Three additional Australian cases of TTS likely linked to vaccine

The Therapeutic Goods Administration (TGA) convened a Vaccine Safety Investigation Group (VSIG) meeting to review three newly reported cases of suspected thrombosis with thrombocytopenia syndrome (TTS) following vaccination with the AstraZeneca COVID-19 vaccine. The cases were in a 35 year old NSW woman, a 49 year old QLD man and an 80 year old Victorian man. Symptom onset ranged from 9 to 26 days after vaccination. TTS is a rare specific syndrome that occurs when a person has blood clots (thrombosis) as well as low blood platelet counts (thrombocytopenia). VSIG assessed the cases using an internationally accepted method to rate the level of certainty of a link between the event and vaccine.

The VSIG concluded that all three of the cases were likely linked to vaccination. All three patients are clinically stable, have responded well to treatment and are recovering. Whilst meeting the international and UK criteria, two of the three cases appear to be milder forms of the syndrome that were recognised very early by the treating health professionals and are responding well to treatment, and in one of the cases platelet counts were depressed to a limited extent and the patient developed symptoms unusually late (26 days after vaccination).

These take the total Australian reports of TTS following the AstraZeneca COVID-19 vaccine to six. Five cases are in people aged less than 50 years, who were vaccinated prior to the decision by the Australian Technical Advisory Group on Immunisation (ATAGI) and the announcement by Government on 8 April 2021 that the Pfizer vaccine was preferred for patients under 50 years old. To 22 April there have been about 1.1 million doses of AstraZeneca COVID-19 vaccine administered in Australia.

All cases included thrombosis, varying levels of thrombocytopenia, positive D-dimer and the presence of anti-PF4 antibodies. However testing for functional anti-PF4 antibodies is still underway, and further imaging is being carried out in some of the patients.

One case included venous sinus thrombosis (a blood clot in one of the sinuses in the brain, which prevents blood from draining from the brain) and presented as headache, nosebleed, nausea and vomiting. The other two cases involved more common sites for blood clots: in one case a deep vein thrombosis in the calf, which presented as leg pain 9 days after vaccination, and in the other case a deep vein thrombosis in the upper leg, but with thromboembolism in lungs and cerebral venous sinus thrombosis detected on further investigation.

The VSIG concluded that the events were TTS very likely linked to vaccination because of the consistency of the cases with the current working case definition for TTS, and the absence of known alternative risk factors and causes for the events. However, further follow-up of some remaining details, including information about the patient's medical histories, and some imaging and blood test results, is still being completed. Any significant information that arises from this follow-up will be referred to the VSIG for consideration.

These data are consistent with the evolving pattern, both in Australia and internationally, that the majority of cases have been observed in people aged under 50 years. The risk for TTS appears lower in older adults. While there have been some cases have been seen in this group, this also reflects that many countries are currently only using the AstraZeneca vaccine in older age groups. Although Australia has seen more cases of COVID-19 in the under 50s, hospitalisation and deaths data clearly demonstrate that the risk of serious harm from infection with COVID-19 remains much higher in over 50s, and the benefits of COVID-19 vaccination outweigh the risks.

TGA will require further updates to the approved Product Information to provide information for health professionals about the syndrome.

People who have received COVID-19 vaccines should be aware of the common side effects, which include fever, sore muscles, tiredness and headache. These usually start within 24 hours of vaccination and last for 1-2 days. These side effects are expected and are not of concern unless severe or persistent. The reports of these rare clotting complications have occurred later (usually between day 4 and 20 after vaccination) and have generally been severe, requiring hospitalisation.

Consumers should seek immediate medical attention if, a few days after vaccination, they develop symptoms such as:

• as a severe or persistent headache or blurred vision
• shortness of breath, chest pain, leg swelling or persistent abdominal pain
• unusual skin bruising and/or pinpoint round spots beyond the site of injection.

Information for health professionals about recognising and managing possible cases of TTS is available in an updated ATAGI statement (also reproduced below).

The TGA encourages health professionals and consumers to report suspected side effects following immunisation with COVID-19 vaccines. Every report is valuable and contributes to our safety monitoring. Further information about how to report suspected side effects to a COVID-19 vaccine is available on our website.

The TGA is carefully reviewing all Australian reports of blood clots following the AstraZeneca vaccine, although local and international experience continues to be that the overwhelming majority of cases of typical thromboembolism that are temporally related to vaccination do not meet the case criteria for TTS and are not considered likely to have been caused by the vaccine.

The overall number of reports received for blood clots following vaccination so far has been no higher than the expected background rate for the more common type of blood clots in Australia. These can occur in around 50 Australians every day separate to vaccination and are not related to the rare TTS clotting disorder.

