Thrombosis with Thrombocytopenia Syndrome (TTS) following AstraZeneca ChAdOx1 nCoV-19 (AZD1222) COVID-19 vaccination - A risk-benefit analysis for people < 60 years in Australia.

The AstraZeneca ChAdOx1 nCoV-19 (AZD1222) vaccine is associated with Thrombosis with Thrombocytopenia Syndrome (TTS) in 3/100,000 vaccinations with high fatality rates reported in many countries. We conducted a risk-benefit analysis for Australians aged 18-59 years, comparing the risk of vaccination versus infection, and rate of TTS to other vaccines which prompted policy change following rare adverse events - rotavirus, smallpox and oral polio vaccines. COVID-19 deaths over 12 months range from 0 to 417 in current and future worst case scenarios. In the past 15 months 20 COVID-19 deaths occurred in people < 60 years compared to 890 deaths over 60 years. The estimated possible number of TTS cases is 347, with vaccine-related deaths ranging from 17 to 153if 80% of adults 18-59 years are vaccinated. The reported rate of TTS is in the same range as rare but serious adverse events associated with other vaccines that have been subject to policy change. In Australia, the potential risks of the AZD1222 vaccine in younger adults, who are at low risk of dying from COVID-19, may outweigh the benefits.

MacIntyre CR ，Veness B ，Berger D ，Hamad N ，Bari N ... -  《-》

Thrombosis with thrombocytopenia after AZD1222 (ChAdOx1 nCov-19) vaccination: Case characteristics and associations.

Post-marketing surveillance for COVID-19 vaccines during the pandemic identified an extremely rare thrombosis with thrombocytopenia syndrome (TTS) reported post-vaccination, requiring further characterisation to improve diagnosis and management. We searched the AstraZeneca Global Safety Database (through April 26, 2021) for cases with co-reported thrombocytopenia and thrombosis (using standardised MedDRA queries/high-level terms) following AZD1222 (ChAdOx1 nCoV-19). Cases were adjudicated by experts as 'typical','possible', 'no' or 'unknown' according to available TTS criteria. Additional confirmatory datasets (May 20-June 20, October 1-December 28) were evaluated. We identified 573 reports, including 273 (47.6 %) 'typical' and 171 (29.8 %) 'possible' TTS cases. Of these 444 cases, 275 (61.9 %) were female, median age was 50.0 years (IQR: 38.0-60.0). Cerebral venous sinus thrombosis was reported in 196 (44.1 %) cases, splanchnic venous thrombosis in 65 (14.6 %) and thromboses at multiple sites in 119 (26.8 %). Median time to onset was 12.0 days (IQR: 9.0-15.0). Comparison with a pre-pandemic reference population indicated higher rates of autoimmune disorders (13.8 %, 4.4 %), previous heparin therapy (7.4 %, 1.2 %), history of thrombosis (5.5 %, 1.4 %), and immune thrombocytopenia (6.1 %, 0.2 %). Fatality rate was 22.2 % (127/573) overall and 23.6 % (105/444) in 'typical'/'possible' TTS, which decreased from 39.0 % (60/154) in February/March to 15.5 % (45/290) in April. Overall patterns were similar in confirmatory datasets. The reporting rate of 'typical'/'possible' TTS post first-dose vaccination in this dataset is 7.5 per million vaccinated persons; few cases were reported after subsequent doses, including booster doses. Peak reporting coincided with media-driven attention. Medical history differences versus a reference population indicate potentially unidentified risk factors. The decreasing fatality rate correlates with increasing awareness and publication of diagnostic/treatment guidelines. Adjudication was hindered by unreported parameters, and an algorithm was developed to classify potential TTS cases; comprehensive reporting could help further improve definition and management of this extremely rare syndrome.

Laffan MA ，Rees S ，Yadavalli M ，Ferstenberg LB ，Kumar Shankar N ，Medin J ，Foskett N ，Arnold M ，Gomes da Silva H ，Bhuyan P ，Nord M ... -  《-》

Thrombosis with thrombocytopenia syndrome (TTS) following adenovirus vector COVID-19 vaccination in Canada.

Identifying and monitoring adverse events following vaccination contributed to the safety and effectiveness of COVID-19 mass vaccination campaigns. In March 2021, international reports emerged of an adverse event following vaccination with adenovirus vector COVID-19 vaccines (ChAdOx1-S [recombinant] and Ad26.COV2.S) of thrombosis with low platelet counts, referred to as thrombosis with thrombocytopenia syndrome (TTS). We described TTS reports in Canada following adenovirus vector COVID-19 vaccines and investigated whether the observed number of events were higher than expected. Reports of TTS following receipt of ChAdOx1-S [recombinant] or Ad26.COV2.S meeting the Canadian case definition for TTS and diagnostic certainty levels 1-3 of the Brighton Collaboration case definition, submitted to the Canadian Adverse Events Following Immunization Surveillance System and Canada Vigilance Database between February 26, 2021 and October 31, 2022 were included. Demographics and characteristics of the TTS reports are described along with an analysis comparing the observed number of reports to the expected number. As of October 31, 2022, 56 reports of TTS following administration of ChAdOx1-S [recombinant] and no reports following Ad26.COV2.S vaccines were reported in Canada, of which 37 had functionally positive anti-PF4 antibodies. The median age was 56 years; males accounted for 54 % of reports. Five deaths were reported. The observed number of reports exceeded the expected for all ages and sexes combined, as well as for males aged 30-49 and 60-69 years, and females aged 40-59 years. Based on international surveillance data, Canada evaluated a statistical signal of TTS following adenovirus vector vaccines. The investigation of this signal demonstrated how post-market vaccine safety surveillance systems were successful in investigating rare adverse events during the rollout of COVID-19 vaccines in Canada. As adenovirus vector vaccines continue to be administered, characterization of the association between the vaccine and TTS informs immunization programs and policies.

