Blood Clots and the AZ Vaccine, Revisited

By Derek Lowe

Once again, what’s going on with vascular events and the AZ/Oxford vaccine? I last wrote about this situation a couple of weeks ago, and it’s taken some real turns since then. At that point several EU countries had suspended dosing, but over the next week several began administering the vaccine again after the European Medicines Agency recommended it, in some cases with advisories about which age groups should be targeted.

But there’s more to the story, it seems. Here’s an excellent writeup at Science (open access) by Kai Kupferschmidt and Gretchen Vogel.   A possible concern is what’s being called vaccine-induced prothrombotic immune thrombocytopenia (VIPIT) by Andreas Greinacher at Univ. Griefswald. This is a blood clotting syndrome that’s similar to what’s observed with the (already known) syndrome of heparin-induced thrombocytopenia. That problem, first over 40 years ago, is a paradoxical effect that occurs in a few people of administering heparin for blood clotting problems and actually making the situation worse. The mechanism for HIT is apparently the generation of antibodies to the complex of heparin bound to platelet factor 4 (PF4) protein. That binding sets off further inappropriate platelet activation, and that’s why the free platelet count drops (the “thrombocytopenia” part) as new clots form and existing blood clots become larger and more dangerous. You’d be used to someone presenting with thrombocytopenia to be at risk for bleeding disorders, not suffering from too many blood clots, but HIT is coming around from the other direction.

Greinacher’s team showed that patients who developed clotting disorders after vaccination showed the anti-heparin/PF4 antibodies, as in HIT, but it looks like these also bind to PF4 even when it’s not complexed to heparin. It’s possible that this happens (at least partially) via the adenovirus vector binding to platelets, but the details aren’t clear. There apparently is a subset of “classic” HIT cases who have shown this atypical PF4-alone antibody binding, so it’s a phenomenon that can happen without vaccination. The question, though, is whether vaccination is making it more likely, and whether there are particular populations who are more at risk.

Kupferschmidt passed on more information from Germany’s Paul-Ehrlich Institute just this morning. 2.7 million people have received the AZ/Oxford vaccine there, and 31 patients have been identified with cerebral venous thrombosis. Not all of those are HIT or VIPIT, though, because only 19 of the 31 had thrombocytopenia. There have been nine deaths, and as always, key questions are how many cases one would expect in the population that’s been dosed so far. Earlier this month, the figures were 1.7 million vaccinated and 7  cases of CVT, and the institute said that they would have expected about one case as normal background. The EMA, when they came out recommending the vaccine earlier this month, noted that figuring these background rates is not easy. But they found that if there is indeed an imbalance, it’s most noticeable in the younger age cohort and not in the older. The PEI mentioned today that of the 31 cases they have analyzed, 29 of them have been women, which certainly seems significant as well.

The UK experience with this vaccine has apparently shown no overall increase in thrombotic events – if anything, the vaccinated cohort has been slightly lower in that regard than the general population. But if there is an increased risk in people under 50, especially women, that’s actionable, as they say, even if the risk is very small (as it certainly appears to be). Other vaccines need to be available so that the doses can be aimed better. It’s also worth remembering that HIT (and presumably VIPIT, if it does turn out to be a real subset) can be treated with non-heparin anti-clotting drugs and/or by immunoglobin infusions, so the attempts by the EMA and others to raise awareness among physicians of this side effect are well worth it.

This is all happening against a background of increased infection in many European countries, of course. A worry is that some people will decide not to get vaccinated at all after hearing about these side effects, and regions where most of the available vaccine is the AZ/Oxford one may well see people deciding to wait for a different one, if that’s a possibility. If such things noticeably affect the number of people getting vaccinated, they could easily end up killing off more people in general than any of the vascular side effects will. But it’ll be in different groups – if the information we have now holds up, then younger women would be at small-but-greater-than-others risk of side effects, but the pandemic fatalities would probably be more in older men. A grim thing to be totaling up – more on this as we get more information.

https://blogs.sciencemag.org/pipeline/archives/2021/03/30/blood-clots-and-the-az-vaccine-revisited