Abstract
Background
Hepatitis‑associated aplastic anemia (HAAA) is a rare but life‑threatening immune‑mediated complication of acute viral hepatitis, and hepatitis A virus is an uncommon cause of this syndrome.
Case Presentation
We report the case of a 24‑year‑old woman who developed acute hepatitis A followed by rapidly progressive pancytopenia fulfilling the criteria for very severe aplastic anemia. Her clinical course was complicated by febrile neutropenia, transfusion dependence, gastrointestinal bleeding, and Stenotrophomonas maltophilia bacteremia. Bone marrow biopsy demonstrated marked hypocellularity with severe trilineage suppression. Despite intensive supportive care including broad-spectrum antimicrobial therapy and transfusion support, her clinical condition deteriorated, and she died from infectious and hemorrhagic complications before definitive therapy could be initiated. This case emphasizes the importance of early recognition of cytopenias during the acute phase of hepatitis and prompt hematology referral for definitive management.
Conclusion
Aplastic anemia following acute hepatitis A infection is rare but potentially fatal. Early recognition of cytopenias during or following acute hepatitis, prompt bone marrow evaluation, and urgent hematology referral is essential for timely definitive treatment and improved outcomes.
Keywords: hepatitis-associated aplastic anemia, hepatitis A virus, pancytopenia, bone marrow failure, very severe aplastic anemia
Introduction
Hepatitis‑associated aplastic anemia (HAAA) represents approximately 2–5% of acquired aplastic anemia cases and is most commonly reported in children and young adults. The syndrome develops weeks after an episode of acute hepatitis and is characterized by peripheral pancytopenia and hypocellular bone marrow. Although hepatitis B and seronegative hepatitis account for the majority of cases, hepatitis A–associated disease remains rare.1–4
Severe aplastic anemia is characterized by bone marrow cellularity of less than 25% and at least two of the following: absolute neutrophil count < 0.5×109 /L, platelet count < 20×109 /L, or absolute reticulocyte count < 60×109 /L. Very severe aplastic anemia fulfills the criteria for severe aplastic anemia with an absolute neutrophil count < 0.2×109 /L.5
Case Presentation
A 24‑year‑old Yemeni woman was admitted on 15 October 2025 with symptomatic hypocalcemia following thyroidectomy. On 16 October she developed fever, fatigue, abdominal pain, and progressive jaundice. Liver biochemistry demonstrated a cholestatic pattern of liver injury.
Over the following days she developed rapidly progressive leukopenia, anemia, and thrombocytopenia with profound neutropenia and an absolute neutrophil count approaching zero (Tables 1 and 2). During hospitalization, her clinical course was complicated by massive gastrointestinal bleeding, and she became transfusion dependent.
Table 1.
Complete Blood Count Trend
| Date | WBC (×109/L) | Hemoglobin (g/dL) | Platelets (×109/L) | ANC (×109/L) |
|---|---|---|---|---|
| 17 October 2025 | 1.27 | 10.2 | 136 | 0.75 |
| 19 October 2025 | 0.17 | 8.7 | 326 | 0.01 |
| 26 October 2025 | 0.22 | 9.6 | 58 | 0.02 |
| 30 October 2025 | 0.06 | 4.7 | 23 | 0.04 |
| 03 November 2025 | 0.08 | 7.5 | 2 | 0.01 |
| 05 November 2025 | <0.5 | 1.98 | <9 | 0.01 |
| 07 November 2025 | <0.5 | 1.67 | <9 | 0.01 |
| 09 November 2025 | <0.5 | 2.32 | <9 | 0.00 |
| 10 November 2025 | <0.5 | 1.66 | <9 | 0.00 |
Notes: Platelet counts below 9 × 109/L were reported as <9 × 109/L, representing the laboratory’s lower reporting limit. The patient received platelet transfusions during hospitalization, which may have influenced subsequent platelet counts. Authors’ original data extracted from the patient’s electronic medical record and laboratory information system, Dammam Medical Complex, Dammam, Saudi Arabia.
Abbreviations: WBC, white blood cell count; ANC, absolute neutrophil count.
Table 2.
Other Laboratory Investigations
| Date | Reticulocytes % | LDH (U/L) | DAT |
|---|---|---|---|
| 17 October 2025 | 0.09 | 335 | – |
| 26 October 2025 | 0.09 | 183 | Negative |
| 02 November 2025 | 0.08 | – | |
| 04 November 2025 | – | 122 | – |
| 06 November 2025 | 0.48 | 114 | – |
Note: Authors’ original data extracted from the patient’s electronic medical record and laboratory information system, Dammam Medical Complex, Dammam, Saudi Arabia.
