Virus World

The new observation, made by UNC School of Medicine’s Stephan Moll, MD, and Jacquelyn Baskin-Miller, MD, suggests that a life-threatening blood clotting disorder can be caused by an infection with adenovirus, one of the most common respiratory viruses in pediatric and adult patients. 

CHAPEL HILL, N.C. – Platelets, or thrombocytes, are specialized cellular fragments that form blood clots when we get scrapes and traumatic injuries. Viral infections, autoimmune disease, and other conditions can cause platelet levels to drop throughout the body, termed thrombocytopenia. After a robust clinical and research collaboration, Stephan Moll, MD, and Jacquelyn Baskin-Miller, MD, both in the UNC School of Medicine, have linked adenovirus infection with a rare blood clotting disorder. This is the first time that the common respiratory virus, which causes mild cold-and flu-like symptoms, has been reported to be associated with blood clots and severe thrombocytopenia. “This adenovirus-associated disorder is now one of four recognized anti-PF4 disorders,” said Moll, professor of medicine in the Department of Medicine’s Division of Hematology. “We hope that our findings will lead to earlier diagnosis, appropriate and optimized treatment, and better outcomes in patients who develop this life-threatening disorder.” Their new observation, which was published in the New England Journal of Medicine, sheds new light on the virus and its role in causing an anti-platelet factor 4 disorder. Additionally, the discovery opens a whole new door for research, as many questions remain as to how and why this condition occurs – and who is most likely to develop the disorder.

HIT, VITT, and “Spontaneous HIT”

Antibodies are large Y-shaped proteins that can stick to the surface of bacteria and other “foreign” substances, flagging them for destruction by the immune system or neutralizing the threat directly. In anti-PF4 disorders, the person’s immune system makes antibodies against platelet factor-4 (PF4), a protein that is released by platelets. When an antibody forms against PF4 and binds to it, this can trigger the activation and rapid removal of platelets in the bloodstream, leading to blood clotting and low platelets, respectively. Sometimes, the formation of anti-PF4 antibodies is triggered by a patient’s exposure to heparin, called heparin-induced thrombocytopenia (HIT), and sometimes it occurs as an autoimmune condition without heparin exposure, which is referred to as “spontaneous HIT.” In the last three years, thrombocytopenia has been shown to rarely occur after injection with COVID-19 vaccines that are made with inactivated pieces of an adeno–viral vector. These vaccines are different than the ones made in the United States, such as those by Moderna and Pfizer. The condition is referred to as vaccine-induced immune thrombotic thrombocytopenia (VITT).

The Road to Discovery

The road to the discovery started when a young child, who had been diagnosed as an outpatient with adenovirus infection, had to be admitted to the hospital with an aggressive blood clot forming in his brain (called cerebral sinus vein thrombosis) and severe thrombocytopenia. Doctors determined that they hadn’t been exposed to heparin or the adeno-vector COVID-19 vaccination, the classical triggers for HIT and VITT. “The intensive care unit physicians, the neuro-intensivist, and hematology group were working around the clock to determine next steps in the care for this young child,” said Baskin-Miller. “They weren’t responding to therapy and were progressing quickly. We had questioned whether it could have been linked to the adenovirus considering the vaccine data, but there was nothing in the literature at that time to suggest it.” The collaborative clinical effort to help the patient expanded: Baskin-Miller reached out to Moll, who is an expert in thrombosis and has various connections throughout the field. To Moll, it looked like the pediatric patient could have “spontaneous HIT”. They then tested for the HIT platelet activating antibody, which came back positive.

