Reports began to appear from Europe in early March 2021 that several patients who had been vaccinated with the Oxford-AztraZeneca (AZ) COVID-19 vaccine developed blood clots (thrombi) that in some patients broke loose and traveled to the lungs (pulmonary emboli). As the number of reports of thromboembolic events in recipients of this COVID-19 vaccine continued to grow across Europe and the UK, many countries suspended use of the AZ vaccine. Initially, a particular batch (ABV5300) of AZ vaccine, which had been widely distributed in Europe, was suspected to be at fault, but AstraZeneca denied there was any evidence of an increased risk of pulmonary embolism or deep vein thrombosis in any defined age group, gender, or batch, or in any particular country (1).
Then, in mid-March, the clinical picture in the affected AZ vaccine recipients became clearer. Many of the patients had developed moderate to severe thrombocytopenia in addition to blood clots at unusual and critical sites, particularly clots blocking veins that drain blood from the brain (called cerebral venous sinus thrombosis, or CVST). In some patients, CVST was associated with cerebral hemorrhage and blood clots in splanchnic veins (that is, the portal, splenic, gastric, mesenteric, and suprahepatic veins) that drain blood from abdominal organs. Most affected patients were previously healthy women between 20 and 50 years of age. Symptoms included severe headache, abdominal pain, nausea and vomiting, vision changes, shortness of breath, and/or leg pain and swelling that developed 4 to 20 days after COVID-19 vaccination. At that point, several countries decided to reserve AZ vaccine for older age groups in which no increased rate of thromboembolic conditions was observed.
As of April 4, 169 cases of CVST and 53 cases of splanchnic venous thrombosis had been reported in the EU and UK among the 34 million people who had received the AZ vaccine, and more than 30 patients died (2). The clinical picture of severe clotting and thrombocytopenia after COVID-19 vaccination has come to be called vaccine-induced immune thrombotic thrombocytopenia or VITT (3).
At that time, only the mRNA COVID-19 vaccines had been available in the US. At least 17 patients in the US were reported to have developed immune thrombocytopenia (ITP) within 2 weeks after receiving the Pfizer or Moderna COVID-19 mRNA vaccines (4); however, no thrombotic events, such CVST or splanchnic venous thrombosis, were reported to have accompanied thrombocytopenia in these patients (5).
In early to mid-April, a possible mechanism for VITT was delineated in 3 articles published in the New England Journal of Medicine. The articles describe the clinical and laboratory characteristics of VITT in 11 patients in Germany and Austria (6), in 5 patients in Norway (7), and in 23 patients in the UK (8). These studies suggest that VITT is mediated by the development of platelet-activating antibodies against platelet factor 4 (PF4) after vaccination, which clinically mimics heparin-induced thrombocytopenia (HIT). As in HIT, laboratory evaluation of these patients shows thrombocytopenia, markedly elevated D-dimer, low fibrinogen levels, and a positive PF4/heparin enzyme-linked immunosorbent assay (ELISA). Unlike in HIT, however, these AZ vaccinated patients did not receive heparin before the onset of the disease. Clinical and laboratory features of a HIT-like syndrome, in the absence of heparin, have been described in the past following administration of certain drugs, such as polyanionic drugs (eg, pentosan polysulfate), and after infections (6). Such rapid progress in understanding the pathophysiology of VITT is truly amazing, and it is hoped that our further understanding will only continue to rapidly evolve.
HIT is a type of drug-induced immune-mediated thrombocytopenia, accompanied by both venous and arterial thrombosis, that develops in up to 3% of patients usually 5 to 10 days (range 4 to 15 days) after heparin is started, and is caused by IgG antibodies that bind to large heparin/PF4 complexes; the Fc portion of the antibody then binds to a receptor on the platelet surface, which activates the platelet to result in a hypercoagulable state, resulting in thrombocytopenia and thrombosis. Binding of PF4 with endothelial cell-bound heparan sulfate and subsequent antibody binding result in direct activation of endothelial cells, accelerating the procoagulant activity (9). HIT can occur with unfractionated heparin or low molecular weight heparin (eg, enoxaparin). Laboratory diagnosis of HIT is based on the immunological detection of antibodies directed against the PF4/heparin complex, using commercially available enzyme-linked immunosorbent assays (ELISA). The diagnosis is confirmed by a platelet activation assays (eg, heparin-induced platelet-activation [HIPA] test or a serotonin release assay), but these tests are not always readily available.
