COVID, Clots and Platelets
The very rare occurrence of death due to "blood clots following vaccination by AstraZenica's anti SARS-CoV-2 vaccine” (hereafter BCfAZV) is rightly causing concern. It is quite hard to get these rare events into perspective. Not from want of information; the authorities are being exemplary in the amount and clarity of the information they publish. No; it is more the amount of information, its complexity, and the repetitive nature of media coverage laced with strange medical terms that wears you down. And the very “rarity” of rare events is hard to grasp.
Platelets
We are told that these vaccine-induced clots are of a rare type — showing low or very low platelet count. Platelets (also called ’thrombocytes’) are blood cells charged with the job of clotting, and blocking the leakage of blood from blood vessels [1]. Too few platelets (a condition called thrombocytopenia) might indicate potential failure to clot; as when taking too much Warfarin. But in the thrombocytopenia following viral infection it seems that ‘something’ has triggered platelet-activation; the platelets cluster, stick, and die. Clusters of dead/dying platelets can break free and flow in the blood till they reach a narrowing, and block the flow. That is the danger. The remaining blood is depleted of thrombocytes/platelets.
Virus-induced Thrombocytopenia
A somewhat lowered platelet count (< 100 × 10^6/mL blood) has been observed following a number of viral infections, including hepatitis B (and C) viruses, cytomegalovirus, Varicella zoster virus, HIV, and the arboviruses zika and dengue. In this latest COVID-19 pandemic it is found in up to one-third of COVID patients, so we can add wild-type SARS-CoV-2 to that list of viruses that induce thrombocytopenia.
One suggested explanation of the vary rare occurrence of BCfAZV is that after vaccination one or two patients go on to contract COVID, though (to date 2021-04-17) the diagnostic viral RNA has not been detected by PCR [2 (page 37)].
Abnormal clotting can be a factor in the pathology of pandemic and seasonal ‘flu (due to influenza A(H1N1) and other viruses)[3]. In these cases the mechanism may be different, may involve proteases, and pre-disposing genetic polymorphisms in complement proteins. But I flag it because there are a few cases, for that virus disease also, where it seems that it was vaccination that triggered the activation of the platelets.
Rare Events
An early response to the suggestion that the AstraZeneca COVID-19 vaccine causes blood clots was to point out that clots do occur at a similar frequency without vaccination [4,Thromboembolism and the Oxford–AstraZeneca COVID-19 vaccine: side-effect or coincidence?]. The annual incidence of cerebral venous sinus thrombosis is said to be between 2 and 5 per million people [5]. Recent data (as of 4th April 2021) from the 34 million people who have just received the AstraZeneca COVID-19 vaccine are: 169 cases of thrombus in the cerebral venous sinus, and 53 with thrombi in the splanchnic vein. If we restrict ourselves to the cerebral venous sinus, that is 4.97 per million. An observed/expected ratio of 4.97/ 5 is obviously not significant; until you realise that these blood clots occurred within 7 - 30 days of vaccination. So the observed rate could be 12 - 40 times the expected rate.
Some commentators have tried to picture the “5-in-a-million” risk by talking of the risk of a fatal traffic accident on our roads, though that is yet another complicated question. In 2019 there were 1752 fatalities in the UK (population=67 million), which corresponds to 26.5 deaths per million citizens per year [11]; though road-death risk is clearly lower for some and therefore higher for others.
To what new antigens are vaccinees exposed?
The RNA vaccines expose the recipient to the expressed SARS-CoV-2 spike protein and to phospholipid; that is to say, they are rather “pure”.
The AstraZenica vaccine carries DNA for the viral spike protein, together with coding for a 36 aa portion of tissue plasminogen activator leader sequence, plus DNA for all the components of the Chimpanzee Adenovirus vehicle (ChAdOx-1), plus the Adenovirus proteins themselves. (The choice of a replication-incapable Chimpanzee virus instead of a human strain as the vehicle was presumably so that it would be very unlikely that the recipient would already have circulating antibodies against the inoculum.)
The Johnson & Johnson (= Janssen) vaccine uses human Adenovirus HAdV-D26 as vehicle. (There are over 80 different strains of human Adenovirus known, grouped into species (A, B, C, D, etc.)) Fewer doses of this Janssen vaccine than of the AstraZenica one have been administered to date, but a case of abnormal clotting following injection has now been reported [6].
Human Adenovirus vehicles have been used since 2000 in exploratory experiments on gene therapy, and quite a lot of the resulting interactions between virus and host are well known. Thus, it is known that Adenovirus injected into a blood vessel rapidly binds to platelets [7], and coagulation factors in the blood [8][9].
Why, then, is fatal clotting so rare?
If Adenovirus vehicles normally interact with platelets and coagulation factors, why is the problem of thrombocytopenia and clots-in-veins so rare? One possibility is that there may be a rare genetic polymorphism in the human population that predisposes carriers of that rare genotype to full-blown platelet activation, and clots [10]. A second suggestion is that, when a nurse is giving 300 intramuscular injections in a morning, an occasional needle might pierce a blood vessel, and administer an intravenous injection by mistake [10].
The AstraZenica vaccination is still safer than road travel.
References
[1] https://www.verywellhealth.com/thrombocyte-what-is-a-thrombocyte-797228
[2] https://www.ema.europa.eu/en/documents/prac-recommendation/signal-assessment-report-embolic-thrombotic-events-smq-covid-19-vaccine-chadox1-s-recombinant-covid_en.pdf
[3] Pediatr Nephrol. 2018; 33(11): 2009–2025.
[4] The Lancet, Vol. 397, Issue 10283, pp.1441-1443, April 17, 2021.
[5] https://www.ema.europa.eu/en/documents/prac-recommendation/signal-assessment-report-embolic-thrombotic-events-smq-covid-19-vaccine-chadox1-s-recombinant-covid_en.pdf
[6] DOI: 10.1056/NEJMc2105869
[7] https://jvi.asm.org/content/81/9/4866
[8] https://febs.onlinelibrary.wiley.com/doi/10.1002/1873-3468.13649
[9] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4009923/
[10] https://www.ema.europa.eu/en/documents/prac-recommendation/signal-assessment-report-embolic-thrombotic-events-smq-covid-19-vaccine-chadox1-s-recombinant-covid_en.pdf
[11] https://assets.publishing.service.gov.uk/government/uploads/system/uploads/attachment_data/file/922717/reported-road-casualties-annual-report-2019.pdf
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