Case Study: Diagnostic and Therapeutic Challenges in Aplastic Anemia Mimicking Hypoplastic Myelodysplastic Syndrome

Abstract

A 38-year-old woman presented with progressive fatigue, easy bruising, and recurrent infections over two months. Laboratory investigations revealed pancytopenia with markedly hypocellular bone marrow, suggestive of aplastic anemia (AA). However, subtle dysplastic features and mild cytogenetic abnormalities initially raised suspicion for hypoplastic myelodysplastic syndrome (hMDS). A multidisciplinary approach integrating hematologic, cytogenetic, and immunologic analyses was critical to differentiating between these overlapping entities. The patient responded favorably to immunosuppressive therapy with antithymocyte globulin (ATG) and cyclosporine, confirming the immune-mediated pathophysiology of AA. This case underscores the diagnostic complexity of marrow failure syndromes and the therapeutic importance of accurate classification to optimize outcomes.

Introduction

Aplastic anemia and hypoplastic myelodysplastic syndrome (hMDS) represent two distinct yet overlapping bone marrow failure syndromes characterized by pancytopenia and marrow hypoplasia. The diagnostic overlap poses a significant clinical challenge due to shared features such as hypocellular marrow, cytopenias, and subtle dysplasia. However, their underlying mechanisms and management differ markedly - AA being primarily immune-mediated, while hMDS reflects clonal hematopoietic dysfunction.

Timely differentiation influences prognosis and treatment: AA typically responds to immunosuppression or stem cell transplantation, whereas hMDS may progress to acute myeloid leukemia (AML) and often requires disease-modifying therapy. This case highlights how an integrated diagnostic approach combining morphology, cytogenetics, flow cytometry, and response to therapy guided precise classification and management.

Patient Information 

Age / Gender: 38-year-old female
Occupation: School teacher
Marital Status: Married
Medical History: Mild hypothyroidism (on levothyroxine 50 µg daily)
Surgical History: None
Family History: Non-contributory (no hematologic malignancies)
Social History: Non-smoker, no alcohol or drug use
Current Medications: Levothyroxine 50 µg once daily
Chief Complaints: Increasing fatigue, petechiae, and two episodes of febrile neutropenia over 8 weeks.

Clinical Findings

General Examination:

• Pale conjunctiva

• Multiple ecchymotic patches on upper limbs

• No lymphadenopathy or hepatosplenomegaly

Vital Signs:

• Temperature: 99°F

• Pulse: 102 bpm

• BP: 118/76 mmHg

• Respiratory rate: 20/min

Systemic Examination: Unremarkable except for signs of anemia and bleeding tendency.

Initial Impression: Pancytopenia with suspected marrow failure syndrome.

Timeline

The patient, a 32-year-old male, initially presented with progressive fatigue and intermittent episodes of gum bleeding over a period of two months. During the first clinical consultation, his hemoglobin level was markedly low, and mild leukopenia was noted, prompting further evaluation.

Over the following three weeks, the patient developed worsening pallor and new-onset petechial rashes on the lower limbs. A local physician initiated supportive management with iron supplementation, but his symptoms persisted, and repeat blood counts revealed a further decline in all three hematopoietic lineages - hemoglobin, leukocytes, and platelets.

At week six, the patient was referred to a tertiary hematology center for advanced evaluation. Comprehensive hematological and bone marrow studies were performed to differentiate between aplastic anemia and hypoplastic myelodysplastic syndrome (MDS). During this diagnostic phase, the patient required multiple transfusions for symptomatic anemia and thrombocytopenia.

After eight weeks from the initial presentation, a confirmed diagnosis of severe aplastic anemia was established, following a detailed exclusion of secondary causes and MDS-like features. Therapeutic discussions were initiated immediately, and the patient was considered for immunosuppressive therapy (IST) with antithymocyte globulin (ATG) and cyclosporine.

Over the next three months, hematologic parameters gradually improved. Regular monitoring showed a slow but consistent rise in neutrophil and platelet counts, indicating a positive therapeutic response. The case underscored the importance of timely differentiation and the challenges posed by overlapping marrow features during diagnosis.

Diagnostic Assessment

Laboratory Findings

The diagnostic pathway was marked by considerable complexity, as both aplastic anemia and hypoplastic MDS can present with pancytopenia and marrow hypoplasia.