Therapeutic recommendations for VITT are based on therapy for HIT because of the similarities between the two conditions (10). Once HIT or VITT is suspected, all forms of heparin therapy should be immediately stopped, including heparin flushes, heparin-coated catheters, and therapeutic intravenous heparin. Use of platelet transfusions, low molecular weight heparins, or warfarin is not recommended. Alternate anticoagulation with argatroban or lepirudin, two direct thrombin inhibitors (DTIs) approved by the US Food and Drug Administration (FDA) for the management of HIT, is recommended. High-dose intravenous immunoglobulin (IVIG) rapidly inhibits HIT or VITT antibody-induced platelet activation and is an important adjunct for the treatment of HIT or VITT (11).
On April 13, after about 7 million doses of the Johnson & Johnson/Janssen (J&J) COVID-19 vaccine had been administered in the US, the US Centers for Disease Control and Prevention (CDC)and FDA reported that 6 J&J vaccine recipients developed CVST and thrombocytopenia 6 to 13 days after vaccination. As of April 21, after about 8 million vaccine doses, the number of cases of CVST rose to 12; 3 patients had other forms of thrombosis (12), and 3 died. All cases were women; 13 were 18 to 49 years old, and 2 were over 50 years. All 11 of the patients tested for PF4-heparin ELISA antibody test were positive. One more case of CVST and thrombocytopenia, a 25-year-old male vaccine recipient, occurred in the approximately 50,000 participants in the J&J clinical trial (13). This vaccine recipient was subsequently found to have had antibodies against PF4 at the time of the event (14, 15). The J&J vaccine is adenovirus (Ad) vectored, as is the AZ vaccine, which led some experts to speculate a link between this type of vaccine platform and VITT (14).
The Ebola vaccine, another Ad vectored vaccine, made by Johnson & Johnson, which is the first Ad vectored vaccine approved for general use, is not known to be complicated by blood clotting problems or thrombocytopenia. Currently, there are 4 COVID-19 Ad vectored vaccines, namely, the AZ (which uses a chimpanzee Ad), J&J (which uses human Ad serotype 26, as does the J&J Ebola vaccine), CanSino (which uses a human Ad5), and Sputnik V (which also uses human Ad26 for the first dose and human Ad serotype 5 for the second dose). However, the AZ vaccine’s chimpanzee Ad and the J&J vaccine’s human Ad26 vectors are from different Ad species and use different host cell receptors. Thrombosis and/or thrombocytopenia are not mentioned as adverse reactions to Sputnik V or CanSino vaccines.
These 4 COVID-19 vaccines use modified (non-replicating) Ad vectors, which cannot by themselves cause infection. Human adenoviruses in nature commonly cause respiratory tract infections, gastroenteritis and keratoconjunctivitis, which are not known to be complicated by blood clotting problems or thrombocytopenia. However, platelets do have a surface receptor for adenoviruses, which may have relevance in recipients of an Ad vectored COVID-19 vaccine (16). In a new preprint of a study (17), constituents of the Ad vaccine components, including adenovirus particles, are shown by transmission electron microscopy (TEM) to bind to PF4, forming multimolecular aggregates that trigger an immune response that leads to highly reactive anti-PF4 antibodies and prothrombotic consequences.
The trigger for thrombosis and thrombocytopenia in recipients of the Ad vectored COVID-19 vaccines, nevertheless, might not be adenovirus vector, but the spike protein these vaccines induce in the vaccine recipients, especially in view of CVST being found in mRNA vaccine recipients (see below) and the fact that both thrombosis and thrombocytopenia are integral components of SARS-CoV-2 infection. Deep-vein thrombosis and associated pulmonary embolism, as well as arterial thrombotic events (stroke, myocardial infarction, limb artery thrombosis) and thrombosis at unusual sites, such as cerebral venous sinus thrombosis, and splanchnic vein thrombosis occur in both COVID-19 and HIT (18). One major distinction: Pulmonary endothelial damage caused by SARS-CoV-2 cell invasion followed by platelet aggregation in the lungs results in extensive in situ pulmonary microvascular thrombosis in COVID-19 (19), which is said to be uncommon in HIT (18).
