Post-vaccination embolic and thrombotic events

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Post-vaccination embolic and thrombotic events, also termed vaccine-induced prothrombotic immune thrombocytopenia (VIPIT),[1] vaccine-induced immune thrombotic thrombocytopenia (VITT),[2][3] or thrombosis with thrombocytopenia syndrome (TTS)[4] are rare types of blood clotting events that were initially observed in a very small number of people who had previously received the Oxford–AstraZeneca COVID-19 vaccine (AZD1222)[a] during the COVID-19 pandemic.[1][8] It was subsequently also described in the Johnson & Johnson COVID-19 vaccine[b] leading to suspension of its use until its safety had been reassessed.[10]

In April 2021, AstraZeneca and the EMA updated their information for healthcare professionals about AZD1222, saying it was "considered plausible" that there was a causal relationship between the vaccination and the occurrence of thrombosis in combination with thrombocytopenia and that, "although such adverse reactions are very rare, they exceeded what would be expected in the general population".[8][11][12][13]

Guidelines from professional societies recommend treatment with alternative anticoagulants instead of heparin, as there is a possibility that it may aggravate the phenomenon.[14][15]

Signs and symptoms[edit]

The thrombosis events associated with the COVID-19 vaccine may occur 5-28 days after its administration. Several relatively unusual types of thrombosis were specifically reported to be occurring in those with the reaction: cerebral venous sinus thrombosis and thrombosis of the splanchnic veins.[16][17] Cerebral venous sinus thrombosis may cause severe headache, stroke-like symptoms (weakness of a limb and/or facial muscles), seizures and coma.[18] Splanchnic vein thrombosis may cause abdominal pain, accumulation of fluid in the abdominal cavity, and gastrointestinal bleeding.[19][20]

Other forms of thrombosis, such as the more common pulmonary embolism, may also occur. Arterial thrombosis has also been reported.[21] The low platelet count may manifest as petechia (tiny blood spots under the skin) beyond the site of the injection.[16]

Disseminated intravascular coagulation (DIC), diffuse formation of blood clots throughout the blood vessels of the body, has been reported as part of the syndrome.[22] DIC may cause a range of symptoms, including abnormal bleeding, breathlessness, chest pain, neurological symptoms, low blood pressure, or swelling.[23]

COVID-19 vaccines have some adverse effects that are listed as common in the two or three days following vaccination which are usually mild and temporary.[16]

Causes[edit]

The rare simultaneous occurrence of thrombocytopenia (low blood platelets) with blood clots after vaccination raised the original concern about this condition.[citation needed] In many cases where acute thrombosis and thrombocytopenia have been found together after COVID-19 vaccination, an antibody against platelet factor 4 has been identified.[24] This phenomenon is mostly encountered in some people who have been administered heparin, but none of the reported cases had received heparin.[24] More rarely, this phenomenon had previously been described as an autoimmune phenomenon in people who had not been exposed to heparin.[25] One striking feature of thrombocytopenia in the presence of anti-PF4 antibodies is the propensity of some to develop thrombosis, a phenomenon called heparin-induced thrombocytopenia if heparin is involved.[26]

Thrombocytopenia is generally a common symptom after or during many viral infections,[27] and it "has been consistently reported" after administration of adenoviral gene transfer vectors,[28] although its mechanisms are not yet clear.

There is no confirmed causal link to the syndrome and any COVID-19 vaccination,[citation needed] however EMA is conducting investigations into AZD1222 and the Johnson & Johnson COVID-19 ("Janssen") vaccine (J&J) for possible causal links.[29]

On 7 April 2021 the EMA noted one "plausible explanation" for the combination of blood clots and low blood platelets is "an immune response, leading to a condition similar to one seen sometimes in patients treated with heparin", that is heparin induced thrombocytopenia (HIT).[30]

Diagnosis[edit]

In the United Kingdom, professional societies led by the Royal College of Emergency Medicine have issued a guideline for suspected cases. Someone presenting with concerning symptoms between five and 28 days after administration of the vaccine is assessed for a possible thrombotic complication, with a full blood count (which includes a platelet count) as the initial investigation. If the platelet count is decreased, determination of the D-dimer and fibrinogen levels may be performed, with hematology expert advice recommended if these are elevated above specific cut offs.[21]

Management[edit]

