What is the most likely diagnosis for an elderly female with anemia, normocytic anemia (normal Mean Corpuscular Volume (MCV)), and schistocytes on blood smear?

Most Likely Diagnosis: Thrombotic Microangiopathy (TMA)

The most likely diagnosis is a thrombotic microangiopathy (TMA), specifically either thrombotic thrombocytopenic purpura (TTP), hemolytic uremic syndrome (HUS), or cancer-associated microangiopathic hemolytic anemia (CA-MAHA), given the classic triad of normocytic anemia, schistocytes on blood smear, and the patient's age. 1

Diagnostic Reasoning

Key Clinical Features Present

• Normocytic anemia (MCV 90 fL) with hemoglobin 10.2 g/dL indicates acute hemolysis rather than chronic nutritional deficiency 2
• Schistocytes on blood smear are pathognomonic for microangiopathic hemolytic anemia and represent intravascular red blood cell fragmentation 1, 3
• Elderly female population is at risk for both primary TMA syndromes and malignancy-associated MAHA 4

Differential Diagnosis Algorithm

The presence of schistocytes with normocytic anemia creates a narrow differential that must be urgently evaluated:

Primary considerations:

1. Thrombotic Thrombocytopenic Purpura (TTP) - characterized by microangiopathic hemolytic anemia, thrombocytopenia, and potential neurological/renal involvement 1, 3

2. Hemolytic Uremic Syndrome (HUS) - defined by the triad of microangiopathic hemolytic anemia with schistocytes, renal injury (hematuria, proteinuria, elevated creatinine), and thrombocytopenia 1

3. Cancer-associated MAHA - particularly gastric, breast, prostate, lung adenocarcinomas, or signet-ring cell carcinoma of the colon in elderly patients 4

4. Disseminated intravascular coagulation (DIC) - though typically presents with more severe coagulopathy 4

Immediate Diagnostic Workup Required

Urgent laboratory tests (must be obtained immediately):

• ADAMTS-13 activity level - severe deficiency (<10 IU/dL) confirms TTP; normal to moderately reduced (>10 IU/dL) suggests alternative TMA diagnosis like aHUS or secondary causes 1, 3
• Complete blood count with platelet count - thrombocytopenia (<150,000/mm³) is expected in TTP/HUS 1
• Lactate dehydrogenase (LDH) - markedly elevated in hemolysis 1, 3
• Haptoglobin - decreased or undetectable in intravascular hemolysis 1, 3
• Direct Coombs test - must be negative to confirm non-immune hemolytic anemia 1
• Serum creatinine - elevated (≥1.5 mg/dL in adults ≥13 years) indicates renal involvement consistent with HUS 1
• Reticulocyte count - should be elevated as appropriate marrow response to hemolysis 2, 5

Additional critical tests:

• Stool culture for Shiga toxin-producing E. coli (STEC) - to identify post-diarrheal HUS 1
• Complement testing (C3, C4, CH50) - for atypical HUS evaluation 1
• Peripheral blood smear quantification - schistocytes >1% strongly supports TMA diagnosis 1

Critical Management Considerations

Time-sensitive treatment decisions:

• If TTP is suspected (thrombocytopenia + schistocytes + neurological symptoms), plasma exchange must be initiated immediately before ADAMTS-13 results return, as delay increases mortality 1, 3
• Do not wait for ADAMTS-13 results if clinical suspicion is high - empiric plasma exchange should begin within hours 3
• If atypical HUS is diagnosed, complement inhibitor therapy (eculizumab) should be initiated urgently 1

Common Pitfalls to Avoid

• Do not dismiss residual schistocytosis - 35.6% of TTP/HUS patients have persistent schistocytes even when platelet counts normalize, and this does not predict relapse 6
• Do not assume vitamin B12 deficiency despite macrocytic indices - while "pseudo-TMA" from B12 deficiency can rarely present with schistocytes, this is exceedingly uncommon and should only be considered after excluding true TMA 7
• Do not delay treatment for complete diagnostic workup - TMA syndromes are medical emergencies requiring immediate intervention 1, 3
• Consider occult malignancy in elderly patients without clear precipitating factors - gastric adenocarcinoma and signet-ring cell carcinoma can present initially as MAHA 4

Age-Specific Considerations

In elderly females specifically:

• Higher likelihood of secondary TMA from underlying malignancy, particularly adenocarcinomas 4
• Atypical HUS can present at any age and may have complement-mediated pathophysiology requiring specific therapy 1
• Medication review is essential - certain drugs can trigger TMA (calcineurin inhibitors, chemotherapy agents) 1

The presence of schistocytes with normocytic anemia in an elderly patient mandates immediate hematology consultation and urgent ADAMTS-13 testing, with empiric plasma exchange considered if TTP cannot be excluded clinically. 1, 3