In a study of COVID-19 patients hospitalized in Wuhan, China, a positive PF4/heparin enzyme-linked immunosorbent assay (ELISA) was found not only in patients who received heparin, but also in COVID-19 patients who had not been exposed to heparin (20), suggesting to the Wuhan investigators the possibility of “spontaneous HIT” in COVID-19, where a HIT-like condition in critically ill COVID-19 patients is occurring in the absence of heparin. Confirmation of the diagnosis of spontaneous HIT in these COVID-19 patients from Wuhan, which would have required referral of serum for specialized laboratory investigations (21), however, was not done. It remains to be established whether spontaneous HIT complicates COVID-19 and whether the trigger is the spike protein, which is common to VITT following COVID-19 vaccines and spontaneous HIT in COVID-19.
To put the occurrence of VITT in proper perspective, it is necessary to compare VITT’s frequency in vaccine recipients with that of thrombosis and thrombocytopenia in patients with COVID-19. CVST, the severe blood clots in the brain, has been of most concern in relation to the vaccine recipients. A recent study compared the frequency of CVST in COVID-19 in the US with its frequency in people vaccinated with one of the two mRNA vaccines (Pfizer and Moderna) in the US, using the same data set (a federated electronic health records network recording anonymized data from 59 healthcare organizations, primarily in the USA, totaling 81 million patients—22). CVST was found to be very rare; but its frequency in COVID-19 (39 cases in a million) was about 10-fold greater than the frequency of CVST in the two weeks after mRNA vaccination (4 in a million) and the frequency of CVST in COVID-19 was about 100-fold greater than the frequency of CVST in the general population (0.41 cases in a million over any two-week period). Comparisons with the frequency of CVST following AZ vaccine (169 cases of CVST in 34 million AZ vaccine recipients or 5 in a million) are difficult, because the AZ vaccine data come from a different, European Medicines Agency (EMA), data source (2).
An additional consideration is the frequency of VITT in vaccine recipients compared to COVID-19 vaccine efficacy: In unvaccinated people, COVID-19, with a case fatality rate of 1 to 2%, will kill an estimated 10,000 to 20,000 people/million symptomatic cases of COVID-19 (23). The AZ, J & J, Pfizer, and Moderna COVID-19 vaccines have been shown to prevent hospitalization and death from COVID-19 in all vaccine recipients. Thus, the risk of VITT following COVID-19 vaccination remains very low compared with the vaccine’s benefits.
All vaccines have rare adverse events. Clinical trials disclose adverse events that are relatively common, but only after FDA approval, when many millions will have been vaccinated, will relatively uncommon adverse events come to light. Post-marketing surveillance, that is, the practice of monitoring safety after a vaccine has been released on the market, is an important component of pharmacovigilance. On April 20, 2021, the safety committee of the EMA concluded that in regard to the J & J vaccine “COVID-19 is associated with a risk of hospitalization and death. The reported combination of blood clots and low blood platelets is very rare, and the overall benefits of [the Johnson & Johnson vaccine] in preventing COVID-19 outweigh the risks of side effects” and also concluded that a warning about blood clots and low blood platelets should be listed as very rare side effects of the vaccine (24). A similar EMA conclusion had been made earlier concerning the AZ vaccine (2). The CDC and FDA reached similar conclusions about the J & J vaccine (25).
