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Post-vaccination embolic and thrombotic events, also termed vaccine-induced prothrombotic immune thrombocytopenia (VIPIT),vaccine-induced immune thrombotic thrombocytopenia (VITT), or thrombosis with thrombocytopenia syndrome (TTS) are rare types of blood clotting syndromes that were initially observed in a number of people who had previously received the Oxford–AstraZeneca COVID-19 vaccine (AZD1222) during the COVID-19 pandemic. It was subsequently also described in the Janssen COVID-19 vaccine (Johnson & Johnson) leading to suspension of its use until its safety had been reassessed.
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".
The thrombosis events associated with the COVID-19 vaccine may occur 4-28 days after its administration and mainly affects women under 55.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. Cerebral venous sinus thrombosis may cause severe headache, stroke-like symptoms (weakness of a limb and/or facial muscles), seizures and coma. Splanchnic vein thrombosis may cause abdominal pain, accumulation of fluid in the abdominal cavity, and gastrointestinal bleeding.
Other forms of thrombosis, such as the more common pulmonary embolism, may also occur. Arterial thrombosis has also been reported.The low platelet count may manifest as petechia (tiny blood spots under the skin) beyond the site of the injection.
Disseminated intravascular coagulation (DIC), diffuse formation of blood clots throughout the blood vessels of the body, has been reported as part of the syndrome.DIC may cause a range of symptoms, including abnormal bleeding, breathlessness, chest pain, neurological symptoms, low blood pressure, or swelling.
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.
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. This phenomenon is mostly encountered in some people who have been administered heparin, but none of the reported cases had received heparin. More rarely, this phenomenon had previously been described as an autoimmune phenomenon in people who had not been exposed to heparin. 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.
Thrombocytopenia is generally a common symptom after or during many viral infections,and it "has been consistently reported" after intravenous administration of adenoviral gene transfer vectors, 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 Janssen COVID-19 vaccine (J&J) for possible causal links.
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).
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.
Guidelines from professional societies recommend treatment with 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. Platelet transfusion is discouraged, as this too may aggravate thrombosis. UK guidelines by the British Society for Haematology recommend the administration of intravenous immunoglobulin (IVIG) to reduce levels of the pathogenic antibody. Low fibrinogen levels may require correction with fibrinogen concentrate or cryoprecipitate.
This section needs to be updated. The reason given is: Needs to ensure latest data is reflected. Marked as inacc as the information presented was not originally the basis of an "Epidemiology" section, but discussion of age and possibly gender on the topic are relevant as vaccinations by countries may not have been spread evenly throughout ages and genders..(April 2021)
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.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. The EMA had earlier said that a link between certain very rare blood clots and the AstraZeneca vaccine is "not proven, but is possible".
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.The UK, in contrast, has applied its Pfizer and AZD1222 vaccines generally to older groups first, then by decreasing age.
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.
According to the European Medicines Agency (EMA), as of 28 March 2021 [update] , the reported number of cases of embolic and thrombotic events after vaccination was lower than the rate of such events in the general population overall. However, the specific syndrome - of embolic and thrombotic events in combination with low levels of blood platelets - presenting in post-vaccination cases raised the possibility of an association between the vaccine and the relatively rare syndrome. 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. 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.
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".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". 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".
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.The UK was to offer under 30s alternative vaccines. 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). For higher age groups the benefit to risk ratio increased.
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".
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.
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:
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.
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".
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.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.
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.
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, amongst people who had taken the Janssen 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.
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, [ better source needed ] their data skewing towards these specific blood clots being more prevalent in AZD1222 vaccinated persons of younger ages.UK MHRA found examples across all genders and ages,
The WHO has continued to stress the administration of vaccines is based on risk versus benefit analysis.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.
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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.
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.
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.
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."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. 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.
A study convened by a group of British hematologists on March 19, 2021, just 2 days after the acknowledgement of the condition, published its finding The New England Journal of Medicine, establishing case definition criteria. The study included 294 patients who presented with symptoms of thrombocytopenia and thrombosis after receipt of the first dose of the Oxford–AstraZeneca COVID-19 vaccine, showing an independent association between baseline platelet count and the presence of intracranial hemorrhage. The study established that 85% of the patients effected by the condition were aged younger than 60 years, and that those patients with a history of thrombosis or prothrombotic disorders did not appear to be at increased risk. The study showed an overall mortality rate of 22% and set out plans for additional research to determine the genetic factors that may increase risk of the condition and identify potential therapeutic agents.
