Overview

Thrombosis is a rare complication of the COVID-19 vaccines, with an incidence rate of 4-5 cases per million doses administered.¹ When severe thrombosis occurs together with thrombocytopenia post-COVID-19 vaccination, the condition is termed as Vaccine-Induced Immune Thrombotic Thrombocytopenia (VITT), which is also known as Thrombosis with Thrombocytopenia syndrome (TTS)^1. VITT/TTS is one of the arising safety concerns since the early vaccination programme.  VITT/TTS has been raised as an Adverse Event of Special Interest (AESI), especially for adenoviral vector-based Vaxzevria (AstraZeneca) and Janssen COVID-19 vaccines. It is important to note that thrombosis with lowered platelets can rarely occur naturally in unvaccinated people as well as in people infected with COVID-19 disease.² 

VITT/TTS has also been reported with other brands of COVID-19 vaccines, such as the Pfizer/BioNTech and Moderna vaccines, but at a much lower reporting rate than those seen with the AstraZeneca and Janssen COVID vaccines. Thus far, the US review revealed that there is a lack of evidence of an association between mRNA COVID-19 vaccines and VITT/TTS³. Based on currently available evidence, VITT/TTS is likely a class effect of the adenoviral vector-based vaccines, including the AstraZeneca and Janssen COVID-19 vaccines.^1,4

Up to 18^th March 2022, the United States Food and Drug Administration (US FDA) had identified 60 confirmed cases (including nine fatal cases) of VITT/TTS, equivalent to a reporting rate of VITT/TTS and VITT/TTS death of 3.23 and 0.48 per million doses of vaccine administered, respectively.⁵ Not only do the risk factors for VITT/TTS remain unknown, individuals with VITT/TTS may also rapidly deteriorate, and this can lead to long-term and debilitating health consequences.⁵ Based on the information, on 5^th May 2022, the US FDA has limited the use of the Janssen COVID-19 Vaccine to individuals 18 years of age and older for whom other approved COVID-19 vaccines (e.g. mRNA COVID-19 vaccines) are not accessible or clinically appropriate, and to individuals 18 years of age and older who opt to receive the Janssen COVID-19 Vaccine because they would otherwise not receive a COVID-19 vaccine.⁵  

In Malaysia, the Janssen COVID-19 Vaccine has been granted conditional approval by the Drug Control Authority (DCA). However, it is not included in the National COVID-19 Immunisation Programme (PICK) and is currently not available in the country.

 

Background of the Safety Issue

VITT/TTS may present in uncommon locations, such as cerebral venous sinus (cerebral venous sinus thrombosis, CVST) or splanchnic veins with marked thrombocytopenia following COVID-19 vaccination.^1,4 Thromboses presented in common locations, such as pulmonary, deep vein thrombosis, coronary arteries, and cerebral arteries, have also been reported following COVID-19 vaccination.⁴

The pathophysiology and exact mechanisms of VITT/TTS are still unclear. However, it has been associated with the presence of anti-platelet factor 4 (anti-PF4) antibodies, similar to autoimmune heparin-induced thrombocytopenia (aHIT). Bindings of anti-PF4 to platelets cause platelet activation and aggregation, thrombosis, platelet consumption, and thrombocytopenia.⁴

About 1-2 cases of VITT/TTS have been reported in every 100,000 vaccinated with the first dose of the AstraZeneca COVID-19 Vaccine.^6-8 In comparison to the first dose, a lower reporting rate was observed during the second dose of the AstraZeneca COVID-19 Vaccine (0.17 cases in every 100,000 vaccinated people in Canada⁶, 0.3 cases in every 100,000 vaccinated people in Australia⁷, and 0.2 cases in every 100,000 vaccinated doses in UK⁸). About 1 in 5 people who developed VITT post-vaccination with the AstraZeneca COVID-19 Vaccine died.⁶ Deaths have been reported post-Janssen COVID-19 vaccination as well.⁶ Since the majority of countries globally are using the Pfizer or Moderna vaccines as boosters, safety information on the AstraZeneca and Janssen COVID-19 vaccines as boosters is currently limited.

 

Risk of VITT/TTS

According to the Clinical Guidelines for COVID-19 Vaccination in Malaysia, the risk of VITT/TTS has been reported to be higher in young females; hence females younger than 50 years are advised to avoid the AstraZeneca and Janssen COVID-19 vaccines.¹ The UK MHRA, on the other hand, does not recommend any age restrictions on the use of the AstraZeneca COVID-19 Vaccine, despite UK data suggesting that there is a slightly higher incidence rate observed in the younger adult age group.² The UK MHRA suggested that people of any age who are at higher risk of blood clots owing to their medical condition should be administered the AstraZeneca COVID-19 Vaccine only if the benefits clearly outweigh the potential risks.² The review by the UK MHRA also indicated that although there is some evidence of higher incidence rates reported in females, this is not seen across all age groups and the difference remains small.⁸ The reported time-to-onset of VITT/TTS cases was around 4 to 42 days (most commonly 4-30 days) following vaccination with COVID-19 vaccines, particularly the AstraZeneca and Janssen COVID-19 vaccines.^4,9-10

