Background rates of five thrombosis with thrombocytopenia syndromes of special interest for COVID-19 vaccine safety surveillance: incidence between 2017 and 2019 and patient profiles from 25.4 million people in six European countries

Background Thrombosis with thrombocytopenia syndrome (TTS) has been reported among individuals vaccinated with adenovirus-vectored COVID-19 vaccines. In this study we describe the background incidence of TTS in 6 European countries. Methods Electronic medical records from France, Netherlands, Italy, Germany, Spain, and the United Kingdom informed the study. Incidence rates of cerebral venous sinus thrombosis (CVST), splanchnic vein thrombosis (SVT), deep vein thrombosis (DVT), pulmonary embolism (PE), and stroke, all with concurrent thrombocytopenia, were estimated among the general population between 2017 to 2019. A range of additional adverse events of special interest for COVID-19 vaccinations were also studied in a similar manner. Findings A total of 20,599,134 individuals were included. Background rates ranged from 1.0 (0.7 to 1.4) to 1.5 (1.0 to 2.0) per 100,000 person-years for DVT with thrombocytopenia, from 0.5 (0.3 to 0.6) to 1.4 (1.1 to 1.8) for PE with thrombocytopenia, from 0.1 (0.0 to 0.1) to 0.7 (0.5 to 0.9) for SVT with thrombocytopenia, and from 0.2 (0.0 to 0.4) to 4.4 (3.9 to 5.0) for stroke with thrombocytopenia. CVST with thrombocytopenia was only identified in one database, with incidence rate of 0.1 (0.0 to 0.2) per 100,000 person-years. The incidence of TTS increased with age, with those affected typically having more comorbidities and greater medication use than the general population. TTS was also more often seen in men than women. A sizeable proportion of those affected were seen to have been taking antithrombotic and anticoagulant therapies prior to their TTS event. Interpretation Although rates vary across databases, TTS has consistently been seen to be a very rare event among the general population. While still very rare, rates of TTS are typically higher among older individuals, and those affected were also seen to generally be male and have more comorbidities and greater medication use than the general population. Funding This study was funded by the European Medicines Agency (EMA/2017/09/PE Lot 3). Research in context Evidence before this study We searched PubMed to identify studies that have previously described the background incidence of the study outcomes. Estimates of the incidence of cerebral venous sinus thrombosis (CVST) among the general population have ranged from 0.3 to 2 per 100,000 person-years. The background incidence of splanchnic vein thrombosis (SVT) is not well-known, although the incidence of portal vein thrombosis, the most commonly involved vein, has been estimated at around 3 per 100,000 person-years. Deep vein thrombosis (DVT) and pulmonary embolism (PE) are far more common with estimates of their incidence among the general population typically around 100 and 60 per 100,000 person-years respectively, while the incidence of stroke is typically estimated to be above 100 per 100,000 person-years. The background incidence of these events with concurrent thrombocytopenia has not, however, previously been described in detail. Added value of this study Based on spontaneous reports from the US, the United Kingdom, and the European Union, thrombosis with thrombocytopenia syndrome (TTS) has been raised as a serious, albeit rare, adverse event that may be caused by adenovirus-vectored COVID-19 vaccines. Assessing this safety signal requires a consideration of whether the rates of TTS being reported after vaccinations against SARS-CoV-2 differ from those normally seen among the general population in the absence of any such vaccinations. This study brings together data from six European countries to estimate the background incidence of TTS. We used six large databases of routinely-collected data allowing for sufficient sample size to study TTS across multiple study populations and in different age and sex strata. Additionally, we characterised patients affected by TTS in historical data, describing their comorbidities and prior medication use. Implications of all the available evidence TTS is very rare and based on the highest estimates among the databases included in this study, one would normally expect approximately 1 case of CVST with thrombocytopenia, 5 of SVT with thrombocytopenia, 11 of DVT with thrombocytopenia, 11 of PE with thrombocytopenia, and 34 of stroke with thrombocytopenia among a general population of 10 million individuals per 28 days. Expected events would however be higher for an older cohort, as patients with TTS are typically older than the general population. Patients with TTS are more often men and appear to typically have more comorbidities and greater medication use, including prior use of antithrombotic and anticoagulant therapies, than the general population. Not only do the rates of TTS being reported among those who had received an adenovirus-based vaccine against SARS-CoV-2 raise a concern, but early evidence from spontaneous reports suggests that TTS among those vaccinated has been more commonly been seen among women and younger persons. While this might be in part explained by potential biases in spontaneous reporting, it also underlines the importance of further evaluation of the safety signal for TTS. As with other adverse events of special interest for COVID-19 vaccines, estimates of TTS vary depending on the data source used. Comparison of observed versus expected TTS rates during the monitoring of COVID-19 vaccines should ideally be done using the same databases for the estimation of post-vaccine (observed) and background (expected) rates, with adjustment for patient characteristics (such as age and sex) done as part of the analysis.