Procter TD ，Ogasawara H ，Spruin S ，Wijayasri S ，Abraham N ，Blaser C ，Hutchings K ，Shaw A ，Ogunnaike-Cooke S ... -  《-》

Assessing Case Fatality on Cases of Thrombosis with Concurrent Thrombocytopenia Following COVID-19 Vaccine AstraZeneca (Vaxzevria) in the United Kingdom: A Review of Spontaneously Reported Data.

Thrombotic thrombocytopenia syndrome (TTS) events were reported very rarely following the coronavirus disease 2019 (COVID-19) vaccine AstraZeneca (Vaxzevria). Clinical and demographic characteristics of the affected people, including the outcomes of TTS events, need to be examined using available information to better understand aspects of this association. To analyse clinical and demographic information of TTS events, including calculating the case fatality of reported cases of TTS by age and sex, using spontaneously reported data from the UK's Yellow Card spontaneous reporting system of suspected adverse drug reactions. TTS events reported to the Yellow Card scheme were extracted at weekly time points between 12 May 2021 and 25 May 2022. Cumulative numbers of TTS cases and deaths were recorded for each weekly interval, overall and stratified by age, sex, and vaccine dose. To 25 May 2022, 443 cases (81 fatal, 18.28%) had been reported in the UK. Events more frequently occurred following the first vaccine dose. No trends were observed for case fatality overall, or by age or sex. In the UK, case fatality of TTS events reported to the Medicines and Health products Regulatory Agency (MHRA) following Vaxzevria has been approximately 17-18% since May 2021. There were no statistical differences in fatality based on age or sex. Most reports followed the first vaccine dose; none have been reported following a third dose to date, although Vaxzervia was not recommended for a third dose of COVID-19 vaccine in the UK. TTS remains very rare, and benefits of vaccination outweigh the risks.

Lane S ，Shakir S 《-》

Characteristics and Outcomes of Patients With Cerebral Venous Sinus Thrombosis in SARS-CoV-2 Vaccine-Induced Immune Thrombotic Thrombocytopenia.

Sánchez van Kammen M ，Aguiar de Sousa D ，Poli S ，Cordonnier C ，Heldner MR ，van de Munckhof A ，Krzywicka K ，van Haaps T ，Ciccone A ，Middeldorp S ，Levi MM ，Kremer Hovinga JA ，Silvis S ，Hiltunen S ，Mansour M ，Arauz A ，Barboza MA ，Field TS ，Tsivgoulis G ，Nagel S ，Lindgren E ，Tatlisumak T ，Jood K ，Putaala J ，Ferro JM ，Arnold M ，Coutinho JM ，Cerebral Venous Sinus Thrombosis With Thrombocytopenia Syndrome Study Group ，Sharma AR ，Elkady A ，Negro A ，Günther A ，Gutschalk A ，Schönenberger S ，Buture A ，Murphy S ，Paiva Nunes A ，Tiede A ，Puthuppallil Philip A ，Mengel A ，Medina A ，Hellström Vogel Å ，Tawa A ，Aujayeb A ，Casolla B ，Buck B ，Zanferrari C ，Garcia-Esperon C ，Vayne C ，Legault C ，Pfrepper C ，Tracol C ，Soriano C ，Guisado-Alonso D ，Bougon D ，Zimatore DS ，Michalski D ，Blacquiere D ，Johansson E ，Cuadrado-Godia E ，De Maistre E ，Carrera E ，Vuillier F ，Bonneville F ，Giammello F ，Bode FJ ，Zimmerman J ，d'Onofrio F ，Grillo F ，Cotton F ，Caparros F ，Puy L ，Maier F ，Gulli G ，Frisullo G ，Polkinghorne G ，Franchineau G ，Cangür H ，Katzberg H ，Sibon I ，Baharoglu I ，Brar J ，Payen JF ，Burrow J ，Fernandes J ，Schouten J ，Althaus K ，Garambois K ，Derex L ，Humbertjean L ，Lebrato Hernandez L ，Kellermair L ，Morin Martin M ，Petruzzellis M ，Cotelli M ，Dubois MC ，Carvalho M ，Wittstock M ，Miranda M ，Skjelland M ，Bandettini di Poggio M ，Scholz MJ ，Raposo N ，Kahnis R ，Kruyt N ，Huet O ，Sharma P ，Candelaresi P ，Reiner P ，Vieira R ，Acampora R ，Kern R ，Leker R ，Coutts S ，Bal S ，Sharma SS ，Susen S ，Cox T ，Geeraerts T ，Gattringer T ，Bartsch T ，Kleinig TJ ，Dizonno V ，Arslan Y ... -  《-》