News internationally has been dominated in the past two days by a string of European countries pausing their use of the AstraZeneca vaccine, due to reports of a possible increased risk of blood clots. European regulators are not concerned, citing that the rates of these disorders just reflect the background population rates. I have taken a deeper look at the figures and the issue is perhaps more complex than we are led to believe.
Let me explain about which clotting problems we are interested in
- A blood clot (aka thrombosis) is where the small blood cells called platelets clump -together with some proteins that are normally dissolved in the blood – and produce a solid mass
- These can occur in arteries and block the blood supply to the heart (causing a heart attack), or the brain (causing a stroke). These normally happen in arteries themselves are already damaged
- The current concern with the AstraZeneca vaccine is focused on clots in the veins, especially in the veins in the leg: so called deep vein thrombosis or DVT-
- (The ‘deep’ vein means that the clot is occurring in the big veins which you can’t see rather than those just under the skin).
- This can occur spontaneously – without an obvious cause, or after a long period of not moving legs such as when on a long flight, after surgery or delivery following pregnancy
- The danger is that a bit of the clot breaks off , shoots up the big veins in the body, travels unstopped through the heart and then blocks the main artery to the lungs – a pulmonary embolus, – potentially causing very severe consequences
- There is also a rare type of thrombosis when the clot develops in one of the big veins in the brain.
- In particular in a very wide vein in the brain: a condition called ‘cavernous sinus thrombosis”
- There are also disorders when there is not enough clotting which can lead to bleeding.
- One of the causes of this is when there are too few platelets – a disorder called thrombocytopenia – which has also been suggested as a complication following vaccination
What are the new data that have filled the news?
- The new data come from reports received both from companies and national drug safety agencies* on the numbers of cases with one of the above disorders
- What especially precipitated the current concern seems to have been:
- 7 reported cases of ‘cavernous sinus thrombosis’ in 1.5 million Germans given the AstraZeneca vaccine
- 4 cases in Norway of clotting problems, although 3 of these were too little clotting due to thrombocytopenia
- In response to this news AstraZeneca said they were aware from their data of about 40 cases of clotting problems:
- 15 deep vein thromboses
- 22 pulmonary embolisms
- (they haven’t publicly mentioned thrombocytopenia)
*I did discuss in a previous post how these data are obtained
What information regulators need to collect when checking such reports
- Before reaching any conclusions on the numbers, the quality of the diagnoses in the cases reported have to be checked
- These case reports to regulators come from many sources and diagnostic accuracy cannot be assumed
- Companies and regulators would thus seek the following confirmatory information from relevant health records
- Information on the risk factors in the table above may be used to identify specific subgroups for whom a warning may be required
What did I find in the UK?
- I have reviewed the data published on the MHRA ( the UK regulator) website for reports of all clotting events up to the end of February
- I cannot find exactly how many doses of AstraZeneca vaccine had been administered by the end of February but
- There had been 1.5 million doses by early February
- I therefore have guessed 3 million by end of February
- I searched through the list of the 200,000 reported side effects to the AstraZeneca vaccine published on 9 March (most were trivial like arm soreness) for any mention of thrombosis or pulmonary embolism –
- This is what I found
- There are also rarer reports on clots at other sites in the body
- I suspect AstraZeneca’s figure publicised yesterday of just 40 cases in total worldwide is an under-estimate
- I cannot emphasise enough times that these cases may, or may not be, related to the vaccine
- A rate of 4/million for pulmonary embolus is also a very low risk
What about data from other vaccines?
- I searched the same UK database for reports of the same disorders from the Pfizer vaccine
- Similar data from other countries on their licensed vaccines are likely to become available
- When the UK database was updated my estimate is that there had been 3 times the number of Pfizer doses given compared to AstraZeneca
- The table below therefore adds the column for the Pfizer vaccine
- I could find no reports of pulmonary embolism from the Pfizer vaccine
- Whatever the inaccuracies, the rates of all these reports are much greater for AstraZeneca than for Pfizer
- Combining all reports that mentioned a clotting problem, the rate/million vaccinated (orange bars) was five times that for AstraZeneca than for Pfizer vaccine
- I have also displayed the key results on a graph
What about the background population risk of these events
- As readers of my previous blogposts on the topic of vaccine safety may remember we have to compare the rates of reports of disorders, such as clotting, to the occurrence of these in the general population
- I must emphasise that accurate data on the occurrence of these conditions in the general population is not easy to find
- There are no population registers, as there are for some disorders such as cancers
- So we are reliant for serious clotting problem such as pulmonary embolism on the number of cases recorded from hospital databases
- The number of such cases from hospitals with DVT or pulmonary emboli can be misleading as a source of the underlying population rate:
- Why: because 60% of these disorders are the result of being in hospital – especially following an operation!
- For what it is worth, given this bias, I have taken one report suggesting that 800/million in the UK are diagnosed with a pulmonary embolism each year*
- I have therefore attempted to do my own calculation on the true background population rate of pulmonary embolism
- I am assuming that pulmonary embolism is likely to be reported as a possible side effect of vaccination within 4 weeks of the vaccine
- So I have estimated the background monthly incidence of new cases
- This is my calculation:
- This rate of 25/million is around 6.5 times the rate of embolism even in the AstraZeneca vaccinated cases
- This might suggest that the AstraZeneca vaccine might even by protective. I think that is very unlikely and that we need to very cautious in interpreting such data
- I have given further commentary on this is a new post published today (17 March): https://makingsenseofcovid19withs.com/2021/03/17/could-vaccines-actually-protect-against-pulmonary-embolus/
Are patients with Covid-19 infection at risk of clots?
- If we are interested in the risks of clots following the vaccine we should also look at the risk of clots following the infection!
- We have known for some time that patients admitted to hospital with severe Covid-19 are at risk of having blood clots
- Indeed clots are one of the major reasons for serious complications following Covid-19
- Perhaps 30% of Covid-19 patients admitted to hospital either have direct evidence of a clot or their blood tests suggest they are at risk
- I can only find a very few reports of severe clotting problems from mild Covid-19, but in those patients too the consequences can be substantial
Is it biologically likely that the vaccine could cause blood clots?
- The story linking AstraZeneca vaccine would be compelling if there was a biological explanation
- There are coherent pathways of how natural Covid-19 infection can lead to clotting
- These are mainly as a consequence of the body’s overactive immune response to the virus damaging the walls of blood vessels
- Other suggestions are that there is an increase of clotting proteins in the blood
- I guess it is just possible that in some people there is an overactive immune response to the vaccine which could have the same effect
- This is pure conjecture (!) but some people do have very severe responses to the vaccines and just possibly a small subset of these have the same potential for damage to the walls of blood vessels to increase the risk of clotting
- Honestly this is a difficult one!
- I accept, though allowing for all the possible inaccuracies, that the rate of events such as pulmonary embolism following the AstraZeneca vaccine is much lower than the expected rate in the general population
- The data though, again with all their inaccuracies, suggest that rates of all these events of concern are greater with the AstraZeneca vaccine than with Pfizer- for reasons that are not easily explained
- It may be that with closer examination of the cases who have reported these problems will identify a group of people who may be at particular high risk of clotting and possibly should not have the AstraZeneca vaccine. We should keep an open mind on this
- Let me finish by emphasising that the risks of having a serious clotting problem are much higher from a bad attack of Covid-19 than from the vaccine
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