Rare Blood Clotting Disorder Risk Higher Following COVID-19 Than Post-Vaccination

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The risk of rare blood clotting in the brain post-COVID-19 infection is several times higher than it is following COVID-19 vaccination, according to a preprint from researchers at the University of Oxford.

COVID-19 and clotting

Blood clotting and COVID-19 recently hit the headlines when regulators responded to concerns over the incidence of blood clotting disorders after administration of the Oxford–AstraZeneca vaccine, Vaxzevria (ChAdOx1 nCoV-19). However, clotting can also occur following COVID-19 infection itself. “COVID-19 is known to be associated with blood venous thrombosis – due to sticky (hypercoagulable) blood – in about one in five patients,” explained David Werring, professor of clinical neurology at University College London.

Such thromboses, or clots, have been found to occur in the lungs, legs and more rarely, the brain – this is known as cerebral venous thrombosis (CVT) and has been reported following use of Vaxzevria. Werring said that this has “led to a lot of discussions about the risks and benefits of vaccination in countries using this vaccine.”

What did the study find?

A new preprint study from the University of Oxford has become part of the discussion by investigating the risk of CVT both after COVID-19 infection and following vaccination. Using data from TriNetX, a global health research network, the researchers first estimated the incidence of CVT occurring in the two weeks post-COVID-19 infection. This estimate was then compared to the incidence of CVT:

• After administration of the first dose of an mRNA-based vaccine – specifically BNT162b2 (Pfizer–BioNTech) or mRNA-1273 (Moderna)
• Following influenza infection
• In the general population

The risk of CVT after vaccination with Vaxzevria was also used as a comparator. However, as this vaccine is not currently administered in the US, the estimate of risk was based on data from the European Medicines Agency (EMA), which currently suggests CVT occurs in approximately five in a million people after the first dose of Vaxzevria.

The researchers found that the risk of CVT was higher after COVID-19 than in any of the comparison groups. The risk was nearly 10 times greater than after receiving either of the mRNA vaccines; in over 480,000 people receiving a COVID-19 mRNA vaccine, CVT occurred in four in a million, whereas out of 500,000 COVID-19 cases, CVT occurred in 39 in a million patients.

How should the findings be interpreted?

Whilst the authors acknowledged that the findings “can help contextualize and inform debate about the risk-benefit ratio for current COVID-19 vaccines”, the study conclusion also heeds caution in interpreting the results.

 “It’s important to note that this data should be interpreted cautiously, especially since the data on the Oxford-AstraZeneca vaccine come from UK MHRA monitoring, whereas the other data uses the TriNetX electronic health records network,” Dr Maxime Taquet, first author on the paper, said in a press release.

The authors also pointed to methodological limitations, such as the lack of age and demographic-matched cohorts, the need for larger samples and absence of information about diagnostic timing and accuracy. Referring to the latter, Beverley Hunt, professor of thrombosis and hemostasis at King’s College London, commented, “The paper is based on International Classification of Disease (ICD) coding [a method for classifying diseases] which is often entered late, so the data on rates after Moderna and Pfizer vaccines may be incomplete.”

The potential drawbacks of the study point to where future research may lead. In their conclusion, the researchers note that a lack of hematological data meant that they could not make any inferences as to whether the mechanisms causing CVT after COVID-19 infection were similar to those following vaccination with the COVID-19 vaccines.

Explaining what is currently known about the mechanisms of CVT and COVID-19, Hunt said: “Patients who are hospitalized with COVID-19 have very prothrombotic (sticky) changes in their blood, which persist after they have been discharged. This will lead to increased rate of blood clots. The mechanism for the very rare blood clots and low platelet counts seen after AstraZeneca vaccine is different.”

Future research may investigate whether the same mechanisms are involved in incidence of CVT with mRNA-based vaccines.

Reference: Taquet M, Husain M, Geddes J et al. Cerebral venous thrombosis: a retrospective cohort study of 513,284 confirmed COVID-19 cases and a comparison with 489,871 people receiving a COVID-19 mRNA vaccine. [Preprint]. 2021. Available from: https://osf.io/a9jdq/.