This article is presented by Spectrum, a point of care tool for infectious diseases.

Last updated: April 18, 2021

Timeline of Data: Thrombosis and the AstraZeneca COVID-19 Vaccine

The timeline below explains the incredible and rapid global response that went into the identification, assessment, monitoring and recommendations associated with a possible rare adverse event correlated with the AstraZeneca COVID-19 vaccine. The speed of this response speaks to the remarkable impact of pharmacovigilance and public health initiatives worldwide.

April 17, 2021

Dr. Deena Hindshaw, Alberta, Canada’s Chief Medical Officer of Health announced that a rare case of thrombosis with thrombocytopenia linked to the AstraZeneca COVID-19 Vaccine was diagnosed. Further information can be found through the Twitter Page for Alberta’s Chief Medical Officer of Health and is also discussed in a CBC news article. The patient was promptly treated and is recovering. This is the second case of these rare adverse events in Canada with more than 700,000 doses of AstraZeneca or COVISHIELD vaccines administered around the country.

April 14, 2021

Health Canada updated the AstraZeneca and COVISHIELD COVID-19 vaccines advisory page based on a thorough and independent assessment of the literature noting a case report of these rare clots occurring post administration of the COVIDSHIELD vaccine in Canada. Health Canada concluded that these rare events may be linked to the vaccine, which is in line with regulators around the world and with the World Health Organization (WHO)’s statement released March 7, 2021. A discussion of the difference between common adverse events after vaccination and persistent or worsening symptoms as well as symptoms that should prompt immediate medical attention are described.

April 13, 2021

The Public Health Agency of Canada shared information, which can be found on this Twitter Post, https://twitter.com/GovCanHealth/status/1382025107447681026?s=20 noting the first reported case of rare blood clots involving thrombosis and thrombocytopenia following immunization with the COVIDSHIELD COVID-19 Vaccine, which is the Serum Institute of India’s version of this ChAdOx10S viral vector vaccine. The post stresses the rarity of this adverse outcome and continuity in review of evidence through pharmacovigilance. A CBC news article also discusses this topic https://www.ctvnews.ca/health/coronavirus/astrazeneca-very-safe-effective-with-extremely-rare-risk-of-clots-health-canada-1.5387083.

April 8, 2021

The Australian Technical Advisory Group on Immunization (ATAGI) released a statement on the AstraZeneca COVID-19 vaccine in response to the safety concern of rare blood clots, noting a recommendation that the alternate vaccines available (Pfizer’s Comirnaty) be preferred over the AstraZeneca vaccine in adults under 50 years of age. The AstraZeneca vaccine can still be used in adults under 50 years of age if benefits outweigh risk or if an informed decision has been made by an individual. For those who have received their first dose of the COVID-19 AstraZeneca vaccine, a second dose can be given if no serious adverse events were experienced.

April 7, 2021

The European Medicines Agency (EMA)’s PRAC committee concluded that the very rare cases of thrombosis with thrombocytopenia should be listed as a very rare adverse effect of the AstraZeneca vaccine vaccine (Vaxzevria). The EMA confirms that the overall benefit of vaccination outweighs risk.

The World Health Organization’s subcommittee on vaccine safety (GACVS) provides an interim statement on the AstraZeneca COVID-19 vaccine based on data from health authorities and notes that based on current information, a causal relationship between the vaccine and these rare blood clots is possible but not confirmed. The GACVS will continue to gather information and review data as it pertains to this rare adverse event to provide further guidance.

March 31, 2021

The Pharmacovigilance Risk Assessment Committee (PRAC) of the European Medicines Agency (EMA) brought together a group of ad hoc experts (hematologists, neurologists and epidemiologists) to discuss:

  • The possible mechanisms underlying the rare cases of the unusual blood clots associated with few people vaccinated with AstraZeneca’s COVID-19 vaccine,
  • Potential identifiable underlying risk factors,
  • Additional data required to further characterize the observed events.

Currently, there are no specific risk factors, such as age, gender or previous medical history of clotting disorders, identified for the observed rare events. There is still no proven causal link with the vaccine; however, further analysis is ongoing. The EMA maintains communication from March 18: the benefits of the AstraZeneca vaccine outweigh the risks of side effects. The EMA directs healthcare professionals and the public to the vaccine’s product information and alerts those who are vaccinated to be aware of the remote possibility of very rare types of blood clots occuring. They suggest that if people see the symptoms as described in the product information, they seek immediate medical attention.

