key: cord-0896419-dosjor44
authors: Shah, Hridaya; Kim, Ann; Sukumar, Senthil; Mazepa, Marshall; Kohli, Ruhail; Braunstein, Evan M.; Brodsky, Robert A.; Cataland, Spero; Chaturvedi, Shruti
title: SARS-CoV-2 vaccination and immune thrombotic thrombocytopenic purpura
date: 2022-03-10
journal: Blood
DOI: 10.1182/blood.2022015545
sha: d8eab016c396bd68500a7fbaf820912906613dbd
doc_id: 896419
cord_uid: dosjor44

nan

This manuscript has a data supplement Vaccine-induced thrombotic thrombocytopenia (VITT) has also been reported after adenoviral 8 COVID-19 vaccines. 5 These reports led to vaccine hesitancy among patients with 9 thrombocytopenic disorders including immune thrombotic thrombocytopenic purpura (iTTP), a 10 relapsing, thrombotic microangiopathy caused by antibody mediated severe ADAMTS13 11 deficiency. These concerns were further compounded by reports of de novo and relapsed iTTP 12 following mRNA vaccines. 6-10 Whether SARS CoV-2 vaccination is associated with iTTP 13 recurrence has significant clinical implications; however, this has not been systematically 14 investigated. We conducted a multicenter retrospective cohort study to evaluate the safety of 15 SARS-CoV2 vaccination in patients with pre-existing iTTP. To estimate the incidence of iTTP 16 (de novo and relapsed) after vaccination, we examined cases of iTTP after COVID-19 17 vaccination reported in the Vaccine Adverse Event Reporting System (VAERS), the US passive 18 surveillance system for adverse events after immunization. 11

Patients with confirmed iTTP (based on documented ADAMTS13 activity <10% during 20 an acute episode of thrombotic microangiopathy) and documented SARS-CoV-2 vaccination 21 followed at Johns Hopkins Hospital, Ohio State University, and University of Minnesota were 22 included. Details of iTTP and SARS-CoV-2 vaccination, and available laboratory data including 23 platelet counts and ADAMTS13 activity before and after vaccination were extracted from the 1 medical record. The primary outcome was iTTP relapse characterized by a platelet count <150 x 2 10 9 /L and microangiopathic hemolysis with ADAMTS13 activity < 10 % occurring within 4 3 weeks of vaccination, the typical window for post-vaccine autoimmune hematologic 4 complications. 12 We separately report iTTP relapses occurring at > 4 weeks after vaccination. 5 We also examined change in ADAMTS13 activity and platelet counts before and after 6 vaccination.

Additionally, we searched the VAERS database for reports of adults (age > 18 years) 8 who developed iTTP after receiving SARS-CoV-2 vaccines. Individual reports were reviewed by 9 two independent investigators to determine whether these were consistent with iTTP. We 10 categorized cases as definite iTTP (documented severe ADAMTS13 deficiency), probable iTTP 11 (presentation and treatment compatible with iTTP but ADAMTS13 not reported), and possible 12 iTTP (presentation and treatment possibly compatible with iTTP but inadequate information to 13 make a definitive determination). Cases more compatible with alternative diagnoses such as ITP 14 or VITT were excluded. 100%). iTTP relapse within 4 weeks of vaccination occurred in one patient (1.3%), a 28-year-old 23 female at 1.5 years from her initial iTTP episode who did not recover ADAMTS13 activity at all 1 (<2%) during remission. Six days after the first dose of the Pfizer vaccine, she developed 2 bruising, petechiae, ataxia, and slurred speech. Laboratory testing revealed thrombocytopenia, 3 schistocytes, and undetectable ADAMTS13 activity. She was successfully treated with 4 caplacizumab, rituximab, and corticosteroids without plasma exchange based on our prior 5 experience treating early relapse with this regimen. 13 She received the second dose of the Pfizer 6 vaccine uneventfully after ADAMTS 13 activity was > 20%. Another three patients were treated 7 for iTTP recurrences between 35 to 143 days after vaccination, which are less likely to be 8 associated with vaccination (Table S1 ). The incidence of iTTP relapse over the entire 9 observation period after vaccination was 0.095 per patient-year. 10 We next examined the VAERS database for de novo and relapsed iTTP after COVID-19 Johnson vaccine (0.244 per million). While the temporal relationship of several cases occurring 23 within a month of vaccination is concerning for an association, the estimated incidence is not 1 higher than the incidence of iTTP in the United States (1.7 to 3.7 per million). 15, 16 2 De novo and relapsed iTTP have been reported after various vaccines 17-19 , including 3 SARS-CoV-2 vaccines 6-10 , where the association is supported by absence of another proximate 4 cause and a temporal relationship with most cases occurring between 5 -15 days after 5 vaccination. Most cases of iTTP following COVID-19 vaccination in VAERS occurred within 6 14 days after vaccination, which is concerning for a possible association. In our cohort, three of 7 four patients with iTTP recurrence presented >30 days after vaccination arguing against vaccine-8 induced autoimmunity in these cases, though it must be noted that VITT has been reported up to 9 48 days after vaccination 5 so an association with iTTP relapse after 30 days is plausible and may 10 apply to the patient who had a relapse 35 days after the second vaccine dose (table S1).

