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Virus World provides a daily blog of the latest news in the Virology field and the COVID-19 pandemic. News on new antiviral drugs, vaccines, diagnostic tests, viral outbreaks, novel viruses and milestone discoveries are curated by expert virologists. Highlighted news include trending and most cited scientific articles in these fields with links to the original publications. Stay up-to-date with the most exciting discoveries in the virus world and the last therapies for COVID-19 without spending hours browsing news and scientific publications. Additional comments by experts on the topics are available in Linkedin (https://www.linkedin.com/in/juanlama/detail/recent-activity/)
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Common Cold Virus Linked to Potentially Fatal Blood Clotting Disorder

Common Cold Virus Linked to Potentially Fatal Blood Clotting Disorder | Virus World | Scoop.it

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 

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SARS-CoV-2 Spike Protein Changes the Morphology of Platelets and Binds Directly to the Platelet Integrin α5β1 and αvβ3 Receptors

SARS-CoV-2 Spike Protein Changes the Morphology of Platelets and Binds Directly to the Platelet Integrin α5β1 and αvβ3 Receptors | Virus World | Scoop.it

A new study by researchers from the United States, Spain and Japan investigated the direct effect of the SARS-CoV-2 spike (S) protein on platelet morphology. For the first time, the researchers directly visualized the binding of the S-protein to the platelet plasma membrane. The S-protein is crucial for understanding the molecular mechanisms of SARS-CoV-2 infection. The S-protein is crucial for understanding the molecular mechanisms of SARS-CoV-2 infection. The SARS-CoV-2 S-protein consists of a S1 and a S2 subunits that are separated by host cell proteases. The receptor-binding domain in the S1 subunit is responsible for attachment to host cells. S-protein is suggested to interact not only with the angiotensin-converting enzyme 2 (ACE-2) receptors, but also with several other host receptors including neuropilin-1 and CD147. SARS-CoV-2 is the only beta-coronavirus containing an RGD (Arg-Gly-Asp) tripeptide motif in the receptor-binding domain, which is typically recognized by several members of the integrin membrane receptor family. SARS-CoV-2 infection is associated with abnormalities in coagulation in severe cases. One of the major pathological symptoms in these patients is abnormal platelet behavior. During SARS-CoV-2 infection, several other procoagulant players, such as the formation of neutrophil extracellular traps, the release of tissue factor, elevated fibrinogen levels and dysregulated release of cytokines, create a hypercoagulative environment in the context of COVID-19.

 

COVID-19 patients have conditions such as a low platelet counts (thrombocytopenia), microvascular thrombosis, and coagulation, suggesting that SARS-CoV-2 can directly cause platelet dysfunction. Platelets isolated from COVID-19 patients exhibit abnormalities such as hyperactivity and increased spreading behaviour. Cytokines, antiphospholipid antibodies, interactions with other immune cells, and direct interaction between SARS-CoV-2 and platelets are potential causes of these abnormalities. The isolated platelets from healthy donors mixed with SARS-CoV-2 or the SARS-CoV-2 S-protein show a faster thrombin-dependent clot retraction, and activate platelets independent of thrombin with upregulation of signaling factors. To assess the direct effect of SARS-CoV-2 S-protein on platelet morphology, the researchers isolated platelets from healthy human blood donors, tested their morphological changes in the presence of S-protein, and visualized the effect of S-protein on platelet morphology using live imaging and cryo-electron tomography. The results showed that the S-protein triggers the dynamic deformation of platelets in elongated morphologies, leading in some cases to their irreversible activation. Platelets incubated with the S-protein showed extensive deformations, consistent with light microscopic observations, while intact platelets showed their typical disc-like morphology. Cryo-electron tomography revealed the formation of actin-rich filopodia at the end of the elongated platelets. The orientation analysis showed that the S-protein binds to the membrane surface through various angular distributions. To test the effects of the S-protein on platelet activation, the researchers performed a solid-phase sandwich ELISA test and a Western blotting. In the ELISA assay, platelet factor 4 was measured to test the secretion of alpha-granules, a marker of platelet activation. The results showed an increase in platelet factor 4 secretion in platelet samples in the presence of S-protein. Moreover, the research team tested the interaction between the S-protein and platelet-expressed integrins. The presence of ACE-2, the main S-protein receptor, on the surface of platelets is still not conclusive. On the contrary, integrin receptors are the main class of receptors expressed in platelets.

 

Given the possibility that ACE-2 is not widely expressed on platelets, the authors speculated that the S-protein could recognize integrin receptors directly. They tested the binding of S-protein to known platelet integrin receptors αIIbβ3, αvβ3, and α5β1, enriched in the tissue but also expressed on platelets, all recognizing the RGD ligand motif. They found a weak but direct binding of integrin α5β1 and αvβ3 to the S-protein, while integrin αIIbβ3 did not interact with it. According to researchers, the binding of the SARS-CoV-2 is mediated by integrin receptors, based on the following reasons; 1) the activation of platelets is governed by filopodia formation; 2) filopodia formation is initiated by integrin receptors; 3) the major receptors on the platelets are integrin receptors and 4) SARS-CoV-2 S protein contains a “RGD” sequence in the receptor binding domain, which is recognized by a subtype of integrin. The researchers noted that a weak affinity of S-protein to platelet integrin receptors and the reversible binding may reflect the fact that blood clotting defects observed in COVID-19 patients are rare complications and occur in severe cases of COVID-19. The researchers also said that other platelet receptors could also be responsible for the interaction with the S-protein. They concluded that their results shed light on the abnormal platelet behavior leading to coagulopathic events and microthrombosis caused by SARS-CoV-2 infection.

 

Research published in Nature Communications (Feb. 4, 2023):

https://doi.org/10.1038/s41467-023-36279-5 

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