March 29, 2021

During a virtual briefing, Dr. Supriya Sharma (Chief Medical Advisor to the Deputy Minister) and Dr. Howard Njoo (Deputy Chief Public Health Officer) explained that Health Canada will soon release additional guidelines for use of the AstraZeneca vaccine. Health Canada will be requiring AstraZeneca manufacturers to conduct a detailed assessment of benefits and risks of the vaccine. These analyses, along with international evidence, will be used to guide future regulatory actions.

The National Advisory Committee on Immunization (NACI) provided a recommendation that the AstraZeneca COVID-19 vaccine not be used in adults under 55 years of age while the safety signal for a rare and newly named type of thrombotic event, Vaccine-Induced Prothrombotic Immune Thrombocytopenia (VIPIT), is investigated further. The NACI update cites an Ontario Science Table Science Brief (March 26, 2021) that provides information on a proposed pathogenesis, presentation, work-up and treatment of VIPIT.

March 26, 2021

Members of the Ontario Science Table released a report regarding a proposed mechanism of VIPIT for the rare cases of blood clots noted in the United Kingdom (UK), European Union and Scandanavian countries (EEA) following AstraZeneca COVID-19 Vaccination. This report, led by Dr. Menaka Pai MSc MD FRCPC, provides a lay summary for the public, as well as information on the pathophysiology, diagnostics, and proposed treatment alternatives of the blood clots associated with the AstraZeneca vaccine, now named VIPIT. The report describes a possible mechanism identified by the Society of Thrombosis and Haemostasis Research (GTH) in Germany, whose research team suspects that VIPIT mimics heparin-induced thrombocytopenia. This research is now available in a preprint awaiting peer review.

March 24, 2021

Health Canada provided an update regarding the AstraZeneca COVID-19 vaccine and risk of thrombosis with thrombocytopenia. In this update, Health Canada explains that according to currently available data focusing on thrombotic events, neither the AstraZeneca nor COVISHIELD vaccines have been associated with increased risk of overall thrombosis. However, a possible risk of thrombosis with thrombocytopenia has been flagged for the AstraZeneca vaccine, and that monitoring and guidance will continue. Instructions were provided regarding when to seek immediate medical attention for signs and symptoms of thrombosis.

March 18, 2021

The Pharmacovigilance Risk Assessment Committee (PRAC) of European Medicines Agency (EMA) provided a preliminary report on a signal of rare blood clots in individuals vaccinated with the AstraZeneca COVID-19 vaccine. The EMA’s statement noted that of 20 million people vaccinated in UK and EEA with the AstraZeneca vaccine as of March 16th 2021, 7 cases of disseminated intravascular coagulation (DIC) and 18 cases of cerebral venous sinus thrombosis (CVST) were noted. To ensure continued pharmacovigilance, the PRAC committee would be monitoring these events to determine correlation and provide updates as details became available.

March 11, 2021

Health Canada shared a statement acknowledging that countries in Europe were noting rare incidences of thromboembolic events following vaccination with the AstraZeneca COVID-19 Vaccine. At that time, Health Canada did not find any indication that the vaccine caused these events according to data that was available and was able to share that no adverse events related to either the AstraZeneca or COVISHIED vaccines were reported in Canada. Initially, there was a question regarding if a specific batch was associated with this adverse outcome but none of these batches under investigation were shipped to Canada. Health Canada initiated an investigation into these thromboembolic events and continued to work with international regulators on gathering further data regarding this adverse event.

An Overview of the Types of Clots Discussed Throughout the Timeline Above

The PRAC committee indicate that the AstraZeneca vaccine may be associated with less common types of clots: 18 cases of cerebral venous sinus thrombosis (CVST) and 7 disseminated intravascular coagulation (DIC) out of 20 million people who received the AstraZeneca Vaccine in the UK and EEA (March 18, 2021). The cases presented with thrombosis and thrombocytopenia (low platelets), similar to heparin induced thrombocytopenia (HIT); however, there was no known exposure to a heparinoid. Below, we are going to briefly touch on each of these specific coagulopathies and their prevalence in the general population.

Venous Thromboembolisms
The most commonly discussed form of blood clot is venous thromboembolism, or VTE. The Centre for Disease Control (CDC) provides a great overview of VTE and describes this presentation as blood clots in the venous circulation with serious complications occurring when a part of the blood clot breaks off and travels through the bloodstream to cause a pulmonary embolism (PE) (CDC, 2020). Thrombosis Canada provides further guidance on the diagnosis and treatment of deep vein thrombosis (DVT), a subcategorization of VTE. The estimated incidence of DVT in Canada is approximately 1-2 cases per 1000 people per year according to Thrombosis Canada, and approximately one third of those who develop DVT have a complication of symptomatic PE. As detailed above, the PRAC committee of the EMA reported on March 18 2021 that there was no indication that these types of clots were occurring with the AstraZeneca vaccine.