AstraZeneca plc is a British-Swedish multinational pharmaceutical and biotechnology company with its headquarters at the Cambridge Biomedical Campus in Cambridge, England. It has a portfolio of products for major diseases in areas including oncology, cardiovascular, gastrointestinal, infection, neuroscience, respiratory, and inflammation. It has been involved in developing the Oxford-AstraZeneca COVID-19 vaccine.
Heparin-induced thrombocytopenia (HIT) is the development of thrombocytopenia, due to the administration of various forms of heparin, an anticoagulant. HIT predisposes to thrombosis because platelets release microparticles that activate thrombin, thereby leading to thrombosis. When thrombosis is identified the condition is called heparin-induced thrombocytopenia and thrombosis (HITT). HIT is caused by the formation of abnormal antibodies that activate platelets. If someone receiving heparin develops new or worsening thrombosis, or if the platelet count falls, HIT can be confirmed with specific blood tests.
The Medicines and Healthcare products Regulatory Agency (MHRA) is an executive agency of the Department of Health and Social Care in the United Kingdom which is responsible for ensuring that medicines and medical devices work and are acceptably safe.
The Therapeutic Goods Administration (TGA) is the medicine and therapeutic regulatory agency of the Australian Government. As part of the Department of Health, the TGA regulates the quality, supply and advertising of medicines, pathology devices, medical devices, blood products and most other therapeutics. Any items that claim to have a therapeutic effect, are involved in the administration of medication, or are otherwise covered by the Therapeutic Goods Act 1989, the Therapeutic Goods Regulations 1990, or a ministerial order, must be approved by the TGA and registered in the Australian Register of Therapeutic Goods.
Platelet factor 4 (PF4) is a small cytokine belonging to the CXC chemokine family that is also known as chemokine ligand 4 (CXCL4). This chemokine is released from alpha-granules of activated platelets during platelet aggregation, and promotes blood coagulation by moderating the effects of heparin-like molecules. Due to these roles, it is predicted to play a role in wound repair and inflammation. It is usually found in a complex with proteoglycan.
The Joint Committee on Vaccination and Immunisation (JCVI) is an independent expert advisory committee that advises United Kingdom health departments on immunisation, making recommendations concerning vaccination schedules and vaccine safety. It has a statutory role in England and Wales, and health departments in Scotland and Northern Ireland may choose to accept its advice.
Cerebral venous sinus thrombosis (CVST), cerebral venous and sinus thrombosis or cerebral venous thrombosis (CVT), is the presence of a blood clot in the dural venous sinuses, the cerebral veins, or both. Symptoms may include severe headache, visual symptoms, any of the symptoms of stroke such as weakness of the face and limbs on one side of the body, and seizures.
A COVID‑19 vaccine is a vaccine intended to provide acquired immunity against severe acute respiratory syndrome coronavirus 2 (SARS‑CoV‑2), the virus that causes coronavirus disease 2019 (COVID‑19). Prior to the COVID‑19 pandemic, an established body of knowledge existed about the structure and function of coronaviruses causing diseases like severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS). This knowledge accelerated the development of various vaccine platforms during early 2020. The initial focus of SARS-CoV-2 vaccines was on preventing symptomatic, often severe illness. On 10 January 2020, the SARS-CoV-2 genetic sequence data was shared through GISAID, and by 19 March, the global pharmaceutical industry announced a major commitment to address COVID-19. The COVID‑19 vaccines are widely credited for their role in reducing the spread, severity, and death caused by COVID-19.
The Oxford–AstraZeneca COVID-19 vaccine, codenamed AZD1222, and sold under the brand names Covishield and Vaxzevria among others, is a viral vector vaccine for prevention of COVID-19. Developed in the United Kingdom by the Oxford University and British-Swedish company AstraZeneca, using as a vector the modified chimpanzee adenovirus ChAdOx1. The vaccine is given by intramuscular injection. Studies carried out in 2020 showed that the efficacy of the vaccine is 76.0% at preventing symptomatic COVID-19 beginning at 22 days following the first dose and 81.3% after the second dose. A study in Scotland found that, for symptomatic COVID-19 infection after the second dose, the vaccine is 81% effective against the Alpha variant, and 61% against the Delta variant.
