In rare cases, symptomatic human adenovirus infection may trigger a life-threatening prothrombotic anti-platelet factor 4 (PF4) disorder resembling vaccine-induced immune thrombotic thrombocytopenia (VITT), according to a report based on two patients.

A 5-year-old boy and a 58-year-old woman based in the U.S. developed serious — and in the case of the boy, ultimately fatal — thrombocytopenia and one or more thrombotic events after being infected with an adenovirus, reported Theodore E. Warkentin, MD, of McMaster University in Hamilton, Ontario, and colleagues in a New England Journal of Medicine correspondence.

Both patients had nasopharyngeal swap samples that tested positive for human adenovirus and negative for 18 other pathogens, including SARS-C0V-2.

Gastrointestinal symptoms occurred in the child, respiratory symptoms occurred in the woman, and both experienced fever. These symptoms were followed 5 to 6 days later by severe thrombocytopenia, coagulopathy, and thrombotic events — fatal cerebral venous sinus thrombosis in the child and multiple arterial strokes, ST-segment elevation myocardial infarction, and multiple deep-vein thromboses in the woman.

Neither patient had previously been exposed to heparin, which is associated with thrombocytopenia (heparin-induced thrombocytopenia [HIT]).

Multiple anti-PF4 assays found VITT-like antibodies to PF4 in serum samples obtained from both patients.

“That is, they are almost identical with the antibodies that were implicated in the COVID-19 vaccine reactions seen in the last few years,” Warkentin told MedPage Today.

VITT is characterized by thrombosis at atypical sites combined with thrombocytopenia. In early 2021, VITT was observed in multiple patients soon after they received the AstraZeneca COVID vaccine. By April of that year, it was also reported in patients who received the Johnson & Johnson vaccine. The woman in this series had been vaccinated against COVID-19 with the Moderna shot 15 months before her adenovirus infection; the mRNA vaccines have not been associated with VITT.

“What made these observations super striking was that both patients developed this VITT-like disorder approximately a week after getting symptomatic adenovirus infection,” Warkentin said. “And the reason that got our attention, and the attention of the editors at the New England Journal of Medicine, is that the vaccines that caused VITT are adenoviral vector vaccines, so it seemed like more than a coincidence that the adenovirus is central to the type of vaccines that were developed to fight COVID-19, and in rare instances caused the VITT reaction.”

“To our knowledge, no one has ever reported that adenovirus infections cause prothrombotic disorder with low platelets, clotting, and anti-PF4 antibodies,” he added. “So that’s the first time that this triad has been put together after an adenovirus infection — so it’s a novel finding.”

Warkentin noted that if a patient presents with thrombocytopenia and thrombosis, clinicians should consider an anti-PF4 disorder as a possible explanation.

“If someone has thrombocytopenia and thrombosis, and a history of viral illness a week or two earlier, that should probably become a leading potential diagnosis,” he said, pointing out that the treatment for this condition will be important.

“Obviously [with] thrombosis, you want to give a blood thinner, so that’s not a surprise,” he added. “But we know from the VITT literature that it’s important to block the antibody’s ability to activate the platelets, and we do that with high-dose intravenous immunoglobulin, and that’s a different treatment you normally don’t use for treating thrombosis. But, in this type of disorder, you need to give it. So right off the bat, it’s an important disorder that has its own unique treatment approach.”

Warkentin suggested that — in hindsight — this disorder associated with adenovirus infection has “been going on for years, decades, centuries.”

“What’s really interesting is that in my practice as a hematologist I have been aware in the past of patients who did develop viral illnesses and a week or so later developed low platelets and blood clotting,” he noted. Thus, he said that he and his colleagues believe an adenovirus can — very rarely — trigger an anti-PF4 disorder.

The onset of the COVID pandemic, and the rare appearance of VITT after hundreds of millions of people were vaccinated over a short period of time, led laboratories like Warkentin’s to study VITT and recognize VITT antibodies and distinguish them from HIT antibodies.

“And we learned how to detect good antibodies,” he explained. “So now that we’ve learned how to detect good antibodies, when patients get these antibodies due to other triggers — for example, adenovirus infection — we now know how to identify them. So, in a way, VITT has allowed us to recognize something that probably has been happening sporadically — and rarely — for years.”

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