Cerebral Venous Sinus Thrombosis (CVST)
Also known as Cerebral Venous Thrombosis, CVST is a rare form of stroke representing 0.5% to 3% of all types of strokes and occurs in the dural sinus veins.¹ Clinically, it is characterized by a highly variable presentation. Young women are more likely to develop CVST as seen in a Dutch cross-sectional study with an average incidence of roughly 1.3 cases per 100,000 person years.² The increased risk in women appears to be primarily driven by oral contraceptive use and pregnancy, though other risk factors such as thrombophilia, malignancy, and infection have also been identified.¹𝄒³ At this time, none of these risk factors have been disclosed as the triggers for CVST episodes seen following administration of the AstraZeneca COVID-19 vaccine.

Disseminated Intravascular Coagulation (DIC)
DIC is a systemic process that can cause both uncontrolled bleeding and clotting that can lead to dysfunction of multiple organs.⁴ The typical pathway of DIC involves procoagulant exposure triggering widespread clotting, which in turn consumes clotting factors faster than they can be synthesized; hence why this presentation can also be referred to as consumptive coagulopathy.⁴ Acute DIC can be triggered by infection, occurring in 30 to 50% of severe sepsis, or trauma.⁴ DIC can also occur in about 20% of metastatic cancer or other lymphoproliferative processes as well as in some obstetrical complications.⁴ This presentation is similar to what is seen in the rare cases of clots with the AstraZeneca vaccine; however, DIC is not triggered by an autoimmune process, whereas VIPIT might be.

Heparin Induced Thrombocytopenia (HIT)
A rare limb and life-threatening immune-mediated response to heparin, HIT, is triggered by antibodies which target a complex of Platelet Factor 4 (PF4) and heparin.⁵ Once the antibodies bind this complex, they activate the associated platelets and others nearby, creating a cascade of further platelet activation and thrombin generation.⁵ This cycle causes widespread clotting in both arteries and veins, as well as thrombocytopenia when immune cells begin removing platelets that have been bound by antibodies.⁵ A similar presentation has been proposed and termed spontaneous HIT when observed without known exposure to a heparinoid. Some of these case studies have been seen with infection or suspected glycosaminoglycans released during surgery.⁶ Our current understanding of the clotting disorders following use of the AstraZeneca COVID-19 vaccine is speculating a similar mechanism of pathogenesis and is being termed Vaccine-Induced Prothrombotic Immune Thrombocytopenia (VIPIT).

What is the Proposed Mechanism for Vaccine-Induced Prothrombotic Immune Thrombocytopenia (VIPIT)?

The proposed mechanism of VIPIT is described in a case series preprint by Greinacher et al., released March 29, 2021.7 VIPIT is thought to mimic HIT, in absence of heparin, following administration of the AstraZeneca COVID-19 Vaccine. It is hypothesized that vaccination stimulates production of antibodies targeting platelet factor 4 (PF4) leading to platelet activation and a hypercoagulable and thrombocytopenic state.⁷

Case Series Overview
A total of 9 patients aged 22 to 49 were identified with thrombotic complications 4 to 16 days after receiving the AstraZeneca vaccine, 7 of which involved CVST, 1 PE and 1 multiple thrombi. Of these, 8 patients were female and 2 had an underlying autoimmune disease. Of the 9 individuals, the associated thrombosis was considered fatal in 4. Platelets ranged from 9 to 100 per cubic millimeter. Sera of 4 of the 9 patients were referred for investigation for evidence of antibodies against PF4/heparin. None of these individuals had been known to receive heparin previously.

Bottomline

The authors hypothesize that the AstraZeneca vaccine may be associated with development of a prothrombotic disorder that resembles HIT with a different serologic profile based on a case series of 9 patients and sera of 4 of these individuals.

Interim Guidance for Health Care Professionals on VIPIT

Dr. Pai et al., from the Ontario Science Table, have created a decision tree type schema for diagnosing and ruling out VIPIT to act as interim guidance for health care providers.

Why the age cutoff of less than 55 years?

