key: cord-0756512-8jqo6trg
authors: Burn, Edward; Li, Xintong; Kostka, Kristin; Stewart, Henry Morgan; Reich, Christian; Seager, Sarah; Duarte‐Salles, Talita; Fernandez‐Bertolin, Sergio; Aragón, María; Reyes, Carlen; Martinez‐Hernandez, Eugenia; Marti, Edelmira; Delmestri, Antonella; Verhamme, Katia; Rijnbeek, Peter; Horban, Scott; Morales, Daniel R.; Prieto‐Alhambra, Daniel
title: 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 38.6 million people in six European countries
date: 2022-02-27
journal: Pharmacoepidemiol Drug Saf
DOI: 10.1002/pds.5419
sha: b05e9ed42f89181b39db9f01eb544b56e1acac3d
doc_id: 756512
cord_uid: 8jqo6trg

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 non‐vaccine induced TTS in six European countries. METHODS: Electronic medical records from France, the 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 myocardial infarction or ischemic stroke, all with concurrent thrombocytopenia, were estimated among the general population of persons in a database between 2017 and 2019. A range of additional potential adverse events of special interest for COVID‐19 vaccinations were also studied in a similar manner. FINDINGS: A total of 38 611 617 individuals were included. Background rates ranged from 1.0 (95% CI: 0.7–1.4) to 8.5 (7.4–9.9) per 100 000 person‐years for DVT with thrombocytopenia, from 0.5 (0.3–0.6) to 20.8 (18.9–22.8) for PE with thrombocytopenia, from 0.1 (0.0–0.1) to 2.5 (2.2–2.7) for SVT with thrombocytopenia, and from 1.0 (0.8–1.2) to 43.4 (40.7–46.3) for myocardial infarction or ischemic stroke with thrombocytopenia. CVST with thrombocytopenia was only identified in one database, with incidence rate of 0.1 (0.1–0.2) per 100 000 person‐years. The incidence of non‐vaccine induced TTS increased with age, and was typically greater among those with more comorbidities and greater medication use than the general population. It was also more often seen in men than women. A large proportion of those affected were seen to have been taking antithrombotic and anticoagulant therapies prior to their event. INTERPRETATION: Although rates vary across databases, non‐vaccine induced TTS has consistently been seen to be a very rare event among the general population. While still remaining very rare, rates were 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.

Interpretation: Although rates vary across databases, non-vaccine induced TTS has consistently been seen to be a very rare event among the general population. While still remaining very rare, rates were 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. were developed based on several platforms. 1 Some have demonstrated a high degree of efficacy in large phase 3 clinical trials, [2] [3] [4] received conditional approvals from regulators, and together they have already been given to over a billion individuals. 5 The benefits of these vaccines are demonstrable. For example, a large study on mass vaccination in Israel finding the estimated effectiveness of BNT162b2 mRNA vaccine to be 94% for symptomatic COVID-19, 87% for hospitalisation, and 92% for severe COVID-19 from 7 days after the second dose. 6 Similarly, the use of the BNT162b2 mRNA and ChAdOx1 in Scotland have been associated with substantial reductions in the risk of developing severe COVID-19 disease. 7 There remains, however, a need to assess the safety of vaccines against SARS-CoV-2 and assess safety signals as and when they arise.

While phase 3 clinical trials provided valuable information on the rates of relatively common, but mostly mild, adverse reactions following vaccination against SARS-CoV-2, they were not powered to study the occurrence of rare adverse events of special interest. Although the risks of rare but serious adverse events might be low, nationwide vaccination campaigns where millions of people are inoculated can lead to a considerable absolute number of any such events to occur.

