Vaccines and Rare Clotting Disorders: What's the Link?

 The possibility of a blood clot is not usually on the minds of most people when they roll up their sleeves for a vaccine, but lately that issue has been on the radar.

Recently, vaccinations with the AstraZeneca COVID-19 shot were put on hold in countries across Europe following reports of rare blood clots, low platelets, and hemorrhage. After formal review, the European Medicines Agency (EMA) and World Health Organization (WHO) both issued statements saying that the overall risk for clotting with this vaccine is no higher than in the general population, that the benefits outweigh the risks, and that vaccinations should continue. The American Society of Hematology has also said that the benefits of the AstraZeneca vaccine outweigh clotting risk.

The AstraZeneca COVID Vaccine

The EMA and WHO reviewed 18 cases of cerebral venous sinus thrombosis (CVST) following administration of over 20 million doses of the AstraZeneca vaccine. Almost all of these events happened in women under age 55. CVST refers to clots forming in veins that drain the brain, which can lead to hemorrhage and stroke. It is very rare, and normally affects about 5 people in 1 million per year.

"CVST is one of those low frequency, high morbidity conditions that attracts attention," said Rajiv Pruthi, MBBS, a hematologist at the Mayo Clinic in Rochester, Minnesota.

In its statement, the EMA said that "some concerns" remain for rare cases of specific thromboses in younger people, and that the vaccine product information should be updated to include the possibility that rare, specific thromboses may occur up to 16 days after vaccination. Both WHO and the EMA have said that further investigation is warranted.

In AstraZeneca's announcement of topline interim results from its U.S. trial, the company said it looked specifically for CVST cases among participants and there were none. About 32,500 people were in the trial, including more than 20,000 receiving the vaccine.

Clots in the U.S.

In the U.S., a Miami physician died following complications of immune thrombocytopenic purpura (ITP) after his first dose of the Pfizer COVID-19 vaccine. ITP is a rare autoimmune condition in which the body generates autoantibodies to its own platelets, resulting in low platelet counts, blood clots, and bleeding if the platelet count drops very low. About 50,000 adults are diagnosed with ITP in the U.S. per year. Risk is increased in young women and people with other autoimmune conditions.

In a case series, James Bussel, MD, and colleagues reviewed 20 reports of thrombocytopenia after receipt of the Pfizer and Moderna COVID-19 vaccines in the U.S. Bussel is professor emeritus of pediatrics at Weill Cornell Medical College in New York City who has published extensively on ITP. His group found that 17 of these patients did not have pre-existing thrombocytopenia. Patients' median age was 41 and 11 were women.

"It is not surprising that 17 possible de novo cases would be detected among the well over 20 million people who have received at least one dose of these two vaccines in the United States as of February 2, 2021," they wrote in the American Journal of Hematology. "The incidence of an immune‐mediated thrombocytopenia post SARS‐CoV‐2 vaccination appears either less than or roughly comparable to what would be seen if the cases were coincidental following vaccination, perhaps enhanced somewhat by heightened surveillance of symptomatic patients."

However, they note that "all but one" of these cases occurred after the first dose of the Pfizer or Moderna vaccine.

"One would assume that if the vaccination was unrelated to development of ITP, case occurrences would divide more evenly between the two doses," they write. "...[W]e cannot exclude the possibility that the Pfizer and Moderna vaccines have the potential to trigger de novo ITP (including clinically undiagnosed cases), albeit very rarely."

Clots After Other Vaccines

ITP has been reported after natural infection with viruses like HIV and hepatitis C. As well, "ITP has been reported after other vaccines, albeit not at high enough numbers to warrant concern," Alfred Lee, MD, PhD, a hematologist and associate professor of medicine at Yale School of Medicine told MedPage Today.

Much of the information about ITP and vaccines relies on small numbers of case reports. The condition has been reported in about 1 to 3 children out of every 100,000 after receiving the MMR vaccine, a rate that is significantly lower than reported after natural infection with these viruses, according to one review. Other cases of ITP -- mostly mild -- have been reported after vaccination for flu, varicella-zoster, and hepatitis B, as well as with the diphtheria/tetanus/pertussis (DTP), diphtheria/tetanus/acellular pertussis (DTaP), and Shingrix zoster vaccines.

It's important to remember that rare adverse events like these rely on voluntary reporting to the CDC's Vaccine Adverse Event Reporting System, which could be biased. The key is to look at the observed incidence following the vaccine compared to the expected incidence in the general population, according to the Mayo Clinic's Pruthi.

"Severe autoimmune thrombocytopenia is really rare," he said.

What's Going On?

Still, scientists are generating hypotheses.

For cases of CVST linked to the AstraZeneca vaccine in Europe, the leading hypothesis is that these few patients may be experiencing an autoimmune reaction. Two teams of researchers in Germany and Norway said they had identified an autoantibody called heparin platelet factor 4 antibody that may be involved in CVST's development. The group, which includes Andreas Greinacher, MD, of the Medical University of Greifswald in Germany, who is well known in the field, issued a statement about their preliminary data (though no formal publication or preprint manuscript). The statement offers guidance on diagnosing and treating this condition if it develops after the AstraZeneca vaccine.

Heparin platelet 4 antibody causes heparin-induced thrombocytopenia (HIT), in which heparin paradoxically activates platelets, leading to platelet depletion and clotting. HIT is a well-known but rare complication of heparin use that develops in about 1%-2% of patients. Some patients who have never been exposed to heparin can also have this autoantibody.

Moreover, this antibody has been linked previously to rare cases of CVST -- about 20 have been reported in the literature, according to Pruthi.

"This is a unique situation because the German and Norwegian researchers actually found a unique antibody for which there's no other explanation than the vaccine," he said. "Although the observed incidence of CVST with the AstraZeneca vaccine does not appear to be higher than expected in the population, I think this deserves further study."

Are the European and U.S. Cases Linked?

Whether these rare clotting events in Europe and the ITP cases in the U.S. bear anything in common is anyone's guess right now.

One hypothesis is that the mRNA vaccines (Pfizer, Moderna) and those using adenoviruses (AstraZeneca, Johnson & Johnson) could induce synthesis of the COVID spike protein within platelets, which may then trigger autoimmune reactions against platelets, Hamid Merchant, PhD, of the University of Huddersfield in England, wrote in a letter to The BMJ.

"COVID genetic vaccines may have a direct role in spurring an autoimmune response against platelets that may clinically manifest in thrombocytopenia, hemorrhage, and blood clots. Clotting risks may be equally possible with all genetic COVID vaccines, and may not be limited only with the AstraZeneca/Oxford vaccine," he told MedPage Today.

Pruthi said ITP related to vaccination is probably a separate process involving a different autoantibody than the HIT reaction linked to the European CVST cases. The important point is that healthcare providers recognize the possibility that platelet factor 4 antibody could be involved in very rare cases of CVST after vaccination for COVID-19.

"Generally when patients develop CVST, the first thing you do is give them heparin. In this situation, that would be the worst thing to do. You would need to avoid heparin and use a different nonheparin anticoagulant," he said. "Hence the importance of making the diagnosis. Providers need to be vigilant to this phenomenon, to make sure they get the right tests, diagnose it quickly, and consult a coagulation expert."

https://www.medpagetoday.com/special-reports/exclusives/91813