What is the likely diagnosis and recommended work‑up and management for a patient with a normal neutrophil count, relative lymphocytosis, normal monocyte count, normal red blood cell count, borderline macrocytic anemia (mean corpuscular volume 96.4 fL) with markedly elevated red cell distribution width (48.1 %) and mild hyperbilirubinemia (bilirubin 1.4 mg/dL)?

Likely Diagnosis: Hemolytic Anemia with Possible Underlying Bone Marrow Disorder

This patient's markedly elevated RDW (48.1%) combined with borderline macrocytic MCV (96.4 fL), mild hyperbilirubinemia (1.4 mg/dL), and relative lymphocytosis strongly suggests active hemolysis, though the normal RBC count and absence of reticulocyte data require urgent clarification to distinguish between hemolytic anemia and an evolving bone marrow disorder such as myelodysplastic syndrome. 1

Critical Initial Diagnostic Steps

Immediate Laboratory Testing Required

• Reticulocyte count and reticulocyte index – This single test determines whether the anemia reflects increased RBC destruction (high reticulocyte count >2.0) versus decreased production (low reticulocyte count <1.0-2.0), fundamentally changing the differential diagnosis and management approach. 1

• Hemolysis panel – Order indirect and direct bilirubin, lactate dehydrogenase (LDH), haptoglobin, and direct antiglobulin test (Coombs test) to confirm or exclude hemolytic anemia. 1

• Peripheral blood smear – Examine for schistocytes (microangiopathic hemolysis), spherocytes (hereditary spherocytosis or autoimmune hemolysis), macro-ovalocytes and hypersegmented neutrophils (megaloblastic anemia), or dysplastic features (myelodysplastic syndrome). 1, 2

• Complete iron studies – Obtain serum ferritin, transferrin saturation, serum iron, and total iron-binding capacity, as combined iron and B12/folate deficiency can produce a normal MCV despite underlying deficiencies. 1

• Vitamin B12 and folate levels – The borderline macrocytic MCV (96.4 fL) may represent early megaloblastic anemia, and combined deficiencies can mask each other. 1, 3

Understanding the Markedly Elevated RDW

Clinical Significance of RDW 48.1%

The RDW of 48.1% is extremely elevated (normal range 11.5-14.5%) and indicates profound red cell size heterogeneity (anisocytosis). 2, 4

• In megaloblastic anemia, mean RDW is approximately 87.7 fL, significantly higher than in aplastic anemia (mean 71.4 fL), and this difference is statistically significant for distinguishing the two conditions. 2

• In untreated pernicious anemia, mean RDW is 21.7 ± 9.1% versus 13.2 ± 1.1% in controls, though 31% of patients have normal RDW, particularly in early deficiency stages. 4

• In hemolytic anemia, markedly elevated RDW reflects the mixture of newly released large reticulocytes with older, smaller RBCs, creating extreme size variation. 1

• In combined deficiency states (iron plus B12/folate), RDW elevation may be even more pronounced as microcytic and macrocytic populations coexist. 1

Differential Diagnosis Based on Reticulocyte Response

If Reticulocyte Count is HIGH (>2.0)

Primary consideration: Hemolytic anemia – The mild hyperbilirubinemia (1.4 mg/dL) supports this diagnosis. 1

• Autoimmune hemolytic anemia – Confirm with positive direct antiglobulin test (Coombs), elevated LDH, low haptoglobin, and elevated indirect bilirubin. 1

• Hereditary spherocytosis – Look for spherocytes on peripheral smear, family history, and splenomegaly. 1

• Microangiopathic hemolytic anemia – Examine smear for schistocytes; consider thrombotic thrombocytopenic purpura or disseminated intravascular coagulation if thrombocytopenia is present. 1

• Acute hemorrhage – Though less likely given normal RBC count, occult gastrointestinal bleeding should be excluded with stool guaiac testing. 1

If Reticulocyte Count is LOW (<1.0-2.0)

Primary considerations: Bone marrow failure or early nutritional deficiency 1

• Myelodysplastic syndrome (MDS) – The combination of borderline macrocytic MCV, low reticulocyte count, relative lymphocytosis, and markedly elevated RDW raises concern for MDS, particularly if dysplastic features are present on peripheral smear. 5