For VITT/TTS, a high index of suspicion is crucial as early clinical recognition and awareness can significantly reduce mortality. In Australia, it was reported that the mortality rate in those affected with VITT/TTS has been reduced from as high as 50 percent in an initial case series to 5 percent in a recent analysis.¹⁰

 

Signs & Symptoms

Any patients presenting with severe and unusual clinical symptoms, especially if the symptoms persist for >72 hours after vaccination, should promptly undergo investigations to rule out VITT/TTS.¹ Thrombocytopenia in VITT/TTS is defined as a platelet count less than 150 x 10⁹/L or a 50% decrease from the baseline platelet count.⁴ Clinical symptoms vary according to the location of thrombosis, and multiple sites may be involved.⁴

1. Cerebral Venous Sinus Thrombosis (CVST) – headache, visual disturbances, seizure, focal neurological symptoms, decreased level of consciousness.
2. Splanchnic Thrombosis – abdominal pain, bloating, nausea, vomiting, diarrhoea, fever, bleeding, anorexia.
3. Ischemic Stroke – sudden onset focal neurological symptoms.
4. Pulmonary Embolism – dyspnoea, chest pain, haemoptysis, syncope, palpitations.
5. Myocardial Infarction – chest pain, shortness of breath, cyanosis, sudden death.
6. Deep Vein Thrombosis – unilateral or bilateral swelling, pain, tenderness, swelling, redness.

 

Investigation^1,4

Once a patient is suspected of having VITT/TTS based on the clinical presentations, laboratory investigations such as urgent full blood count, D-dimer, fibrinogen, peripheral blood film (blood smear to confirm reduced platelets and to rule out platelet clumping), prothrombin time/ activated partial thromboplastin time (PT/APTT) and anti-PF4 antibodies should be conducted. Appropriate imaging for thromboses, such as Ultrasound (± Doppler) or Computed Tomography (CT) venogram of the abdomen, CT or Magnetic Resonance Imaging (MRI) venogram of the brain, should be performed as soon as possible, especially in those who present with thrombocytopenia within 42 days post-vaccination.

 

Treatment¹

Based on the Clinical Guidelines for COVID-19 Vaccination in Malaysia, heparin/low molecular weight heparin (LMWH) or warfarin should be avoided in cases of VITT/TTS. Intravenous immunoglobulin (IVIG), systemic corticosteroids, and non-heparin anticoagulation or direct oral anticoagulation (DOAC) can be considered.

 

Adverse Event Reports¹¹

In Malaysia, up to 18 March 2022, the National Pharmaceutical Regulatory Agency (NPRA) has received five (5) reports of VITT/TTS suspected to be related to COVID-19 vaccines. Four (4) cases reported were related to the use of the AstraZeneca COVID-19 Vaccine, equivalent to a reporting rate of 0.7 cases for every million doses of the AstraZeneca COVID-19 Vaccine used. Only one (1) case was reported with the use of the Comirnaty/Pfizer BioNTech COVID-19 Vaccine.

The NPRA will continue to monitor the use of the COVID-19 vaccines in Malaysia, to identify any emerging safety issues, as well as to ensure the benefits continue to outweigh the risks.

 

Advice for Healthcare Professionals

1. The reported incidence of VITT/TTS is very rare. However, it is important to recognise VITT/TTS early and promptly initiate urgent medical evaluation and management.¹
2. Be alert to the signs and symptoms of VITT/TTS, especially in patients who have recently (4 to 42 days) been administered with any COVID-19 vaccines.^4,9,10
3. Continue to assess patients who present with thrombosis and a normal platelet count post-vaccination, as this might be an early stage of VITT/TTS. Consider referral to a tertiary care centre with a haematologist when VITT/TTS is confirmed.¹
4. Patients who had VITT/TTS following the AstraZeneca and Janssen COVID-19 vaccines should not receive the second dose of this vaccine.^2,4
5. Explain to the vaccinee or caretaker about the signs and symptoms of VITT/TTS, especially those that are severe and unusual, or if these symptoms persist for more than 72 hours.
6. Advise the vaccinee or caretaker to seek medical attention, if any of the symptoms mentioned above occur following COVID-19 vaccination.
7. Refer a patient of suspected VITT/TTS for appropriate investigation and care as early as possible, which is potentially life-saving.
8. Always refer to the latest Clinical Guidelines on COVID-19 Vaccination in Malaysia for more details on the risk of VITT/TTS with COVID-19 vaccination and the recommended management.
9. Report all suspected adverse events, including VITT/TTS following the COVID-19 vaccination, to the NPRA.

 

To report adverse events:

1. Visit www.npra.gov.my
2. Select “Reporting ADR” under Health Professionals.
   1. Choose Online Reporting; or
   2. Download the manual form and email the completed form to This email address is being protected from spambots. You need JavaScript enabled to view it. or This email address is being protected from spambots. You need JavaScript enabled to view it. (for AEFIs related to COVID-19 vaccines); alternatively, mail it to:

The Pharmacovigilance Section,
National Pharmaceutical Regulatory Agency (NPRA),
Lot 36, Jalan Universiti (Jalan Profesor Diraja Ungku Aziz),
46200 Petaling Jaya, Selangor, Malaysia.

