Thrombosis with thrombocytopenia syndrome: Findings from the Advisory Committee on Causality Assessment

Thrombosis with thrombocytopenia syndrome

Thrombosis with thrombocytopenia syndrome (TTS) is a serious health condition involving blood clots (thrombosis) with low platelets (thrombocytopenia). When reports of TTS after vaccination with COVID-19 viral vector vaccines started to emerge in 2021, TTS became a priority for investigation in Canada and globally. The Public Health Agency of Canada (PHAC) and Health Canada continue to closely monitor Canadian and international reports of thrombosis with thrombocytopenia syndrome following vaccination.

Health Canada worked with companies to update the product information (product monograph) based on emerging evidence. Updates included information about these very rare events of blood clots associated with low levels of platelets following immunization:

For more information, please refer to the Janssen and AstraZeneca Vaxzevria/COVISHIELD COVID-19 vaccine public advisory.

Demographics for reviewed case reports

All case reports of thrombosis with thrombocytopenia submitted to PHAC or Health Canada were considered for assessment by the Advisory Committee on Causality Assessment (ACCA). These cases reports followed COVID-19 vaccinations and were submitted to the Canadian Adverse Events Following Immunization Surveillance System (CAEFISS) or Canada Vigilance up to and including October 31, 2022.

In the following tables, all COVID-19 vaccines were the original formulations (no bivalent vaccines). For reporting in Table 1 and 2, the COVID-19 vaccines with case reports, were combined into 2 groups:

viral vector COVID-19 vaccines (column labelled viral vector):
- AstraZeneca Vaxzevria
- AstraZeneca and Verity/SII COVISHIELD
mRNA COVID-19 vaccines (column labelled mRNA):
- Moderna Spikevax
- Pfizer-BioNTech Comirnaty

There were no case reports submitted to Canada Vigilance that met the definition of TTS [Brighton Collaboration case definition Levels of Certainty]. A total of 102 case reports were submitted to CAEFISS. Of those, 19 were excluded by ACCA because:

they did not meet the case definition of TTS (n=12) [Brighton Collaboration case definition Levels of Certainty] or
there was insufficient information provided to conduct a causality assessment (n=7)

No cases reports of TTS were submitted for the following COVID-19 vaccines distributed in Canada:

Janssen Jcovden (Johnson & Johnson)
Novavax Nuvaxovid

There were no cases reports for individuals under 30 years of age. Some rows have been combined to achieve a minimum count of 3 per cell.

The data on this page may change as ACCA receives more information about case reports.

Table 1. Demographics for case reports reviewed by ACCA of TTS submitted up to and including October 31, 2022
Demographics	Viral vector, n=52	mRNA, n=31	Total, n=83
Age group (years)
Less than 50	20	5	25
50 and older	32	26	58
Sex
Female	25	8	33
Male	27	23	50
Dose number associated with event^{table 1 note 1}
Dose number 1	49	19	68
Dose numbers 2 to 4	0	11	11
Anti-PF4 antibody testing
Functionally positive	36	0	36
Functionally negative	1	0	1
Screen negative, not tested or unknown	15	31	46
Brighton Collaboration case definition level of certainty^{table 1 note 2}
Level 1	49	24	73
Level 2 or 3	3	7	10
WHO AEFI classification^{table 1 note 3}
A: Consistent with causal association to immunization A1: Vaccine product-related reaction (as per published literature)	36	0	36
B1: Indeterminate: Temporal relationship is consistent but there is insufficient definitive evidence for vaccine causing event (may be new vaccine-linked event)	0	12	12
B2: Indeterminate: Qualifying factors result in conflicting trends of consistency and inconsistency with causal association to immunization	8	0	8
C: Inconsistent with causal association to immunization: Coincidental underlying or emerging condition(s), or condition(s) caused by exposure to something other than vaccine	8	19	27
Clot location^{table 1 note 4}
Pulmonary embolism	20	13	33
Cerebral venous thrombosis (includes cerebral venous sinus thrombosis)	11	0	11
Deep vein thrombosis	13	9	22
Venous thrombosis, other	12	4	16
Arterial thrombosis^{table 1 note 5}	11	10	21
Outcome
Fatal	5	5	10
Definitions: WHO: World Health Organization AEFI: Adverse event following immunization
Table 1 Notes Table 1 Note 1 Four cases reports did not state COVID-19 vaccine dose number associated with the reported event. Return to table 1 note 1 referrer Table 1 Note 2 Brighton Collaboration case definition Levels of Certainty for TTS shown in this table are limited to: Level 1 Definite case Level 2 Probable case Level 3 Possible case Return to table 1 note 2 referrer Table 1 Note 3 Only WHO AEFI classifications A to C, are shown in this table. Return to table 1 note 3 referrer Table 1 Note 4 Some case reports described more than 1 clot location, resulting in more clot locations than case reports. Return to table 1 note 4 referrer Table 1 Note 5 Arterial thrombosis can include different sites. Return to table 1 note 5 referrer