• Early megaloblastic anemia – Vitamin B12 or folate deficiency can present with borderline macrocytic MCV (96.4 fL) before frank macrocytosis develops, and 35% of untreated pernicious anemia patients have normal MCV. 3, 4

• Combined deficiency states – Iron deficiency plus B12/folate deficiency can produce a normal MCV with markedly elevated RDW, as opposing effects on cell size cancel out. 1

• Aplastic anemia – Though less likely with normal RBC count, this should be considered if pancytopenia develops. 2

Bone Marrow Examination Indications

Proceed to bone marrow aspiration and biopsy if: 1

• Dysplastic features, blasts, or unexplained abnormalities on peripheral smear
• Progressive anemia despite optimal treatment of identified causes
• Unexplained pancytopenia or abnormalities affecting multiple hematologic lineages
• Failure to identify a cause after comprehensive noninvasive workup
• Clinical suspicion for MDS, especially with blunted reticulocyte response

Management Algorithm

Step 1: Obtain Reticulocyte Count and Hemolysis Panel Immediately

• If reticulocyte count is high → Pursue hemolysis workup (LDH, haptoglobin, indirect bilirubin, Coombs test, peripheral smear for schistocytes/spherocytes). 1

• If reticulocyte count is low → Pursue nutritional deficiency workup (B12, folate, iron studies) and evaluate peripheral smear for dysplastic features suggesting MDS. 1

Step 2: Peripheral Smear Interpretation

• Schistocytes → Microangiopathic hemolytic anemia; consider TTP, DIC, or mechanical hemolysis. 1

• Spherocytes → Autoimmune hemolytic anemia or hereditary spherocytosis; confirm with Coombs test. 1

• Macro-ovalocytes and hypersegmented neutrophils → Megaloblastic anemia; confirm with B12 and folate levels. 3, 2

• Dysplastic features → MDS; proceed to bone marrow biopsy for definitive diagnosis. 5

Step 3: Treat Based on Identified Cause

For confirmed hemolytic anemia:

• Autoimmune hemolytic anemia – Initiate corticosteroids (prednisone 1 mg/kg/day) and consider IVIG or rituximab for refractory cases. 1

• Hereditary spherocytosis – Refer to hematology for consideration of splenectomy if symptomatic. 1

For confirmed megaloblastic anemia:

• Vitamin B12 deficiency – Administer cyanocobalamin 100 mcg intramuscularly daily for 6-7 days, then alternate days for seven doses, then every 3-4 days for 2-3 weeks, followed by 100 mcg monthly for life. 6

• Folate deficiency – Administer folic acid 1-5 mg daily orally; concomitant B12 supplementation is required if both deficiencies are present. 6

For confirmed MDS:

• Low-risk MDS – Consider erythropoiesis-stimulating agents if hemoglobin ≤10 g/dL and serum erythropoietin ≤500 mU/mL. 5

• High-risk MDS – Initiate azacitidine (preferred; category 1) or decitabine, and evaluate for allogeneic hematopoietic stem cell transplantation. 5

Common Pitfalls to Avoid

• Do not assume normal RBC count excludes significant pathology – Early hemolysis or compensated bone marrow failure can maintain near-normal RBC counts while RDW becomes markedly elevated. 1

• Do not dismiss borderline macrocytic MCV (96.4 fL) – Over one-third of untreated pernicious anemia patients have normal MCV, and combined deficiencies can mask macrocytosis. 3, 4

• Do not overlook combined deficiency states – Iron deficiency plus B12/folate deficiency produces a normal MCV with markedly elevated RDW, requiring comprehensive iron studies and vitamin levels. 1

• Do not delay bone marrow biopsy if dysplastic features are present – MDS requires definitive diagnosis for appropriate risk stratification and treatment. 5

• Do not confuse relative lymphocytosis with chronic lymphocytic leukemia – Absolute lymphocyte count of 20.8% with normal total WBC represents relative lymphocytosis, not CLL, which requires absolute lymphocytosis >5,000 cells/µL with characteristic immunophenotype. 7