Abbreviations: LDH, lactate dehydrogenase; DAT, direct antiglobulin test.
The patient subsequently developed profound pancytopenia complicated by febrile neutropenia, disseminated intravascular coagulation, Stenotrophomonas maltophilia bacteremia, and platelet refractoriness, for which she received intravenous immunoglobulin without significant improvement in platelet count (Table 3).
Table 3.
Virology and Infectious Work-up
| Test | Result |
|---|---|
| Hepatitis A Virus Immunoglobulin M | Positive |
| Hepatitis B Surface Antigen | Negative |
| Hepatitis C Virus Antibody | Negative |
| Human Immunodeficiency Virus Antigen/Antibody | Negative |
| Parvovirus B19 Polymerase Chain Reaction | Negative |
| Cytomegalovirus Immunoglobulin M | Negative |
| Epstein–Barr Virus Immunoglobulin M | Negative |
| Blood Culture | Stenotrophomonas maltophilia |
Note: Authors’ original data extracted from the patient’s electronic medical record and laboratory information system, Dammam Medical Complex, Dammam, Saudi Arabia.
Abbreviation: PCR, polymerase chain reaction.
The viral serologic and molecular investigations were positive only for hepatitis A virus IgM among the viral tests performed (Table 3). The hepatitis A virus IgM test was performed earlier during the hospitalization, with the positive result becoming available on 2 November 2025. An initial bone marrow aspiration was inadequate because of clotting. A subsequent bone marrow biopsy performed on 6 November 2025 demonstrated markedly hypocellular marrow (10–20%) with severe trilineage suppression, consistent with very severe aplastic anemia (Table 4).
Table 4.
Bone Marrow Findings
| Date | Cellularity | Interpretation |
|---|---|---|
| Late October 2025 | Clotted aspirate | Bone marrow aspiration was inadequate because of clotting; marrow suppression was suspected. |
| 06 November 2025 | 10–20% | Hypocellular marrow for age (10–20% cellularity) with marked serous degeneration and severe suppression of trilineage hematopoiesis. Residual cellularity consisted predominantly of plasma cells and lymphocytes. No morphologic or immunophenotypic evidence of excess blasts, lymphoid aggregates, or marrow infiltration was identified. Findings were consistent with very severe aplastic anemia. |
Note: Authors’ original data extracted from the patient’s electronic medical record and pathology reports, Dammam Medical Complex, Dammam, Saudi Arabia.
The patient received supportive care including blood product transfusions and broad-spectrum antibiotics. She was referred to a tertiary care center for definitive therapy with either hematopoietic stem cell transplantation or immunosuppressive therapy. Despite these measures, her condition deteriorated rapidly. She ultimately succumbed to severe infection and hemorrhagic complications of very severe aplastic anemia (Table 5).
Table 5.
Clinical Timeline of Important Events
| Date | Hospital Day | Important Event |
|---|---|---|
| 15 October 2025 | Day 1 | Admission |
| 16 October 2025 | Day 2 | Hepatitis symptoms begin |
| 17–22 October 2025 | Days 3–8 | Rapid cytopenia progression |
| 29 October 2025 | Day 15 | Gastrointestinal bleeding and febrile neutropenia |
| 31 October 2025 | Day 17 | Stenotrophomonas maltophilia bacteremia detected |
| 02 November 2025 | Day 19 | Hepatitis A virus infection confirmed |
| 04 November 2025 | Day 21 | Referred for definitive therapy |
| 06 November 2025 | Day 23 | Bone marrow biopsy confirms very severe aplastic anemia |
| 11 November 2025 | Day 28 | Death from complications |
Note: Authors’ original data extracted from the patient’s electronic medical record and laboratory information system, Dammam Medical Complex, Dammam, Saudi Arabia.