A particular area of concern has arisen relating to the occurrence of thrombosis (often cerebral or abdominal) with concomitant thrombocytopenia among individuals who had received adenovirus-based vaccine against SARS-CoV-2. As of the 28th April 2021, 242 instances of thromboembolic events with thrombocytopenia among individuals who had recently received the ChAdOx1 vaccine in the United Kingdom had been identified on the basis of spontaneous reports. Of these, cerebral venous sinus thrombosis (CVST) was reported in 93 of the cases. 8 Meanwhile, as of the 23rd April 2021, 15 confirmed reports of thrombosis with thrombocytopenia syndrome (TTS) had been identified for the Ad. 26 .COV2.S vaccine in the United States. 9 These spontaneous reports of TTS came at a time when 22.6 million first doses and 5.9 million second doses of the ChAdOx1 vaccine had been given in the United Kingdom and more than 8 million doses of the Ad.26.COV2.S had been given in the United States. 8, 9 T A B L E 1 Database descriptions 

Although our understanding of pathogenesis of TTS after vaccination against SARS-CoV-2 is still evolving, current evidence indicates its mechanism includes the formation of antibodies directed against the cationic platelet chemokine, platelet factor 4 (PF4), that act against platelet antigens which result in massive platelet activation, aggregation, and consumption, which reduces platelet count and results in thrombosis. 10 In TTS, the location of thrombosis appears to often be atypical, with CVST and splanchnic vein thrombosis (SVT) observed in many cases. 11 This clinical presentation of TTS after vaccination shares important similarities with immune heparin-induced thrombocytopenia (HIT) and other spontaneous HIT syndromes, but remains itself a novel disorder. 12 The degree to which the reported TTS events after vaccination against SARS-CoV-2 exceed the number of non-vaccine induced TTS otherwise expected to happen is not yet well-known, nor is how the profiles of the persons with such events after vaccination have differed from those who typically experience them. Establishing the rates of non-vaccine induced TTS events among the general population in previous years will help to provide context for the observed rates being seen among those vaccinated. 13 Moreover, a description of the characteristics of the individuals who have had non-vaccine induced TTS events in the past will also help to inform a consideration of whether the profiles of individuals with TTS after a vaccination against COVID-19 differ to those who typically have such events.

In this study, we set out to estimate the background incidence rates of non-vaccine induced TTS and to describe the profiles of individuals who typically have these types of events. We did this using In summary, all the included databases captured outpatient diagnoses and outpatient lab measurements. SIDIAP CMBD-HA and HIC Dundee also directly captured diagnoses from linked hospital data.

HIC Dundee was the only database that, in addition, included hospital lab measurements (Table 1) . 

The primary study cohort consisted of individuals present in a database as of the 1st January 2017, with this date used as the index date for all study participants. These individuals were followed up to whichever came first: the outcome of interest, exit from the database, or the 31st December 2019 (the end of study period). A second study cohort which was made up of active patients was used for a sensitivity analysis, where individuals entered the cohort on the date of their first visit occurrence after 1st January 2017. As with the primary study cohorts these individuals were followed up to whichever came first: the outcome of interest, exit from the database, or 31st

December 2019. As a further sensitivity analysis, study cohorts were also generated with the additional requirement that individuals had a minimum of 1 year of history available in the database prior to their index date.

Here we summarise results for five specific TTS events of interest: 

The characteristics of the study population were extracted relative to their index date, as were those of individuals with a particular out- F I G U R E 2 Incidence rates (with 95% confidence intervals) per 100 000 of non-vaccine induced thrombocytopenia syndrome among the general population, stratified by age and sex

The profiles of the study cohorts and those with an outcome of interest were summarised, with median and interquartile range (IQR) used for continuous variables and counts and percentages used for categorical variables. For each study outcome, the number of events, the observed time at risk, and the incidence rate per 100 000 personyears are summarised along with 95% confidence intervals. For a given outcome, any study participants with the outcome in the year prior were excluded from the analysis of that outcome. These results are provided for the study cohorts and stratified by data source as a whole and by age (≤44, 45-64, or ≥65 years old) and sex. To aid in comparison with rates being reported after vaccinations, the expected number of events per 36 days for a population of 10 million were calculated based on the incidence rates calculated for the overall study cohorts and age strata.

All analytic code used for the study is available at https://github.com/ oxford-pharmacoepi/CovCoagBackgroundIncidence. Code lists are provided in the Appendix S1.

This study was funded by the European Medicines Agency (EMA).

