Causality matters: comparative research cannot address the relationship between a vaccine and adverse events in certain individuals
First, do not harm. Anecdotically, about 17 million of Astrazeneca's COVID-19 vaccines have been administered, of which a relatively low number of severe cases of thrombosis and thrombocytopenia have been reported. It is not clear yet (as of March 18, 2021) whether there is causality between the vaccine and thrombotic events in patients who have recently developed thrombosis after receiving the vaccine. However, some very specific and rare events could possibly be attributed to the vaccine in some patients, who might have had unknown (genetic) predispositions which might be unreconcilable with the vaccine's effect.
Nevertheless, comparative research cannot address causality questions by design. The EMA and national governments have stated earlier this week that "There is no reason to assume that the AZ vaccine is responsible for causing thrombosis and thrombotic thrombocytopenia, because these events occur in coronavirus infection and because millions of people have received the vaccine without adverse events". The latter cannot explain why rare adverse events have occurred in some individuals who have developed thrombotic events within one day to 14 days after receiving the COVID vaccine.
Pharmacovigilance: medical predispositions should be addressed in the instruction folder
To be able to draw conclusions on the relation between the AstraZeneca COVID vaccine and adverse events, it is of the highest necessity to provide insight into the case reports. These should be published in the PubMed database to provide data on patient-specific factors. As a matter of fact, AstraZeneca has warned that caution is warranted with regards to individuals with a history of thrombotic events and individuals with pro-thrombotic predispositions.
Why is it necessary to address the causality question? For one main, foremost principle reason: factors that may contribute to adverse events and therefore put individuals at risk of severe disease or injury, need be included in the manufacturers' instructions folder. No, we need not speculate whether AZ is "dangerous", what is needed is that pharmacovigilance is ensured. Everything should be done to make sure that individuals might become victim of inoculation in conflict with contra-indications.
Vaccine-associated disease is an actual phenomenon. A variety of possible routes is known as "Vaccine-associated enhanced disease", abbreviation: "VAED" (Vaccine-associated enhanced disease: Case definition and guidelines for data collection, analysis and presentation of immunization safety data, Vaccine 2021 Feb 23).
Thrombocytopenia and thrombosis: antibody response, ITP, HIT and COVID
A few reports of individuals who have developed thrombotic events following inoculation with AstraZeneca's COVID vaccine have made headlines. These reported events are thrombotic thrombocytopenia and cerebral thrombotic events. Both thrombosis and thrombocytopenia are typically associated with SARS-coronavirus infection (as summarized in the following slides, from my message from 6 May 2020), but these thrombotic events might also occur when antibodies are directed against one's platelets. Idiopathic Thrombocytopenia or Immune Thrombocytopenia (ITP) refers to bleeding disorders that might be caused by pathogens or administration of pharmaceuttical agents and vaccines. This is when the body mistakenly attacks its own platelets, as sometimes happens in autoimmune diseases.
Antiphospholipid antibodies, anticardiolipin antibodies and Heparine-induced thrombocytopenia (HIT) are known to occur in COVID-19. In spite of its noun, HIT is not always a consequence of heparin administration, but a consequence of formation of antiplatelet antibodies as a failed response to pathogens. This is why a redefinition of "HIT" to cover differentiations is welcomed since 2004. Typically, HIT is characterized by the occurrence of thrombosis and thrombocytopenia. This is what sets HIT apart from other etiologies involving thrombocytopenia.
Typically, heparin administration is avoided following a HIT diagnosis, even in the light of HIT occuring without any prior heparin administration. In a 2004 report I have discussed in abovementioned May 2020 message, patients with differential diagnoses of HIT and thrombocytopenia with antiplatelet antibodies were (succesfully) placed on Enoxaparin, Danaparoid, unfractioned heparin and Warfarin (Thrombocytopenia due to Acute Venous Thromboembolism and its role in expanding the differential diagnosis of Heparin-Induced Thrombocytopenia, American Journal of Hematology 76:69-73 (2004)).
Thrombocytopenia as an adverse reaction to vaccines could be caused by development of platelet-targeting antibodies, occurring independently of previous coronavirus infection. Another explanation is that patients who have developed adverse events following inoculation with AstraZeneca, have been infected prior to administration of the vaccine. In that case, a detrimental inflammatory response might be strengthened by the vaccine.
Causality questions involving VAES need be addressed with urgence
The EMA has updated their viewpoint on the AstraZeneca COVID vaccine on 18 March 2021. The EMA maintains its view that "No significant thrombosis and thrombocytopenia risks are associated with the vaccine". This view is "proved" by the argument that "Benefits outweigh risks of the AstraZeneca vaccine", which is no evidence at all. Its statement does not address whether the events are actual VAES, a topical issue with regards to pharmacovigilance. The causality question remains unanswered. Still, no conclusions can be drawn as long as the case reports are not available.
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| COVID and thrombocytopenia: a progressive picture |
