European medical regulators on Wednesday concluded that there is a strong link between AstraZeneca’s COVID-19 vaccine and life-threatening conditions involving the unusual combination of blood clots and low levels of blood platelets.
As such, the conditions should be listed as a “very rare side effects” of the vaccine, according to the European Medicines Agency, a regulatory agency of the European Union.
The conclusion was based on the EMA’s in-depth review of 86 blood-clotting events among around 25 million people vaccinated with the AstraZeneca vaccine in Europe and the UK. Of the 86 blood-clotting events, 18 people died. Most—but not all—of the cases occurred in women under the age of 60.
The events reviewed by the EMA included 62 cases of cerebral venous sinus thrombosis (CVST), a rare form of stroke in which a clot prevents blood from draining out of the brain. The remaining 24 cases involved splanchnic vein thrombosis, which involves blood clots in the veins that drain blood from the abdomen.
Beyond the 86 cases examined, the EMA estimated that there’s a reporting rate of one case of the side effect in 100,000 people vaccinated.
Oddly, the clotting events have been accompanied by low levels of blood platelets, which are the blood cell fragments that stick together to form clots. Typically, low platelets lead to increased bleeding, not clotting. Regulators noted that this unusual combination resembles a condition called heparin-induced thrombocytopenia or HIT. In rare cases, patients who are given heparin—an anticlotting drug—see a drop in their platelets yet go into a hyperclotting state, which can lead to widespread clotting and death.
HIT develops because of an aberrant immune response. In a reaction to heparin that’s not completely understood, some patients’ immune systems produce antibodies that attack a common platelet protein called Platelet Factor 4, or PF4. This in turn triggers platelet activation and pro-clotting particles, leading to HIT.
Some researchers suspect that the blood-clotting events linked to AstraZeneca’s vaccine may also be down to a similar berserk immune response—and it may be treatable. Extremely preliminary data—posted online but not yet published in a journal or peer-reviewed—hints that the rare condition in some vaccinees could be treated with nonheparin anticlotting drugs as well as a high-dose of immunoglobulin, which has been shown to inhibit platelet activation in HIT patients.
In its announcement Wednesday, the EMA noted that recognizing the early signs of blood clots and low platelets are critical, and getting specialized treatment quickly can avoid serious outcomes.
The EMA noted that recently vaccinated people should watch out for:
- shortness of breath
- chest pain
- swelling in your leg
- persistent abdominal (belly) pain
- neurological symptoms, including severe and persistent headaches or blurred vision
- tiny blood spots under the skin beyond the site of injection
As seen in people who develop HIT after heparin, the blood-clotting events and low platelets seen in vaccinees usually develop within two weeks of getting their first dose.
Though the EMA solidified the connection between the clots and the AstraZeneca vaccine, it still recommends using the vaccine. “The reported combination of blood clots and low blood platelets is very rare,” the agency noted, “and the overall benefits of the vaccine in preventing COVID-19 outweigh the risks of side effects.”
The conclusion follows weeks of drama around the vaccine, in which more than a dozen countries that had already authorized the vaccine’s use abruptly halted vaccinations out of concern for the blood clots—then resumed use out of concerns for the spread of COVID-19.
Along with the EMA, World Health Organization still strongly contends that the benefits of the AstraZeneca vaccine’s effectiveness at preventing deadly COVID-19 infections strongly outweigh the risks of extremely rare blood-clotting conditions.
Nevertheless, Germany moved last week to restrict the vaccine’s use in people under age 60, the age group in which most—but not all—of the rare clotting events have occurred. And on Tuesday, the University of Oxford, which co-developed the vaccine with AstraZeneca, said that it had paused a small UK trial of the vaccine in children and teenagers.
Meanwhile, AstraZeneca has continued to be mired in communication bungles. In the latest misstep, the company got into a highly unusual and concerning spat with a panel of US experts tasked with overseeing its COVID-19 vaccine trial and data. The panel, called the Data and Safety Monitoring Board, claimed that AstraZeneca had cherry-picked the trial data results it trumpeted in a press release, potentially misleading the public on the vaccine’s true effectiveness.
The company has defended its actions but has not yet submitted its data to the US Food and Drug Administration in order to obtain an Emergency Use Authorization. Last week, top infectious disease expert Anthony Fauci suggested that, even if it is authorized, the US may not need AstraZeneca’s vaccine because it will have enough supply of the three vaccines already authorized for use in the US.
Trouble for Johnson & Johnson
The new side effect listing in the EU will only make things more difficult for AstraZeneca. And it’s also likely to cast a shadow over the Johnson & Johnson COVID-19 vaccine, which is authorized in the US and elsewhere and uses the same design as AstraZeneca’s vaccine.
Both vaccines use an adenovirus vector. Adenoviruses are common viruses that can cause cold-like infections and other mild illnesses in people. For vaccine delivery, they’re engineered so they can’t replicate in cells or cause disease, but they can deliver to cells the genetic code of a more dangerous germ. In the case of the COVID-19 vaccines, the engineered adenoviruses deliver the code of the SARS-CoV-2 spike protein, which adorns the outside of the virus’s particle. The spike protein is what SARS-CoV-2 uses to grab onto human cells and get inside—and it’s a key target for potent antibodies and other immune responses. Once the adenovirus vector delivers the code for spike, our cells can make their own versions of the protein and use it to train immune responses that will recognize and destroy the SARS-CoV-2 virus.
A potential pitfall of adenovirus-based vaccines is that adenoviruses can also bind to platelets and cause problems. In fact, some prepandemic data has suggested that adenoviruses can activate platelets and lead to low platelet counts. But the connection between this and the vaccine and the mechanism causing the blood clotting in vaccinees needs far more data to understand.
Still, the side effects seen in AstraZeneca’s vaccine raise worries for Johnson & Johnson’s. During the clinical trials of the Johnson & Johnson vaccine, there was an early sign of an increased risk of these blood-clotting conditions in vaccinated people, Peter Arlett, head of data analytics at the EMA, said in a press briefing Wednesday. But the link was never confirmed, he added.
Of the approximately 4.5 million people who have received the Johnson & Johnson vaccine worldwide, there have been three reported cases of blood-clotting events similar to those seen in people given the AstraZeneca vaccine, Arlett said. These numbers are “extremely small,” he emphasized. “This is, however, under close scrutiny… I think it would be fair to say there’s intensive monitoring of this issue across the vaccines.”