With input from Dr Monica Vasudev

1559:

Two scientific studies have established a causal link between the AstraZeneca COVID-19 vaccine and severe thrombotic complications. The two studies, one from a German-Austrian-Canadian collaboration and the other from a group in Norway have been published online April 9 in the New England Journal of Medicine. 

1. Both articles have concluded that the rare severe thrombotic events along with thrombocytopenia are caused by antibodies directed against platelet factor 4 (PF4), which results in aggregation of platelets as well as thrombosis, leading to diminished platelet count elsewhere. This results in bleeding. Patients thus develop both severe thrombosis and severe bleeding.
2. The syndrome is similar to heparin-induced thrombocytopenia (HIT).
3. It is treated the same way.
4. Treatment: Intravenous immunoglobulins (IVIG) and anticoagulants.
5. The syndrome linked with the vaccine has been termed as vaccine-induced immune thrombotic thrombocytopenia (VITT).
6. Lead author of the German-led study stated that there was clear evidence of a very close link of severe thrombotic complication and the AstraZeneca vaccine.
7. The German study reported 28 cases of this condition, and described in detail the first 11 patients, aged 22-49 years, who had serious thrombotic complications, including cerebral venous sinus thrombosis (CVST), splanchnic vein thrombosis, disseminated intravascular coagulation (DIC), and pulmonary embolism within 5-16 days of administration of the AstraZeneca vaccine. Six patients died.
8. The researchers have now analyzed 40-50 cases, all of which had the presence of PF4 antibodies.
9. Thrombotic complications develop within weeks of receiving the AstraZeneca vaccine and the association between the vaccine and the occurrence of this antibody is quite robust.
10. In the Norwegian study, investigators noted that older people have been given the Pfizer vaccine, while the AstraZeneca vaccine was generally being given to healthcare workers below 65 years of age. As of March 20, when administration of the AstraZeneca vaccine was halted, 132,686 individuals in Norway had received one dose of the vaccine while the second dose had been administered to none.
11. They noted five cases of severe thromboembolism in unusual sites and associated thrombocytopenia occurring 7-10 days following vaccination with the AstraZeneca vaccine in healthcare workers 32-54 years of age who were admitted to Oslo University Hospital.
12. Four patients developed severe CVST with intracranial hemorrhage and three patients had a fatal outcome. A common denominator in all five cases was high levels of antibodies to PF4-polyanion complexes.
13. The Norwegian researchers concluded that VITT is a new phenomenon with catastrophic outcomes for otherwise healthy young adults and a thorough risk–benefit analysis is needed.
14. Since the AstraZeneca vaccine was paused in Norway on March 20, no more cases were seen.
15. The European Medicines Agency last week stated that 169 cases of CVST and 53 cases of DIC have been reported to its drug safety database among 34 million first doses of the AstraZeneca vaccine.
16. The United Kingdom reported 79 reports of unusual thrombotic events associated with low platelet count in people aged 18-79 years (19 fatal), among 20.2 million doses of the vaccine, translating to an event rate of about 4 in a million and a fatality rate of 1 in a million.
17. Norway and Denmark have completely stopped the use of the vaccine, and several other European countries have restricted the use of this vaccine to those aged above 55 or 65, owing to fewer cases of this complication in older individuals. The UK has recommended using an alternative vaccine in those below 30 years of age.
18. An analysis from the Winton Centre for Risk and Evidence Communication at Cambridge University, UK, which assessed potential benefits and harms of the AstraZeneca vaccine on the basis of UK data, noted that the risk of the vaccine only outweighed the benefits for the 20-29 years age group and only when the COVID exposure risk is low (an incidence of 2 in 10,000 per day as is the current situation in the UK).  
19. In case the COVID risk is medium (incidence of 6 in 10,000 per day), the benefits of the vaccine outweighed the risk even in the 20-29 years age group in the analysis. 
20. Greinacher and colleagues noted that enzyme-linked immunosorbent assays (ELISA) to detect PF4-heparin antibodies in patients with HIT are available extensively and can be used to detect patients for potential post-vaccination thrombocytopenia or thrombosis associated with antibodies against PF4. A strongly positive ELISA result in a patient who has not been exposed to heparin would be a striking abnormality.
21. Administration of IVIG and starting anticoagulation do not need to wait for laboratory diagnosis. Identification of these unusual platelet-activating antibodies is relevant for case identification and future risk–benefit assessment of this and other vaccines.
22. Patients who develop symptoms of clot — severe headache, unusual pain or neurological symptoms — must be assessed for platelet count and a D-dimer test needs to be done. If it has been a few weeks since receiving the AstraZeneca vaccine and they have high D-dimer and low platelet count, they are very likely to have this reaction.
23. They should receive an anticoagulant and IVIG as early as possible. The pathogenic antibody can be detected with the HIT test and can be confirmed eventually using a specialized test.
24. According to Greinacher, anticoagulant was required to stop the growth of the thrombus, while the immunoglobulin product blocks the rogue immune response that causes the problem.
25. The antibodies that bind to PF4 are still in the body of patients and cause more and more activation of the clotting system. The human antibody product IVIG can stop this process by itself binding to the PF4 receptor and blocking the pathogenic antibody. The earlier IVIG is started, the better.
26. If detected in time, these patients can be successfully treated.
27. The platelet count quickly came back up after treatment with IVIG and steroids. The patients who died already had severe cerebral bleeding and it was too late to save them.
28. This is a rapidly progressing reaction and can be fatal.
29. Patients need to immediately visit the emergency department if they experience a severe headache, neurological symptoms, unusual pain.
30. However, there is a problem. Headache, and sometimes even a bad headache, is a frequent side effect of the AstraZeneca vaccine, and a common unrelated occurrence.
31. There is also debate about whether heparin can be used as the anticoagulant in these patients. Non-heparin anticoagulants are recommended unless a functional test has excluded heparin-dependent enhancement of platelet activation.
32. Other thrombotic risks factors such taking the oral contraceptive pill increasing the risk of this reaction seems unlikely.
33. This anti-PF4 antibody is causing a highly strong reaction. The contraceptive pill is a mild thrombotic risk factor.
34. There also have been discussions on the chances that the rogue antibody is produced by the immune response to the virus spike protein in the vaccine, as the structure of part of the spike protein resembles part of the PF4 molecule. However, evidence indicates that this is not a cross-reacting antibody.
35. Is the reaction caused by the adenoviral vector used in the AstraZeneca vaccine? It is quite early for a scientific argument to be drawn on a direct association.
36. Adenovirus interacts with platelets, so theoretically, it could make sense. But if this was the case, there would have been many more patients with these problems.
37. In the NEJM paper, Greinacher et al stated that the amount of adenovirus in a 500 microliter vaccine injection administered 1 or 2 weeks earlier would seem unlikely to be linked with subsequent platelet activation seen in these patients.
38. The EMA reported last week that a safety review has been initiated on the J&J vaccine after four cases of a similar condition linked to the vaccine were reported.
39. The numbers of these severe reactions with the J&J vaccine are very small.
40. While this vaccine has not yet been used in Europe, it has been widely used in the US. It seems likely that as many, or even more, doses of the J&J vaccine have been used in the US as the AstraZeneca vaccine in Europe.
41. Pertaining to reports indicating that these reactions are more common in younger people, experts stated that the numbers appear to be less in older people, though there have been reports in Europe in those above 65 years of age. The higher numbers in younger age groups could be explained by the fact that younger people usually have more active immune systems.(Medscape)

 Dr KK Aggarwal

President CMAAO, HCFI and Past National President IMA