What are the diagnostic criteria for Microangiopathic Hemolytic Anemia (MAHA)?

Diagnostic Criteria for Microangiopathic Hemolytic Anemia (MAHA)

MAHA is diagnosed by the presence of acute-onset hemolytic anemia with microangiopathic changes (schistocytes, burr cells, or helmet cells) on peripheral blood smear, combined with a negative direct Coombs test, elevated LDH, and reduced haptoglobin levels. 1, 2

Core Laboratory Criteria

The diagnosis requires both of the following features present at some point during the illness:

• Anemia (acute onset) with microangiopathic changes on peripheral blood smear, specifically:

  • Schistocytes (fragmented red blood cells) 1, 2, 3
  • Burr cells 1, 3
  • Helmet cells 1, 3

• Evidence of hemolysis with:

  • Negative direct and indirect Coombs tests (confirming non-immune hemolysis) 1, 2
  • Elevated lactate dehydrogenase (LDH) levels 1, 2
  • Reduced/undetectable haptoglobin levels 1, 2

Associated Features (Not Required for MAHA Diagnosis Itself)

While MAHA can occur in isolation, it is frequently accompanied by:

• Thrombocytopenia (platelets <150,000/mm³ or 25% reduction from baseline) 1, 3
• Organ dysfunction depending on the underlying cause (renal injury, neurological symptoms, fever) 1, 2

Critical caveat: The classic pentad of microangiopathic hemolytic anemia, thrombocytopenia, fever, neurological abnormalities, and renal dysfunction is specific to TTP, not MAHA in general. 2 MAHA is the laboratory finding that can occur in multiple conditions including TTP, HUS, DIC, malignancy, and drug reactions. 4, 5, 6

Pathophysiologic Mechanism

The hemolysis occurs through mechanical fragmentation of red blood cells as they traverse damaged small blood vessels containing platelet-rich thrombi and fibrin networks. 2 Endothelial damage leads to coagulation activation, platelet activation, and fibrin formation, resulting in RBC trapping and destruction within the fibrin network. 2

Diagnostic Workflow After Confirming MAHA

Once MAHA is established, the critical next step is determining the underlying etiology:

1. Exclude DIC: Check PT, PTT, fibrinogen, and D-dimer 5, 6

2. Assess for TTP: Obtain ADAMTS13 activity level urgently (activity <10% confirms TTP) 2, 5

   • The PLASMIC score can help risk-stratify for TTP likelihood while awaiting ADAMTS13 results 2, 4

3. Evaluate for HUS:

   • History of diarrheal illness in preceding 3 weeks suggests typical (STEC) HUS 1, 3
   • Assess renal function (creatinine ≥1.0 mg/dL in children <13 years or ≥1.5 mg/dL in those ≥13 years) 1, 3
   • Consider complement testing if atypical HUS suspected 2, 3

4. Screen for malignancy: CR-MAHA most commonly associated with gastric, breast, prostate, lung cancers, and lymphoma 6, 7

   • 91.8% of solid cancers causing MAHA are metastatic 7
   • Bone marrow involvement or widespread microvascular metastases can cause MAHA 6, 7

5. Review medications: Drug-induced TMA should be considered and any putative causal agent stopped immediately 5, 6

Important Clinical Pitfalls

• Not all three features (anemia, thrombocytopenia, organ dysfunction) may be present initially: Up to 50% of cases at onset do not show all clinical signs clearly. 1 Do not wait for the complete triad before initiating workup.

• Platelet count may normalize: In HUS, platelets may be low early but can become normal or even elevated later in the illness. 1, 3 If platelet count within 7 days of symptom onset is not <150,000/mm³, consider alternative diagnoses. 1

• Cancer-related MAHA rarely responds to plasma exchange: Unlike TTP, CR-MAHA typically requires treatment of the underlying malignancy rather than plasma exchange (exception: prostate cancer with aHUS features). 6, 7