(I know I'm going to regret trying to answer Jo's questions! Realistically they're unanswerable at this time - which is, I guess, his point. Apologies for the rehashing, I think we've taken this subject about as far as we can until there are other publications that support or deafening silence refutes.)
I'm enthusiastic about the idea of amyloid-form clotting, with abnormal fibrinogen, small fibrin monomers and larger fibrin aggregates, being resistant to fibrinolysis. I'm not enthusiastic about apheresis, which does not appear to have usefully held up over time. I was more interested in it at the beginning, although thought it would be difficult to subject to an RCT. Many commentators here warned back then that it would not pass scrutiny.
As Jo says, no-one has yet reported these in living people. The closest related report I came across was descriptions of microvascular thrombosis appearing during clot-retrieval interventions. As I recall this was said to be a new phenomenon, not previously noted by experienced operators. I can't recall whether that was a Twitter post or elsewhere. Of course that only describes de novo observed microvascular clotting, it doesn't say they were due to microclots in circulation or that they were amyloid in nature.
Microclots have been described in postmortem studies, but needless to say, those patients are dead, so quite different and of limited study value. The other related data point I guess is the multiple reports from embalmers that postmortem clots, with which they are very experienced, had become very abnormal in extent and consistency. This was said to be a new finding, shown in people who had died of COVID-19 (or, more contentiously, following recent vaccination).
None of that is particularly helpful for the questions though.
How could apheresis help? (Or: how might it have helped?). The hypothesis is that the microclots they were seeing in vitro, were present in vivo. In their papers they have stated that the microclots they show must have already been in circulation, because no thrombin was subsequently added. The logic I presume being that thrombin is required to turn soluble fibrinogen into insoluble fibrin. I don't know that that follows exclusively. As far as I understand fibrin exists on a continuum that as a small fibrin monomer (that has not yet cross-linked) can still be soluble. I imagine there is opportunity for soluble or near-soluble fibrin to form larger aggregates in vitro, such that microclots could simply be an artefact (as Jo has always maintained).
Assuming they were circulating in vivo though, the hypothesis was that they were abnormally formed: not tightly compacted as clots should be, but instead nebulous and deformable enough to pass through small capillaries even if they were themselves quite large. (c.f. RBCs turning into tacos in small capillaries). In this way they would continue to circulate, not be filtered in lung or kidney and persist. The in vitro microclot analysis showed they contained a2-antiplasmin which would tip the balance away from fibrinolysis and help explain their longevity.
As Jo says, no-one appears to have replicated this in a publication. What has been shown recently is the mechanism for how spike protein causes amyloid fibrin(-ogen), again in vitro (also in silico). See this thread detailing that basic science work by an unrelated Swedish group. That demonstration goes lower level, whereas we need to go "up" and show circulating amyloid microclots. The Swedish group did demonstrate two PET tracers that tag the amyloid fibrin. They suggest this could be used in patient investigations.
Presumably if a patient had lots of amyloid fibrin (small) in blood, then the blood pool would be generally "hot" on PET. I'm surmising that if there were larger circulating microclots, then, notwithstanding the deformability mentioned above, they might be expected to pass much more slowly through some organs with obligate capillary networks, compared to organs with opportunity for arteriovenous anastomotic bypass, which could have the effect of appearing to accumulate tracer preferentially in eg lungs or kidney, despite not ultimately being filtered out there, as above.
I'm enthusiastic about the idea of amyloid-form clotting, with abnormal fibrinogen, small fibrin monomers and larger fibrin aggregates, being resistant to fibrinolysis. I'm not enthusiastic about apheresis, which does not appear to have usefully held up over time. I was more interested in it at the beginning, although thought it would be difficult to subject to an RCT. Many commentators here warned back then that it would not pass scrutiny.
As Jo says, no-one has yet reported these in living people. The closest related report I came across was descriptions of microvascular thrombosis appearing during clot-retrieval interventions. As I recall this was said to be a new phenomenon, not previously noted by experienced operators. I can't recall whether that was a Twitter post or elsewhere. Of course that only describes de novo observed microvascular clotting, it doesn't say they were due to microclots in circulation or that they were amyloid in nature.
Microclots have been described in postmortem studies, but needless to say, those patients are dead, so quite different and of limited study value. The other related data point I guess is the multiple reports from embalmers that postmortem clots, with which they are very experienced, had become very abnormal in extent and consistency. This was said to be a new finding, shown in people who had died of COVID-19 (or, more contentiously, following recent vaccination).
None of that is particularly helpful for the questions though.
How could apheresis help? (Or: how might it have helped?). The hypothesis is that the microclots they were seeing in vitro, were present in vivo. In their papers they have stated that the microclots they show must have already been in circulation, because no thrombin was subsequently added. The logic I presume being that thrombin is required to turn soluble fibrinogen into insoluble fibrin. I don't know that that follows exclusively. As far as I understand fibrin exists on a continuum that as a small fibrin monomer (that has not yet cross-linked) can still be soluble. I imagine there is opportunity for soluble or near-soluble fibrin to form larger aggregates in vitro, such that microclots could simply be an artefact (as Jo has always maintained).
Assuming they were circulating in vivo though, the hypothesis was that they were abnormally formed: not tightly compacted as clots should be, but instead nebulous and deformable enough to pass through small capillaries even if they were themselves quite large. (c.f. RBCs turning into tacos in small capillaries). In this way they would continue to circulate, not be filtered in lung or kidney and persist. The in vitro microclot analysis showed they contained a2-antiplasmin which would tip the balance away from fibrinolysis and help explain their longevity.
As Jo says, no-one appears to have replicated this in a publication. What has been shown recently is the mechanism for how spike protein causes amyloid fibrin(-ogen), again in vitro (also in silico). See this thread detailing that basic science work by an unrelated Swedish group. That demonstration goes lower level, whereas we need to go "up" and show circulating amyloid microclots. The Swedish group did demonstrate two PET tracers that tag the amyloid fibrin. They suggest this could be used in patient investigations.
Presumably if a patient had lots of amyloid fibrin (small) in blood, then the blood pool would be generally "hot" on PET. I'm surmising that if there were larger circulating microclots, then, notwithstanding the deformability mentioned above, they might be expected to pass much more slowly through some organs with obligate capillary networks, compared to organs with opportunity for arteriovenous anastomotic bypass, which could have the effect of appearing to accumulate tracer preferentially in eg lungs or kidney, despite not ultimately being filtered out there, as above.
