Some scientists in Europe have wondered whether AstraZeneca’s inclusion of a partial tPA sequence could throw off normal clotting. The European Medicines Agency said in March that there is insufficient evidence to support this theory. And if tPA were somehow involved in the strange blood disorder, there’s no reason to expect that the same problem would show up among people who received vaccines that don’t include the sequence, such as Johnson & Johnson’s.
It’s possible that some other aspect of the adenovirus technology might be in play, which would explain why the only two vaccines to raise major red flags so far both use that delivery system. A couple of past laboratory studies of blood cells have found evidence that adenoviruses can trigger platelets to secrete clotting-related molecules. Still, it’s important to remember that regulators have not yet confirmed a causal link between the unusual blood disorder and the Johnson & Johnson vaccine.
Theory 4: The Mixed Bag
It could be that lots of things are going on at once. We shouldn’t assume that the same thing is happening in every affected patient, says David Lee, an emergency-medicine doctor at NYU Langone Health. “When you just say, ‘Hey, everybody who had a clotting issue, yeah, let’s pile up all those cases,’ you’re mixing a bag,” he told me. Lee and others have shown that COVID-19 patients produce many different antibodies that go after the body’s own proteins, including one that gloms onto a clotting molecule called annexin A2. If platelet factor 4 is involved in some cases of abnormal clotting after vaccination, Lee said, then annexin A2 or other factors might play important roles in others. He pointed, for example, to another molecule involved in clotting, called fibrinogen. The molecule shows up at abnormal levels both in people with severe COVID-19 and some of those who have suffered rare blood disorders following the AstraZeneca vaccine.
Lee is not alone in thinking that this story might have many different plots. Saskia Middeldorp, a vascular internist at Radboud University Medical Center in the Netherlands, says she was initially convinced by the VITT theory. “I was really, really excited because I figured, ‘Wow, now we’ve got a case definition. It’s not great, of course, that this is occurring, but we know better what to do.’” But when she and her colleagues analyzed blood samples from one Dutch patient who developed strange blood issues after receiving the AstraZeneca vaccine, they did not find antibodies against platelet factor 4. (Greinacher says there might be differences in the laboratory assays used to detect the antibodies, which could explain the different results.)
At any rate, it’s clear that multiple mechanisms could lead to the formation of clots when people get sick with COVID-19. That’s one reason it’s so much safer to develop immunity from vaccination than from being naturally infected, according to David Kaslow, the vice president for essential medicines at PATH, a Seattle nonprofit. When your body is presented with one specific portion of a virus—the spike protein, for example—there may be some tiny risk of immune dysfunction. But this is far, far better than the alternative, where the body is exposed to a full pathogen. Natural infections may lead to all sorts of unexpected effects, including platelet damage and abnormal blood clots. A vaccine that whittles down the virus to a single subcomponent is a huge benefit, Kaslow says, because it provides fewer opportunities for something to go wrong.