Researchers have linked adenovirus to a rare blood clotting disorder, expanding knowledge about the causes of severe thrombocytopenia and prompting more studies into its treatment and prevalence.
Platelets, or thrombocytes, are specialized cell fragments that form blood clots when we suffer scratches and traumatic injuries. Conditions such as viral infections, autoimmune diseases and others can cause a decrease in the platelet count in the body, a condition known as thrombocytopenia.
Through an extensive clinical and research partnership, Dr. Stephan Moll and Dr. Jacquelyn Baskin-Miller, both of the UNC School of Medicine, have identified a connection between adenovirus infections and a rare blood clotting disorder. This discovery marks the first time that widespread respiratory disease viruswhich is known to cause mild symptoms similar to the common cold and flu, has been linked to blood clotting and severe thrombocytopenia.
“This adenovirus-associated disorder is now one of four recognized anti-PF4 disorders,” said Moll, a 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 potentially life-threatening disorder.”
Dr. Stephan Moll. Credit: UNC Blood Research Center
His new observation, which was published in the New England Journal of Medicine, sheds new light on the virus and its role in causing an antiplatelet factor 4 disorder. Additionally, the discovery opens a whole new door for research, as many questions remain about 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 attach to the surface of bacteria and other “foreign” substances, signaling them for the immune system to destroy or neutralize the threat directly.
In anti-PF4 disorders, the person’s immune system produces antibodies against platelet factor 4 (PF4), a protein released by platelets. When an antibody against PF4 forms and binds to it, this can trigger the activation and rapid removal of platelets from the bloodstream, causing blood clotting and low platelet levels, respectively.
Sometimes the formation of anti-PF4 antibodies is triggered by the patient’s exposure to heparin, called heparin-induced thrombocytopenia (HIT), and sometimes it occurs as an autoimmune condition without exposure to heparin, called as “spontaneous HIT.”
In the last three years, it has been shown that thrombocytopenia rarely occurs after injection of COVID-19 vaccines that are made with inactivated parts of an adenoviral vector. These vaccines are different from those manufactured in the United States, such as those from Moderna and Pfizer. The condition is known as vaccine-induced immune thrombotic thrombocytopenia (VITT).
The path to discovery
The path to discovery began when a 5-year-old boy who had been diagnosed with an adenovirus infection as an outpatient had to be admitted to the hospital with an aggressive blood clot forming in his brain (called sinus vein thrombosis). brain) and severe thrombocytopenia. . Doctors determined that he had not been exposed to heparin or the adenovector COVID-19 vaccine, the classic triggers of HIT and VITT.
“The intensive care unit physicians, neurointensivist and hematology group worked around the clock to determine the next steps in this young man’s care,” Baskin-Miller said. “He did not respond to therapy and progressed rapidly. We had wondered if it might have been related to his adenovirus considering the vaccine data, but there was nothing in the literature at the 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 several connections throughout the field. To Moll, it seemed like the pediatric patient might have “spontaneous HIT.” They then performed the HIT platelet-activating antibody test, which came back positive.
Collaboration is key
Moll contacted Theodore E. Warkentin, MD, professor of pathology and molecular medicine at McMaster University in Hamilton, Ontario, who has been researching anti-PF4 disorders for three decades, to find out if he was aware of an association between adenovirus infection. and spontaneous HIT. Warkentin, one of the leading international researchers on anti-PF-4 disorders, was unaware of the condition.
Around the same time, Moll received a phone call from Alison L. Raybould, MD, a hematologist-oncologist in Richmond, Virginia, and former UNC trainee. She was caring for a patient who had multiple blood clots, a stroke and heart attack, deep vein thrombosis (DVT) in his arms and legs, and severe thrombocytopenia.
The patient had not been exposed to heparin or vaccines. However, this patient’s severe illness also began with viral symptoms of cough and fever, and the test for adenoviral infection was positive. The anti-PF4 antibody test was also positive.
To help clarify the diagnosis of the two patients, Warkentin immediately offered to perform further blood tests on the patients and the samples went directly to his laboratory at Hamilton General Hospital for further study. They confirmed that the antibodies targeted platelet factor 4, as did the HIT antibodies.
Surprisingly, the antibody resembled that of VITT and bound to PF4 in the same region as the VITT antibodies. They concluded that both patients had “spontaneous HIT” or a VITT-like disorder, associated with adenovirus infection.
More questions
After such a groundbreaking conclusion, Moll and his colleagues now have many questions about the prevalence of the new anti-PF4 disorder, whether the condition can be caused by other viruses, and why this condition does not occur with all adenovirus infections.
They also wonder what preventative or treatment measures can be taken to help patients who develop the new, potentially fatal anti-PF4 disorder.
“How common is the disorder?” Moll asked. “What degree of thrombocytopenia raises the threshold for testing for anti-PF4 antibodies? And finally, what is the best way to treat these patients to optimize their chances of surviving a life-threatening disease?”
Reference: “Thrombocytopenia, thrombosis, and adenovirus-associated VITT-like antibodies” by Theodore E. Warkentin, Jacquelyn Baskin-Miller, Alison L. Raybould, Jo-Ann I. Sheppard, Mercy Daka, Ishac Nazy, and Stephan Moll, August 10 2023, New England Journal of Medicine.
DOI: 10.1056/NEJMc2307721