Cerebral venous sinus thrombosis and AstraZeneca vaccine: understanding the risk

In my post on March 16, I considered the evolving information on rare blood clotting events in relation to the AstraZeneca vaccine.  I concluded that the risk of pulmonary embolism, although higher with the AstraZeneca than the Pfizer vaccine, was no higher than that in the general population.  Attention recently has focused on the rarer brain clotting disorder: cerebral venous sinus thrombosis. More cases of this disorder have been reported in the past few weeks and in this post I review the new data and discuss the link to the AstraZeneca vaccine and the nature of any risk.

How many cases of cerebral venous sinus thrombosis (CVST) have there been following vaccination?

  • Obviously the numbers are changing and different reports give different numbers
  • Credible rates of CVST in UK and the rest of Europe are as follows:
    • 62 cases have been reported in the European Union from around 9 million vaccinated
    • Half of these were reported in Germany from around 3.4 million vaccinated
    • 79 cases have been reported in the UK from around 20 million vaccinated
  • The numbers of cases are higher in younger people (aged under 50)
  • Approximately a third of those with CVST have died
  • I have not been able to find any reports of this disorder following the Pfizer or Moderna vaccines 

What is the exact nature of this brain disorder?

  • The disorder reported in people following the AstraZeneca vaccine is an unusual one – it is actually combination of two separate disorders
  • The first is a thrombosis (blood clot) in one of the large veins (called sinuses) in the brain
    • These sinuses are much wider than normal veins, (the largest is so wide it is referred to as the cavernous sinus) 
    • CVST can occur on its own, and prior to the current scare was considered a very rare complication of a severe bacterial infection for example in the mouth or an abscess in the face 
  • The second abnormality seen in the CVST patients following vaccination is the development of antibodies against their own platelets
    • There are a number of other causes of having low platelets, for example it can be a complication of some prescribed drugs
    • We need enough platelets to help us clot normally and stop bleeding
    • Having a low platelet count is actually quite common and indeed it is known that many cases are due to people developing antibodies against their own platelets – although this is normally an easily treated disorder
    • What is weird about the loss of platelets in the post-vaccine patients is that, instead of increasing the risk of bleeding, it increases the risk of clotting

How common is this combination in the general population?

The combination of a low platelet count and CVST is so rare we do not know how common this combination is in the general population

If we look at the two parts separately:

  1. CVST
  • CVST is very rare and accurate figures of the incidence are difficult to obtain
    • My reading suggests that a rate of 2-4/million per year is a reasonable estimate
    • Most cases of CVST in the population are due to infection

2. Low platelet count and increased risk of clotting:

  • The overall incidence of a low platelet count with thrombosis (which has been reported in many different blood vessels – both arteries and veins)  is also around 2/million/year
    • It is mainly seen in people aged under 45
    • Most cases have occurred as a strange reaction to the anticoagulant injection heparin
    • In such cases, there is also both a low platelet count and a blood clot – the latter can be in either an artery or a vein
  • The combination seems very rare
  • This headline from an article published in January last year showed the disorder is so unusual that the existence of a single case is enough for it to warrant publication in the medical press

Do these data prove that there is a link?

  • Proving cause and effect is almost impossible with such a rare disorder
  • It is also difficult to compare the numbers in the short period after being vaccinated with general population rates that are calculated over a year
  • I think that the chances of these cases being random is small and that the points below all point to the link being causal:
    • the number of cases
    • the timing in relation to the vaccine
    • the immune nature of the likely cause
  • Unlike the situation I discussed a few weeks ago in relation to pulmonary embolism, where the data did not prove the rate of that disorder post-vaccine was greater than the underlying risk, my take on CVST is that all cases need to be considered as a consequence of the AstraZeneca vaccine 

What then is the risk of CVST in people who have had the vaccine?

  • The question then is not “is there an increased risk of CVST compared to ‘normal’?” but rather
    • “what is the size of the risk?”
    • “does this risk vary in particular sub-groups of the population?”
  • From the available information, which is limited, the German data suggests an incidence of around 1/100,000 vaccinated 
  • The UK data suggests a lower rate of around 1/250,000
  • BUT although I have not seen a detailed breakdown by age and gender, about 2/3 of the cases of CVST are reported to be in women and more in those under the age of 55
  • Given that most of the vaccine programmes have been focussed above the age of 50, the overall rates of CVST in younger women could be even higher

Could this problem have been identified earlier?

  • I cannot see how this could have been foreseen
  • I am not aware of any other vaccines that have been linked to this complication
  • Even if the incidence is as frequent as 1/100,000, then the clinical trials of the vaccines, which studied around 30,000 subjects, would have been too small to detect any cases

How does this risk compare with risks of other rare severe medical events?

  • In thinking about a risk that say lies between 1/100,000 and 1/250,000, a frame of reference is the risk of other severe medical events in previously healthy people 
  • I have taken two comparisons:
    • Deaths in pregnancy and childbirth
    • Deaths and severe complications from having an anaesthetic in people with no prior health problems 
  • The results are shown below:
  • The results show that for these two comparators, which most would consider non-risky (getting pregnant or having an elective operation), the rates of CVST – even taking the most pessimistic (German) data – are lower

What can happen now?

  • More intensive analysis of the cases of CVST that have happened will quantify a more accurate risk in the different age and gender groups 
  • The risk of dying or having a serious complication from contracting Covid-19 in younger people is small (and indeed women do not have as many  serious complications as men) 
  • Thus it is possible that the risks of CVST in younger women are greater than the risks from Covid-19 infection 
  • My view is that regulators should be open and accept:
    • that it is highly probable there is a link
    • the issue has only come to light because of the many millions who have been vaccinated
    • the absolute risk to those most at risk of the serious consequences from Covid-19 is far greater than the risk of CVST from the AstraZeneca vaccine; the same may not be true for younger people
  • I have to accept that regulators’ views on ‘who to vaccinate and with what’ may need to change to allow public confidence 

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  • This is a sensible move both from an epidemiological perspective and reducing vaccine hesitancy in those at lower risk from the effects of Covid-19.

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