Discussion
Hepatitis‑associated aplastic anemia is a distinctive clinical entity in which acute hepatic inflammation is followed by profound bone marrow failure. Although rare, the syndrome carries substantial morbidity and mortality if diagnosis and treatment are delayed. The pathogenesis is widely considered to be immune-mediated. Previous studies have demonstrated expansion of activated cytotoxic CD8+ T lymphocytes and increased levels of interferon‑γ and tumor necrosis factor‑α in affected patients. These cytokines inhibit hematopoietic stem cell proliferation and induce apoptosis, leading to marked hypocellularity of the marrow. This mechanism explains the transition from apparent hepatic recovery to progressive pancytopenia.1,2,6
Hepatitis A virus is rarely implicated compared with hepatitis B or seronegative hepatitis.4 Only a small number of individual cases and case series of hepatitis-associated aplastic anemia have been reported in the literature, making this association noteworthy.7–11 The proposed mechanism may involve molecular mimicry between viral antigens and marrow stem cell targets, triggering cross‑reactive immune responses. Alternatively, generalized immune activation during viral clearance may result in nonspecific T‑cell mediated marrow suppression.12 The rarity of hepatitis A–associated cases underscores the importance of additional case reporting to improve understanding of the epidemiology, pathogenesis, and outcome of this condition.
A limited number of cases of this uncommon syndrome have been reported in the literature (Table 6). In 1986, Doménech et al reported a 3-year-old child who developed aplastic anemia following acute hepatitis A and subsequently died from an infectious complication.7 In 2016, Bhatt et al reported a 17-year-old girl who developed severe aplastic anemia following hepatitis A infection, although the final outcome was not clearly reported.8 Botero et al described in 2018 a 10-year-old boy with fulminant hepatitis A complicated by aplastic anemia and acute liver failure who subsequently required liver transplantation.9 In 2019, Alsakkal et al reported a case series from Syria involving three young male patients, all younger than 20 years, with hepatitis A-associated aplastic anemia, the patients had poor outcomes and limited access to definitive treatment.10 More recently, in 2023, Rehman et al reported a 23-year-old woman from Pakistan who developed aplastic anemia following hepatitis A infection. The patient subsequently developed severe pancytopenia and infectious complications, including suspected invasive fungal infection, and died before she could undergo bone marrow transplantation.11 Our case adds to the limited literature by describing a 24-year-old woman who developed very severe aplastic anemia during the acute phase of hepatitis A, followed by severe infectious and hemorrhagic complications and death before definitive therapy could be initiated.
Table 6.
Reported Cases of Hepatitis A–Associated Aplastic Anemia: Clinical Characteristics, Management, and Outcomes
| Study | Patient Characteristics | Interval from Hepatitis to Aplastic Anemia* | Hematologic Severity | Management | Outcome |
|---|---|---|---|---|---|
| Doménech et al, 19867 | 3-year-old child | Not clearly stated | Severe aplastic anemia | Supportive treatment | Died from infectious complications |
| Bhatt et al, 20168 | 17-year-old female | 3 months | Severe aplastic anemia | Medical/supportive management; definitive treatment not reported | Outcome not clearly reported |
| Botero et al, 20189 | 10-year-old boy | 15 days | Aplastic anemia with acute liver failure | Liver transplantation and supportive management | Outcome reported in the original case report |
| Alsakkal et al, 201910 | 3 males, all <20 years | Not clearly stated | Hepatitis-associated aplastic anemia | Supportive care; limited access to definitive therapy | Poor outcomes reported |
| Rehman et al, 202311 | 23-year-old female | Not clearly stated | Severe pancytopenia/aplastic anemia | Supportive treatment; hematopoietic stem cell transplantation not performed | Died following infectious complications |
| Present case, 2025 | 24-year-old female | Cytopenias began approximately 1 day after onset of hepatitis symptoms; very severe aplastic anemia confirmed on day 23. | Very severe aplastic anemia; ANC declined to 0.01 × 109/L and subsequently 0, with profound thrombocytopenia and reticulocytopenia | Supportive care with transfusions and broad-spectrum antimicrobials; referred for definitive therapy | Died from infectious and hemorrhagic complications before definitive therapy could be initiated |
Notes: * The interval represents the reported time between the onset or recognition of acute hepatitis and the development or diagnosis of aplastic anemia. Timing was not consistently reported across published cases and therefore should be interpreted with caution. Hematologic severity terminology reflects the description provided in each original report and was not retrospectively reclassified unless sufficient data were available. The present case was classified as very severe aplastic anemia based on marked bone marrow hypocellularity and an absolute neutrophil count <0.2 × 109/L. Management and outcomes are summarized as reported in the original publications. Adapted from the published case reports cited in references7–11 and the authors’ original clinical data for the present case.
