the benefits far outweigh the risks.