At this time NACI is recommending against administration of the AstraZeneca COVID-19 vaccine to those younger than 55 years of age primarily due to the fact that these rare clotting events have only been seen in those under age of 55. The majority of these events have been identified in females; however, this may be because the majority of those under 55 who received the vaccine in the EU are female healthcare workers.

Monitoring for Signs and Symptoms of Blood Clots

Health Canada, Thrombosis Canada, and the Ontario Science Table provide valuable resources for patients to be able to recognize signs and symptoms of clots. With the proposed mechanism of VIPIT that has been associated in rare instances with the AstraZeneca vaccine, symptoms began to occur within 4 to 20 days after vaccination. Therefore, if any of the following symptoms are experienced, or if you are concerned, it is important to seek medical care right away.

Signs and symptoms of clots:

  • Shortness of breath or feeling out of breath
  • Chest pain
  • Swelling or pain in abdomen
  • Sudden onset headache
  • Persistent headache
  • Dizziness or lightheadedness
  • New widespread bruises or petechiae (small pinprick spots that may be red, brown, or purple) visible on the skin

Current Guidance

The precautionary recommendation to temporarily cease administration of the AstraZeneca COVID-19 vaccine in individuals younger than 55 years of age is an important aspect of pharmacovigilance. Balancing risks and benefits of an intervention is the cornerstone of healthcare, and as data continues to emerge, NACI and Health Canada will continue to assess overall risk, monitor the global situation, and provide updates to health care providers and the public. It is important to note that at this time, reports of these rare proposed VIPIT events have not been seen following over 300,000 doses of the AstraZeneca vaccine administered in Canada.

3 Useful Resources

1. VIPIT - COVID-19 Science Table Brief

2. Thrombosis Canada CLOTS Patient Resources

3. NACI March 29, 2021 Recommendations: AstraZeneca COVID-19 Vaccine Use in Canada

Biographies

Dr. Kimberley Gauthier is a research fellow at The Hospital for Sick Children in Toronto where she studies embryogenesis, tissue development, and lipids in Drosophila (fruit flies). She completed her PhD in Cell Biology at McGill University where she specialized in cell signaling, protein trafficking, genetics, and model organism (C. elegans) development. Since January 2021, she has been volunteering alongside scientists and clinicians from COVID-19 Resources Canada as a science communicator for COVID-19 vaccine Q&A town halls hosted for the public. You can follow her on Twitter @thekimgauthier.

Dr. Amir Imani is a clinical pharmacist working in stroke and neurological rehabilitation and an instructor at the Leslie Dan Faculty of Pharmacy. You can follow him on Twitter @TheAmirImani.

Dr. Krishana Sankar completed her PhD from the Faculty of Medicine at the University of Toronto where she specialized in cellular & molecular biology and used bioengineering with the aim of improving islet transplantation for type 1 diabetes. She is currently the science communication lead for COVID-19 Resources Canada and Advisory committee member for ScienceUpFirst. Dr. Sankar is passionate about countering misinformation and has been dispelling misconceptions around healthcare issues for several years. Since the COVID-19 pandemic was declared in March 2020, she has been sharing accurate scientific information with her communities. You can follow her on Twitter @KrishanaSankar.

Dr. Mira Maximos (PharmD) completed an Honours Specialization in Health Sciences and Major in Physiology at Western University & Bachelor of Science in Pharmacy at the University of Waterloo. She then completed a hospital pharmacy residency at London Health Sciences Centre concomitantly with a Master of Science in Pharmacy and went on to pursue a Doctor of Pharmacy degree at the University of Waterloo. Dr. Maximos works at Woodstock Hospital in Ontario as the Antimicrobial Stewardship Pharmacy Lead, with @Spectrum as the Knowledge Mobilization pharmacist, and the Centre of Excellence in Women’s Health as a Research Associate, on contract. She has been involved in research in different areas from medication taking behaviours, to medication safety and knowledge translation. Dr. Maximos lectures at the University of Waterloo in areas such as drug induced disease and infectious diseases in the elderly. Like Dr. Sankar and Dr. Gauthier, she participates in the COVID-19 Resource Canada Q&A town halls as a clinician-scientist. You can follow her on Twitter @miramaximos.

Conflicts of Interest

  • Kimberley Gauthier declares no conflicts of interest
  • Amir Imani declares no conflicts of interest
  • Krishana Sankar declares no conflicts of interest
  • Mira Maximos is employed with Spectrum Mobile Health as a Knowledge Mobilization pharmacist

This blog post is for information/educational purposes only, and does not substitute professional medical advice. Also please note that opinions are those of the authors and do not necessarily reflect that of their employers.