Guidelines from professional societies recommend alternative anticoagulants instead of heparin, as there is a possibility that it may aggravate the phenomenon. Alternative options as the directly-acting oral anticoagulants (DOACs), argatroban, fondaparinux or danaparoid depending on the circumstances.[14] Platelet transfusion is discouraged, as this too may aggravate thrombosis.[14] UK guidelines by the British Society for Haematology recommend the administration of intravenous immunoglobulin (IVIG) to reduce levels of the pathogenic antibody.[14] Low fibrinogen levels may require correction with fibrinogen concentrate or cryoprecipitate.[14]

Epidemiology[edit]

The Paul Ehrlich Institute has recorded 31 cerebral venous sinus thromboses (CVST) and nine deaths out of 2.7 million vaccinated in Germany with the AZD1222.[31] On 2 April 2021 the UK's Medicines and Healthcare products Regulatory Agency reported 22 cases of CVST and a further eight cases of clotting problems both associated with a low level of blood platelets following a "rigorous review" of its Yellow Card reporting. The institute also reported finding no events of this type which occurred after vaccination with the Pfizer–BioNTech COVID-19 vaccine.[32] The EMA had earlier said that a link between certain very rare blood clots and the AstraZeneca vaccine is "not proven, but is possible".[32]

Observations in Germany of these rare events seemed to relate mostly women aged under 55. However, because Germany had previously restricted AZD1222 to under 65s, the population vaccinated there with AZD1222 was comparatively younger, and consequently contained a higher proportion of women taking the contraceptive pill. As CVSTs are more likely in women using hormonal contraceptives, this inherent risk factor may be an influence on the reported preponderance of women experiencing these events following vaccination.[31][2] The UK, in contrast, has applied its Pfizer and AZD1222 vaccines generally to older groups first, then by decreasing age.[31]

The UK MHRA reporting regards AZD1222 to 9 June 2021 recording 71 deaths out of 390 cases (18%) in the context of 24.6 million first doses administered.[33][34]

Regulatory status[edit]

According to the European Medicines Agency (EMA), as of 28 March 2021, the reported rate of such events was lower than in the general population overall, but higher than in the population prior to the pandemic.[clarification needed] The EMA also said that there is no proof that these events are caused by the vaccines, but that the possibility could not yet be ruled out completely.[8] Accordingly, the EMA advised that people who received the vaccine and experienced symptoms suggestive of thrombosis, including shortness of breath, blurred vision and severe or persistent headache, should seek medical attention.[8]

In a press briefing in the Afternoon of 7 April 2021 by Emer Cooke executive director of the EMA began by stating "Our safety committee, the Pharmacovigilance and Risk Assessment Committee (PRAC) of the European Medicines Agency, has confirmed that the benefits of the AstraZeneca vaccine in preventing COVID-19 overall outweigh the risks of side effects. COVID-19 is a very serious disease with high hospitalization and death rates and every day COVID is still causing thousands of deaths across the EU. This vaccine has proven to be highly effective, it prevents severe disease and hospitalization, and it is saving lives. Vaccination is extremely important in helping us in the fight against COVID-19 and we need to use the vaccines we have to protect us from the devastating effects".[35] She went on to say "The PRAC after a very in-depth analysis has concluded that the reported cases of unusual blood clotting following vaccination with the AstraZeneca vaccine should be listed as possible side effects of the vaccine".[36] At the same briefing Dr. Samina Strauss of PRAC confirmed "our conclusion is that these clotting disorders are very rare side effects of the vaccine".[37]

The UK MHRA also held a news conference on 7 April 2021 and while there was no proof the AZD1222 vaccination caused the rare blood clots but indicated the possibility of a link was getting stronger.[38] The UK was to offer under 30s alternative vaccines.[38] The reasoning was because in the 20-29 age range the benefits to individual of vaccination were less as their likelihood of harm from COVID-19 was less and closer to the potential risk of harm from the vaccine (at a medium exposure risk with COVID-19 infection cases running at a rate of 60 per 100,000).[39][38] For higher age groups the benefit to risk ratio increased.[38]

Also on 7 April 2021 an interim statement from the WHO said its advisory body, GACVS, found any "causal relationship" between the rare blood clot cases and AZD1222 to be "plausible but is not confirmed".[40]

On 20 April 2021 the safety committee of the EMA (PRAC) found a "possible link to very rare cases of unusual blood clots with low blood platelets" for the J&J Janssen vaccine; and required that these rare events, similar to those noted for AZD1222, should be listed as a very rare side effect. The EMA states the overall risk-benefit for the J&J vaccine remains positive.[41]

History[edit]

Organisations[edit]

Global vaccine safety comes under the remit of the World Health Organization (WHO), and in particular its Global Advisory Committee on Vaccine Safety (GAVCS). Other drug regulatory agencies significantly involved include:

Syndrome identification[edit]

A number of COVID-19 vaccines began to become approved and available at scale in late 2020 with vaccinations beginning to ramp up at scale from the beginning of 2021, among them the Oxford–AstraZeneca COVID-19 vaccine, based on an adenovirus vector and internally termed AZD1222.

