Thrombosis and Thrombocytopenia After ChAdOx1 nCoV-19 Vaccination

These two papers describe 16 European and Scandinavian patients who developed unusual thromboses within a short period of time after receiving Astra Zeneca’s COVID-19 vaccine CHaDOx1 nCov-19, which uses a chimpanzee adenoviral delivery system.^1,2 This syndrome is designated “vaccine-induced immune thrombotic thrombocytopenia,” or VITT. These findings prompted a pause in the use of this vaccine, most narrowly executed in the United Kingdom for those under 30 years of age. Johnson and Johnson’s AD26.COV2.s vaccine, which uses a relatively non-immunogenic human adenoviral delivery vector and has been deployed in the United States, appears to be associated with a similar syndrome in approximately 1/1,000,000 doses for a total of approximately 8 cases as of mid-April, the details of which have not yet been reported. This prompted the US FDA and CDC to pause vaccinating anyone by this method for at least 10 days beginning April 13, 2021.

Patients affected outside the United States were relatively young and mainly women; 13 of them suffered cerebral venous thromboses, and 4 suffered splanchnic vein thromboses (3 of whom also suffered cerebral venous thromboses). None received heparin, although all showed the presence in their serum of anti-heparin/PF4 antibodies using an ELISA, suggesting that the vaccine may have caused a platelet PF4 epitope change that recapitulates that caused by heparin, inducing antibodies that bound to this complex and activated platelets, leading to thrombocytopenia and, perhaps as in heparin-induced thrombocytopenia with thrombosis (HITT), binding to immunogenic PF4 on other blood cells and the vascular endothelium to promote thrombosis. Of note, intravenous adenoviral vector gene delivery systems are known to cause platelet activation, endothelial cell activation, and thrombocytopenia, and it is likely that these vaccine delivery systems, while engineered very differently from those used in gene therapy, contain the same structural elements allegedly involved in these phenomena.³

Heparin/PF4 binding and platelet activation were inhibited by heparin (suggesting competition for the antibody), and platelet activation was inhibited and clinical outcomes were improved by immunoglobulin (suggesting competition for the activating platelet Fc receptor). These observations directed the authors to recommend avoiding heparin anticoagulants (treat like HITT) and consider administering high-dose IVIG (treat like ITP). A detailed set of recommendations for diagnosis and treatment, including these, have been presented by the American Society of Hematology. They can be accessed at https://www.hematology.org/covid-19/vaccine-induced-immune-thrombotic-thrombocytopenia.

References

1. Greinacher A, Thiele T, Warkentin TE, et al. Thrombotic Thrombocytopenia after ChAdOx1 nCov-19 Vaccination. N Engl J Med. 2021 Apr 9. doi: 10.1056/NEJMoa2104840. Online ahead of print. https://www.nejm.org/doi/10.1056/NEJMoa2104840
2. Schultz NH, Sørvoll IH, Michelsen AE, et al. Thrombosis and Thrombocytopenia after ChAdOx1 nCoV-19 Vaccination. N Engl J Med. 2021 Apr 9. doi: 10.1056/NEJMoa2104882. Online ahead of print. https://www.nejm.org/doi/10.1056/NEJMoa2104882
3. Hofherr SE, Mok H, Gushiken FC, Lopez JA, Barry MA. Polyethylene glycol modification of adenovirus reduces platelet activation, endothelial cell activation, and thrombocytopenia. Hum Gene Ther. 2007;18(9):837-848. https://www.liebertpub.com/doi/10.1089/hum.2007.0051

VITT—Vaccine-Induced Immune Thrombotic Thrombocytopenia

This new entity VITT (vaccine-induced immune thrombotic thrombocytopenia) has been in the news recently. Initially, it was only associated with the AstraZeneca/Oxford vaccine; but, more recently, the Johnson & Johnson vaccine has been implicated as well.

This all started with a few patients who had received the AstraZeneca vaccine. These patients developed thrombosis, a low platelet count, and bleeding. Smart clinicians realized that this looked very similar to heparin-induced thrombocytopenia (HIT).

With HIT, the patient takes heparin and the heparin forms a complex with PF4 (platelet factor 4). Certain patients have B cells that can make an antibody that binds onto the PF4–heparin complex. This new antibody complex can now attach to platelets and activate them. This unregulated platelet activation is believed to be the cause of the thrombosis in these cases.