Vaccination could precipitate acute iTTP in patients who already have low ADAMTS13. This is 12 supported by the observation that ADAMTS13 deficiency is necessary but not sufficient for TTP 13 and that the only relapses in our cohort occurred in individuals with low/unknown ADAMTS13 14 activity within 3 months prior. Our combined cohort is relatively mature, and we offer 15 preemptive rituximab to patients with ADAMTS13 activity <20% during clinical remission, 16 which may explain the high pre-vaccination ADAMTS13 activity and corresponding low relapse 17 rate. Patients in clinical remission without ADAMTS13 remission 20 might be at increased risk 18 for relapse 21,22 following COVID-19 vaccination. We check ADAMTS13 activity every 3 19 months in all patients to estimate risk of recurrence (including post-vaccination). We recommend 20 checking a platelet count and ADAMTS13 activity weekly for 2-4 weeks after vaccination in 21 those with lowADAMTS13 activity (<20-30%). 22 1 medical record. However, we are unable to report other vaccine-associated adverse events since 2 these were not consistently documented. A limitation of VAERS data is that some cases have 3 limited clinical and laboratory information (including ADAMTS13). 23 To address this challenge, 4 we categorized cases based on certainty of the TTP diagnosis. Finally, VAERS is a passive 5 surveillance system and iTTP after vaccination may be underreported, 23 which is a limitation. To 6 avoid underestimating incidence, we included all reported cases of iTTP (rather than only 7 ADAMTS13 cases) and used only fully vaccinated individuals as the denominator.

In summary, data from a large multicenter cohort and VAERS appear to be reassuring 9 that COVID-19 vaccination does not increase risk of de novo or relapsed iTTP except in 10 individuals with extremely low ADAMTS13 activity (<20%) in remission. Prospective studies to 11 confirm this finding are needed. Until then, these data may help individuals with iTTP and their 12 physicians make informed decisions about vaccination. 

Thrombocytopenia including immune 2 thrombocytopenia after receipt of mRNA COVID-19 vaccines reported to the Vaccine Adverse Event 3 Reporting System (VAERS)

First-dose ChAdOx1 and BNT162b2 COVID-19 vaccines and 5 thrombocytopenic, thromboembolic and hemorrhagic events in Scotland

SARS-CoV-2 Vaccination and Immune 8 Thrombocytopenia in de novo and pre-existing ITP patients

Exacerbation of immune thrombocytopenia following COVID-19 vaccination

Insights in ChAdOx1 nCoV-19 vaccine-induced immune 12 thrombotic thrombocytopenia

First report of a de novo iTTP 14 episode associated with an mRNA-based anti-COVID-19 vaccination

Acquired thrombotic thrombocytopenic purpura after 17 first vaccination dose of BNT162b2 mRNA COVID-19 vaccine

Acquired thrombotic thrombocytopenic purpura 19 following Pfizer COVID-19 vaccination

Relapse of thrombotic thrombocytopenic purpura after 21 COVID-19 vaccine

Recurrence of Thrombotic Thrombocytopenic Purpura 23 after mRNA-1273 COVID-19 Vaccine Administered Shortly after COVID-19

Vaccine Adverse Event Reporting System (VAERS) 27 1990 -12/17/2021, CDC Wonder Online Database

Vaccinations and Autoimmune Diseases. Vaccines (Basel)

Shared decision making, thrombotic thrombocytopenic 31 purpura, and caplacizumab

A: Centers for 33 Disease Control

The incidence of 35 thrombotic thrombocytopenic purpura-hemolytic uremic syndrome: all patients, idiopathic patients, and 36 patients with severe ADAMTS-13 deficiency

Increasing mortality from thrombotic thrombocytopenic 38 purpura in the United States--analysis of national mortality data

Refractory thrombotic thrombocytopenic purpura following influenza 41 vaccination

Acute thrombotic thrombocytopenic purpura after 43 pneumococcal vaccination

Thrombotic thrombocytopenic purpura after ChAdOx1 45 nCoV-19 vaccine