We are requesting further timely and complete information from reporters where needed, to identify any further possible cases of TTS. No cases of TTS associated with the Pfizer CORMIRNATY vaccine have been detected in Australia.

ATAGI reinforce recommendations on use of COVID-19 vaccines following review of vaccine safety data and benefits

23 April 2021

Vaccination remains the best way to protect against severe illness and death from COVID-19 and is a core element of the pandemic response.

ATAGI is continuing to monitor local and international data on a rare and new condition that occurs after AstraZeneca vaccine called thrombosis with thrombocytopenia syndrome (TTS).

ATAGI has reviewed the additional three cases of TTS confirmed by the TGA on 22 April 2021 in Australia, bringing the total confirmed cases to six. Of these cases, five people were under 50 years of age. All had received their first dose of AstraZeneca COVID vaccine between 4 and 26 days before the onset of symptoms.

Cases have varied in severity but included one fatal case. People who have had TTS can make a full recovery, although some may have ongoing organ damage, including to the brain (similar to stroke) and to abdominal organs, that can result in long term health impacts.

These TTS cases have occurred amongst approximately 730,000 individuals administered an AstraZeneca COVID-19 vaccine prior to the 11th April 2020. ATAGI estimates that the overall rate of TTS is about 6 cases per million people vaccinated, but the rate is currently estimated to be higher (20-40 cases per million) in those under 50 years of age. However, Australian estimated age-specific incidence rates are imprecise due to small numbers and will be updated as further information become available.

ATAGI have made previous recommendations on this issue, most recently on 8 April.

ATAGI reinforces its previous advice that:

• Comirnaty (Pfizer) is preferred over AstraZeneca vaccine in people under the age of 50 years. The AstraZeneca vaccine can still be given to adults under 50 years if Comirnaty is not available, if the benefit of vaccination is likely to outweigh risk, and where informed consent has been obtained.
• In people aged 50 years and over, the benefits of AstraZeneca COVID-19 vaccine outweigh the risks associated with vaccination. This is due to the ongoing potential for COVID-19 outbreaks, the widespread susceptibility of the Australian population, and the strong relationship of severe COVID-19 and mortality with increasing age.
• Overseas, cases of TTS have occurred in people of all ages, but the risk of TTS appears to be lower in those 50 years and over than in younger adults. The TGA and ATAGI are continuing to monitor the rates of cases in this age group and will advise as more data becomes available.

People who are considering vaccination with AstraZeneca COVID-19 vaccine should be aware of this potential complication as part of providing informed consent. Those who choose to delay vaccination until a vaccine other than AstraZeneca COVID-19 vaccine is available should be aware that they may not be protected against COVID-19 for many months. ATAGI acknowledges the challenges of decision making as information continues to emerge.

ATAGI continues to recommend that people who have received a first dose of AstraZeneca vaccine without serious adverse events can be given a second dose. Current data suggest that the risk of TTS following a second dose is considerably lower than with a first dose (with one case reported from more than 2 million second doses given in the UK to 14 April 2021), and there are no studies of the effectiveness of mixed schedules of different vaccine types. ATAGI will continue to review evidence on this issue.

Background

ATAGI notes that a total of 168 cases of thrombosis with thrombocytopenia following AstraZeneca vaccine have been reported in the UK as of 14th April 2021, out of a total of 21.2 million first doses and 2.3 million second doses given. Additional cases have been reported in Europe but total case numbers are not clear.

The assessment and advice provided by ATAGI is specific to the context of no current but potential future community transmission of COVID-19 and will need to be reviewed should circumstances change. Other considerations were noted in ATAGI’s previous statement on 8 April.

ATAGI notes the potential for incursion of COVID-19 in the Australian community remains high with the worsening global situation, including in many countries in our region. The risk-benefit assessment and advice will be different in situations with higher community incidence of COVID-19.

Resources for providers and consumers will be updated in the coming days.

Definitions

• Thrombosis with thrombocytopenia syndrome (TTS) is a rare and new syndrome which has been reported after being given the AstraZeneca COVID-19 vaccine. It may be caused by this vaccine. The condition involves blood clots (occurring in body sites like the brain or abdomen) together with low platelet levels.
• Thrombosis is the formation of a blood clot, which prevents blood flowing normally through the body. While thrombosis is usually a normal response to prevent bleeding (e.g. following injury), in this case this process is abnormal.
• Thrombocytopenia is a condition in which you have a low blood platelet count. Platelets (thrombocytes) are blood cells that help blood clot. Platelets stop bleeding by clumping and forming plugs in blood vessel injuries.