Abbreviations: HAAA, hepatitis-associated aplastic anemia; ANC, absolute neutrophil count.
Unlike the more typical presentation of hepatitis A-associated aplastic anemia, in which pancytopenia develops after an interval of apparent hepatic recovery, our patient experienced rapid hematologic deterioration during the acute phase of hepatitis A. Although the pathophysiological mechanisms implicated in hepatitis A-associated aplastic anemia, including cytotoxic T-cell activation and cytokine-mediated suppression of hematopoiesis, are well established, our case does not provide direct evidence of a novel immunological mechanism. Rather, its clinical significance lies in the rare association with hepatitis A and the unusually rapid progression to very severe aplastic anemia, emphasizing the need for early recognition of cytopenias even during the acute phase of hepatitis.
Differential diagnoses must be carefully considered. Drug‑induced marrow suppression, sepsis‑related cytopenias, nutritional deficiencies, hemophagocytic lymphohistiocytosis, leukemia, and myelodysplastic syndromes can present similarly. In this case, absence of offending medications, lack of dysplastic or malignant cells, and marrow hypocellularity without infiltration made these possibilities less likely.
Complications of very severe aplastic anemia are primarily infectious and hemorrhagic.2 Our patient developed febrile neutropenia and opportunistic bacteremia with Stenotrophomonas maltophilia, a pathogen typically affecting immunocompromised hosts. Gastrointestinal bleeding occurred due to profound thrombocytopenia. These events reflect the major causes of mortality described in historical cohorts. Intensive supportive care, including broad‑spectrum antibiotics and transfusions, is therefore essential.
Management strategies depend on age, donor availability, and disease severity. Hematopoietic stem cell transplantation is the preferred first‑line therapy for young patients with matched donors and offers long‑term survival exceeding 80–90%. For those without donors, immunosuppressive therapy using antithymocyte globulin and cyclosporine remains an effective alternative. Early referral to specialized centers improves outcomes. In addition, strict infection precautions, growth factor support, and transfusion therapy play critical roles in stabilization.2–4,6
To our knowledge, this is the first reported case of hepatitis A-associated aplastic anemia from our institution. Hepatitis A virus-associated aplastic anemia remains rare, with only sporadic cases reported in literature. This case highlights several important clinical considerations. First, clinicians should monitor complete blood counts closely during the active and recovery phases of acute hepatitis. Second, unexplained cytopenias warrant urgent hematology consultation and marrow evaluation. Third, early diagnosis enables timely initiation of definitive therapy before life‑threatening complications occur. Recognition of hepatitis A as a potential trigger expands the differential for post‑hepatitis cytopenias, particularly in endemic regions.
Limitations
This case report has several limitations. First, although the temporal association between acute hepatitis A infection and the subsequent development of very severe aplastic anemia supports a possible association, a definitive causal relationship cannot be established from a single case. Other potential causes of bone marrow failure were considered and investigated; however, the possibility of an unrecognized contributing factor cannot be completely excluded. Second, immunological investigations, including assessment of cytotoxic T-cell activity, cytokine profiles, or molecular evidence of immune cross-reactivity, were not performed. Therefore, the proposed immune-mediated mechanisms remain theoretical in this patient and cannot be directly confirmed. Third, the rapid clinical deterioration and death before definitive therapy could be initiated limited the ability to evaluate treatment response and long-term outcome. Finally, as this is a single case report, the findings cannot be generalized to all patients with hepatitis A infection or hepatitis-associated aplastic anemia. Nevertheless, the case highlights the importance of close hematologic monitoring and early recognition of progressive cytopenias during acute hepatitis A infection.
Conclusion
Hepatitis‑associated aplastic anemia remains uncommon but potentially fatal. Early recognition, prompt investigation, and timely definitive therapy are essential to improve survival. Continued reporting of similar cases may improve understanding of the epidemiology, pathogenesis, and optimal management of this rare complication.
Ethical Approval
Ethical approval was not required for this case report according to the institutional policies of Dammam Medical Complex, Dammam, Saudi Arabia. No separate institutional approval was required for publication of the case details. The report was prepared in accordance with institutional ethical standards and the principles of the Declaration of Helsinki.
Consent for Publication
Written informed consent for publication was obtained from the patient’s next of kin following the patient’s death. All identifying patient information has been removed to preserve anonymity and confidentiality.
Disclosure
The authors declare no conflicts of interest related to this publication.
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