Virus World

Biomarker discovery indicates that sufferers from brain fog and fatigue post-virus could be treated with anticoagulants. Scientists have identified molecular signatures in the blood that are linked to brain fog, other cognitive problems and fatigue in patients who are diagnosed with long Covid after catching the virus. Raised levels of two different proteins were more common in people who developed long Covid symptoms that affected their brains, the researchers found. Both are hallmarks of blood clots in the body, the likely cause of the symptoms reported. The work, described as “an important step forward” by one independent expert, bolsters thinking that emerged at the height of the pandemic that Covid leaves some patients with tiny clots in their lungs, and potentially in their brains, leading to a wide range of long-term memory, concentration and thinking problems. The findings could prove useful if clinical trials such as Stimulate-ICP, which are testing a range of treatments for long Covid, conclude that anticoagulants can improve brain fog and fatigue in some patients. Testing patients’ blood protein levels could alert doctors to those who should be treated for clots early and those who are less at risk.

The researchers looked at blood proteins in more than 1,800 hospitalised Covid patients and found that at the time of infection, those who went on to develop long-lasting cognitive problems were more likely than others to have raised levels of a protein called fibrinogen, or a protein fragment called D-dimer. High levels of fibrinogen are a sign of blood clots in the body. According to Max Taquet, an author on the study at the University of Oxford, patients could have blood clots on the brain that cause cognitive problems, or fibrinogen itself could be affecting the brain. Raised levels of D-dimer also signify blood clots in the body, but patients with high concentrations of the protein also tended to have post-Covid fatigue and breathlessness, leading the researchers to suspect blood clots on the lungs which can reduce blood flow to the brain and also cause fatigue.

“Individuals with elevated D-dimer levels were not only more prone to brain fog but also displayed a heightened risk of respiratory challenges,” Taquet said. Danny Altmann, a professor of immunology at Imperial College London, and a leading long Covid expert, said: “This is an important step forward in our understanding of the stratification of Long Covid and, potentially, some of the underlying mechanisms – they argue the case in support of possible input from effects on clotting pathways.” While a blood test to look for raised levels of the proteins could help doctors flag Covid patients most likely to develop brain fog and other long Covid symptoms, the biomarkers will not spot all patients at risk. “Real care is needed,” said Dr Michael Zandi at UCL’s Queen Square Institute of Neurology. “The associations do not give us yet a clear one-size-fits-all mechanism, and treatments need to pass through rigorous clinical trial first.”

The work, reported in Nature Medicine, comes as health officials in England raised concerns over a new, highly mutated variant of Covid that has been detected in the UK and several other countries. “The UK has entered a period of very lightweight mitigations with a very narrowed booster rollout,” Altmann said. “Large cohort studies remind us what a gamble we face when getting infected by this virus. We accrued more than 700,000 new long Covid cases during the period of ‘mild’ Omicron infections.” Chris Brightling, professor of respiratory medicine at the University of Leicester and a co-author on the latest study, said he feared long Covid patients might not receive the attention they need. “What I’m still disappointed in is that there are still a lot of patients that are suffering who haven’t fully recovered and we don’t know how long it will take for them to recover or whether they will need treatment. “We are now in a situation where Covid is in competition with all the other needs of the healthcare system, meaning there’s a risk patients with long Covid will not have the attention that is required because this is a condition that is still not going away.” Altman added “Most patients feel they have less and less support and negligible access to any treatment options.”

Research published in Nature Medicine (August 31, 2023):

https://doi.org/10.1038/s41591-023-02525-y 

Frank Ruschitzka told his pathologist to be ready before the first COVID-19 patient died. In early March, Ruschitzka, who leads the cardiology department at University Hospital Zürich, noticed that patients with the disease had strange symptoms for what was then thought to be chiefly a respiratory infection. Many patients had acute kidney failure, organ damage, and mysterious blood clots. Several weeks later, the first body was autopsied: Tiny clots and dead cells littered the capillaries of the lungs, and inflammation had distended blood vessels supplying every organ in the body. The pathologist had never seen anything like it. But the results showed Ruschitzka why his patients were suffering so much: The virus had targeted their blood vessels.

Since the Zürich team’s findings were published in mid-April, dozens of studies have revealed similar patterns of vascular damage in people who died of COVID-19. For example, a 21 May paper in The New England Journal of Medicine showed that the lungs of COVID-19 victims had nine times as many clots as those who died of the H1N1 flu. Other studies have noted inflammatory symptoms in children and strokes in otherwise healthy young adults. Now, researchers have woven these findings into a new hypothesis explaining why some patients slip into a fatal “second phase” of COVID-19, 1 week or so after hospitalization.

The key is direct and indirect damage to the endothelial cells that line the blood vessels, particularly in the lungs, explains Peter Carmeliet, a vascular biologist at the Belgian research institute VIB and co-author of a 21 May paper in Nature Reviews Immunology. By attacking those cells, COVID-19 infection causes vessels to leak and blood to clot. Those changes in turn spark inflammation throughout the body and fuel the acute respiratory distress syndrome (ARDS) responsible for most patient deaths...

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