Q&A on the Rare Clotting Events That Caused the J&J Pause
By Lori Robertson and Eugene Kiely
Posted on April 22, 2021
The Centers for Disease Control and Prevention’s Advisory Committee on Immunization Practices will meet April 23 to “provide further recommendations” on the use of the Johnson & Johnson COVID-19 vaccine, possibly clearing the way for its resumption.
The CDC and Food and Drug Administration on April 13 recommended “a pause in the use” of the Johnson & Johnson COVID-19 vaccine “out of an abundance of caution,” due to six reports of a rare blood clot combined with low levels of blood platelets among more than 7 million J&J vaccines administered.
We’ll take a look at these rare conditions, their frequency and the risks of COVID-19.
What do we know about the six cases, and have there been more since the pause was recommended on April 13?
The six cases were among 7.2 million J&J vaccines administered. They involved women, age 18 to 48, who suffered from a combination of a type of blood clot called cerebral venous sinus thrombosis, or CVST, and low levels of blood platelets, a condition known as thrombocytopenia.
The CDC and FDA have not said that the vaccine caused these conditions. But the combination of blood clotting and a drop in platelets, which help form clots to stop bleeding, “makes a pattern,” Peter Marks, director of the FDA’s Center for Biologics Evaluation and Research, said in an April 13 press conference. And that pattern has similarly been reported in Europe in relatively few cases among the millions who have received the AstraZeneca vaccine.
Both the AstraZeneca and J&J vaccines use the same type of technology — a modified, harmless adenovirus to prompt the body to produce an immune response to SARS-CoV-2, the virus that causes COVID-19. However, J&J scientists have pointed out that there are differences in the makeup of the vaccines.
The U.S. agencies cautioned health care providers that the anticoagulant drug normally used to treat blood clots — heparin — “may be dangerous” in these cases and “alternative treatments need to be given.”
In the U.S. cases, the six women had severe headache, abdominal pain, leg pain or shortness of breath six to 13 days after they received the J&J vaccine. One died. On April 19, CDC Director Dr. Rochelle Walensky said the agency was reviewing “a handful” of other potential reported cases to verify whether they fit the pattern of the six cases already identified.
The CDC declined to provide information on any of those other cases. “Any additional, confirmed cases will be provided to the Advisory Committee on Immunization Practices at its Friday meeting,” CDC spokesperson Jasmine Reed told us in an email.
How rare or common are these two conditions normally — the blood clots and low levels of platelets?
This type of blood clot — cerebral venous sinus thrombosis, or CVST — is rare. It occurs in the veins in the sinuses that drain blood away from the brain.
It occurs in 2 to 14 people out of 1 million each year in the general population, according to Marks.
An April 15 CDC presentation for clinicians included similar estimates of the expected risk (0.5 to 2 per 100,000 people) and said CVST occurred in about 0.5% to 1% of all strokes. The median age for patients was 37 years. The condition was three times more common in women.
The risk factors included prothrombotic conditions, meaning a tendency to develop blood clots; birth control pills; pregnancy and post-partum; cancer; infection and lumbar puncture.
The CDC said the cases following J&J vaccination were at least three times greater than the expected rate of CVST for women in the 20-50 age group. “Observed cases following Janssen COVID-19 vaccines appear to exceed expected based on background rates of CVST among women aged 20–50 years (3-fold or greater),” the presentation said, referring to Janssen Biotech Inc., a Johnson & Johnson pharmaceutical company.
But in the six cases, the women also had low levels of blood platelets.
A low level of platelets, without accompanying CVST, is more common. Dr. Robert Brodsky, director of the division of hematology and professor of medicine at Johns Hopkins Medicine, told us, “We have people in all the time with low platelets.”
But the expected rate in the general population of the combination of CVST and low levels of blood platelets is unknown, the CDC presentation said.
What similarities are there between these cases and heparin-induced thrombocytopenia?
These reported cases after vaccination with the J&J and AstraZeneca vaccines appear to be similar to heparin-induced thrombocytopenia, or HIT, a condition in which the body has an immune response after a patient receives the anticoagulant heparin, causing both low levels of blood platelets and blood clots. “It appears that there is overlap between the two disorders,” Dr. Mortimer Poncz, division chief of pediatric hematology at the Children’s Hospital of Philadelphia, told us.
With HIT, antibodies attach to platelet factor 4, a protein in blood platelets. Patients can be tested for those antibodies. Five of the U.S. cases that occurred after the J&J vaccination tested positive for the HIT antibody, and in the sixth case, the test wasn’t done, according to the CDC.
Brodsky said that with the reports after the J&J and AstraZeneca vaccines, the “clinical manifestations resemble” HIT. And Poncz said there are “subtle differences” that, for instance, suggest antibodies in HIT and the vaccine cases “may or may not be recognizing distinct targets on the PF4.”
In terms of how common HIT normally is, Poncz provided statistics that would only apply for hospitalized people who receive forms of the drug heparin. In that population, HIT occurs in about 1 case in every 100 for unfractionated heparin and 1 in 1,000 for low molecular weight heparin, he said. It’s more common in the elderly.
“The thrombocytopenia often is mild,” Poncz said of HIT cases, “but the thrombosis in veins more than arteries can be striking leading to limb or life lost.”
However, CVST, the type of blood clot in the six U.S. cases, is “rare in HIT,” he said, as well as abdomen clots. The CVST occurrence stands out in these cases after vaccination, Poncz said.
“There are other causes of a combination of the paradox of low platelet counts (which causes bleeding) and thrombosis,” Poncz said in an email, citing an autoimmune disorder called antiphospholipid syndrome, sepsis and severe COVID-19. With severe COVID-19, “it’s more of a diffuse all over the body process going on.”
Now that health care providers know not to use heparin, how treatable is the combination of conditions?