The COVID-19 vaccination programme in the United Kingdom is an ongoing mass immunisation campaign for coronavirus disease 2019 (COVID-19) during the COVID-19 pandemic in the United Kingdom. The UK's vaccination rollout was the world's first mass immunisation programme for the disease when it began on 8 December 2020 after Margaret Keenan received her first dose of two. As of 6 October 2021, 49,068,705 first doses and 45,078,529 second doses of a vaccine had been administered across the UK.
The COVID-19 vaccination campaign in Italy is a mass immunization campaign that was put in place by the Italian government in order to respond to the ongoing COVID-19 pandemic. It started on 27 December 2020, together with most countries in the European Union.
The Janssen COVID-19 vaccine or Johnson & Johnson COVID-19 vaccine is a COVID-19 vaccine that was developed by Janssen Vaccines in Leiden, Netherlands, and its Belgian parent company Janssen Pharmaceuticals, subsidiary of American company Johnson & Johnson.
COVID-19's caused virus, SARS-CoV-2, was isolated in late 2019. Its genetic sequence was published on 11 January 2020, triggering an urgent international response to prepare for an outbreak and hasten development of a preventive COVID-19 vaccine. Since 2020, vaccine development has been expedited via unprecedented collaboration in the multinational pharmaceutical industry and between governments. By June 2020, tens of billions of dollars were invested by corporations, governments, international health organizations, and university research groups to develop dozens of vaccine candidates and prepare for global vaccination programs to immunize against COVID‑19 infection. According to the Coalition for Epidemic Preparedness Innovations (CEPI), the geographic distribution of COVID‑19 vaccine development shows North American entities to have about 40% of the activity, compared to 30% in Asia and Australia, 26% in Europe, and a few projects in South America and Africa.
The general COVID-19 vaccination in Australia program began on 22 February 2021 in response to the COVID-19 pandemic, and will continue with the goal of vaccinating all willing Australians before 2022. Front-line workers and aged care staff and residents will be the first Australians to be inoculated, before a gradual phased release to less-vulnerable and lower-risk population groups throughout 2021. The Therapeutic Goods Administration (TGA) approved four vaccines for Australian use in 2021: the Pfizer–BioNTech vaccine on 25 January, the Oxford–AstraZeneca vaccine on 16 February, Janssen vaccine on 25 June and the Moderna vaccine on 9 August. Although approved for use, the Janssen vaccine is not included in the Australian vaccination program.
A dispute broke out in January 2021 between the European Commission and the pharmaceutical company AstraZeneca AB about the provision of COVID-19 vaccines during the COVID-19 pandemic, and, in February, spilled out into a dispute over Article 16 of the Northern Ireland Protocol. Vaccination proceeded apace in the UK but more slowly in the EU, and by the end of March 2021, over 30% of the UK population had received at least one dose of vaccine compared to about 8% of the EU population. This was partly due to limited availability of the AstraZeneca vaccine in the EU. The World Health Organization and the European Medicines Agency continued to state that the vaccine was safe and effective. However, a representative of the European Medicines Agency said in June that vaccines based on the mRNA technology should be preferred if available for all age groups, including for the over 60s.
COVID-19 vaccination in Romania started on 27 December 2020. It was announced that the process would be divided into three phases. Medical personnel would be vaccinated first, followed by the population at risk, and finally by the rest of the population. Vaccination was declared free and non-mandatory. As of May 2021, four types of vaccines were authorized to be used in Romania. This is the largest vaccination campaign in the modern history of Romania.
The COVID-19 vaccination programme in the Republic of Ireland is an ongoing mass immunisation campaign that began on 29 December 2020 in response to the COVID-19 pandemic in the Republic of Ireland. Ireland's vaccination rollout has been praised as one of the most successful rollouts in the world and is currently ranked number one in the European Union in terms of its percentage of adult population fully vaccinated.
Shelley Deeks is a Canadian public health expert who is the Chair of the National Advisory Committee on Immunization. Her advertised "specialities include communicable disease control, outbreak investigations, vaccine safety, epidemiology and program evaluation." She is a fellow of the Royal College of Physicians of Canada and the Australian Faculty of Public Health Medicine.
The COVID-19 vaccination campaign in Germany began on 26 December 2020. As of 19 September 2021, 55,869,314 people have received at least one dose, while 52,503,166 people have been fully vaccinated.
Denmark started vaccinating against COVID-19 on 27 December 2020. Vaccination in Denmark is free of cost and voluntary. It is available to all residents of Denmark and those from abroad staying for more than 30 days in Denmark. Denmark has one of the highest levels of COVID-19 vaccination in the European Union as of the end of September 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.
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.