On 11 March 2021 the EMA issued a statement noting Denmark had suspended AZD1222 vaccinations due to a vaccinated patient dying with blood clots. While noting there had been reports of other vaccinated people having blood clots and that its safety committee was already reviewing such cases, the number of thromboembolic events in vaccinated people was no higher than in the general population.[43]

The World Health Organization (WHO) Global Advisory Committee on Vaccine Safety thought necessary on 19 March 2021 to issue a statement relating to safety signals related to AZD1222 relating to thromboembolic events and thrombocytopenia following review of available data and conclusions included that AZD1222 "a positive benefit-risk profile, with tremendous potential to prevent infections and reduce deaths across the world".[44]

In its safety update of 29 March 2021 the EMA indicated it had initiated investigations into the very rare cases of specific embolic and thrombotic events in combination with thrombocytopenia (low levels of blood platelets) and related bleeding including disseminated intravascular coagulation and cerebral venous sinus thrombosis (CVST), noting any link with AZD1222 was not proven but could not be excluded.[8] The EMA also initiated an assessment for all COVID-19 vaccines used in the EU for immune thrombocytopenia (ITP), described as low blood platelet levels that could lead to bruising and bleeding, as a possible side effect, whilst also stating that up to this point no link with any COVID-19 had been established.[8]

On 7 April 2021 the EMA determined that that unusual blood clots with low blood platelets should be listed as very rare side effects of AZD1222, with WHO and UK EHRA issuing generally similar statements on the same day. None of the agencies found a confirmed causal link between the vaccine and these incidents at the time, but were listing them out of an abundance of caution.[16][38][40]

A highlight of minutes of the EMA's Pharmacovigilance Risk Assessment Committee (PRAC) concluding 9 April 2021 indicating they also were investigating four cases of unusual blood clots with low blood platelets, including 1 death, from the Johnson & Johnson COVID-19 vaccine (J&J). The J&J vaccine was approved but not yet deployed in the EU, though vaccinations are in progress in the USA. PRAC has determined that it is currently not clear if there is a causal association. Should regulatory action prove necessary, PRAC have indicated the likely outcome would be an update to product information characteristics.[45]

Vaccination campaign responses[edit]

Early reports of the events of concern seemed to indicate the presentation rate for the specific blood clots of concern might be higher for women of younger ages,[2] UK MHRA found examples across all genders and ages,[34][better source needed] their data skewing towards these specific blood clots being more prevalent in AZD1222 vaccinated persons of younger ages.[39]

The WHO has continued to stress the administration of vaccines is based on risk versus benefit analysis.[40] Some variables that may be factored into such analysis include risk of an individual from catching COVID-19, which relate to the infection rate in that area, and the benefits to that individual if vaccinated and exposed to COVID-19 which varies with age, versus whatever the risks of vaccination are to that individual.[39]

Regional and national responses[edit]

The advisory panel for the government of Ontario, Canada has recommended against the use of heparin for management of thrombosis after vaccination until more is known.[46]

In response to the concerns over the adverse effects relating to rare blood clotting types Germany has suspended use of the AZD1222 in those under 60 years of age; in contrast to a period previously having suspended use of AZD1222 to over–65s due to limited data of the efficacy of the vaccine to this age group at that time.[47]

Following a few days of suspended use of AZD1222, the Ministry of Health, Welfare and Sport of the Netherlands decided to continue administering the vaccine only to persons above the age of 60.[48]

On 8 April 2021, the Australian Technical Advisory Group on Immunisation (ATAGI) advised the Australian Government that the Pfizer COVID-19 vaccine is recommended over AZD1222 for adults aged under 50 years. The advice is "based on the increasing risk of severe outcomes from COVID-19 in older adults (and hence a higher benefit from vaccination) and a potentially increased risk of thrombosis with thrombocytopenia following AstraZeneca vaccination in those under 50 years."[17] AZD1222 is still recommended by ATAGI for people over 50, and those under 50 who have already had their first dose with no ill effects.[17] In the state of Victoria, there were reports of some, aged under 50, being turned away from vaccination centres, despite having confirmed appointments. It is understood a special consent process will be developed by the Australian Government for people under 50 who choose to receive the AZD1222 vaccine.[49]

