Commentary—COVID-19 Vaccines: Vaccine-Induced Immune Thrombotic Thrombocytopenia

Reports began to appear from Europe in early March 2021 that several people who had been vaccinated with the Oxford-AztraZeneca (AZ) COVID-19 vaccine developed abnormal blood clots (thrombi). Many had developed blood clots at unusual and critical sites, particularly clots blocking veins that drain blood from the brain (called cerebral venous sinus thrombosis or CVST). In some people, CVST was associated with bleeding in the brain. People also developed blood clots in veins that drain blood from abdominal organs or the legs (see Deep Vein Thrombosis). Symptoms included severe headache, abdominal pain, nausea and vomiting, vision changes, shortness of breath, and/or leg pain.

As of April 4, 2021, 169 cases of CVST had been reported in the European Union and United Kingdom among the 34 million people who had received the AZ vaccine (about 5 cases of CVST in a million AZ vaccine recipients), and more than 30 people died (1). On April 21, after about 8 million doses of the Johnson & Johnson/Janssen (J&J) COVID-19 vaccine had been given in the United States, there were similar reports of CVST in 15 people in the United States following use of this vaccine (almost 2 cases of CVST in a million J&J vaccine recipients), and 3 died. All cases in the United States were in women; 13 were 18 to 49 years old, and 2 were over 50 years. The blood clots developed 4 to 20 days after COVID-19 vaccination and mostly in people who were previously healthy.

As doctors studied this abnormal blood clotting, it became clear that people had low levels of platelets in their blood (called thrombocytopenia). This is paradoxical because platelets are cells that circulate in the blood stream and help blood clot. Usually, when platelet levels are low, people bleed too easily. However, doctors found that platelet levels were low because the platelets were being used up to form the abnormal blood clots. The clinical picture of severe clotting and thrombocytopenia after COVID-19 vaccination has come to be called vaccine-induced immune thrombotic thrombocytopenia or VITT (2).

The question was why this might occur after vaccination.

Doctors realized that this picture of abnormal new blood clots along with low platelet levels also occurred in a disorder called heparin-induced thrombocytopenia (HIT), which is a rare complication that can occur about 5 to 10 days after receiving the anti-clotting drug, heparin. Doctors knew this was caused by a complicated immune system reaction to heparin in which antibodies are formed that cause platelets to activate (and thus form clots and decrease in number). Researchers then discovered a similar antibody occurring in some people following COVID-19 vaccination. Tests can be done to detect this antibody and confirm the diagnosis of VITT.

Both the J&J and AZ vaccines are made using a harmless form adenovirus to deliver the active portion of the vaccine, and the Moderna and Pfizer vaccines do not use a virus. Thus, some experts speculate a link between the adenovirus and VITT. On the other hand, there are Russian and Chinese vaccines that use adenoviruses, and there are no reports of VITT following use of these vaccines.

The mRNA COVID-19 vaccines from Moderna and Pfizer-BioNTech that were the first vaccines available in the United States were initially thought not to cause blood clots, but a recent study of mRNA vaccine recipients in the United States has reported the rare occurrence of CVST within 2 weeks after vaccination in this group as well, at a rate of about 4 cases of CVST in a million mRNA vaccine recipients (3).

CVST also can develop after natural COVID-19 infection (about 40 cases of CVST in a million COVID-19 patients), which is about 10-fold more than after COVID-19 vaccination. The disorder is very rare in otherwise healthy people (about 0.4 cases of CVST in a million people) who have not received heparin or similar drugs (3).

A particular danger of VITT is that the most common treatment for excessive blood clotting is the drug heparin. However, in people with VITT, heparin actually worsens the problem. So, if people have a low platelet count and tests that show a blood clot after receiving a COVID-19 vaccine, doctors should suspect VITT and do tests for the antibody and also avoid giving heparin. If people need an anti-clotting drug, doctors instead give one of the newer anticoagulants, argatroban or lepirudin. They also give high-dose intravenous immunoglobulin (IVIG), which quickly helps block VITT antibody-induced platelet activation (4).

When thinking about adverse effects of a treatment, it is important to compare the risks of treatment to the risks of no treatment. In unvaccinated people, for every million people who develop symptomatic COVID-19, about 10,000 to 20,000 will die (5). The AZ, J&J, Pfizer, and Moderna COVID-19 vaccines have been shown to prevent virtually all these deaths from COVID-19. In every million people vaccinated with the AZ or J&J vaccines, less than 1 will die from CVST.  Thus, the risk of CVST following COVID-19 vaccination remains very low compared with the vaccine’s benefits.

On April 20, 2021, the safety committee of the European Medicines Agency (EMA) concluded that in regard to the J&J vaccine “COVID-19 is associated with a risk of hospitalization and death. The reported combination of blood clots and low blood platelets is very rare, and the overall benefits of [the Johnson & Johnson vaccine] in preventing COVID-19 outweigh the risks of side effects.” They also concluded that a warning about blood clots and low blood platelets should be listed as very rare side effects of the vaccine (6). A similar EMA conclusion had been made earlier concerning the AZ vaccine (1). The CDC and FDA reached similar conclusions about the J & J vaccine (7).

References

1. European Medicines Agency: AstraZeneca’s COVID-19 vaccine: EMA finds possible link to very rare cases of unusual blood clots with low blood platelets. April 7, 2021. Accessed April 26, 2021. Available at https://www.ema.europa.eu/en/news/astrazenecas-covid-19-vaccine-ema-finds-possible-link-very-rare-cases-unusual-blood-clots-low-blood

2. Bussel JB, Connors JM, Cines DB, et al: Thrombosis with thrombocytopenia syndrome (also termed vaccine-induced thrombotic thrombocytopenia. Version 1.2. American Society of Hematology April 25, 2021. https://www.hematology.org/covid-19/vaccine-induced-immune-thrombotic-thrombocytopenia

3. Taquet M, Husain M, Geddes JR, et al: Cerebral venous thrombosis and portal vein thrombosis: a retrospective cohort study of 537,913 COVID-19 cases. OSF https://osf.io/a9jdq/

4. Warkentin TE: High-dose intravenous immunoglobulin for the treatment and prevention of heparin-induced thrombocytopenia: A review. Expert Review of Hematology 12(8):685–698, 2019. https://www.tandfonline.com/doi/full/10.1080/17474086.2019.1636645

5. Ritchie H, Ortiz-Ospina E, Beltekian D, et al: Mortality risk of COVID-19: How did confirmed deaths and cases change over time? Published online at OurWorldInData.org Available at https://ourworldindata.org/mortality-risk-covid#how-did-confirmed-deaths-and-cases-change-over-time

6. European Medicines Agency: COVID-19 vaccine Janssen: EMA finds possible link to very rare cases of unusual blood clots with low blood platelets. April 20, 2021. https://www.ema.europa.eu/en/news/covid-19-vaccine-janssen-ema-finds-possible-link-very-rare-cases-unusual-blood-clots-low-blood

7. US Food and Drug Administration: Janssen COVID-19 vaccine. Updated April 23, 2021. https://www.fda.gov/emergency-preparedness-and-response/coronavirus-disease-2019-covid-19/janssen-covid-19-vaccine