The development of vaccines against COVID-19 has made it possible to reduce the risk for and severity of SARS-CoV-2 infection; however, concerns about the safety of vaccines continue to be raised [3,4,5]. Several cases of AA after COVID-19 vaccination including new onset and recurrence with variable severity and various outcomes have been reported [6,7,8,9,10,11]. Cases of AA that developed after vaccination with either adenoviral-vectored or mRNA vaccine subtypes and after vaccination with the first dose or multiple doses have been reported [6,7,8,9,10,11]. Historically, vaccines for hepatitis B virus, H1N1 influenza, and varicella-zoster virus have been shown to possibly induce AA [13,14,15,16,17]. Two important mechanisms of depletion of hematopoietic stem cells (HSCs) in AA have been reported: qualitative abnormalities of the HSCs themselves and damage to HSCs by immunologic mechanisms [2, 18]. In patients with AA, immune-mediated destruction of HSCs plays a central role in the pathophysiology, and inflammatory cytokines, such as tumor necrosis factor-α, γ-interferon and transforming growth factor-β, which are secreted from activated immune cells are thought to inhibit hematopoiesis [19,20,21,22,23]. A mechanism that is similar to the mechanism for the development of AA may exist in HMT patients with thrombocytopenia alone, possibly because the levels of myelosuppressive cytokines in the bone marrow of HMT patients are lower than those in AA patients [2].

Some cases of AA after COVID-19 vaccination recovered without treatment, but in most cases, various treatments, including blood transfusion, use of cyclosporine, thrombopoietin receptor agonists, rabbit anti-thymocyte globulin, corticosteroid, and granulocyte colony-stimulating factor and allogeneic hematopoietic stem cell transplantation, were needed [6,7,8,9,10,11]. It is currently unknown what factors contribute to the differences in prognosis. A recent study showed that patients with HMT that does not meet the diagnostic criteria for AA may potentially progress to AA [2]. Plasma TPO level is useful in assessing megakaryocyte counts, which tend to be higher in AA/HMT and lower in ITP [2, 24]. In this case, plasma TPO level was above the normal range, and considering his bone marrow findings, ITP was not suspected. Furthermore, it was shown that HMT patients with high levels of plasma TPO had better outcomes when treated with cyclosporine [2]. That study revealed that about half of the HMT patients had a pathophysiology similar to that of AA and suggested that early treatment with cyclosporine may improve the prognosis [2]. Measurement of the plasma TPO level might be useful for selecting the appropriate treatment in HMT patients. Although our case showed severe hypocellular marrow that was typical for AA, it did not strictly meet the diagnostic criteria for AA and was diagnosed as HMT. Since the patient’s plasma TPO level at the time of diagnosis was above the normal range, treatment with cyclosporine was considered to have been successful by referring to the previous report [2].

Although it is difficult to determine whether the development of a disease after vaccination was vaccine induced or accidental, various cases of autoimmune disease have been reported after COVID-19 vaccination including autoimmune hepatitis, type 1 diabetes mellitus, acquired hemophilia, ITP, and autoimmune hemolytic anemia as well as aggravation of pre-existing hematologic diseases such as PNH [7, 25,26,27,28,29,30,31,32,33,34,35]. Although the pathogenetic mechanisms by which vaccines cause the development of autoimmune diseases are not yet understood, almost all of the hematologic manifestations after COVID-19 vaccination in previous studies were thought to be related to autoimmune pathways [11]. In addition, there has been no method for predicting the development of autoimmune diseases after vaccination. Previous case reports showed that the initial symptoms related to cytopenia or the first complete blood count abnormalities were merged between the day after vaccination and three months later [6,7,8,9]. Before vaccination, our patient had no history of infection, change of medications, or other possible causes of cytopenia. Our patient’s timeline is consistent with that of other previously reported patients. Consequently, this case was most likely to have been COVID-19 vaccine-induced HMT rather than the expression of a pre-existing disease. However, one month has elapsed between the confirmation of a normal platelet count and vaccination. Therefore, we cannot rule out the possibility that thrombocytopenia had already occurred prior to the fourth vaccination. In addition to the accidental onset of the disease, the possibility that the previous vaccination was the cause cannot be ruled out.

It cannot be ruled out that the patient had a transient immunologic mechanism of cytopenia after the fourth vaccination and blood cell counts may have recovered in a few days without treatment. In contrast, anti-TPO receptor antibodies were reported to inhibit the binding of TPO to the TPO receptor and suppress megakaryocyte differentiation in the bone marrow [36]. Anti-TPO receptor antibody-positive cases also existed in ITP patients, with higher TPO levels and poorer responses to TPO receptor agonists [37]. High anti-TPO receptor antibody titers may cause a reactive increase in TPO. In our case, it may be possible that the patient had anti-TPO receptor antibodies, and the platelet count may have recovered rapidly due to the initial steroid therapy, cyclosporine or eltrombopag. Unfortunately, the measurement of anti-TPO receptor antibodies is unavailable in the usual laboratories, therefore, anti-TPO receptor antibodies could not be measured in this case.

In conclusion, vaccination with an mRNA-based COVID-19 vaccine may be associated with the development of HMT/AA and physicians should be aware of this rare but serious adverse event. If symptoms suggestive of cytopenia are merged after COVID-19 vaccination, hematologic evaluation should be performed promptly. Patients with high levels of plasma TPO, as in the present case, are likely to respond to cyclosporine and the use of cyclosporine should be considered as soon as possible. Further studies in large and prospective cohorts are required to elucidate the associations between COVID-19 vaccination and HMT/AA.