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Thrombotic Thrombocytopenia After ChAdOx1 nCov-19 Vaccination
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This study was designed to evaluate clinical and laboratory features of 11 patients who developed thrombosis or thrombocytopenia after vaccination with ChAdOx1 nCov-19. Of the patients who developed thrombotic events, 9 had cerebral venous thrombosis, 3 had splanchnic vein thrombosis, 3 had pulmonary embolism, and 4 had other thromboses. Overall, 6 patients died. These patients were a median age of 36 years without prior heparin exposure and had a median platelet nadir of approximately 20,000 per cubic millimeter. The majority of samples had strong reactivity on platelet factor 4 (PF4) heparin and PF4 ELISA.
- At 1 to 2 weeks after vaccination with ChAdOx1 nCov-19, these young patients without heparin exposure developed a vaccine-induced immune thrombotic thrombocytopenia that resembles autoimmune heparin-induced thrombocytopenia. The authors offer therapeutic strategies such as treatment with high-dose IVIG to inhibit platelet activation by platelet-activating anti-PF4 antibodies.
abstract
This abstract is available on the publisher's site.
Access this abstract nowBACKGROUND
Several cases of unusual thrombotic events and thrombocytopenia have developed after vaccination with the recombinant adenoviral vector encoding the spike protein antigen of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) (ChAdOx1 nCov-19, AstraZeneca). More data were needed on the pathogenesis of this unusual clotting disorder.
METHODS
We assessed the clinical and laboratory features of 11 patients in Germany and Austria in whom thrombosis or thrombocytopenia had developed after vaccination with ChAdOx1 nCov-19. We used a standard enzyme-linked immunosorbent assay to detect platelet factor 4 (PF4)–heparin antibodies and a modified (PF4-enhanced) platelet-activation test to detect platelet-activating antibodies under various reaction conditions. Included in this testing were samples from patients who had blood samples referred for investigation of vaccine-associated thrombotic events, with 28 testing positive on a screening PF4–heparin immunoassay.
RESULTS
Of the 11 original patients, 9 were women, with a median age of 36 years (range, 22 to 49). Beginning 5 to 16 days after vaccination, the patients presented with one or more thrombotic events, with the exception of 1 patient, who presented with fatal intracranial hemorrhage. Of the patients with one or more thrombotic events, 9 had cerebral venous thrombosis, 3 had splanchnic-vein thrombosis, 3 had pulmonary embolism, and 4 had other thromboses; of these patients, 6 died. Five patients had disseminated intravascular coagulation. None of the patients had received heparin before symptom onset. All 28 patients who tested positive for antibodies against PF4–heparin tested positive on the platelet-activation assay in the presence of PF4 independent of heparin. Platelet activation was inhibited by high levels of heparin, Fc receptor–blocking monoclonal antibody, and immune globulin (10 mg per milliliter). Additional studies with PF4 or PF4–heparin affinity purified antibodies in 2 patients confirmed PF4-dependent platelet activation.
CONCLUSIONS
Vaccination with ChAdOx1 nCov-19 can result in the rare development of immune thrombotic thrombocytopenia mediated by platelet-activating antibodies against PF4, which clinically mimics autoimmune heparin-induced thrombocytopenia.
Additional Info
- Thrombosis and Thrombocytopenia After ChAdOx1 nCoV-19 Vaccination
- Thrombotic Thrombocytopenia After COVID-19 Vaccination
- Antibodies to Platelet Factor 4 After ChAdOx1 nCoV-19 Vaccination
- Pulmonary Embolism and Thrombocytopenia After COVID-19 Vaccination
- Adjunct Immune Globulin for Vaccine-Induced Thrombotic Thrombocytopenia
- Plasma Exchange in Vaccine-Induced Thrombocytopenia
Disclosure statements are available on the authors' profiles:
Thrombotic Thrombocytopenia After ChAdOx1 nCov-19 Vaccination
N. Engl. J. Med 2021 Apr 09;[EPub Ahead of Print], A Greinacher, T Thiele, TE Warkentin, K Weisser, PA Kyrle, S EichingerFrom MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
ChAdOx1 nCov-19 vaccine (AstraZeneca), approved by the European Medicines Agency since December 2020, has been widely administered to fight the Covid-19 pandemic. However, after being vaccinated with this vaccine, abnormal thrombotic events in combination with thrombocytopenia were observed in some individuals. This study by Greinacher et al used: 1) standard platelet factor 4 (PF4) enzyme-linked immunosorbent assay (PF4-ELISA); and 2) platelet-activation assay to provide evidence that this vaccine is the cause of those serious side effects. In more detail, 11 patients without heparin exposure who developed thrombosis or thrombocytopenia after vaccination with ChAdOx1 nCov-19 were assessed. The researchers found that patients’ sera that had tested positive in PF4-ELISA (confirmation of developing anti-PF4/heparin antibodies) would also be positive in the platelet-activation assay in the presence of PF4 (confirmation of having platelet-activating anti-PF4 antibodies). This means that the ChAdOx1 nCov-19 vaccine can trigger the immune system to produce aggressive platelet-activating antibodies against PF4 (similar to autoimmune heparin-induced thrombocytopenia antibodies). These antibodies mediated and activated platelets, causing the rare but severe immune thrombotic thrombocytopenia, which can lead to death. This, however, occurs in some rare cases, those with rare biological characteristics. Based on these results, the authors suggested potential diagnostic and therapeutic strategies for the management of suspected vaccine-induced immune thrombotic thrombocytopenia. Thus, this study provides insight into the side effects that the ChAdOx1 vaccine can create, and, in the current pandemic context, it urgently prompts a change in treatment and contributes to clinical management. This also poses a challenge in producing rapid test kits to detect potential risk factors in individuals prior to using this vaccine to avoid severe side effects.
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
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