embolic and thrombotic events after covid-19 vaccination embolic and thrombotic events after covid-19 vaccination post-vaccination embolic and thrombotic events, termed vaccine-induced immune thrombotic thrombocytopenia (vitt), vaccine-induced prothrombotic immune thrombocytopenia (vipit), thrombosis with thrombocytopenia syndrome (tts), vaccine-induced immune thrombocytopenia and thrombosis (vitt), or vaccine-associated thrombotic thrombocytopenia (vatt), 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. on 5 may 2022 the fda posted a bulletin limiting the use of the janssen vaccine to very specific cases due to further reassesment of the risks of tts, although the fda also stated 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xenophobia and racism society ireland malaysia new zealand russia uk us covid-19 portal in april 2021, astrazeneca and the european medicines agency (ema) updated their information for healthcare professionals about azd1222, saying it is "considered plausible" that there is 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". signs and symptoms 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. causes the rare simultaneous occurrence of thrombocytopenia (low blood platelets) with blood clots after vaccination raised the original concern about this condition. 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, however ema is conducting investigations into azd1222 and the janssen covid‑19 vaccine (johnson & johnson) 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 people treated with heparin", that is heparin induced thrombocytopenia (hit). diagnosis 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. management 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. epidemiology 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 is 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 medicines and healthcare products regulatory agency (mhra) reporting regards azd1222 to 3 november 2021, recording 73 deaths out of 425 cases (17%) in the context of 24.9 million first doses administered. regulatory status according to the european medicines agency (ema), as of 28 march 2021, the reported number of cases of embolic and thrombotic events after vaccination is 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 on 7 april 2021, emer cooke, the executive director of the european medicines agency (ema) began by stating "our safety committee, the pharmacovigilance 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 medicines and healthcare products regulatory agency (mhra) held a news conference on 7 april 2021, and while there is no proof that the azd1222 vaccination caused the rare blood clots, they indicated the possibility of a link is getting stronger. the uk is to offer under 30s alternative vaccines. the reasoning is because in the 20-29 age range the benefits to individual of vaccination were less as their likelihood of harm from covid‑19 is 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 johnson & johnson 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 janssen vaccine remains positive. on 16 december 2021, the us centers for disease control and prevention (cdc) recommended the moderna and pfizer-biontech vaccines should be preferred over the janssen vaccine, following growing concerns about rare blood clots. janssen should still be offered to people who specifically request it. history organizations 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: european