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OPINION

Mysterious blood clots. Good and bad news on AstraZeneca vaccine side effects

Since mid-March, many European countries have halted AstraZeneca rollout or stopped administering the shot to people under 55. The reason is a specific rare side effect observed in some of those vaccinated. At first, it was unclear what exactly was going on, but now scientists have a plausible explanation and, most importantly, a conception of how to cope with the pathology.



Since mid-March, many European countries have halted AstraZeneca rollout or stopped administering the shot to people under 55. The reason is a specific rare side effect observed in some of those vaccinated. At first, it was unclear what exactly was going on, but now scientists have a plausible explanation and, most importantly, a conception of how to cope with the pathology.

The unusual life-threatening condition has a complex name, dural venous sinus thrombosis (DVST). It occurs when blood clots block certain veins that drain blood from the brain. As a result, normal drainage is impaired, which, in the worst-case scenario, can lead to so-called cerebral edema. Without timely diagnosis, this condition is life-threatening. DVST was known even before the start of the anti-COVID vaccination campaign, but the disease was extremely rare: its annual frequency in Europe is 3-4 cases per million population. By comparison, deep vein thrombosis (DVT), one of the most common disorders associated with venous blood flow impairment, is diagnosed annually with the frequency of 800 to 3000 cases per million. DVT is not life-threatening in itself, but blood clots which form in the lower extremities can break off, invade other parts of the body via bloodstream and block blood vessels. A common consequence of DVT is pulmonary thromboembolism, a blockage of the pulmonary arteries that kills nearly 40,000 people in Europe every year.

During the first few months of COVID-19 vaccination, European doctors noted a dramatic increase in the number of DVST cases, far exceeding statistical probability. For example, by March 27 in Germany alone, 31 patients with this side effect were identified among those who got the AstraZeneca vaccine. A similar picture was observed in other European countries, and as a result on or about March 15 several countries simultaneously announced they were temporarily halting AstraZeneca rollout. As early as March 18, the European Medical Agency (EMA) issued a statement saying the rare pathology might be associated with the vaccine but stressed that the benefits of vaccination still far outweighed any possible risks and called for the continuation of the vaccine rollout. Some EU member states resumed vaccination, while others preferred to keep it on hold until researchers found new evidence which could clarify the nature of the strange phenomenon. And they did.

Opposites attract

The concern of doctors and scientists overseeing the vaccine rollout was caused not only by the rare health disorder becoming more frequent but also by DVST being accompanied by another pathology called thrombocytopenia. The term means a sharp decline in platelet count, platelets being blood elements responsible for clotting. The fewer there are, the worse the blood clotting ability and, consequently, the higher the risk of bleeding. In other words, doctors simultaneously observed in patients two pathologies that are opposite in their outcome: one associated with a higher, and the other with a lower blood clotting activity. It seems absurd, but actually the paradoxical combination was already known to doctors and provided them with a key to unravelling the mechanism of life-threatening side effects.

Doctors simultaneously observed in patients two pathologies that are opposite in their outcome

The first hypothesis, proposed by the expert community following the news of patients with DVST and thrombocytopenia, focused on the similarities between the new disorder and DIC. The abbreviation DIC stands for «disseminated intravascular coagulation», i.e. the formation of blood clots in blood vessels throughout the body. With disseminated intravascular coagulation (DIC) in patients with multiple thrombosis, the platelet count decreases which leads to bleeding. Very roughly, development of the disseminated intravascular coagulation syndrome is caused by the formation of numerous blood clots which use up most of the platelets swimming in the blood. As a result, the platelet count is too low to prevent internal bleeding.

The DIC syndrome may develop as a consequence of various conditions – from cancer to pregnancy disorders and extensive injuries – that result in a variety of blood clotting substances entering the bloodstream. For this reason, the disseminated intravascular coagulation syndrome often has a rapid onset – for example, it is observed in patients with severe injuries caused by an accident. Yet, in the case of that particular suspicious disorder associated with the AstraZeneca vaccine, the initial symptoms are usually headache, blurred vision, or skin bruising, all of which occur 4 to 16 days after vaccination. This clinical picture is much more similar to another pathology known to doctors as HIT, or heparin-induced thrombocytopenia. In this condition, the platelet count in the patient's blood lowers in response to the introduction of heparin, probably the best-known drug that prevents blood clotting.

Main hypothesis

There are two types of heparin-induced thrombocytopenia. The first type is more common, it manifests several days after the start of heparin therapy, and the platelet count in this condition declines slightly, by nearly 30%, after which it gradually returns to normal. HIT1 is probably associated with the direct action of heparin on platelets: it activates them, forcing them to stick together and attach to various surfaces, for example, the walls of blood vessels. In addition, activated platelets trigger a chain of reactions releasing a variety of substances that further contribute to the formation of a blood clot.

Heparin-induced thrombocytopenia of the second type (HIT2) is much less common, and it is based on an immunological process, namely the development of antibodies in response to complexes formed by protein-cytokine, the so-called platelet factor-4 (PF4), bound to heparin. It is one of the proteins produced by activated platelets that increase the efficiency of clotting. PF4 binds tightly to heparin-like molecules present on the walls of blood vessels, physically interfering with their function. Such heparin-like molecules are part of the body's anticoagulation system, which exists in a complex dynamic balance with the coagulation system. Normally, after the process of formation of blood clots in a damaged area is completed, the balance shifts towards anticoagulation, with new platelets no longer activated.