1. AstraZeneca blood clotting fear: What’s wrong with Covid vaccine? Business Today March 16, 2021. Accessed April 26, 2021. Available at https://www.businesstoday.in/current/economy-politics/aztrazeneca-blood-clotting-fear-whats-wrong-with-covid-vaccine/story/433992.html
2. European Medicines Agency: AstraZeneca’s COVID-19 vaccine: EMA finds possible link to very rare cases of unusual blood clots with low blood platelets. April 7, 2021. Accessed April 26, 2021. Available at https://www.ema.europa.eu/en/news/astrazenecas-covid-19-vaccine-ema-finds-possible-link-very-rare-cases-unusual-blood-clots-low-blood
3. Bussel JB, Connors JM, Cines DB, et al: Thrombosis with thrombocytopenia syndrome (also termed vaccine-induced thrombotic thrombocytopenia. Version 1.2. American Society of Hematology April 25, 2021. https://www.hematology.org/covid-19/vaccine-induced-immune-thrombotic-thrombocytopenia
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11. Warkentin TE: High-dose intravenous immunoglobulin for the treatment and prevention of heparin-induced thrombocytopenia: A review. Expert Review of Hematology 12(8):685–698, 2019. https://www.tandfonline.com/doi/full/10.1080/17474086.2019.1636645
12. Frellick M: CDC panel: End pause of J & J vaccine, but add warning. Medscape Medical News April 23, 2021. https://www.medscape.com/viewarticle/949910?src=mkm_covid_update_210423_MSCPEDIT&uac=130759PG&impID=3331302&faf=1
13. Sadoff J, Davis K, Douoguih M: Thrombotic thrombocytopenia after Ad26.COV2.S vaccination—response from the manufacturer [letter]. New Engl J Med April 16, 2021. DOI: 10.1056/NEJMc2106075 https://www.nejm.org/doi/full/10.1056/NEJMc2106075
14. Muir KL, Kallam A, Koepsell SA, Gundabolu K: Thrombotic thrombocytopenia after Ad26.COV2.S vaccination [letter]. New Engl J Med April 14, 2021. DOI: 10.1056/NEJMc2105869 https://www.nejm.org/doi/full/10.1056/NEJMc2105869
15. Gallagher G: European regulators recommend adding blood clot warning to J & J vaccine. Healio infectious Disease News April 20, 2021. https://www.healio.com/news/infectious-disease/20210420/european-regulators-recommend-adding-blood-clot-warning-to-jj-vaccine?utm_source=selligent&utm_medium=email&utm_campaign=news&M_BT=3679670404669
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17. Greinacher A, Selleng K, Wesche J, et al: Towards understanding ChAdOx1 nCov-19 vaccine-induced immune thrombotic thrombocytopenia (VITT). April 20, 2021 PREPRINT version1. Available at Research Square DOI: 10.21203/rs.3.rs-440461/v1 https://www.researchsquare.com/article/rs-440461/v1
18. Warkentin TE, Kaatz S: COVID-19 versus HIT hypercoagulability. Thromb Res 196:38-51, 2020. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7416717/
19. Chen W, Pan JY: Anatomical and pathological observation and analysis of SARS and COVID-19: Microthrombosis is the main cause of death. Biological Procedures Online 23,4 (2021). https://biologicalproceduresonline.biomedcentral.com/articles/10.1186/s12575-021-00142-y
20. Liu X, Zhang X, Xiao Y, et al: Heparin-induced thrombocytopenia is associated with a high risk of mortality in critical COVID-19 patients receiving heparin-involved treatment. April 28, 2020.PREPRINT Available at medRxiv 2020.04.23.20076851. https://www.medrxiv.org/content/10.1101/2020.04.23.20076851v1.full#F4
21. Warkentin TE, Basciano PA, Knopman J, et al: Spontaneous heparin-induced thrombocytopenia syndrome: 2 new cases and a proposal for defining this disorder. Blood 123(23):3651-3654, 2014. https://ashpublications.org/blood/article/123/23/3651/33171
22. Taquet M, Husain M, Geddes JR, et al: Cerebral venous thrombosis and portal vein thrombosis: a retrospective cohort study of 537,913 COVID-19 cases. OSF https://osf.io/a9jdq/
23. Ritchie H, Ortiz-Ospina E, Beltekian D, et al: Mortality risk of COVID-19: How did confirmed deaths and cases change over time? Published online at OurWorldInData.org. Available at https://ourworldindata.org/mortality-risk-covid#how-did-confirmed-deaths-and-cases-change-over-time
24. European Medicines Agency: COVID-19 vaccine Janssen: EMA finds possible link to very rare cases of unusual blood clots with low blood platelets. April 20, 2021. https://www.ema.europa.eu/en/news/covid-19-vaccine-janssen-ema-finds-possible-link-very-rare-cases-unusual-blood-clots-low-blood
25. US Food and Drug Administration: Janssen COVID-19 vaccine. Updated April 23, 2021. Janssen COVID-19 Vaccine | FDA