Professor Mannucci, could you please discuss a patient story that illustrates some of the clinical topics we discussed today? Perhaps it is a composite case from your clinical practice.

Probably, let us say, another example could be the recent story of VITT, vaccine-induced thrombotic thrombocytopenia. That is a completely new syndrome, totally unknown until March of this year. VITT is clearly and inevitably due to using the COVID-19 vaccine with a viral vector. So it is the AstraZeneca and also Johnson and Johnson COVID-19 vaccines. VITT affects almost exclusively young people. VITT is caused, at the same time, by the opposite processes, like, Scylla and Charybdis, as I mentioned. VITT is caused by thrombosis, particularly in unusual sites, such as the veins of the brain and the veins of the abdomen. So, cerebral vein thrombosis and portal or mesenteric and splenic vein thrombosis. And also, besides thrombosis, VITT causes the opposite effect, thrombocytopenia. This is due to the formation of antibodies that activate platelets. Some component of the vaccine has substances that are charged negatively. So they are polyanionic. When you inject the vaccine into the people, these substances get absorbed on the platelets. They react with the cathodic protein of the platelet, so-called platelet factor 4. They elicit the formation of the new antibodies, which are different, of course, from the antibody induced by the vaccine. And these antibodies have the property to activate the platelets. They bind to the platelets, activate them, they release pro coagulation substances. So platelets decrease in number because they are captured by the antibody. They're clear by the spleen. So the patient becomes thrombocytopenic, and they bleed. But at the same time, they activate coagulation. So they develop thrombosis with thrombocytopenia. These problems are very difficult to treat because, of course, for venous thrombosis, you would give heparin or an anticoagulant. But, of course, the patient bleeds, so they are thrombocytopenic. So if there are 3,000 platelets and if we give the patient an anticoagulant, they may also have a bleeding complication besides thrombosis. So it is a very complex situation that is completely new. Now we know better than before how to diagnose VITT and treat VITT. We are trying to avoid as much as possible anticoagulants, particularly when the platelets are very low. So we gave immunoglobulins that inactivate the antibodies and permit the platelets to increase. When platelets increase, we can give the anticoagulants to tackle the problem of thrombosis.

So VITT is really, for us, a new challenge. Because for people like me and my colleagues, it did challenge the double experience that we have between Scylla and Charybdis, that is, bleeding and thrombosis. So you mentioned the example of atrial fibrillation and anticoagulation. But VITT is a new syndrome. It is called VITT, vaccine-induced thrombotic thrombocytopenia. VITT is described to be due to some COVID-19 vaccines. Fortunately, s far as we know, VITT is not due to mRNA COVID-19 vaccines. VITT occurs mainly in young people. That is why it is particularly dramatic. Why VITT occurs mainly in young people? Well, I can answer because younger people tend to react more easily to the formation of antibodies. They react neurologically or strongly. That's why they produce more antibodies than me when given the vaccine. But unfortunately, younger people also produce more auto-antibodies. So that is what we did for VITT. But if you are welcome, if I were not clear enough, to ask specific questions. So we can perhaps complete the interview in that way.

Well, vaccine-induced thrombotic thrombocytopenia (VITT) is a new syndrome. But does it affect men and women equally?

In young people, yes, even though VITT happens more frequently in women. Why? Because women are more affected than men at that age, but particularly at a young age, by the risk of autoimmunity. They produce antibodies towards their cells and organs, like thyroiditis or thrombocytopenia alone. So that's why [VITT happens more often in women]. But in young people, the difference between men and women is trivial. And it's not even very solid; young people are more likely to give a strong autoimmune reaction, which is good for the vaccine. It is why young people do not need the third COVID-19 vaccine dose. It's for the people like me, who will soon need it. Because young people produce more antibodies. But, of course, there is always an advantage and a disadvantage. The only thing that is quite clear is that. And of course, if you look at the literature, the average age [of patients with VITT] is probably around 30 years. But if you look at the literature, you'll find bona fide cases [of VITT], even up to the age of 60. That's why the recommendations were given to avoid these vaccines [in younger people]. And every country has taken up this advice in people about these COVID-19 vaccines for people younger than 60, just to be on the safe side. Some people in the UK chose 30 and probably it is more reasonable. In a way, your example is the typical example. The Johnson and Johnson vaccine is involved as much as the AstraZeneca Vaxzevria COVID-19 vaccine. But it was given later and less expensively than the Vaxzevria vaccine, a vaccine that in the UK was given a very large scale. So the most affected were North European countries, and also the UK. But the UK is our example for many cases of these rare VITT syndrome.

