Acquired Pure Red Cell Aplasia Following BNT162b2 mRNA COVID-19 Vaccination

Abstract

Pure red cell aplasia (PRCA) is a rare disorder characterized by a significant reduction in red blood cell production. A 65-year-old man with myelodysplastic syndrome and monoclonal gammopathy of undetermined significance developed acquired PRCA (aPRCA) 2 weeks after receiving the BNT162b2 mRNA coronavirus disease 2019 vaccine, with Epstein-Barr virus DNA detected at the onset. The patient did not respond to immunosuppressive therapy and required red blood cell transfusion every one to two weeks. Although the causal relationship between vaccination and aPRCA remains unclear, adequate attention should be paid to post-vaccination aPRCA in patients with hematological disorders.

Introduction

Acquired pure red cell aplasia (aPRCA) is a rare hematological disorder characterized by anemia, a decreased reticulocyte count, and marked reduction in erythroid progenitors in the bone marrow. Background diseases associated with aPRCA include idiopathic PRCA (69.0%), thymoma (9.4%), large granular lymphocytic leukemia (2.5%), chronic lymphocytic leukemia (0.6%), and others (14.3%) (1). The pathogenesis of aPRCA may involve direct attacks by parvovirus B19 on erythroid progenitors or the involvement of antibodies or autoreactive lymphocytes (2). Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection causes several hematological abnormalities, including aPRCA (3,4). There have also been reported autoimmune hematological disorders following coronavirus disease 2019 (COVID-19) vaccination, including aplastic anemia (AA), autoimmune hemolytic anemia (AIHA), idiopathic thrombocytopenic purpura (ITP), and thrombotic thrombocytopenic purpura (TTP) (5-8). However, a clear causal relationship between the BNT162b2 mRNA COVID-19 vaccine and aPRCA has not yet been documented.

We herein report the development of aPRCA in a 65-year-old man with myelodysplastic syndrome (MDS) and monoclonal gammopathy of undetermined significance (MGUS) 2 weeks after the administration of the BNT162b2 mRNA COVID-19 vaccine.

Case Report

A 65-year-old man was referred to us for the evaluation of anemia in October 2019. Peripheral blood and bone marrow aspiration (BMA) results are shown in Tables 1, 22, respectively. Serum immunofixation electrophoresis detected IgG lambda paraprotein. BMA revealed erythroid hyperplasia and dysplasia, such as megaloblastic changes in erythroblasts, and a few erythroblasts with multinucleation or budding, consistent with the diagnosis of MDS (Fig. 1). The patient risk group was classified as low according to the International Prognostic Scoring System (IPSS) and revised IPSS. Whole-body magnetic resonance imaging and 18F-fluorodeoxyglucose positron emission tomography revealed no significant bone lesion. The patient was diagnosed with MDS accompanied by MGUS and followed up without treatment for two years because of transfusion independence.

Table 1.

Blood Tests before and after COVID-19 Vaccination.

	October, 2019	July, 2021	August, 2021
Leukocyte (×109/L)	4.6	5.0	4.0
Basophil (%)	0.4	0.6	0.5
Eosinophil (%)	1.5	1.6	1.0
Neutrophil (%)	58.0	61.5	59.7
Monocyte (%)	2.0	4.8	6.5
Lymphocyte (%)	36.2	31.5	32.3
Hemoglobin (g/dL)	7.5	6.6	5.6
Reticulocyte (×109/L)	47	68	7
Platelet (×109/L)	407	458	432
Total protein (g/dL)	6.1	6.6	6.2
Albumin (g/dL)	3.7	4.3	3.9
Lactate dehydrogenase (IU/L)	112	144	96
Creatinine (mg/dL)	0.88	0.81	0.81
C-reactive protein (U/L)	0.03	0.14	0.25
Serum iron (μg/dL)	145	195	161
Unsaturated iron binding capacity (μg/dL)	95	10	46
Ferritin (ng/mL)	459.9	415.8	527.7
Erythropoietin (mIU/mL)	33.7	2,580	3,170
IgG (mg/dL)	1,054	1,149	1,054
IgA (mg/dL)	117	131	117
IgM (mg/dL)	47	49	47
Kappa free light-chain (mg/dL)	16.5	20.3	21.8
Lambda free light-chain (mg/dL)	91.1	142	140
Wilms tumor 1 mRNA (copy/µgRNA)	<50	<50	<50

Table 2.

Bone Marrow Examination before and after COVID-19 Vaccination.

Date	October, 2019	July, 2021	October, 2021
Nucleated cell count (×109/L)	150	112	23.2
Megakaryocyte (×106/L)	63	13	13
Myeloid/erythroid ratio	0.4	0.8	66.6
Blast (%)	0.4	1.4	1.4
Promyelocyte (%)	0.0	0.4	0.4
Myelocyte (%)	4.6	5.7	13.0
Metamyelocyte (%)	4.4	4.4	2.6
Band neutrophil (%)	4.6	7.8	11.8
Segmented neutrophil (%)	11.4	16.7	33.0
Eosinophil (%)	2.4	2.2	4.0
Basophil (%)	0.2	0	0.4
Monocyte (%)	2.6	2.2	7.6
Lymphocyte (%)	2.0	11.2	24.6
Plasma cell (%)	2.4	0.4	0.2
Erythroid cell (%)	63.0	46.4	1.0
Cytogenetics	46, XY	46, XY	46, XY

Figure 1.

