Emergence of VITT: The Role of Prompt and Intensified Worldwide Research Collaboration
By Aaron Iding, M.D, and Maha Othman, M.D., Ph.D.
The Coronavirus Disease 2019 (COVID-19) pandemic is estimated to have affected 170 million people worldwide with close to 4 million deaths reported to date. To control the pandemic, countries have had to rely on lockdowns and social distancing, which have had a profound economic and psychologic impact. Fortunately, highly effective vaccines were developed at an unprecedented speed, making them ready for deployment in less than a year. Over 2 billion vaccine doses have been administered globally at the time of writing this article.
The emergence of “vaccine-induced immune thrombotic thrombocytopenia” (VITT) has caused huge concerns among physicians, researchers, and the public worldwide. This newly described syndrome is characterized by thrombosis and thrombocytopenia occurring post-COVID-19 vaccinations. Most cases happened following administration of the adenoviral-vector based vaccines ChAdOx1nCov-19 (AstraZeneca/Oxford, AZ) and AD26.COV2.S (Johnson & Johnson), but more recently exceptionally rare cases were also reported following mRNA-based vaccines. We interviewed three scientists who were involved in the discovery of VITT to capture their views, insights and experiences.
Nina H. Schultz, M.D., Ph.D., works at Oslo University Hospital (Norway) and remembers vividly how they were first alarmed of this new condition.
“We noticed that five patients - all healthcare workers - were admitted with a similar clinical picture within 10 days after receiving the AZ vaccine,” Schultz said. “All had severe thrombocytopenia, thrombosis, some in atypical sites with bleeding. The diagnosis was challenging. It did not fit with DIC, TTP or HIT; patients did not have previous heparin exposure.”
Schultz and her colleagues suspected an immunological process, and indeed all patients had high titer of antibodies against the platelet factor 4 (PF4)-polyanion complex.
“Discussing this with colleagues from other hospitals in Europe who were also seeing these rare cases, we postulated this immune process was initiated by another non-heparin molecule, and we were quite sure it was the vaccine that had initiated it,” she said. The condition fit with spontaneous HIT. “Our decision was to stick with low-molecular weight heparin for which we saw improvement. We recommended anticoagulation treatment for six months.”
Schultz and her colleagues’ theories on the trigger for VITT include: the SARS-CoV-2 spike protein, the viral vector, other constituents in the vaccine, and/or possibly pre-existing conditions or antibodies.
Clinicians and scientists from all over the world reached out to discuss what to do with this newly emerging serious condition. To quickly and effectively communicate, a daily mailing list was created for extensive discussion on VITT that quickly grew to over 100 experts in the field, including one of the authors of this article, Maha Othman, M.D., Ph.D. The correspondence and discussion inspired more science, research collaboration, and publications. Close to 30 articles on VITT appeared in less than a couple of months.
To effectively identify cases of VITT, it was crucial that diagnostic tests were evaluated on short term. Marie Scully, M.D., Ph.D., and her team at University College London (UK) collaborated with several reference laboratories to assess the sensitivity of various anti-PF4 antibody assays.
“We found that currently used rapid immunoassays for HIT are not positive in VITT cases,” Scully said. “It may be something about these assays, perhaps as simple as the incubation time, which is not easily reversed as they are automated.”
Moreover, no single ELISA method detected all probable cases of VITT either. “Our advice: if it looks and feels like VITT but you have a negative ELISA, you should do another ELISA assay or check for functional testing,” Scully added.
Thankfully interim guidance documents for VITT were published very quickly, including one by the International Society of Thrombosis and Haemostasis (ISTH), and recently the ISTH Scientific and Standardization Committee (SSC) published a new recommendation. The European Medicines Agency is also very active in enhancing awareness and supporting international collaboration to better understand and diagnose VITT.
To advance diagnostics, therapeutics and possibly prevention of VITT, basic research is needed to gain a deeper understanding of its underlying mechanisms. In collaboration with clinicians, Andreas Greinacher, M.D., Ph.D, and his team at the University of Greifswald (Germany) obtained serum and even cerebral vein thrombi from VITT cases. His group revealed that VITT has similarities to spontaneous HIT. Moreover, with blood from healthy vaccinated individuals, they showed that anti-PF4 antibodies are actually quite common following both adenovirus vector-based and mRNA-based COVID-19 vaccines.
“This means that screening for anti-PF4 antibodies in vaccinated individuals without clinical suspicion of VITT is not useful,” Greinacher said. However, antibody levels in VITT cases were much higher, and it seems that only the subset that can bind to PF4 independent of heparin is important in VITT.
“A major question we are currently trying to answer is which vaccine constituent induces these antibodies,” he added. Working together with various scientists, their group is exploring this question using cutting-edge technologies.
Key unanswered questions remain: What is the trigger and mechanism behind VITT? What is the role of heparin? Who is at risk? What is the actual global incidence and are there long-term outcomes? Time will tell. For now, the above experiences demonstrate how a new and urgent global clinical diagnostic challenge can trigger prompt and intense collaboration between basic scientists and clinicians and lead to impressive achievements in a brief period of time.
This is just one of the many lessons from the COVID-19 pandemic. Hopefully, such openness, accessibility, and scientific communication will continue to conquer COVID-19, and even beyond to other diseases, towards the benefit of all across the globe.
View the ISTH interim guidance on VITT here.
View the ISTH SSC recommendations for clinical and laboratory diagnosis of VITT here.