This document expresses the opinion of the authors of the paper, and may not be understood or quoted as being made on behalf of or reflecting the position of the EMA or one of its committees or working parties. The study outcomes were chosen in collaboration with the EMA so as to best reflect the events of interest. The study protocol was reviewed by the EMA and registered in the European Union F I G U R E 3 Expected cases (with 95% confidence intervals) of non-vaccine induced thrombocytopenia syndrome per 36 days in a population of 10 000 000 people in a given age strata or overall. Blank cells are where there were fewer than five people with the event and incidence rates were not estimated 

Comorbidities and prior medication use among patients with non-vaccine induced thrombocytopenia syndrome compared to the overall study population. Any characteristic seen in less than five people in a cohort is not reported infarction or ischemic stroke with thrombocytopenia. As with thrombosis in general, see Figure 1 , incidence rates for non-vaccine induced TTS were typically higher for older age groups, see Figure 2 . The age and sex profiles of those with non-vaccine induced TTS are summarised in Table 4 Coagulopathies potentially associated with TTS were mostly rare:

immune thrombocytopenia was the most common with rates up to almost 47 per 100 000 person-years, followed by HIT (up to 38 per 100 000), DIC (up to 4 per 100 000), and TTP (up to 3 per 100 000).

A number of previous studies have estimated the incidence of venous thromboembolism in the general population, with its incidence rate estimated to be around 100 cases per 100 000 person-years. 22 Approximately two-thirds of venous thromboembolism can be expected to present as DVT, with the other third presenting as PE with or without DVT. 23 Meanwhile the incidence of myocardial infarction has been seen to be above 20 cases per 100 000 person-years, 24 while the incidence of stroke generally estimated to be more than 100 persons per 100 000 person-years. 25, 26 The incidence of each of these events is seen to be much higher among older persons. The incidence of SVT and CVST is far less well-known. Estimates for the incidence of CVST have ranged from 0.2 to 2 per 100 000 personyears. [27] [28] [29] [30] Meanwhile there is little research describing the incidence of SVT in the general population, although the incidence of portal vein thrombosis, the most commonly involved vein, has been estimated at around 3 per 100 000 person-years, while the incidence of Budd-Chiari syndrome was estimated at around 2 per 100 000 person-years in the same study. 31 In one recent study, data from Denmark and Norway was used to assess 28-day rates of thromboembolic events and coagulation disorders among a cohort of people who had received the ChAdOx1 vaccine and in historical comparator cohorts. 32 Another recent European network study has also assessed the background incidence of thromboembolic events, coagulation disorders, and non-vaccine induced TTS. 33 There is some overlap in data sources used, with their study also including data from CPRD GOLD and SIDIAP CMBD-HA. Although in many instances our estimates are comparable to theirs, there are discrepancies. These seem to be driven primarily by differences in cohort definitions. For example, they estimated the incidence of rate of CVST to be 0.6 (0.3-1.1) and 0.1 (0.0-0.3) per 100 000 person-years for SIDIAP CMBD-HA and CPRD GOLD respectively, which compared to our estimates of 0.7 (0.6-0.9) and 1.2 (1.0-1.5). While the estimates for SIDIAP CMBD-HA are similar, the difference between results for CPRD GOLD appears to be due to the code "Nonpyogenic venous sinus thrombosis," which was included in our definition of CVST (and was the most common code that led to cohort entry in CPRD GOLD) but does not appear to have been included in their definition. Meanwhile, even greater differences were seen for estimates of non-vaccine induced TTS. 8 The profile of patients with TTS after vaccination also appears to differ to the typical profiles of those with TTS as seen in our data. While in this study we have seen those with TTS to typically be older than the general population of people in the database, more commonly male, and with more comorbidities and greater prior medication use, initial studies describing the profiles of patients with vaccine-induced TTS have most often presented the cases of people who were aged under 60, more often female, and with relatively few comorbidities described. 11, [34] [35] [36] This dissimilarity in patient profiles of those with TTS in previous years and those for whom it has been reported following a vaccination is notable.

Substantial heterogeneity can though be seen in estimates of across databases, particularly where platelet measurements are required to identify an outcome. For PE, for example, a twofold difference was seen between the databases with the highest and lowest incidence rates. This increased to a more than 20-fold difference between databases for PE with thrombocytopenia. This heterogeneity was observed even though we used data mapped to a common data model and applied the same analytic code across the databases. Given that the data sources used come from different countries some differences in estimates can be expected. However, the heterogeneity in results seen here can also be explained by substantial differences in data capture across databases and source coding systems. Two of the databases had patient-level linkage to hospital records and one of these also captured inpatient platelet measurements. Incidence rates were often higher for these two databases. Moreover, while the databases were mapped to a common data model the source data used different medical vocabularies. For example, while read codes were used to represent condition-related concepts in CPRD GOLD, ICD-9

was used in IQVIA LPD Italy and ICD-10CM in SIDIAP. These coding systems differ in the granularity by which they describe clinical events, and this can have a meaningful impact on research findings.