Initial complete blood count (CBC) results revealed pancytopenia characterized by severe anemia (Hb 6.8 g/dL), leukopenia (WBC 2.1 × 10⁹/L), and thrombocytopenia (Platelets 25 × 10⁹/L). Peripheral smear examination demonstrated normocytic normochromic red cells without dysplastic changes, ruling against overt MDS at this stage.

A reticulocyte count was significantly reduced, suggesting decreased marrow activity rather than peripheral destruction. Serum vitamin B12 and folate levels were within normal limits, excluding nutritional causes of marrow suppression.

The bone marrow aspiration yielded a markedly hypocellular sample, while the trephine biopsy confirmed a cellularity of less than 10%, consistent with aplastic marrow. Importantly, no abnormal blast population or dysplastic morphology was detected.

Cytogenetic analysis and fluorescence in situ hybridization (FISH) studies were performed to rule out clonal abnormalities typically associated with MDS. The karyotype was normal (46,XY), and no chromosomal aberrations such as del(5q), del(7q), or trisomy 8 were detected.

Additionally, flow cytometric analysis did not reveal abnormal myeloid or lymphoid clones, and PNH (Paroxysmal Nocturnal Hemoglobinuria) testing was negative. Immunohistochemical staining further excluded infiltration by malignant or fibrotic processes.

Taken together, these findings supported a final diagnosis of severe acquired aplastic anemia, despite the initial clinical resemblance to hypoplastic MDS. The diagnostic journey exemplified the importance of integrating morphology, cytogenetics, and immunophenotyping to establish diagnostic clarity in bone marrow failure syndromes.

Bone Marrow Examination

• Aspirate: Markedly hypocellular with reduced trilineage precursors.

• Biopsy: Cellularity 10–15%, no blasts, mild megaloblastoid erythroid changes, absent fibrosis.

• Cytogenetics: Normal female karyotype (46,XX); no MDS-defining abnormalities.

• Flow Cytometry: No increase in CD34+ blasts or aberrant myeloid markers.

• Paroxysmal Nocturnal Hemoglobinuria (PNH) clone: Detected in 1.5% granulocytes supporting immune-mediated marrow suppression.

Differential Diagnosis

1. Severe Aplastic Anemia (SAA)

2. Hypoplastic MDS

3. PNH–AA overlap syndrome

Diagnostic Challenge

The subtle dysplastic morphology initially suggested hMDS; however, lack of cytogenetic abnormalities, presence of small PNH clone, and response to immunotherapy confirmed aplastic anemia.

Therapeutic Intervention

Step 1 – Supportive Management

• Red cell and platelet transfusions as needed.

• Broad-spectrum antibiotics during neutropenic episodes.

• Folic acid and oral iron supplementation.

• Growth factor (G-CSF) support intermittently.

Step 2 – Immunosuppressive Therapy

• ATG (Horse-derived): 40 mg/kg/day for 4 days.

• Cyclosporine A: 5 mg/kg/day (adjusted to trough level 150–200 ng/mL).

• Prednisolone: Short tapering course to prevent serum sickness.

• Prophylaxis: Cotrimoxazole and acyclovir.

Step 3 – Monitoring and Follow-Up

• Weekly CBCs for 3 months.

• Monthly cyclosporine level and renal/liver function monitoring.

• Repeat bone marrow biopsy at 6 months.

Challenges Faced

• Diagnostic Overlap: Distinguishing AA from hMDS required advanced cytogenetic and flow studies.

• Therapy Timing: Avoiding delay in initiating ATG pending confirmatory cytogenetics.

• Transfusion Dependence: Managed via restrictive transfusion protocol to prevent alloimmunization.

• Infection Control: Neutropenic precautions and antibiotic prophylaxis essential.

• Emotional Stress: Counseling and psychological support provided due to chronic fatigue and uncertainty.

Follow-Up and Outcomes

Following the confirmation of severe aplastic anemia, the patient was initiated on immunosuppressive therapy (IST) comprising horse antithymocyte globulin (hATG) and oral cyclosporine A (CsA). Corticosteroids were administered concurrently for a short duration to mitigate serum sickness associated with ATG. Prophylactic antimicrobials were prescribed to minimize infection risk during the initial neutropenic phase.