Bone marrow aspirate revealed erythroid hyperplasia at the time of the diagnosis of myelodysplastic syndrome (A) and erythroid aplasia following BNT162b2 mRNA COVID-19 vaccination (B) (May-Giemsa staining, original magnification: ×400).

The patient received the first dose of the BNT162b2 mRNA COVID-19 vaccine in July, 2021. After vaccination, no fever, fatigue, dyspnea, or other signs of inflammation were observed. In August, 2021, the patient underwent a routine blood test as part of follow-up for MDS, which revealed a significantly decreased reticulocyte count of 7×10⁹/L compared to 68×10⁹/L in July (Table 1). After vaccination, the BMA performed in October, 2021, revealed erythroblast hypoplasia, suggesting impaired erythropoiesis, compared with the BMA performed in July, 2021, during follow-up of MDS (Table 2, Fig. 1). Plasma erythropoietin increased from 33.7 to 2,580 mIU/mL. Using high-resolution flow cytometry, paroxysmal nocturnal hemoglobinuria-type red blood cells and granulocytes were detected at 0.001% and 0.004%, respectively. Peripheral blood smears did not reveal an increase in the number of large granular lymphocytes. Serological tests for human parvovirus B19, cytomegalovirus, and human immunodeficiency virus were negative; however, Epstein-Barr virus (EBV) DNA was detected at 2.46 Log IU/mL. No malignancies were identified on upper or lower gastrointestinal endoscopy, and computed tomography revealed no evidence of thymoma. There were no changes in the medications.

The clinical course of the patient is shown in Fig. 2. Based on the above findings, the patient was diagnosed with aPRCA. Immunosuppressive therapy with cyclosporine (3 mg/kg/day) and subsequent methenolone administration were ineffective. As of April 2025, the patient has remained transfusion-dependent.

Figure 2.

A significant decrease in reticulocyte count was observed two weeks after receiving the BNT162b2 mRNA COVID-19 vaccine. The reticulocyte count remained persistently low despite treatment with cyclosporine.

Discussion

We encountered a case of aPRCA that developed in a patient with MDS and MGUS after BNT162b2 mRNA COVID-19 vaccination with EBV DNA detected at the onset. The clinical course of this case suggests a possible association between the BNT162b2 mRNA COVID-19 vaccine and the development of aPRCA. To our knowledge, only two cases reported in Japan suggest that aPRCA may develop after SARS-CoV-2 infection (3,4). Although several autoimmune hematological disorders, such as AA, AIHA, ITP, and TTP, have been reported following COVID-19 vaccination (5-8), there are no reports documenting aPRCA after vaccination against COVID-19.

However, the pathogenic mechanisms by which vaccines cause autoimmune diseases remain unknown. Several mechanisms have been hypothesized, including vaccine epitopes that can initiate the development of antibodies and T-cells (9). Vaccine-induced enrichment of SARS-CoV-2-specific CD8⁺ T cells has been implicated in the development of autoimmune disease (10). However, we could not measure immunological indicators, such as antibody levels or T-cell response data. Future studies should measure these factors to investigate the possible association between the COVID-19 vaccine and PRCA development.

The case reported herein was complicated by MDS, MGUS, and EBV infection. aPRCA has been reported to occur in 1.6-4.0% of patients with MDS (11-13). Clonal stem cell differentiation and immune abnormalities reportedly cause aPRCA in MDS patients (14). The patient's erythropoietin level, measured in July, 2021, before vaccination, was significantly higher than that at the initial diagnosis. This suggests that erythropoiesis may have been altered prior to vaccination. PRCA may also occur during natural progression of MDS. In contrast, aPRCA associated with monoclonal gamma globulinemia has also been reported to result in anemia, despite the absence of a prominent increase in plasma cells, and treatment similar to that used for multiple myeloma can improve anemia (15). PRCA associated with EBV infection is uncommon and its pathophysiology remains unclear. Previous reports have suggested that EBV-associated PRCA may result from T cell-mediated suppression of erythroid progenitor cells (16). Unlike previously reported cases of aPRCA associated with COVID-19 that showed improvement (3,4), our patient exhibited prolonged transfusion dependency. Although the precise cause of prolonged transfusion dependency, despite the lack of therapeutic efficacy, remains unclear, it is possible that pre-existing MDS contributed to this condition.

Conclusion

We encountered a case of aPRCA following vaccination with the BNT162b2 mRNA COVID-19 vaccine. This case emphasizes the need for close monitoring of the adverse immunological effects of COVID-19 vaccine in patients with hematological disorders. The further accumulation of cases is necessary to clarify the relationship between PRCA and the SARS-CoV-2 vaccine. Although vaccination is essential to prevent COVID-19, careful precautions should be taken in patients with hematological disorders to promptly recognize and treat adverse events.

Written informed consent was obtained from the patient for the publication of this case report and accompanying images.

The authors state that they have no Conflict of Interest (COI).