27th March 2021, Dr Chee L Khoo
It all started when the Austrian regulatory authority suspended the use of a batch of AstraZeneca (AZ) vaccine on March 9th after a patient was diagnosed with multiple thrombosis and died 10 days after vaccination, and another was hospitalised with pulmonary embolism after being vaccinated. At least 16 other countries follow suit and suspended the use of AZ vaccine. After preliminary investigations, the European Medicines Agency (EMA) and the UK’s regulatory body concluded that there is no indication that vaccination is linked to thromboembolic events. So far, the number of thromboembolic events in vaccinated people is no higher than that seen in the general population. Another media hype or is there some truth about the clots?
In total 30 cases of thromboembolic events have been reported among the 5 million people vaccinated with AZ vaccine in the European Economic Area (EU). The prevalence is a tiny 0.0006% of those vaccinated. Hardly a worry?
Generally, yes, the numbers are in the realm of “background” rate of thromboembolism in the general community. What sort of thromboembolic events are we talking about, though? These are not your usual DVTs and pulmonary embolisms. There were seven cases of blood clots in multiple blood vessels (disseminated intravascular coagulation) and 18 cases of cerebral venous sinus thrombosis (CVST) had been reported as of 17 March. Most of us would probably see a handful of these conditions in our career. And to see them coming up following covid-19 vaccination raised some eyebrows. The EMA is still investigating.
Cerebral venous sinus thrombosis
It is a rare form of stroke associated with an increased mortality rate. It can present with a multitude of signs and symptoms, making it difficult to distinguish from other neurological conditions. The incidence of CVST has increased over the past few years due to the advancement of imaging techniques helping detection of the disease in its early stages. Although the autopsy series approximates the incidence to be 3–4 cases per million, clinical series have shown a 10-fold increase in these numbers (1). An increased incidence is seen among children, younger adults, females of the reproductive age-group, and low-income countries. The estimated female-to-male ratio was 3:1 and comprises 0.5–1% of all stroke occurrences.
CVST is a multifactorial disease with at least one risk factor implicated in 85% of affected adults (2). These risk factors are usually always associated with thrombogenic triad of Virchow – vessel wall injury, blood stasis, and hypercoagulability. Prothrombotic conditions are the most common implicated risk factor for CVST.
Thromboembolism & Covid-19
Immune thrombocytopenia (ITP) secondary to Covid-19 have been reported in many patients with Covid-19 and coagulopathy have been a major contributing factor to the high mortality associated with CoViD-19. It has been proposed that the antibodies produced by the body to clear the virus have a potential cross reactivity with surface antigens on platelets or megakaryocytes. It may also be likely that RNA viruses can directly infect platelets and mRNA translation within platelets is a possible explanation for the autoimmune response against platelets. It is, therefore, not unreasonable to hypothesise that the genetic covid-19 vaccines may also directly infect platelets and megakaryocytes triggering mRNA translation and consequent spike protein synthesis intracellularly.
There have been over 150 reports of post- covid-19 vaccination thrombocytopenia recorded in the pharmacovigilance databases in the US (3). ITP have also been previously reported with a number of other vaccines, such as flu, poliomyelitis, pneumococcal, hepatitis, MMR, and rabies.
It is thus, plausible that genetic Covid-19 vaccines may have a direct role in spurring autoimmune response against platelets that may clinically manifest in thrombocytopenia, haemorrhage, and blood clots.
Thromboembolism & other Covid-19 vaccines?
Cases of apparent secondary ITP after Covid-19 vaccination with both the Pfizer and Moderna vaccines have been reported (4). Twenty case reports of patients with thrombocytopenia following vaccination, 17 without pre‐existing thrombocytopenia and 14 with reported bleeding symptoms prior to hospitalisation were identified upon review of data available from the Centers for Disease Control and Prevention (CDC), the Food and Drug Administration (FDA), agencies of the U.S. Department of Health and Human Services (HHS) Vaccine Adverse Events Reporting System (VAERS), published reports and via direct communication with patients and treating providers (5,6).
The Australian Technical Advisory Group on Immunisation (ATAGI) considers that there is no evidence of a risk of thrombotic disease after COVID-19 vaccination in people with a history of clotting conditions. ATAGI continues to recommend vaccination with either AstraZeneca or Pfizer COVID-19 in such people. This includes those with deep venous thrombosis and/or pulmonary embolism; people with risk factors for thrombosis (such as use of oral contraceptives or smoking); people with thrombocytopenia (low platelets that can occur with clotting conditions); people with known thrombophilic disorders; people on anticoagulants (e.g. warfarin) and people with a history of cardiovascular disease (such as myocardial infarction or stroke).
However, for the time being, ATAGI recommends that vaccination with any COVID-19 vaccine should be deferred for people who have a history of the following rare conditions. This is until further information from ongoing investigations in Europe is available and is only a precautionary measure:
- People with a confirmed medical history of CVST; and/or
- People with a confirmed medical history of heparin induced thrombocytopenia (HIT). HIT is an immune-mediated complication of treatment with heparin that affects platelet function. A HIT-like mechanism is being investigated as a potential, but unconfirmed, pathway to CVST post COVID-19 vaccination.
- Guenther G, Arauz A. Cerebral venous thrombosis: a diagnostic and treatment update. Neurologia. 2011; 26(8): 488–98.
- Ferro JM, Canhão P, Stam J, Bousser MG, Barinagarrementeria F. Prognosis of cerebral vein and dural sinus thrombosis: results of the International Study on Cerebral Vein and Dural Sinus Thrombosis (ISCVT). Stroke. 2004; 35(3): 664–70.
- Lee EJ, Cines DB, Gernsheimer T, Kessler C, Michel M, Tarantino MD, Semple JW, Arnold DM, Godeau B, Lambert MP, Bussel JB. Thrombocytopenia following Pfizer and Moderna SARS-CoV-2 vaccination. Am J Hematol. 2021 Feb 19. doi: 10.1002/ajh.26132. Epub ahead of print. PMID: 33606296.
- Tarawneh OH, Tarawneh HS. Immune thrombocytopenia in a 22‐year‐old post Covid‐19 vaccine. Am J Hematol. 2021. https://doi.org/10.1002/ajh.26106.
- Toom SWB, Avula A, Peeke S, Becker K. Familial thrombocytopenia flare‐up following the first dose of mRA‐1273 COVID‐19 vaccine. Am J Hematol. 2021. https://doi.org/10.1002/ajh.26128.
- ATAGI statement for health care providers on suitability of COVID-19 vaccination in people with history of clotting conditions | Australian Government Department of Health