References[edit]

Notes[edit]

  1. ^ The Oxford–AstraZeneca COVID-19 vaccine is codenamed AZD1222,[5] and later supplied under trade names, including Vaxzevria[6] and Covishield.[7]
  2. ^ The Johnson & Johnson COVID-19 vaccine also known as the Janssen COVID-19 vaccine,[9] having been developed by the J&J-owned Janssen Pharmaceuticals.

Footnotes[edit]

  1. ^ a b Public Health Agency of Canada, [Agence de la santé publique du Canada] (29 March 2021). "Use of AstraZeneca COVID-19 vaccine in younger adults" (Utilisation du vaccin AstraZeneca contre la COVID-19 chez les jeunes adultes). Government of Canada. Retrieved 2 April 2021.
  2. ^ a b c Greinacher, Andreas; Thiele, Thomas; Warkentin, Theodore E.; Weisser, Karin; Kyrle, Paul A.; Eichinger, Sabine (9 April 2021). "Thrombotic Thrombocytopenia after ChAdOx1 nCov-19 Vaccination". New England Journal of Medicine: NEJMoa2104840. doi:10.1056/NEJMoa2104840. PMID 33835769. Retrieved 11 April 2021.
  3. ^ Cines, Douglas B.; Bussel, James B. (16 April 2021). "SARS-CoV-2 Vaccine–Induced Immune Thrombotic Thrombocytopenia". New England Journal of Medicine: NEJMe2106315. doi:10.1056/NEJMe2106315. PMID 33861524. Retrieved 20 April 2021.
  4. ^ Long, Brit; Bridwell, Rachel; Gottlieb, Michael (2021). "Thrombosis with thrombocytopenia syndrome associated with COVID-19 vaccines". The American Journal of Emergency Medicine. doi:10.1016/j.ajem.2021.05.054. ISSN 0735-6757. PMC 8143907.
  5. ^ "AstraZeneca COVID-19 Vaccine (AZD1222)" (PDF). ACIP COVID-19 Emergency Meeting. AstraZeneca. 27 January 2021. Retrieved 16 April 2021.
  6. ^ "Vaxzevria (previously COVID-19 Vaccine AstraZeneca): EPAR - Medicine overview (update)". European Medicines Agency (EMA). 12 April 2021 [18 February 2021]. Retrieved 16 April 2021. The name of the vaccine was changed to Vaxzevria on 25 March 2021. Vaxzevria (COVID-19 Vaccine (ChAdOx1-S recombinant) EMA/182334/2021 Text was copied from this source which is © European Medicines Agency. Reproduction is authorized provided the source is acknowledged.
  7. ^ "Serum Institute Of India - ChAdOx1 nCoV- 19 Corona Virus Vaccine (Recombinant) - COVISHIELD". www.seruminstitute.com. Retrieved 16 April 2021.
  8. ^ a b c d e f "COVID-19 vaccine safety update: VAXZEVRIA" (PDF). European Medicines Agency. 28 March 2021. Retrieved 31 March 2021.
  9. ^ "Janssen COVID-19 vaccine [Ad26.COV2.S, recombinant] Product monograph" (PDF). 5 March 2021. Retrieved 16 April 2021.
  10. ^ Marks, Peter. "Joint CDC and FDA Statement on Johnson & Johnson COVID-19 Vaccine". Retrieved 13 April 2021.
  11. ^ Medical Director of AstraZeneca AB (13 April 2021). "Direct healthcare professional communication (DHPC): Vaxzevria (previously COVID-19 Vaccine AstraZeneca): link between the vaccine and the occurrence of thrombosis in combination with thrombocytopenia" (PDF). European Medicines Agency. Retrieved 13 April 2021.
  12. ^ MHRA (1 April 2021). "Research and analysis — Coronavirus vaccine - weekly summary of Yellow Card reporting". gov.UK. Retrieved 3 April 2020.
  13. ^ EMA (2021).
  14. ^ a b c d e Expert Haematology Panel (7 April 2021). "Guidance produced from the Expert Haematology Panel (EHP) focussed on Covid-19 Vaccine induced Thrombosis and Thrombocytopenia (VITT)" (PDF). BSH.org.uk. British Society for Haematology. Retrieved 15 April 2021.
