Platelets, or platelets, are specialized cell fragments that form blood clots when we get scratches and trauma. Conditions such as viral infections and autoimmune diseases can cause a decrease in the number of platelets in the body, a condition known as thrombocytopenia.
Through an extensive clinical and research collaboration, Stephan Moll, Ph.D., and Jacquelyn Baskin-Miller, Ph.D., of the United Nations University School of Medicine, discovered a link between adenovirus infection and a rare blood clotting disorder. The discovery marks the first time this widespread respiratory virus, which 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 disease is one of four currently recognized anti-PF4 diseases. We hope our findings will lead to earlier diagnosis, appropriate and optimized treatment, and better prognosis for patients suffering from this life-threatening disease," said Mohr, professor of medicine in the Division of Hematology in the Department of Medicine.
Their new observations, published in the New England Journal of Medicine, shed light on the virus and its role in causing antiplatelet factor 4 disorders. Additionally, the discovery opens a whole new door for research, as many questions remain about how and why the disease occurs and who is most likely to develop it.
HIT, VITT and "spontaneous HIT"
Antibodies are large, Y-shaped proteins that stick to the surfaces of bacteria and other "foreign" substances, marking them for destruction by the immune system or directly neutralizing the threat.
In antiplatelet factor 4 disease, a patient's immune system produces antibodies against platelet factor 4 (PF4), a protein released by platelets. When anti-platelet factor-4 antibodies form and bind to them, they trigger activation and rapid clearance of platelets from the blood, leading to blood clotting and low platelets respectively.
Sometimes the formation of anti-PF4 antibodies is triggered by a patient's exposure to heparin, which is called heparin-induced thrombocytopenia (HIT), and sometimes it is an autoimmune disease that occurs in the absence of heparin exposure, which is called "spontaneous HIT."
Over the past three years, studies have shown that thrombocytopenia rarely occurs after injections of COVID-19 vaccines, which are made with inactivated adenoviral vector fragments. These vaccines are different from those produced in the United States, such as those produced by Moderna and Pfizer. This condition is called vaccine-induced immune thrombocytopenia (VITT).
road of discovery
Vaccine-induced immune thrombocytopenia was discovered when a 5-year-old boy with an outpatient diagnosis of adenovirus infection had to be hospitalized due to the formation of an aggressive blood clot in his brain (called cerebral sinus venous thrombosis) and severe thrombocytopenia. Doctors determined that he had not been exposed to heparin or the adenoviral vector COVID-19 vaccine, which are typical triggers of HIT and VITT.
"Intensive care unit physicians, neurointensivists and the hematology team worked around the clock to determine the next steps in this little boy's treatment," Baskin-Miller said. "He was not responding to treatment and his condition was progressing rapidly. Given the vaccine data, we had wondered if this was related to his adenovirus, but there was nothing in the literature to suggest it at the time."
Clinical collaborative efforts to help patients expanded: Baskin-Miller approached Mohr, an expert on blood clots with various connections in the field. In Mohr's opinion, the child patient may have suffered from "spontaneous HIT." They then tested for HIT platelet-activating antibodies, which came back positive.
Cooperation is key
Mohr contacted Theodore E. Warkentin, MD, professor of pathology and molecular medicine at McMaster University in Hamilton, Ontario, to hear if he knew of a link between adenovirus infection and spontaneous HIT. Warkentin, one of the leading international researchers on anti-PF-4 diseases, didn't understand the situation.
Around the same time, Mohr received a call from Alison L. Raybould, a hematology oncologist in Richmond, Virginia, who had previously trained at UND. She is seeing a patient with multiple blood clots, stroke and heart disease, deep vein thrombosis (DVT) in the arms and legs, and severe thrombocytopenia.
The patient had no exposure to heparin or vaccines. However, this patient's severe illness also began with viral symptoms of cough and fever, and she tested positive for an adenovirus infection. Test results for anti-PF4 antibodies were also positive.
To help clarify the diagnosis for both patients, Warkentin immediately offered to run further tests on the patients' blood and send the samples directly to his laboratory at Hamilton General Hospital for further study. They confirmed that the antibody targets platelet factor 4, much like the HIT antibody.
Surprisingly, this antibody was similar to the VITT antibody, binding to the same region of PF4 as the VITT antibody. They concluded that both patients suffered from "idiopathic HIT," or VITT-like disease, related to adenovirus infection.
more questions
After coming to such a groundbreaking conclusion, Mohr and colleagues now have many questions: about the incidence of new PF4-resistant disorders, whether the disease might be caused by other viruses, and why it doesn't occur with every adenovirus infection. They also want to know what preventive or therapeutic measures might help patients with new, potentially fatal, anti-PF4 diseases.
"How common is this disease?" Moore asked. "At what level of thrombocytopenia does one need to test for anti-PF4 antibodies? Finally, how can we best treat these patients to improve their chances of surviving this potentially fatal disease?"