Specific clotting condition reported after COVID-19 vaccination

Some rare cases of thrombosis associated with thrombocytopenia have been reported overseas following the administration of COVID-19 Vaccine AstraZeneca.

Overnight, the TGA has received one report of a case of thrombosis involving abdominal blood vessels and thrombocytopenia with symptom onset 7 days following COVID-19 Vaccine AstraZeneca in Australia. It is emphasised that no cause-and-effect relationship between COVID-19 vaccination and this case (or those reported internationally) has been established at this stage.

This case, together with the overseas reports, are under active investigation by the TGA and a panel of external experts (the TGA Vaccine Safety Investigation Group, VSIG). TGA is also working closely with international regulators and is participating in meetings with the UK medicines regulator (MHRA) and the European Medicines Agency to discuss these rare cases over the coming few days.

The TGA is working closely with the Australian Technical Advisory Group on Immunisation (ATAGI) and expert haematologists on the investigation of case reports. ATAGI has today published a statement for healthcare providers (https://health.gov.au/news/atagi-statement-healthcare-providers-specific-clotting-condition-reported-after-covid-19-vaccination; reproduced in full below).

The TGA's assessment is that the benefits of vaccination against COVID-19 continue to outweigh any risks. More information on the outcomes of investigations into these rare cases will be communicated soon.

Updated ATAGI statement for healthcare providers on a specific clotting condition being reported after COVID-19 vaccination

A statement from the Australian Technical Advisory Group on Immunisation (ATAGI) for healthcare providers on a specific clotting condition being reported after COVID-19 vaccination.

Summary of current recommendations

• Rare cases of thrombosis associated with thrombocytopenia were reported following administration of COVID-19 Vaccine AstraZeneca overseas.
• The onset of reported cases was between 4 to 20 days after vaccination.
• Providers should be aware of warning signs of a severe condition associated with thrombosis and thrombocytopenia. This has presented as either central venous sinus thrombosis (CVST) or thrombosis in other sites, such as intra-abdominal venous systems. CVST may present as a new onset persistent headache not settling with analgesia, features of raised intracranial pressure (including acute severe headache, vomiting, confusion), focal neurological deficits, and/or seizures.
• If CVST or another severe thrombotic complication with thrombocytopenia is suspected in a patient who has received COVID-19 Vaccine AstraZeneca, refer them to an emergency department for further assessment and haematology consultation.
• Clinical investigations should include a full blood count (to look for thrombocytopenia), a D-dimer test and radiological imaging.
• Patients suspected to have this condition should NOT receive any heparin or platelet transfusions.
• The TGA has received one report of a case of thrombosis and thrombocytopenia following COVID-19 Vaccine AstraZeneca in Australia. The clinical details of this case are currently under review by the TGA.

Vaccination against COVID-19 continues to be important in populations at high risk of COVID.

What is the background to this issue?

There have been reports of rare cases of a distinct type of thrombosis associated with thrombocytopenia following administration of COVID-19 Vaccine AstraZeneca in European countries. The European Medicines Agency (EMA) and the UK Medicines and Healthcare Products Regulatory Agency (MHRA) are investigating these reports. The underlying cause of this syndrome has not been confirmed.

Most of these cases involved a type of clot in the brain called cerebral venous sinus thrombosis (CVST). The pattern and mechanism being suggested in these cases resembles a condition called heparin induced thrombocytopenia (HIT), which is caused by antibodies affecting platelet function. In the reported CVST cases, however, there has been no reported exposure to heparin.

This statement is to provide more information and raise awareness of the potential for this condition, plus to provide information on clinical management.

What do we know from investigations into this rare clotting disorder?

The investigations in Europe and the UK are looking at unusual cases of thrombosis (predominantly CVST) with occurs with thrombocytopenia. Investigators have not confirmed a causal link with the AstraZeneca COVID-19 vaccine. However, the investigation is ongoing. CVST is a very rare disorder that has not previously been known to be associated with vaccination, however it has been noted as a complication of COVID-19.