  15. ^ Nazy, Ishac; Sachs, Ulrich J; Arnold, Donald M.; McKenzie, Steven E; Choi, Phil; Althaus, Karina; Ahlen, Maria Therese; Sharma, Ruchika; Grace, Rachael F; Bakchoul, Tamam (22 April 2021). "Recommendations for the clinical and laboratory diagnosis of vaccine‐induced immune thrombotic thrombocytopenia (VITT) for SARS‐CoV‐2 infections: Communication from the ISTH SSC Subcommittee on Platelet Immunology". Journal of Thrombosis and Haemostasis. Online first. doi:10.1111/jth.15341.
  16. ^ a b c d EMA (7 April 2021). "AstraZeneca's COVID-19 vaccine: EMA finds possible link to very rare cases of unusual blood clots with low blood platelets". EMA. Retrieved 9 April 2021.
  17. ^ a b c Australian Government, Department of Health (8 April 2021). "ATAGI statement on AstraZeneca vaccine in response to new vaccine safety concerns". Australian Technical Advisory Group on Immunisation. Retrieved 9 April 2021.
  18. ^ Capecchi, M.; Abbattista, M.; Martinelli, I. (October 2018). "Cerebral venous sinus thrombosis". Journal of Thrombosis and Haemostasis. 16 (10): 1918–1931. doi:10.1111/jth.14210. PMID 29923367.
  19. ^ Valeriani, Emanuele; Riva, Nicoletta; Nisio, Marcello Di; Ageno, Walter (22 October 2019). "Splanchnic Vein Thrombosis: Current Perspectives". Vascular Health and Risk Management. 15: 449–461. doi:10.2147/VHRM.S197732. PMC 6815215. PMID 31695400.
  20. ^ Riva, N; Ageno, W (10 March 2020). "Cerebral and Splanchnic Vein Thrombosis: Advances, Challenges, and Unanswered Questions". Journal of Clinical Medicine. 9 (3): 743. doi:10.3390/jcm9030743. PMC 7141239. PMID 32164214.
  21. ^ a b RCEM/SAM/RCP (11 April 2021). "Management of patients presenting to the Emergency Department/ Acute Medicine with symptoms" (PDF). RCEM.ac.uk. Royal College of Emergency Medicine. Retrieved 15 April 2021.
  22. ^ "COVID-19 Vaccine AstraZeneca: benefits still outweigh the risks despite possible link to rare blood clots with low blood platelets | European Medicines Agency".
  23. ^ "Disseminated Intravascular Coagulation | NHLBI, NIH". www.nhlbi.nih.gov. National Heart, Lung and Blood Institute. 8 October 2019. Retrieved 15 April 2021.
  24. ^ a b Greinacher, Andreas; Thiele, Thomas; Warkentin, Theodore E.; Weisser, Karin; Kyrle, Paul A.; Eichinger, Sabine (9 April 2021). "Thrombotic Thrombocytopenia after ChAdOx1 nCov-19 Vaccination". New England Journal of Medicine: NEJMoa2104840. doi:10.1056/NEJMoa2104840. PMID 33835769.
  25. ^ Greinacher, A.; Selleng, K.; Warkentin, T. E. (2017). "Autoimmune heparin-induced thrombocytopenia". Journal of Thrombosis and Haemostasis. 15 (11): 2099–2114. doi:10.1111/jth.13813. PMID 28846826.
  26. ^ Sahu, Kamal K.; Jindal, Vishal; Anderson, Joseph; Siddiqui, Ahmad D.; Jaiyesimi, Ishmael A. (17 August 2020). "Current Perspectives on Diagnostic Assays and Anti-PF4 Antibodies for the Diagnosis of Heparin-Induced Thrombocytopenia". Journal of Blood Medicine. 11: 267–277. doi:10.2147/JBM.S232648. PMC 7443028. PMID 32884385.
  27. ^ Raadsen, Matthijs; Du Toit, Justin; Langerak, Thomas; van Bussel, Bas; van Gorp, Eric; Goeijenbier, Marco (15 January 2021). "Thrombocytopenia in Virus Infections". Journal of Clinical Medicine. 10 (4): 877. doi:10.3390/jcm10040877. PMC 7924611. PMID 33672766.
  28. ^ Othman, Maha; Labelle, Andrea; Mazzetti, Ian; Elbatarny, Hisham S.; Lillicrap, David (5 December 2006). "Adenovirus-induced thrombocytopenia: the role of von Willebrand factor and P-selectin in mediating accelerated platelet clearance". Blood. 109 (7): 2832–2839. doi:10.1182/blood-2006-06-032524. PMID 17148587.
  29. ^ "Meeting highlights from the Pharmacovigilance Risk Assessment Committee (PRAC) 6-9 April 2021 | European Medicines Agency".