Demographics for case reports classified as consistent with causal association to immunization

In the following table, ACCA reviewed the demographics for a subset of Table 1 for TTS case reports. The demographics are for case reports that were submitted up to and including October 31, 2022. These case reports have a WHO classification consistent with causal association to immunization (A A1). All case reports represent events following immunization with a viral vector COVID-19 vaccine. All events occurred between March 1, 2021, and May 31, 2021.

Over 90 million doses of COVID-19 vaccines were administered in Canada between December 2020 and October 31, 2022. More than 87 million of these doses were with mRNA vaccines (Pfizer-BioNTech Comirnaty and Moderna Spikevax) and 2.8 million were with AstraZeneca Vaxzevria and COVISHIELD (Table 1: COVID-19 Vaccination in Canada). As 36 case reports of Thrombosis with Thrombocytopenia Syndrome (TTS) were found to be consistent with a causal association to immunization, the overall reporting rate is 1.3 per 100,000 doses of viral vector COVID-19 doses administered.

Table 2. Demographics for case reports of TTS submitted up to and including October 31, 2022, with a WHO classification consistent with causal association to immunization (A A1)
Demographics	WHO AEFI Classification A A1, n=36
Age group (years)
Less than 50	19
50 and older	17
Sex
Female	18
Male	18
Dose number associated with event
Dose number one^{table 2 note 1}	33
Anti-PF4 antibody testing
Functionally positive	36
Brighton Collaboration case definition level of certainty^{table 2 note 2}^{table 2 note 3}
Level 1	36
Clot location^{table 2 note 4}
Pulmonary embolism	15
Cerebral venous thrombosis (includes cerebral venous sinus thrombosis)	10
Deep vein thrombosis	7
Venous thrombosis, other	9
Arterial thrombosis^{table 2 note 5}	9
Outcome
Fatal	4
Definitions: WHO: World Health Organization AEFI: Adverse event following immunization
Table 2 Notes Table 2 Note 1 Three cases reports did not state COVID-19 vaccine dose number associated with the reported event. Return to table 2 note 1 referrer Table 2 Note 2 Brighton Collaboration case definition Levels of Certainty for TTS are: Level 1 Definite case Level 2 Probable case Level 3 Possible case Return to table 2 note 2 referrer Table 2 Note 3 All case reports with a WHO AEFI classification of A A1, had a Brighton Collaboration case definition Level of Certainty 1. Return to table 2 note 3 referrer Table 2 Note 4 Some case reports described more than 1 clot location, resulting in more clot locations than case reports. Return to table 2 note 4 referrer Table 2 Note 5 Arterial thrombosis can include different sites. Return to table 2 note 5 referrer

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Date modified:: 2024-05-30

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Thrombosis with thrombocytopenia syndrome: Findings from the Advisory Committee on Causality Assessment

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