Over the first month of therapy, the patient experienced transient fever and malaise post-ATG infusion, which were managed symptomatically. Hematologic monitoring was conducted weekly, tracking hemoglobin, absolute neutrophil count (ANC), and platelet levels to assess marrow recovery.

By the sixth week, the patient’s ANC rose above 1,000/µL, and platelet counts stabilized without the need for additional transfusions. This early response indicated marrow recovery. Supportive care, including erythrocyte transfusions and growth factor support, was gradually reduced.

At three months, the patient exhibited marked clinical improvement reduced fatigue, resolution of bleeding tendencies, and sustained blood counts (Hb 10.5 g/dL, WBC 3.8 × 10⁹/L, Platelets 110 × 10⁹/L). Repeat bone marrow evaluation demonstrated partial restoration of cellularity, confirming therapeutic success.

Cyclosporine therapy was continued for 12 months with gradual tapering under close supervision. Throughout the follow-up period, no evidence of clonal evolution or cytogenetic abnormalities was detected, which effectively ruled out transformation into hypoplastic MDS or acute leukemia.

Regular liver and renal function assessments ensured drug safety, and patient adherence was supported through structured counseling. The individual resumed normal occupational activity within six months of initiating therapy, maintaining a good quality of life.

At the one-year follow-up, the patient remained transfusion-independent, with stable hematological parameters and no relapse. The case illustrated that early initiation of IST, vigilant follow-up, and differentiation from MDS significantly improve prognosis in aplastic anemia.

Discussion

Differentiating aplastic anemia from hypoplastic MDS remains a frequent dilemma in hematology due to overlapping features of marrow hypocellularity, cytopenia, and mild dysplasia. The absence of clonal cytogenetic abnormalities (e.g., del(5q), monosomy 7), low blast percentage, and presence of a PNH clone strongly favor immune-mediated AA over clonal MDS.

In this patient, the therapeutic response to ATG and cyclosporine provided functional confirmation of the diagnosis. Studies suggest that up to 20% of apparent AA cases may evolve into MDS or AML, underscoring the need for vigilant long-term surveillance.

Multidisciplinary Approach

Effective management required coordination between:

• Hematologists: Diagnosis, immunotherapy, follow-up

• Pathologists: Morphology and cytogenetic interpretation

• Transfusion Medicine: Blood product optimization

• Nursing & Psychosocial Team: Infection care and counseling

This collaboration ensured comprehensive care and timely therapeutic adjustment.

Key Takeaways

• Differentiation between aplastic anemia and hypoplastic MDS is critical for prognosis and therapy.
• Immune markers (PNH clone, T-cell activation) can aid diagnostic clarification.
• Immunosuppressive therapy remains the mainstay for non-transplant candidates.
• Early recognition and multidisciplinary coordination improve outcomes.
• Regular follow-up is vital to detect relapse or clonal evolution.

Patient’s Perspective

“I was terrified when I was told I had a bone marrow failure. Doctors explained every test patiently. Once treatment started, I slowly regained energy. The constant monitoring and teamwork made me feel supported. Today, I’m living normally again.”

Conclusion

This case illustrates the intricate overlap between aplastic anemia and hypoplastic myelodysplastic syndrome, emphasizing the necessity of a multimodal diagnostic strategy. In ambiguous marrow failure cases, integrating clinical, morphologic, cytogenetic, and therapeutic response data is essential to reach an accurate diagnosis.
 Early immunosuppressive therapy under multidisciplinary supervision led to a sustained hematologic response, highlighting that prompt, precise, and coordinated management can transform potentially life-threatening marrow failure into a reversible condition.

References

1. Kulasekararaj AG, et al. Aplastic anemia and hypoplastic myelodysplastic syndromes: diagnostic challenges and treatment strategies. Blood Rev. 2018.

2. Young NS, et al. Pathophysiology and treatment of aplastic anemia. N Engl J Med. 2018.

3. Tichelli A, et al. Differentiating aplastic anemia from hypocellular myelodysplastic syndromes. Haematologica. 2011.

4. Scheinberg P, et al. Immunosuppressive therapy in aplastic anemia: response predictors and long-term outcomes. Blood. 2009.

5. HiDoc Dr. – Clinical Insights Platform. Aplastic Anemia: Case-based Approaches in Diagnosis and Treatment. (Accessed 2025).

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