  30. ^ "AstraZeneca's COVID-19 vaccine: EMA finds possible link to very rare cases of unusual blood clots with low blood platelets | European Medicines Agency".
  31. ^ a b c Gallagher J (2 April 2021). "AstraZeneca: Is there a blood clot risk?". BBC. Retrieved 3 April 2021.
  32. ^ a b Gallagher J (3 April 2021). "Covid-19: Seven UK blood clot deaths after AstraZeneca vaccine". BBC. Retrieved 3 April 2021.
  33. ^ "Coronavirus vaccine - weekly summary of Yellow Card reporting". GOV.UK. Retrieved 16 May 2021.
  34. ^ a b Medicines and Healthcare products Regulatory Agency (7 April 2021). "MHRA issues new advice, concluding a possible link between COVID-19 Vaccine AstraZeneca and extremely rare, unlikely to occur blood clots" (Press release). GOV.UK. Retrieved 12 April 2021. Up to and including 31 March 2021, the MHRA had received 79 UK reports of blood clotting cases alongside low levels of platelets following the use of the COVID-19 Vaccine AstraZeneca:" [occurring in] "in 51 women and 28 men, aged from 18 to 79 years.
  35. ^ EMA (2021), 8m.
  36. ^ EMA (2021), 9m.
  37. ^ EMA (2021), 14m.
  38. ^ a b c d e Triggle, Nick (7 April 2021). "Covid: Under-30s offered alternative to Oxford-AstraZeneca jab". BBC News. Retrieved 8 April 2021.
  39. ^ a b c Winton Centre for Risk and Evidence Communication, University of Cambridge (7 April 2021). "Communicating the potential benefits and harms of the Astra-Zeneca COVID-19 vaccine" (Presentation PDF). wintoncentre.maths.cam.ac.uk. Retrieved 9 April 2021.
  40. ^ a b c GACVS (7 April 2021). Interim statement of the COVID-19 subcommittee of the WHO Global Advisory Committee on Vaccine Safety on AstraZeneca COVID-19 vaccine (Report). World Health Organization. Retrieved 9 April 2021.
  41. ^ "COVID-19 Vaccine Janssen: EMA finds possible link to very rare cases of unusual blood clots with low blood platelets". ema.europa.eu. European Medicines Agency. 20 April 2021. Retrieved 28 April 2021.
  42. ^ World Health Organization. "Collaborating centres: Blood products and related biologicals". www.who.int. Retrieved 10 April 2021.
  43. ^ "COVID-19 Vaccine AstraZeneca: PRAC investigating cases of thromboembolic events - vaccine's benefits currently still outweigh risks - Update". European Medicines Agency. 11 March 2021. Retrieved 9 April 2021.
  44. ^ GACVS (19 March 2021). "Statement of the WHO Global Advisory Committee on Vaccine Safety (GACVS) COVID-19 subcommittee on safety signals related to the AstraZeneca COVID-19 vaccine". World Health Organization. Retrieved 6 April 2021.
  45. ^ PRAC (9 April 2021). "Meeting highlights from the Pharmacovigilance Risk Assessment Committee (PRAC)". EMA. Retrieved 9 April 2021.
  46. ^ "Vaccine-Induced Prothrombotic Immune Thrombocytopenia (VIPIT) Following AstraZeneca COVID-19 Vaccination". Ontario COVID-19 Science Advisory Table. Retrieved 3 April 2021.
  47. ^ "Covid: How does the Oxford-AstraZeneca vaccine work?". BBC. 6 April 2021. Retrieved 6 April 2021.
  48. ^ Ministerie van Volksgezondheid, Welzijn en Sport (8 April 2021). "Prikken met AstraZeneca voor mensen van 60 jaar en ouder gaat door - Nieuwsbericht - Rijksoverheid.nl". www.rijksoverheid.nl (in Dutch). Retrieved 8 April 2021.
  49. ^ ABC News (9 April 2021). "People under 50 turned away from Melbourne vaccination centre after new AstraZeneca advice". www.abc.net.au. Retrieved 9 April 2021.

Sources[edit]

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