No cases of CVST have been reported in Australia to date in the time period of concern post vaccination (i.e. 4 to 20 days). One case of thrombosis involving a different site with thrombocytopenia with symptom onset in the second week after vaccination has been reported in Australia on 1 April 2021. The details of this case are currently being reviewed by the TGA.

There is not a higher overall rate of relatively common types of blood clots (including deep vein thrombosis [DVT] and pulmonary embolism [PE]) reported after COVID-19 vaccination.

What do we not yet know?

It is also not yet known whether there are any specific risk factors that might predispose an individual to this condition. Many of the cases reported were in adults aged under 55 years, and the majority were in women. However it is not yet clear if age and sex are risk factors, since the AstraZeneca vaccine was preferentially given to younger people in some countries, and since women make up a large proportion of the frontline healthcare workers that were prioritised for vaccination. The European Medicines Agency (EMA) and the UK MHRA intend to provide updated information about their investigation into these cases in early April.

What are the features of this rare condition?

The small number of cases that have been reported to date have been characterised by thrombosis associated with thrombocytopenia. Most reported cases involve cerebral veins (presenting as CVST), but thrombosis of other parts of the body have also been reported. The pathophysiology of this disorder appears to involve platelet activation and thrombosis, resulting in platelet consumption and thrombocytopenia. Anti-platelet antibodies have been reported in a case series. These cases appear to be similar to a disorder known as heparin induced thrombocytopenia (HIT), however, these patients have not reportedly had any history of exposure to heparin.

The symptoms of these rare clotting disorders are distinguishable from common vaccine side effects by time after dose. This is because the onset of these recent cases was between 4 and 20 days after vaccination. Conversely, the common and expected side effects that occur after COVID-19 vaccines have an onset within the first 24 hours and last 1 to 2 days. This includes symptoms such as headache, muscle aches, fever and chills. For more information on the reported pattern of expected adverse events following both AstraZeneca and Pfizer COVID-19 vaccine doses in Australia, see active safety surveillance in Australia for >100,000 vaccinated persons at AusVaxSafety.

What are the warning signs to look out for after vaccination?

Providers should be alert to any new, severe, persistent headache or other significant symptoms, such as severe abdominal pain with an onset between 4 to 20 days after vaccination with COVID-19 Vaccine AstraZeneca. For CVST 'red flag' features include new onset of severe persistent headache that is not settling with analgesia. Patients may also present with features of raised intracranial pressure (acute severe headache, vomiting, confusion), focal neurological deficits and/or seizures.

Providers should also consider discussion with a specialist haematologist in any patient presenting with features suggestive of thrombosis in any other body systems, and associated with thrombocytopenia, with onset 4 to 20 days post vaccination. As for all vaccines including COVID-19 vaccines, health care providers should be alert for persistent, unexpected and/or severe adverse events following immunisation in their patients.

What should I do if I suspect a possible case of this clotting disorder?

It is important that clinicians refer patients to hospital for further investigation and specialist consultation, including with a haematologist if they suspect CVST (new, severe persistent headache) or another severe thrombotic complication with thrombocytopenia with an onset 4-20 days post receipt of COVID-19 Vaccine AstraZeneca. Patients should be referred to an emergency department for further investigation and specialist consultation.

Initial investigations should include:

• Full blood count (to look for thrombocytopenia)
• D-dimer
• Fibrinogen
• Imaging as clinically indicated (for example brain CT or MRI for CVST).

If screening tests suggest HIT-like thromboses (low platelets <100x109/L together with elevated D-dimer 2 x upper limit of normal [ULN] or reduced fibrinogen), a haematologist or haemostasis-thrombosis specialist should be consulted to advise on further investigations (including a HIT screen).

CAUTION: Patients with this suspected condition should NOT receive any heparin or platelet transfusions. These treatments may potentially worsen the clinical course.

In those with a past history of CVST or heparin induced thrombocytopenia (HIT) we continue to advise not receiving the COVID19 vaccine as a precautionary measure, until further information is available.

Further advice can be obtained by phone from the local state and territory specialist immunisation services (or with a haematologist)

ATAGI also encourages health care providers and the public to report any unexpected or serious adverse events occurring following any COVID-19 vaccines.