Thread by @ToshiAkima

Could PolyP be a key player in COVID contact-pathway thromboinflammation-driven microthrombi? Some thoughts from an emerging area of molecular wizardry. 🧵
#LongCOVID #TeamClots #PolyP

There is evidence in COVID of immunothrombosis being driven through the kallikrein-kinin-contact pathway—we'll just call it the “contact system”. It feeds into the renin-angiotensin system (SARS-CoV-2 binds to ACE2). @JTHjournal onlinelibrary.wiley.com/doi/10.1111/jt…

The still mysterious contact system, once mistaken for a haemostatic pathway, is now regarded as an immunothrombosis pathway. It may yet hold some secrets to how #longCOVID leads to #microclots. frontiersin.org/articles/10.33…

One area of active research is the use of #PolyP inhibitors to block contact activation. PolyP is secreted by activated human platelets expressing P-selectin and may be a key modulator of immunothrombosis. @JTHjournal jthjournal.org/article/S1538-…

Microclots are thought to be a feature of #longCOVID and they stain positive for P-selectin (AKA “CD62P”, a marker of platelet activation). Platelets possibly play a crucial role in COVID immunothrombosis through the contact system.

https://twitter.com/virusesimmunity/status/1589762087597019137?s=61&t=xxEd4_Vs1HwLL2JQR8k_Kw

One thing such activated platelets release is #PolyP. The use of PolyP inhibitors is an area of active research because you could knock out contact system immunothrombosis without impairing haemostasis, i.e. stop clots without causing bleeding! ashpublications.org/blood/article/…

This review by @JHMorrissey & SA Smith in @JTHjournal notes mast cells also secrete PolyP. Mast cells have been implicated in #longCOVID. #PolyP may be a missing link connecting mast cell activation syndrome with microclots produced by activated platelet. jthjournal.org/article/S1538-…

Different groups are actively working on developing drugs to inhibit PolyP. The role of #PolyP in #longCOVID deserves investigation because you might be able to knock out microclots and the associated inflammation without causing bleeding.

We do have old drugs that can inhibit contact activation, such as heparins and vitamin K antagonists (Warfarin). However, they inhibit haemostasis and cause bleeding. Newer DOACs do not inhibit contact activation and it is unclear if they are ideal for microclots.

Finally, here is a nice #PolyP summary review article from @RPTHjournal with excellent pics, once again from the @JHMorrissey team. rpthjournal.org/article/S2475-…

[A tantalising afterthought]. #LongCOVID patients often complain of vascular problems like flushing. Could this be explained by being a contact system disorder caused by bradykinin-induced vasodilation? onlinelibrary.wiley.com/doi/10.1111/jt…

Footnote. From @JHMorrissey et al. At Med School, we were taught to call the contact system the “intrinsic pathway”. It's non-descriptive. It's initiated by contact with -ve charged surfaces eg catheters, dialysis circuits. Modulated by platelet PolyP jthjournal.org/article/S1538-…

Footnote. I forgot to tell you how to say “PolyP”. It's pronounced “Polly-Pea”! And not like “polyp”.