 

References:

1. Ministry of Health (MoH), Clinical Guidelines on COVID-19 Vaccination in Malaysia, 4^th Edition [Internet]. Garis Panduan Kementerian Kesihatan Malaysia, Annex 48, 2021 Oct 19. [cited 2022 Mar 23]. Available from: https://covid-19.moh.gov.my/garis-panduan/garis-panduan-kkm/ANNEX_48_CLINICAL_GUIDELINES_FOR_COVID_IN_MALAYSIA_4th_EDITION_19102021_FINALE.pdf
2. United Kingdom Medicines and Healthcare Products Regulatory Agency (MHRA). MHRA issues new advice, concluding a possible link between COVID-19 Vaccine AstraZeneca and extremely rare, unlikely to occur blood clots [Internet]. 2021 Apr 7 [cited 2022 Mar 24]. Available from: https://www.gov.uk/government/news/mhra-issues-new-advice-concluding-a-possible-link-between-covid-19-vaccine-astrazeneca-and-extremely-rare-unlikely-to-occur-blood-clots
3. Shimabukuro T. Thrombosis with thrombocytopenia syndrome (TTS) following Janssen COVID-19 vaccine [Internet]. Advisory Committee on Immunization Practices (ACIP). 2021 Apr 23 [cited 2022 Mar 23]. Available from: https://www.cdc.gov/vaccines/acip/meetings/downloads/slides-2021-04-23/03-COVID-Shimabukuro-508.pdf
4. World Health Organisation (WHO). Guidance for clinical case management of thrombosis with thrombocytopenia syndrome (TTS) following vaccination to prevent coronavirus disease (COVID-19) [Internet]. Interim guidance. 2021 Jul 19 [cited 2022 Mar 23]. Available from: https://apps.who.int/iris/bitstream/handle/10665/342999/WHO-2019-nCoV-TTS-2021.1-eng.pdf?sequence=1&isAllowed=y
5. US FDA. Coronavirus (COVID-19) Update: FDA Limits Use of Janssen COVID-19 Vaccine to Certain Indivituals. [Internet] FDA News Release, 2022 May 5. [cited 2022 May 10]. Available from: https://www.fda.gov/news-events/press-announcements/coronavirus-covid-19-update-fda-limits-use-janssen-covid-19-vaccine-certain-individuals
6. Health Canada. COVID-19 vaccine guide for youth and adults (12 years and over): Recommendations for use [Internet] 2022 Feb 3 [cited 2022 Mar 23]. Available from: https://www.canada.ca/en/public-health/services/diseases/2019-novel-coronavirus-infection/guidance-documents/quick-reference-guide-covid-19-vaccines/recommendations-for-use.html
7. TGA Australia. COVID-19 Vaccine Weekly Safety Report [Internet]. 2022 Mar 17 [cited 2022 Mar 23]. Available from: https://www.tga.gov.au/periodic/covid-19-vaccine-weekly-safety-report-17-03-2022
8. United Kingdom Medicines and Healthcare Products Regulatory Agency (MHRA). Coronavirus vaccine – weekly summary of Yellow Card reporting [Internet]. Research and analysis. 2022 Mar 17 [cited 2022 Mar 24]. Available from: https://www.gov.uk/government/publications/coronavirus-covid-19-vaccine-adverse-reactions/coronavirus-vaccine-summary-of-yellow-card-reporting
9. TGA Australia. COVID-19 Vaccination Patient Information on Thrombosis with Thrombocytopenia Syndrome [Internet]. Version 3.3. 2021 Jul 30 [cited 2022 Mar 23]. Available from: https://www.health.gov.au/sites/default/files/documents/2021/08/patient-information-sheet-on-astrazeneca-covid-19-vaccine-and-thrombosis-with-thrombocytopenia-syndrome-tts_0.pdf
10. James B. Bussel et al. Vaccine-induced Immune Thrombotic Thrombocytopenia [Internet]. Version 1.8. American Society of Hematology; 2022 Jan 28 [cited 2022 Mar 23]. Available from: https://www.hematology.org/covid-19/vaccine-induced-immune-thrombotic-thrombocytopenia
11. National Pharmaceutical Regulatory Agency (NPRA). The Malaysian National ADR Database (QUEST) [Internet]. 2022 [cited 2022 Mar 18]. Available from: https://www.npra.gov.my (access restricted)

 

DISCLAIMER

This publication is aimed at health professionals. The information is meant to provide updates on medication safety issues, and not as a substitute for clinical judgement. While reasonable care has been taken to verify the accuracy of the information at the time of publication, the NPRA shall not be held liable for any loss whatsoever arising from the use of or reliance on this publication.

 

Written by: Wang Khee Ing
Reviewed/Edited by: Noor'ain Shamsuddin, Dr Azuana Ramli