This can be seen in the literature by the impact on research findings when databases switched from using ICD-9 to ICD-10 codes for instance. 37 This all further underlines the importance of using consistent data sources in vaccine safety research with a historical comparator design. In the case of TTS it can also be expected that full linkage capturing both outpatient and inpatient lab measurements is required for accurate outcome ascertainment.

This study relies on routinely-collected health care data and while this has allowed for the inclusion of a large study population, the recording of TTS has not previously been evaluated in the databases used.

A degree of measurement error can thus be expected, and further research is required to validate the recording of TTS. This includes not only the identification of the constituent events themselves, but also the time period over which they can be considered concurrent. The findings from this study demonstrate that data sources that do not capture inpatient lab measurements can be expected to underestimate the true incidence of TTS. Studies that rely solely on records of diagnoses can be expected to miss many of the cases of thrombocytopenia that can be observed from available measurements of platelet counts.

The degree to which the TTS events being described after vaccinations against SARS-CoV-2 are comparable to non-vaccine induced TTS events previously seen in the general population is as yet unclear.

TTS after vaccination appears to occur at unusual sites, with a large proportion of spontaneous reports and case series describing cerebral or abdominal thromboses, and with high levels of antibodies to platelet factor 4 often observed despite the absence of an exposure to heparin. 11, 38 In this study we have focused on specific sites of thrombosis with concomitant thrombocytopenia. We believe that this is more instructive than providing a singular background incidence rate for venous thromboembolism with thrombocytopenia, which would be driven in large part by commonly seen events (such as DVT and PE) and would not necessarily reflect the presentation of TTS after vaccination. In particular, we do not have measurements of anti-PF4

antibodies and so could not use this for defining study outcomes. As the pathophysiology of TTS after vaccination becomes better understood, definitions of the appropriate historical comparator can also be expected to evolve so as to best match the condition being described among those who have been recently vaccinated. In particular this may mean the exclusion of patients with history of other rare disorders who may present with TTS without proximate heparin, such as patients with antiphospholipid syndrome.

Based on data from over 38 million people from six European databases, non-vaccine induced TTS has been seen to be very rare. While rates varied across databases, the highest incidence rates for DVT, PE, and stroke with thrombocytopenia were 8.5, 20.8, and 30.9 per 100 000 person-years, respectively. Meanwhile the highest incidence rates for CVST and SVT with thrombocytopenia were 0.1 and 2.5 per 100 000 person-years. Non-vaccine induced TTS was typically seen among individuals older, more often male, and in worse health than the general population. While these findings help to provide context for the rates of adverse events being reported by spontaneous reports following vaccinations against SARS-CoV-2, a full assessment of the safety signal for TTS would benefit from within-database comparisons which account for individual-level characteristics such as age and sex.

Italy and utilisation of DA Germany data for COVID-19 related research. Katia Verhamme and Peter Rijnbeek work for a research group that received unconditional research grants from Yamanouchi

Edward Burn led the data analysis and wrote the initial draft of the manuscript with Daniel Prieto-Alhambra. Edward Burn, Talita Duarte-Salles, Carlen Reyes, María Arag on, and Sergio Fernandez-Bertolin had access to the SIDIAP data

Alhambra had access to the CPRD data

IQVIA DA Germany) in these analyses are commercially available, syndicated data assets that are licenced by contributing authors for observational research. These assets are deidentified commercially available data products that could be purchased and licenced by any researcher. As these data are deemed commercial assets, there is no Institutional Review Board applicable to the usage and dissemination of these result sets or required registration of the protocol with additional ethics oversight. Compliance with Data Use Agreement terms, which stipulate how these data can be used and for what purpose, is sufficient for the licencing commercial entities. Further inquiry related to the governance oversight of these assets can be made with the respective commercial entity, IQVIA (iqvia.com). For HIC Dundee

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