Embolic and thrombotic events after COVID-19 vaccination

Post-vaccination embolic and thrombotic events, termed vaccine-induced immune thrombotic thrombocytopenia (VITT),[1][2][3] vaccine-induced prothrombotic immune thrombocytopenia (VIPIT), thrombosis with thrombocytopenia syndrome (TTS),[4][3] vaccine-induced immune thrombocytopenia and thrombosis (VITT),[5] or vaccine-associated thrombotic thrombocytopenia (VATT),[5] 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.[10] It was subsequently also described in the Janssen COVID‑19 vaccine (Johnson & Johnson), leading to the suspension of its use until its safety had been reassessed.[11]

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".[12][13][14] AstraZeneca initially denied the link, saying "we do not accept that TTS is caused by the vaccine at a generic level". However, later in legal documents filed in February 2024, AstraZeneca admitted its vaccine 'can, in very rare cases, cause TTS'.[15][16]

On 5 May 2022, the FDA posted a bulletin limiting the use of the Janssen Vaccine to very specific cases due to further reassessment of the risks of TTS, while also FDA also stating in the same bulletin that the benefits of the vaccine outweigh the risks.[17]

Multiple large cohort studies have demonstrated that thrombotic complications after COVID-19 vaccination are very rare, and occur far less frequently than after SARS-CoV-2 infection. A large study using data from more than 29 million people in England found that the risk of cerebral venous sinus thrombosis (CVST) after COVID-19 infection was roughly 8–10 times higher than after the Oxford–AstraZeneca vaccine, and several-fold higher than after mRNA vaccines.[18]

Another population-level analysis published in The BMJ showed that the incidence of thrombocytopenia and thromboembolic events after vaccination was orders of magnitude lower than after COVID-19 infection, concluding that "the risks of these adverse events are substantially higher following SARS-CoV-2 infection than after vaccination".[19] A third population-level analysis conculded similar, with its cohort studies revealing a "higher risk of arterial and venous thromboses after COVID-19 infection compared to vaccination".[20] Overall, the scientific consensus is that while rare vaccine-associated clotting syndromes can occur, COVID-19 infection poses a far greater thrombotic risk.

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.[10][1][21] 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.[22] Splanchnic vein thrombosis may cause abdominal pain, accumulation of fluid in the abdominal cavity, and gastrointestinal bleeding.[23][24]

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.[28] This phenomenon is mostly encountered in some people who have been administered heparin, but none of the reported cases had received heparin.[28] More rarely, this phenomenon had previously been described as an autoimmune phenomenon in people who had not been exposed to heparin.[29] 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.[30]

Thrombocytopenia is generally a common symptom after or during many viral infections,[31]

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.[25]

Management

Guidelines from professional societies recommend treatment with alternative anticoagulants instead of heparin, as there is a possibility that it may aggravate the phenomenon.[34][35] Alternative options as the directly acting oral anticoagulants (DOACs), argatroban, fondaparinux or danaparoid depending on the circumstances.[34] Platelet transfusion is discouraged, as this too may aggravate thrombosis.[34] UK guidelines by the British Society for Haematology recommend the administration of intravenous immunoglobulin (IVIG) to reduce levels of the pathogenic antibody.[34] Low fibrinogen levels may require correction with fibrinogen concentrate or cryoprecipitate.[34]

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.[36] 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.[37] The EMA had earlier said that a link between certain very rare blood clots and the AstraZeneca vaccine is "not proven, but is possible".[37]

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.[36]

History

Studies

A study convened by a group of British hematologists on 19 March 2021, just two days after the acknowledgement of the condition, published its finding in The New England Journal of Medicine, establishing case definition criteria. The study included 294 participants 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 haemorrhage. The study established that 85% of the participants affected by the condition were younger than 60 years, and that those participants 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.[61]

Multiple large cohort studies have demonstrated that thrombotic complications after COVID-19 vaccination are very rare, and occur far less frequently than after SARS-CoV-2 infection. A large study using data from more than 29 million people in England found that the risk of cerebral venous sinus thrombosis (CVST) after COVID-19 infection was roughly 8–10 times higher than after the Oxford–AstraZeneca vaccine, and several-fold higher than after mRNA vaccines.[62] Another population-level analysis published in The BMJ showed that the incidence of thrombocytopenia and thromboembolic events after vaccination was orders of magnitude lower than after COVID-19 infection, concluding that “the risks of these adverse events are substantially higher following SARS-CoV-2 infection than after vaccination.”[63]

Further reading