Microangiopathic Hemolytic Anemia (MAHA) or Thrombotic Microangiopathy (TMA)
The combination of anemia, schistocytes, and elevated reticulocyte count is diagnostic of microangiopathic hemolytic anemia (MAHA), most commonly representing a thrombotic microangiopathy such as thrombotic thrombocytopenic purpura (TTP), hemolytic uremic syndrome (HUS), or other complement-mediated TMA. 1, 2
Diagnostic Criteria
The diagnosis is established by the triad of:
- Non-immune hemolytic anemia with negative direct Coombs test 1
- Schistocytes on peripheral blood smear indicating mechanical red cell destruction 1, 2
- Elevated reticulocyte count demonstrating appropriate bone marrow response to hemolysis 3, 2
Additional supportive laboratory findings include:
- Elevated lactate dehydrogenase (LDH) 1, 2
- Decreased haptoglobin 1, 2
- Elevated indirect bilirubin 2
- Thrombocytopenia (platelets <150,000/mm³ or 25% reduction from baseline) 1
Algorithmic Diagnostic Approach
Step 1: Confirm Hemolysis
- Verify schistocytes on peripheral smear by qualified hematologist 1
- Check LDH (elevated), haptoglobin (decreased), indirect bilirubin (elevated) 1, 3
- Confirm negative direct Coombs test to exclude immune-mediated hemolysis 1
Step 2: Assess Platelet Count
- If thrombocytopenia present: Proceed immediately to TMA workup 1
- If platelets normal: Consider other causes of MAHA (malignant hypertension, mechanical heart valves, disseminated malignancy) 2
Step 3: Urgent ADAMTS13 Testing
- ADAMTS13 activity <10% with inhibitor confirms TTP—initiate plasma exchange immediately 1
- ADAMTS13 activity >10% suggests complement-mediated TMA (aHUS) or secondary TMA 1
Step 4: Evaluate for Secondary Causes
- Stool culture for Shiga toxin-producing E. coli (STEC-HUS), especially if diarrhea present 1
- Complement studies (C3, C4, CH50, AP50) for complement-mediated aHUS 1
- Drug history for medication-induced TMA (quinine, calcineurin inhibitors, chemotherapy) 1, 2
- Pregnancy status for HELLP syndrome or pregnancy-associated TMA 1
- Infection screening including HIV, malaria in endemic areas 2, 4
Critical Pitfalls to Avoid
Do not delay plasma exchange while awaiting ADAMTS13 results if TTP is suspected clinically—mortality is high without immediate treatment 1. The presence of neurologic symptoms, fever, or renal dysfunction alongside the hemolytic anemia and thrombocytopenia should trigger urgent plasma exchange 1.
Do not confuse with vitamin B12 deficiency pseudo-TMA, which can mimic TMA with schistocytes but has:
- Much higher LDH levels (often >7000 IU/L) 5
- Paradoxically low reticulocyte count (inappropriately low for degree of anemia) 5
- Neutropenia (not typical in true TMA) 5
- Macrocytosis on blood smear 5
Distinguish pediatric STEC-HUS from aHUS by timing: STEC-HUS typically appears 4-5 days after diarrhea onset, while aHUS may present with concurrent or minimal diarrhea 1.
Specific Diagnostic Entities
TTP (Thrombotic Thrombocytopenic Purpura)
- ADAMTS13 activity <10% with or without inhibitor 1
- Neurologic symptoms common 1
- Requires urgent plasma exchange 1
Complement-Mediated aHUS
- Normal ADAMTS13 activity 1
- Renal involvement (elevated creatinine, hematuria, proteinuria) 1
- May require complement blockade therapy (eculizumab) 1
- Genetic testing for complement pathway mutations 1
STEC-HUS
- Positive stool culture or PCR for Shiga toxin 1
- Diarrhea preceding HUS by several days 1
- More common in children 1
When Reticulocyte Count Interpretation Matters
An elevated reticulocyte count confirms the bone marrow is responding appropriately to hemolysis and excludes deficiency states (iron, B12, folate) as primary causes 3. However, calculate the reticulocyte index to ensure the elevation is truly appropriate for the degree of anemia 3.
If reticulocytes are paradoxically low or normal despite anemia and schistocytes, strongly consider vitamin B12 deficiency pseudo-TMA rather than true TMA 5. This distinction is critical as treatment differs completely—B12 supplementation versus plasma exchange 5.