The remaining platelets still have an antibody complex on them. The immune cells in the spleen remove them as if they are foreign entities that been tagged by the antibody. This removal of the platelets by the spleen leads to a low platelet count. This low platelet count increases the risk of bleeding. This is the explanation as to why HIT patients experienced thrombosis, low platelets, and bleeding. With VITT, the mechanism is the same except there is no heparin. The trigger event is from the adenovirus-based vaccines.

These two articles detail 5 patients in Norway and 11 in Germany who developed VITT after receiving the AstraZeneca/Oxford vaccine.^1,2 Both papers reported that the patients had high levels of the anti–PF4–heparin antibodies, which were seen in the HIT patients. The symptoms of thrombosis started between 5 to 16 days after the vaccine was delivered. The theory currently is that the adenovirus, which is used to deliver the DNA for the spike protein, may be the trigger for this antibody complex. That is why there have been cases of VITT reported with both AstraZeneca and the Johnson & Johnson vaccines; they are both adenovirus-based vaccines.

With the great similarity to HIT, patients with VITT are now being managed in the same way as a patient with HIT. For now, heparin is avoided and NOACs are used in its place and high-dose IVIG (immunoglobulin) is used, which inhibits the anti–PF4–heparin antibodies. This results in a rapid rise in platelet counts, and, despite higher platelet counts, there is no increase in thrombosis, which means that, once the abnormal antibody is neutralized, the platelets are able to function normally. So, this is not a platelet issue.

The real question is how many people have these antibodies. In a study of 4000 samples from blood donors,³ the anti–PF4–heparin antibody was detected in 4.3% to 6.6% of the samples, which makes it quite a common antibody. But we don’t see these patients that often. It turns out that many people have the B cells that can make the anti–PF4–heparin antibody, but they are suppressed. So, even if people have the ability to make this antibody, the B cells are told not to make it, which is why this clotting phenomenon is rare. Mice that are missing protein kinase Cδ (PKCδ), which helps control the B-cell antibody production, produce anti–PF4–heparin antibodies spontaneously.⁴ These mice do not need heparin or an adenovirus vaccine to trigger the production.

As long as those B cells have a normal regulation system, these antibodies will not be made in any significant quantities, and hence the majority of people will not develop VITT. However, if this suppression is not functioning there are clinical consequences. Could it be that younger females may not be suppressing that production, which is why more cases were seen in younger females? Yet, a 63-year-old male developed VITT as well. And how do the adenovirus-based vaccines trigger these B cells? So, there is much more to learn about what makes our B cells produce or not produce antibodies.

We may never get a complete answer, but at least we know which antibody is the culprit and we have a strategy on how to manage these patients.

Now, for HIT, if a patient never gets heparin his whole life, he will never know he had those antibodies. But, with a mass vaccination program, these patients will turn up, and so we need to be alert and identify them early on in order to avoid any permanent damage from the thrombosis. Early recognition of clinical symptoms and rapid testing for the antibodies will help us to protect these patients.

Monitor for severe headache, visual changes, shortness of breath or chest pain, abdominal pain, nausea/vomiting, swelling or pain in the legs, bruising, or petechia.

References

1. Schultz NH, Sørvoll IH, Michelsen AE, et al. Thrombosis and Thrombocytopenia after ChAdOx1 nCoV-19 Vaccination. N Engl J Med. 2021 Apr 9. doi: 10.1056/NEJMoa2104882. Online ahead of print. https://www.nejm.org/doi/10.1056/NEJMoa2104882
2. Greinacher A, Thiele T, Warkentin TE, et al. Thrombotic Thrombocytopenia after ChAdOx1 nCov-19 Vaccination. N Engl J Med. 2021 Apr 9. doi: 10.1056/NEJMoa2104840. Online ahead of print. https://www.nejm.org/doi/10.1056/NEJMoa2104840
3. Hursting MJ, Pai PJ, McCracken JE, et al. Platelet factor 4/heparin antibodies in blood bank donors. Am J Clin Pathol. 2010;134(5):774-780. https://academic.oup.com/ajcp/article/134/5/774/1766185
4. Zheng Y, Wang AW, Yu M, et al. B-cell tolerance regulates production of antibodies causing heparin-induced thrombocytopenia. Blood. 2014;123(6):931-934. https://ashpublications.org/blood/article/123/6/931/32598/B-cell-tolerance-regulates-production-of