Understanding Mechanisms of Thrombosis and Thrombocytopenia in COVID-19 and with SARS-CoV-2 Vaccines

Background Clusters of cases of cerebral venous sinus thrombosis (CVST) or thrombosis in other major veins, together with thrombocytopenia (thrombotic thrombocytopenia syndrome (TTS)) began to emerge following roll-out of SARS-CoV-2 vaccines. Although a mechanistic link is not yet proven, there is strong epidemiological evidence that TTS is a very rare adverse effect of SARS-CoV-2 vaccines, and in particular, adenoviral vectored vaccines. The incidence of vaccine-induced TTS is thought to range between 1 in 100,000 and 1 in 1,000,000 with a fatal outcome in up to 20% of cases. Research question We aim to investigate the mechanisms underlying TTS in response to SARS-CoV-2 vaccination with the ultimate goal of developing novel preventive and interventional strategies. Aims Evaluate SARS-CoV-2 vaccine safety using real world epidemiology data. Understand the prevalence of anti-platelet factor 4 (PF4) antibody positivity. Understand the relationship between the immune response initiated by COVID-19, vaccines and haemostatic dysfunction including the underlying genetic factors. Develop in vitro platelet models to understand mechanisms of vaccine associated adverse events, and identify potential therapeutic interventions. Timelines for delivery We expect important findings of relevance to public health to be delivered during the funding period (before August 2022). Our expected outcomes are: Epidemiological data that provides robust evidence of background rates of thrombocytopenia, thrombosis and TTS, and whether TTS is associated with any of the COVID-19 vaccines, including the magnitude of the effect. Robust laboratory data to show the background rates of anti-PF4 antibodies, and whether they are sensitive and specific indicators of TTS. Novel methods for preventing TTS including potential avenues to modify the vaccines to prevent TTS. Development of a clinical assay for TTS. Identification of improved treatment approaches for TTS to improve its prognosis. Anticipated impact and dissemination Our work will enable regulatory authorities to assess the relative risk of developing TTS in response to SAR-CoV-2 vaccine against that of becoming seriously ill with COVID-19. This understanding is important to ensure that populations worldwide receive maximum benefit from vaccination programmes. Understanding the mechanism for vaccine-induced TTS will inform development of second-generation COVID-19 vaccines and help to identify new therapies to reduce the case fatality rate associated with TTS. Our outputs will be of national and international importance. Initially, we will share new findings with the Vaccine Task Force (VTF), the Joint Committee on Vaccination and Immunisation, and other representatives of the Department of Health and Social Care (DHSC) . The DHSC will determine whether the findings are of ministerial interest. Press releases will be cleared with NIHR, DHSC and the VTF. Investigating the Genetic basis for TTS Genomics England, part of the consortium, is leading and funding complementary work investigating the genomics of thrombosis and thrombocytopenia related to COVID-19 and SARS-CoV-2 vaccines. The whole consortium will work together, and collaborate with other researchers worldwide, to develop a better understanding of TTS and maximise public health impact.