Collaboration is Key

Moll reached out to, Theodore E. Warkentin, MD, a professor of pathology and molecular medicine at McMaster University in Hamilton, Ontario, who has been researching anti-PF4 disorders for three decades, to hear if he was aware of an association between adenoviral infection and spontaneous HIT. Warkentin, who is one of the premier international anti-PF-4 disorders researcher, wasn’t aware of the condition. Around the same time, Moll received a phone call from Alison L. Raybould, MD, a hematologist-oncologist in Richmond, Virginia, a previous trainee from UNC. She was seeing a patient who had multiple blood clots, a stroke and heart attack, arm and leg deep-vein thromboses (DVT), and severe thrombocytopenia. The patient had not been exposed to heparin or vaccines. However, this patient’s severe illness had also started with viral symptoms of cough and fever, and she had tested positive for adenoviral infection. Testing for an anti-PF4 antibody also turned out to be positive. To help clarify the diagnoses of the two patients, Warkentin immediately offered to further test the patients’ blood and samples were directly to his laboratory in the Hamilton General Hospital for further study. They confirmed that the antibodies were targeting platelet factor 4, much like the HIT antibodies. Surprisingly, the antibody resembled that of the VITT and bound to PF4 in the same region as VITT antibodies do. They concluded that both the patients had “spontaneous HIT” or a VITT-like disorder, associated with an adenovirus infection.

More Questions

Following such a groundbreaking conclusion, Moll and colleagues are now left with many questions about the prevalence of the new anti-PF4 disorder, whether the condition can be caused by other viruses, and why this condition doesn’t occur with every infection with adenovirus. They also wonder what preventative or treatment measures can be made to help patients who develop the new, potentially deadly anti-PF4 disorder. “How common is the disorder?” asked Moll. “What degree of thrombocytopenia raises the threshold to test for anti-PF4 antibodies? And then finally, how do we best treat these patients to optimize the chance that they will survive such a potentially deadly disease?”

Media contact: Kendall Daniels, Communications Specialist, UNC Health | UNC School of Medicine

Original research published in New England J. Medic. (August 10, 2023):

https://doi.org/10.1056/NEJMc2307721 

A link to the vaccines is not certain, and investigations are underway in some reported cases. One day after receiving her first dose of Moderna’s Covid vaccine, Luz Legaspi, 72, woke up with bruises on her arms and legs, and blisters that bled inside her mouth.  She was hospitalized in New York City that day, Jan. 19, with a severe case of immune thrombocytopenia — a lack of platelets, a blood component essential for clotting. The same condition led to the death in January of Dr. Gregory Michael, 56, an obstetrician in Miami Beach whose symptoms appeared three days after he received the Pfizer-BioNTech vaccine. Treatments failed to restore his platelets, and after two weeks in the hospital he died from a brain hemorrhage. It is not known whether this blood disorder is related to the Covid vaccines. More than 31 million people in the United States have received at least one dose, and 36 similar cases had been reported to the government’s Vaccine Adverse Event Reporting System, VAERS, by the end of January. The cases involved either the Pfizer-BioNTech or Moderna vaccine, the only two authorized so far for emergency use in the United States. But the reporting system shows only problems described by health care providers or patients after vaccination, and does not indicate whether the shots actually caused the problems.

Officials with the Food and Drug Administration and the Centers for Disease Control and Prevention said that they were looking into the reports, but that so far, rates of the condition in vaccinated people did not appear higher than the rates normally found in the U.S. population, so the cases could be coincidental. Overall, the vaccines are considered safe. A small number of severe allergic reactions have been reported, but they are treatable, and the rates are in line with those reported for other vaccines, regulators say. In a statement, Pfizer said: “We take reports of adverse events very seriously,” and added that it was aware of thrombocytopenia cases in vaccine recipients. The statement also said: “We are collecting relevant information to share with the F.D.A. However, at this time, we have not been able to establish a causal association with our vaccine.”  Moderna also provided a statement, which did not address the question of the platelet disorder, but said the company “continuously monitors the safety of the Moderna Covid-19 vaccine using all sources of data” and routinely shares safety information with regulators. Hematologists with expertise in treating immune thrombocytopenia said they suspected that the vaccine did play a role. But they said that cases after vaccination were likely to be exceedingly rare, possibly the result of an unknown predisposition in some people to react to the vaccine by developing an immune response that destroys their platelets. The disorder has occurred, rarely, in people who received other inoculations, particularly the measles-mumps-rubella one.