Yes, probably I forgot to mention a very important thing. But this complication is extremely rare. In the worst situation at a population level, VITT is one case in 50,000. And in the majority of cases, it is one case of VITT in 100,000 [people who received the vaccine]. So it's very, very rare. I think it was a good decision to stop the administration of the Vaxzevria vaccine, whether up to the age of 30 or to be on the safe side up to 60 years of age. I think they did well. They did stop rather early, rather precociously. So since the application in the UK, which again is our example for the number of people that took the Vaxzevria vaccine, and now they are having the second dose. There are, all together, nearly 450 cases of VITT. The majority of VITT cases were after the first Vaxzevria vaccine. There were very few cases of VITT with the second dose of the Vaxzevria vaccine. There was nothing after they stopped giving Vaxzevria vaccine to people; if I remember, they took the age of 30 to 40 [as a cutoff age for the vaccine]. They changed it. Since then, there have been no further VITT cases. So this is an example of coagulation syndrome caused by the vaccine. It was a good idea to use the vaccine, which is still being used in older people, at a lower risk for VITT. Young men were also hit by VITT.

But I think it's also important to emphasize that coronavirus clinical disease also can lead to the thrombosis at an even higher frequency, on average.

Sure. Oh yes. We don't know yet why your VITT hits the visceral veins of the brain and the abdomen. Probably it is because the defensive properties against thrombosis are weaker in the brain and abdomen. But certainly, these are very rare thrombosis events in a general population. So the reason we pay attention to it is that we see from time to time these thrombosis cases, but not in such young women, young men, and not after vaccination. So I know that thromboses in unusual sites, as we call them, do occur. But they are even rarer, let us say, one in 1 million. So even if it is one in 100,000 or 1 in 50,000, it was very rare. And that explains why they were not picked up during clinical studies of COVID-19 vaccines. During the vaccination clinical trials, particularly for the Vaxzevria vaccine, there were no cases of VITT because they studied the 1000 and 1000s of cases, but not enough. Whereas in the US, during the Johnson and Johnson vaccine studies, one VITT case was picked up during the registration for the phase three clinical study in a volunteer, but only one case of VITT. And then VITT was already known because VITT first happened in Europe, particularly Northern Europe. After all, they vaccinated very actively young women, in the medical staff for nurses, and the UK, okay. After all, it was their vaccine. So before they had access to the mRNA vaccine, they vaccinated many people of all ages with the Vaxzevria vaccine. Also, if you want to know, to begin with, there was the story that the AstraZeneca vaccine Vaxzevria was used mainly in younger people. They said we haven't got evidence that Vaxzevria works in older people. The evidence was subsequently acquired. So that's why they give it mainly to young people, even in the UK, because there was no other alternative. And because Vaxzevria was originally early thought to be effective mainly in young people. There was a question mark of Vaxzevria efficacy in older people simply because the clinical studies have been done, originally in not so many older people to establish Vaxzevria efficacy and effectiveness in older people.

Well, I think here, and there I gave some clinical examples like the man who was aware of eating too much. Too much meat. Because also, I have some laboratory tests, not show any symptomatic disease, but then he chose himself to move to a quasi-vegetarian diet. 'Quasi' because, of course, you should not exaggerate. I also mentioned as an example of the two opposite things that I'm dealing with in my specialty, bleeding, and thrombosis. The story when you have too many platelets, that, on the one hand, may cause a risk of thrombosis, and they cause thrombosis. But then you realize that there is also a risk of bleeding because you can get bleeding.

Is there a topic or a question that I didn't ask but should have asked? Is there anything else in your interests or your wisdom and experience that you'd like to share?

No, thank you. I enjoyed the conversation. I spoke on things, which I believe in having some knowledge, perhaps a little bit, the story of cancer. But I am quite sure what I said is state of the art. I know, of course, because, let us say, the topics that you dealt with, that you chose very wisely are those which I tackle with my research. So you chose them very well. There are maybe other topics, but I don't think it is worth it. Those topics we discussed are all the better than others.

Professor Mannucci, thank you very much for this most informative conversation, and we hope to continue following up with you on the topics of thrombosis and bleeding. Of course on the environmental pollution and the nutrition - they are very wide but very important topics. Thank you so very much!