Poncz told us that early recognition and the use of other anticoagulants is important, and there are new, effective therapeutics for some cases. But treatment is “still a significant challenge. It doesn’t eliminate the risk of limb or life loss.”
How common have these cases been among those who have received the J&J vaccine and those who have received the AstraZeneca vaccine in Europe?
In the U.S., those six cases of CVST and low platelet levels represent less than 1 in 1 million of the more than 7 million J&J vaccines administered. Since all of those cases were among women under 50, the incidence would be 4 in 1 million for women ages 20 to 50. (The CDC said 1.4 million J&J vaccine doses had been administered to women in that age group as of April 12.)
Brodsky said there has been a wide range among the countries reviewing cases of blood clots with low platelets, with the high end being 1 in 250,000 in Norway. He noted that’s “probably a little on the high side,” while the 1 in 1 million estimate in the U.S. was probably too low.
Most of the worldwide cases have been in women, he said, and many of them under age 50. These are “rare, very severe life-threatening complications … that tend to occur in younger women” but not exclusively, he said.
Brodsky said there was “clearly an association with the vaccine that appears to be higher than what you would expect in the general population. To put it in perspective, Germany estimates 9-fold higher than what you’d expect in the general population.” As we said above, the CDC estimated a 3-fold higher incidence than what one would expect. But it’s “still very rare,” Brodsky said.
An April 11 news report in Science said there had been at least 222 suspected cases reported in Europe after 34 million individuals had received their first dose of the AstraZeneca vaccine. That would be a rate of 6.5 per 1 million.
The European Medicines Agency’s safety committee said on April 7 that “unusual blood clots with low blood platelets should be listed as very rare side effects” of the AstraZeneca vaccine, also known as Vaxzevria vaccine. On April 20, it said “a warning about unusual blood clots with low blood platelets should be added to the product information” for the J&J vaccine, saying that the conditions were “very rare” and that the benefits of the vaccine “outweigh the risks of side effects.”
How do these rare clotting incidents compare with the risk of dying from COVID-19?
Even among the group believed to be most affected — women between the ages of 18 and 48 — the chance of dying of COVID-19 is about 100 times more likely than dying of this very rare clotting event. We arrived at that rate by using the Census Bureau’s 2019 population estimates and CDC’s demographic data for COVID-19 deaths, as of April 20.
Here’s what we know:
Dr. Tom Shimabukuro, head of the CDC’s Vaccine Safety Team, said in his presentation at the April 14 ACIP meeting that there were six reported cases of CVST with thrombocytopenia in 6.86 million people who had received the J&J vaccine, as of April 12. That’s a reported rate of 0.87 cases per million doses administered, he said.
Of course, all six cases initially reported by the CDC involved women between the ages of 18 and 48 — so the reported case rate per million doses is higher among women in that age group.
According to Shimabukuro’s presentation, there were 1,402,712 doses of the J&J vaccine administered to women 20 to 50 years old. By our calculations, that is roughly 4.3 reported cases of CVST with thrombocytopenia per million doses administered to women ages 20 to 50.
More cases may yet emerge. The New York Times reported that two more people, including one man, were added to the list of cases being investigated by federal health regulators. But Reed, the CDC spokesperson, declined to confirm that or provide any information on the two individuals.
One of the six women identified by the CDC and FDA died. That roughly results in a reported rate of less than 1 clotting death per million doses administered among women ages 20 to 50, based on the data presented at the April 14 ACIP meeting.
As for COVID-19 deaths, the CDC reports death totals by age groups and percentage of deaths by gender.
As of April 20, the CDC website had data for 437,186 deaths by age group, including 19,727 deaths for those 18 to 49. Women ages 18 to 49 represented 34.7% of the 19,727 deaths, meaning they accounted for 6,841 deaths. Using Census Bureau population estimates for 2019, we determined there were 100 COVID deaths per 1 million women ages 18 to 49.
Below is chart of COVID-19 deaths per 1 million population by age group for both sexes.
Clearly, older people are at the highest risk of dying of COVID-19 and even among younger women the risk is higher than the rare clotting issue identified in people who have received the J&J vaccine. Still, Brodsky said the potential risk isn’t something that should be ignored. “Your benefit of a vaccine and risk of dying from COVID really change with age.”
For a 75-year-old woman who is overweight and has conditions such as diabetes and high blood pressure, “absolutely that vaccine is going to be more helpful than harmful.” For a healthy 28-year-old woman, who has a “negligible if not zero chance of dying from COVID. … I don’t know,” he said. “Especially if other vaccines are available.”
Have vaccines been linked to other bleeding disorders?
As for the other COVID-19 vaccines authorized in the U.S., there have been reports of thrombocytopenia, the low blood platelets, but not in combination with blood clots among a few recipients of the Pfizer/BioNTech and Moderna vaccines. Whether that’s “causal or coincidental” isn’t known yet, Dr. Paul Offit, director of the Vaccine Education Center at the Children’s Hospital of Philadelphia and a member of the FDA’s Vaccines and Related Biological Products Advisory Committee, told us.
One study that examined 20 reports of thrombocytopenia following vaccination with those shots said the “incidence … appears either less than or roughly comparable to what would be seen if the cases were coincidental following vaccination.” The study, published Feb. 19 in the American Journal of Hematology, concluded that it was “impossible at this time” to distinguish between a vaccine-induced condition and a coincidental one.
Offit said thrombocytopenia occurred in 1 in 25,000 to 30,000 recipients of the measles, mumps and rubella vaccine. But natural measles infection can lead to the condition, so it’s “not surprising” that a weakened, live virus vaccine would do so but more rarely, he said.
But those occurrences, Offit said, are “completely different” from the reported cases of thrombocytopenia and blood clots after the J&J vaccination.
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