References:

1 Alvis-Miranda, Hernando Raphael, Sandra Milena Castellar-Leones, Gabriel Alcala-Cerra, and Luis Rafael Moscote-Salazar. 2013. Cerebral Sinus Venous Thrombosis. Journal of neurosciences in rural practice 4(4): 427–38.

2 Coutinho JM, Zuurbier SM, Aramideh M, Stam J. The incidence of cerebral venous thrombosis: a cross-sectional study. Stroke. 2012 Dec;43(12):3375-7. doi: 10.1161/STROKEAHA.112.671453. Epub 2012 Sep 20. PMID: 22996960.

3 Ferro José M., Canhão Patrícia, Stam Jan, Bousser Marie-Germaine, and Barinagarrementeria Fernando. (2004). Prognosis of Cerebral Vein and Dural Sinus Thrombosis. Stroke, 35(3), 664–670.

4 Costello RA, Nehring SM. Disseminated Intravascular Coagulation. 2020 Jul 17. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2021 Jan–. PMID: 28722864.

5 Selleng K, Selleng S, Greinacher A. Heparin-induced thrombocytopenia in intensive care patients. Semin Thromb Hemost. 2008 Jul;34(5):425-38. doi: 10.1055/s-0028-1092872. Epub 2008 Oct 27. PMID: 18956282.

6 Warkentin TE, Basciano PA, Knopman J, Bernstein RA. Spontaneous heparin-induced thrombocytopenia syndrome: 2 new cases and a proposal for defining this disorder. Blood. 2014 Jun 5;123(23):3651-4. doi: 10.1182/blood-2014-01-549741. Epub 2014 Mar 27. PMID: 24677540.

7 Greinacher, Andreas, Thomas Thiele, Theodore E Warkentin, and Karin Weisser. 2021. A Prothrombotic Thrombocytopenic Disorder Resembling Heparin-Induced Thrombocytopenia Following Coronavirus-19 Vaccination.: 1–8

Websites and Videos:

Centre for Disease Control. 2020. Venous Thromboembolisms (Blood Clots). (March 30, 2021).

European Medicines Agency (EMA). 2021. AstraZeneca COVID-19 Vaccine: review of very rare cases of unusual blood clots continues. (March 31, 2021)

Health Canada. 2021. AstraZeneca COVID-19 Vaccine and COVISHIELD: Risk of Thrombosis with Thrombocytopenia. (Mar 24, 2021)

Health Canada. 2021. Health Canada provides update on the AstraZeneca and COVISHIELD COVID-19 vaccines. (April 14 2021)

National Advisory Committee on Immunization (NACI). 2021. NACI rapid response: Recommended use of AstraZeneca COVID-19 Vaccine in younger adults. (March 29, 2021)

Ontario COVID-19 Science Advisory Table. (2021). Vaccine-Induced Prothrombotic Immune Thrombocytopenia (VIPIT) Following AstraZeneca COVID-19 Vaccination. (March 26, 2021)

The Australian Technical Advisory Group on Immunization (ATAGI)’s statement on the AstraZeneca COVID-19 Vaccine. (April 8, 2021)

The Canadian Broadcasting Corporation (CBC). 2021. Alberta confirms 1st case of rare blood clots after AstraZeneca Vaccine.. (April 17, 2021)

The Canadian Broadcasting Corporation (CBC). 2021. AstraZeneca very safe, effective, with extremely rare risk of clots: Health Canada. (April 14, 2021)

The Canadian Broadcasting Corporation (CBC). 2021. Why Canada is suspending use of Astrazeneca vaccine in people under 55. (March 29, 2021)

The European Medicines Agency’s Safety Committee (PRAC) Updated Statement on AstraZeneca’s COVID-19vaccine Finding Possible Link to Very Rare Cases of Unusual Blood Clots with Low Blood Platelets. (April 7, 2021)

The World Health ORganization’s Global Advisory Committee on Vaccine Safety (GACVS)’s Interim Statement of the AstraZeneca COVID-19 Vaccine’s Safety.ß (April 7, 2021)

Thrombosis Canada. 2020. Deep Vein Thrombosis (DVT): Diagnosis. (March 30, 2021)

Thrombosis Canada. 2020. Deep Vein Thrombosis (DVT): Treatment (March 30, 2021)

Virtual Briefing Accessible Through YouTube. 2021. Canada pauses use of AstraZeneca COVID-19 Vaccine for people under 55. (Mar 29, 2021)