Thread by @ToshiAkima

There has been a lot of talk about microthrombosis (“microclots”) in #LongCOVID, along with the usual knee-jerk reactions about anticoagulation. But that may be mistaking effects for causes. A thread theguardian.com/commentisfree/…

Note the author states: “We found high levels of various inflammatory molecules trapped in the persistent microclots, including clotting proteins like plasminogen, fibrinogen and Von Willebrand factor (VWF), and also Alpha-2 antiplasmin” ncbi.nlm.nih.gov/pmc/articles/P…

In the immunothrombosis world, we have known for a long time that thrombosis is an ancient form of innate immunity. Molluscs use coagulation to barricade off pathogens. In this 2011 talk, Prof Esmon says: “coagulation is part of the innate immune response” academy.isth.org/isth/2011/kyot…

This slide from Chuck Esmon's 2011 @ISTH talk remains just as current today. Thrombosis is such an inherent part of the immune response, we now use the term “immunothrombosis” or “thromboinflammation” to emphasise their profound unity

And no, this ancient immune response isn't just seen in molluscs. If you give healthy human volunteers an immune challenge (LPS), you immediately see molecular signals of coagulation activation (eg TAT complexes, TF mRNA) ashpublications.org/blood/article/…

If the immune response is overwhelming, it can even lead to catastrophic hyperactivation of immunothrombosis pathways leading to disseminated intravascular coagulation (DIC). [BTW I studied this in response to islet cell and kidney xenotransplants]

Treating immunothrombosis with anticoagulants works poorly (and causes bleeding) because you are mopping the floor without turning off the tap. The tap is the source of inflammation. You must go upstream to turn off the tap to stop the thromboinflammation

When treating microthrombosis in #longCOVID, I agree with @fearnley_k that if the source of the thromboinflammation is persistent infection, then we must first treat that to turn off the tap at the source, rather than just mopping the floor

https://twitter.com/fearnley_k/status/1514904255844556801?s=20&t=fTwJjBwKatEkYYoQoGiBrw

There is some suggestion that chronic infection is the source of the inflammatory signalling in many or perhaps most #longCOVID cases, in which case immunothrombosis is more of an effect rather than a cause assets.researchsquare.com/files/rs-14433…

And no, you don't want to rush in with immunosuppression either because that may make the infection worse (opening the tap while mopping the floor). You need to exclude chronic infection first before considering post-infectious autoimmunity as a driver of immunothrombosis

Autoimmune diseases that cause immunothrombosis (thrombotic microangiopathy, antiphospholipid syndrome) are horrid to treat. Proving infection-induced autoantibodies are pathogenic is very difficult. It would be far better to switch off immunothrombosis by treating an infection

Beware the false prophets who say that plasmapheresis/apheresis/PLEX to wash off autoantibodies is a cure-all. This happens with every novel disease, and it invariably tends to fail. It would be impossible to scale the service up to treat millions of #longCOVID sufferers

If it turns out that apheresis or even IVIg turns out to be the treatment for #longCOVID, consider that more an abject disaster than a breakthrough because it would be impossible to treat anything but a tiny minority of sufferers

This is not to deny the possibility that once chronic infection is excluded, some may have post-infectious autoimmune conditions. If we're forced to immunosuppress them, it might leave them vulnerable to another COVID infection, leaving them worse off. Catch-22

But there has always been this theory that autoimmune conditions like SLE, AAV and anti-GBM disease are induced by viruses. The new evidence that MS is caused by EBV makes it more suspicious. So maybe COVID is inducing POST-infectious autoimmune disease? Let's hope not

ADDIT: note I divide between infection-associated autoimmune disease (eg chronic Hep C induced cryoglobulinaemia) and POST-infectious autoimmune disease (virus has gone but autoimmunity persists). The former is treatable with antivirals but the latter needs immunotherapy🧐