Immune thrombotic thrombocytopenia ( VITT) is caused by antibodies against PF4 that recognize the heparin binding site. Thrombocytopenia and thrombosis associated with the specificity of VITT-like antibodies developed in a child and an adult after adenovirus infection.
Disorders caused by platelet-activating antibodies against platelet factor 4 (PF4) include heparin-induced thrombocytopenia (HIT) and vaccine-induced immune thrombotic thrombocytopenia (VITT); the latter is caused by vaccination against coronavirus disease 2019 with adenoviral vector vaccines.
Heparin- and VITT-dependent antibodies are distinguished by binding to different epitopes of PF4; heparin-dependent antibodies recognize PF4-heparin complexes, while VITT antibodies recognize PF4 without heparin because they bind to the heparin-binding region on PF4.
Other rare anti-PF4 disorders such as autoimmune HIT (decreases in platelet count that worsen or persist despite discontinuation of heparin treatment) are explained by the presence of both types of antibodies. An anti-PF4 disorder associated with adenovirus infection (without vaccination) has not been previously reported.
We report the development of symptomatic adenovirus infection in a 5-year-old boy and a 58-year-old woman. Both patients had nasopharyngeal swab samples positive for human adenovirus and negative for 18 other pathogens, including severe acute respiratory syndrome coronavirus 2, as determined with the BioFire Respiratory 2.1 panel (bioMérieux), a multiplexed nucleic acid test based on Polymerase chain reaction.
Both patients had fever, with gastrointestinal symptoms in the child and respiratory symptoms in the adult. These symptoms were followed 5 to 6 days later by severe thrombocytopenia in both patients, coagulopathy (hypofibrinogenemia in both patients and a very elevated D-dimer level in the child [D-dimer levels were not measured in the adult]), and events. thrombotics (fatal cerebral venous sinus thrombosis in children and multiple arterial cerebrovascular accidents, ST-segment elevation myocardial infarction and multiple deep vein thrombosis in adults). None of the patients had been previously exposed to heparin.
Our observations suggest that a symptomatic human adenovirus infection can trigger a life-threatening anti-PF4 prothrombotic disorder with clinical and serological features resembling VITT. It is currently not known whether a VITT-like disorder can be associated with other viral infections. However, an anti-PF4 disorder should be included in the differential diagnosis in patients who present with clinically significant thrombocytopenia and thrombosis, particularly cerebral venous sinus thrombosis .
Performing a solid-phase ELISA for antibodies against PF4 is important for timely recognition. Treatment strategies modeled after those used for VITT (ie, anticoagulation, high-dose immunoglobulin, plasma exchange, and minimization of platelet and fibrinogen transfusions) can be life-saving.
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Viral infections, autoimmune diseases, and other conditions can cause platelet levels to decrease throughout the body, thrombocytopenia .
After a strong clinical and research collaboration, Dr. Stephan Moll and Dr. Jacquelyn Baskin-Miller, both of the UNC School of Medicine, have linked adenovirus infection to a rare blood clotting disorder. blood. This is the first time 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, 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.”
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 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.
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, 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 exposure to heparin, which is called heparin-induced thrombocytopenia (HIT). known as “spontaneous HIT” .
Over the past three years, it has been shown that thrombocytopenia rarely occurs after injection of COVID-19 vaccines that are made from inactivated parts of an adenoviral vector. These vaccines are different than those made 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 as an outpatient with an adenovirus infection had to be admitted to the hospital with an aggressive blood clot forming in his brain (cerebral sinus vein thrombosis). 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, the neurointensivist and the hematology group were working around the clock to determine the next steps in caring for this child,” Baskin-Miller said. “He was not responding to therapy and was progressing rapidly. We had questioned whether it might have been related to his adenovirus given 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 contacted Moll, who is an expert in thrombosis and has several connections in this field. To Moll, it seemed that the pediatric patient could have "spontaneous thrombocytopenia . " They then tested the platelet-activating antibody HIT, 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 see if he was aware of an association between infection by adenovirus and spontaneous HIT. Warkentin, who is one of the leading international researchers of 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 and oncologist in Richmond, Virginia, a former UNC student. She was seeing 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 had also begun with viral symptoms of cough and fever, and she had tested positive for adenoviral infection. Testing for an anti-PF4 antibody was also positive.
To help clarify the diagnoses of the two patients, Warkentin immediately offered to further test the patients’ blood and the samples were sent 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 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 every adenovirus infection.
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 anti-PF4 antibody testing? And finally, how do we best treat these patients to optimize their chance of surviving a life-threatening disease?