PF4 binds both to heparin-like substances synthesized within the body, and to heparin itself, which is similar to them in structure. For reasons that are not completely clear, some patients' immune system is triggered by such PF4-heparin complexes into developing protective antibodies against them. An antibody is a Y-shaped molecule: each antibody has different «horns» which can recognize fragments that are extraneous or deemed as such by the immune system; the Y-base is the same for each type of antibody, it serves as bait for other immune system components and also interacts with the receptors of multiple cells. In the case of type 2 heparin-induced thrombocytopenia, the bases of antibodies clinging to heparin-PF4 complexes attach to certain receptors on platelets (although platelets are not cells but rather cell fragments, their receptors work in the same manner) and activate them. As a result, rather than forming in a specific place, e.g. at the site of a damaged blood vessel, blood clots appear throughout the body.

Evidence

Specific antibodies do not form instantly. On average, if an extraneous agent is encountered, the process of formation takes 6 to 14 days - and it was during this period that patients who got the AstraZeneca vaccine developed first signs of dural venous sinus thrombosis. Moreover, just a few days after the German Paul Ehrlich Institute (agency responsible for the research and approval of vaccines in Germany) named the pathology in question for the first time – prior to that news reports had been calling it thrombosis of unknown origin – an international team of researchers led by transfusion medicine specialist Andreas Greinacher of the University of Greifswald produced evidence that the patients were developing a disease very similar to HIT2.

For nearly thirty years Grainacher and his colleagues have been studying heparin-induced thrombocytopenia and autoimmune thrombocytopenia which produce similar clinical pictures, with pathological platelets being activated through PF4 and antibodies without heparin administration. During that time, they developed specific tests for detecting such autoantibodies and determining abnormal platelet activation. Moreover, the scientists said they had created a test that could distinguish between classic type II heparin-induced thrombocytopenia (either heparin-induced or autoimmune) from thrombocytopenia caused by AstraZeneca vaccination. Obviously, blood clotting in those vaccinated is not triggered by heparin; most likely it's an autoimmune reaction triggered by a vaccination-related factor.

The Greifswald doctors examined the blood of patients with the unusual disorder that developed as a result of AstraZeneca vaccination, and found antibodies that activated platelets. The excessive platelet activation test also turned out to be positive. So far, those results have not been published; however, the researchers say they are going to submit an article describing the results to a scientific journal.

Based on the work done by Greinacher and his colleagues, the German Society for the Study of Thrombosis and Hemostasis issued guidelines for diagnosing and treating patients with the complication. The guidelines prescribe tests that should be performed in order to rule out or confirm HIT-like pathology. Until an autoimmune reaction is ruled out, patients should not be given heparin – a usual drug for thrombosis, especially unfractionated, since that drug contains longer molecules that bind a large number of PF4, which means they are more effective in provoking a pathological autoimmune reaction.

Different anticoagulant drugs are proposed as an alternative, supplemented with high doses of immunoglobulins, i.e. a mixture of antibodies produced from donor plasma. Immunoglobulin therapy is often used to relieve the symptoms of autoimmune diseases. The mechanism or rather mechanisms of action are not known in detail, but it is assumed that at least one of them is associated with the fact that foreign antibodies have lots of Y-bases, the parts of the molecule that can be recognized by receptors of a variety of important cells, particularly immune cells. By physically clogging the available receptors in the literal sense, external immunoglobulins prevent autoantibodies from binding to those receptors, blocking the development of a pathological reaction. A similar algorithm is used for treating patients with HIT2.

What we don't know

If the data obtained by the German doctors are confirmed, scientists will have a clear way of understanding in detail the nature of the pathology that occurs in some patients who got the AstraZeneca vaccine. Although almost no one doubts there is a connection between vaccination and dural venous sinus thrombosis accompanied by a drop in platelet count, it is still unclear why only certain patients develop this disease. Most of the patients are women aged between 20 and 55, but this is not surprising: women are generally at risk of developing both thrombosis and autoimmune diseases. Vascular complications are associated with the action of estrogens, female sex hormones, and higher susceptibility to autoimmune diseases – nearly 80% of such patients are women – with higher immune system activity. One can say it's a side effect of women's better ability to resist pathogens.

Women are generally at risk of developing both thrombosis and autoimmune diseases

But the average frequency of DVST with simultaneous thrombocytopenia in women today is about 1 incident per 100 thousand vaccinated, i.e. there are some other factors that increase the risk for some of them. First of all, factors that increase the overall risk of thrombosis, including taking oral contraceptives, recent pregnancy, and smoking, are suspect. Perhaps, genetic peculiarities and/or medical history (e.g. being affected by similar pathologies in the past) play a certain role. It is also unclear which of the vaccine components triggers the pathology. It can be the chimpanzee adenovirus used as a viral vector that guides the coronavirus spike protein gene into the cell, the actual spike protein produced in cells after vaccination, or other related substance. In addition, the reaction can develop as a response to high concentrations of the viral vector – autoimmune disorders of this kind sometimes result from viral infections. But whatever the provoking factor, it's effective only in certain people, obviously due to certain individual characteristics.

It is also unclear why dural sinuses are targeted. However, such precise targeting is nothing new: there were cases described in medical literature where type 2 heparin-induced thrombocytopenia resulted in DVST.

But no matter what the exact mechanism of the pathology turns out to be, doctors already know how to successfully cope with it. For the therapy to be successful, it is important to seek help as early as possible. The first signs of HIT-like pathology typically begin to emerge around the fourth day after getting a dose of the vaccine. Symptoms include severe headache, especially around the eyes and back of the head, that cannot be relieved with conventional painkillers. Later, the patient may develop vision problems. Another typical symptom is hemorrhages and skin bruising other than at the injection site. Patients with any of those signs should immediately seek medical attention. The guidelines of the German Society for the Study of Thrombosis and Hemostasis have already been circulated to European hospitals. The good news is that all medium to large hospitals have the required medicines, so the prognosis is good for patients who may develop DVST complicated by thrombocytopenia.


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