Doctors with long experience in diagnosing very sick patients describe it as one of the rarest and most perplexing scenarios they have seen: A patient arrives in a hospital emergency department with one or more life-threatening blood clots in the brain, lungs, legs or abdomen despite having low levels of platelets, the cells that are the raw material for clots.
It’s the medical equivalent of a traffic light flashing red and green at the same time.
“Whoa!” said Mayo Clinic internist Dr. Gregory Poland. “This catches everyone’s attention.”
The condition is called autoimmune thrombocytopenia. It occurs when the immune system misfires and generates antibodies to the patient’s own blood platelets — sometimes spontaneously but most often in patients treated with the blood thinner heparin.
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Poland said he’s seen it once, maybe twice, in a decades-long career studying immune responses to diseases and vaccines.
But in the span of just a few weeks, it has been reported in six patients in the United States.
All were women. All were between the ages of 18 and 48. And all had received Johnson & Johnson’s single-shot COVID-19 vaccine between six and 13 days before developing one of several telltale signs of a blood clot: sudden shortness of breath, a painful, swollen leg, a bout of extreme and unusual stomach pain, or severe, rapid-onset headache or neurological symptoms like blurred vision, disorientation or muscle weakness.
The six reports emerged after 6.8 million doses of the J&J vaccine have gone into Americans’ arms. While exceedingly rare — apparently less than one-in-a-million — those cases have left one U.S. patient dead and a second in critical condition.
And on Tuesday, they prompted the U.S. Centers for Disease Control and Prevention and the Food and Drug Administration to recommend a “pause” in the administration of Johnson & Johnson’s COVID-19 vaccine.
During that pause, independent and federal experts will study whether the nation’s most recent addition to its vaccine arsenal is the cause of those clotting disorders, and whether the vaccine should continue to be recommended for use in all adults over age 18. The CDC will convene its Advisory Committee on Immunization Practices on Wednesday to consider those questions.
The pause comes on the heels of a decision by the European Union to temporarily halt the administration of a similar COVID-19 vaccine made by AstraZeneca.
After 20.2 million doses of the two-dose vaccine were administered, European regulators collected some 44 reports of vaccine-induced immune thrombotic thrombocytopenia, or VITT. These are thought to have been brought on not by heparin or a random autoimmune reaction but by the AstraZeneca vaccine.
Most of those cases were seen in patients younger than 40, and 4 in 5 were reported in women.
In a study of 11 patients in Germany and Austria who suffered VITT, six died. All showed high levels of antiplatelet factor 4 antibodies, which are implicated in autoimmune thrombocytopenia.
The authors of that report speculated that free DNA in the AstraZeneca vaccine could potentially trigger these abnormal antibodies.
While distinct in many ways, the vaccines made by AstraZeneca and Johnson & Johnson are linked in one important respect. Both use an adenovirus — a common cold germ stripped of its ability to sicken — to deliver to the immune system the prompt it needs to recognize and attack the SARS-CoV-2 virus.
The AstraZeneca vaccine uses an adenovirus derived from chimpanzees, while Johnson & Johnson’s vaccine uses a human adenovirus.
“It’s plainly obvious to us already that what we’re seeing with [the Johnson & Johnson] vaccines is very similar to what we’re seeing with the AstraZeneca vaccine,” said Dr. Peter Marks, the FDA’s chief of drug evaluation.
Regulators, he added, would look at “the totality of evidence” to determine whether the rare immune response is linked to the two vaccines’ common vectors.
AstraZeneca has not yet sought emergency use authorization from the FDA for its COVID-19 vaccine, though the company said it plans to do so soon.
No cases of blood clots in the presence of low platelet counts have been reported among patients who have received the COVID-19 vaccines made by Pfizer-BioNTech or Moderna, both of which use mRNA technology instead of adenoviruses.
The warnings from the FDA and CDC also alerted physicians to the symptoms and proper treatment of blood-clotting complications in patients who have had a recent dose of the Johnson & Johnson vaccine.
“You get these clots and doctors would normally reach for heparin, and that’s a no-no in this disorder,” said Dr. Jeffrey Weitz, president of the International Society of Thrombosis and Haemostasis and a professor of Medicine at McMaster University in Canada. Instead, he said, doctors are urged to treat such clotting disorders with intravenous immunoglobulin.
The cause of these rare blood clots is unknown. But Dr. Hanny Al-Samkari, a hematologist and researcher at Massachusetts General Hospital and Harvard Medical School, said the immune system may form antibodies against some component of those adenovirus vaccines, which then cross-react with blood platelets and cause them to activate, creating “clots where they shouldn’t be.”
Women’s stronger immune systems may make these reactions more common in them than in men, Al-Samkari said.
And while it’s far too early to draw a link to oral contraceptives, Poland says that researchers will probably also explore the possibility that women who take birth control pills — which can raise the risk of developing blood clots — might be advised to steer clear of the adenovirus vaccines.
In a statement released Tuesday, Johnson & Johnson said it was “aware of an extremely rare disorder” involving people with blood clots in combination with low platelets in a small number of individuals who have received its COVID-19 vaccine.
The company said it was reviewing the cases with both U.S. and European regulators and “made the decision to proactively delay the rollout of our vaccine in Europe.”
The blood clot reports are likely to deepen the concerns of the roughly 30% of Americans who have are reluctant to get vaccinated or have said they will not get a COVID shot. But federal officials said Tuesday that the “pause” was necessary and that the government’s transparency should be reassuring to Americans.
Poland, who has served as a consultant to Johnson & Johnson, AstraZeneca and other vaccine makers, added that the speed with which the government watchdogs detected and responded to a weak signal of potential trouble should inspire confidence.
“Even in the midst of all this fog, our safety signals picked this up,” he said. “In a pea-soup fog, you see a light: Is it a ship? Is it a lighthouse, is it the coast? We can’t tell yet. These things are so hard to tease out, and they are so rare. It’s a logical reason for a pause.”