What is Microangiopathic Hemolytic Anemia (MAHA)?

What is Microangiopathic Hemolytic Anemia (MAHA)?

MAHA is a mechanical hemolytic anemia caused by intravascular fragmentation of red blood cells as they pass through damaged small blood vessels containing platelet-rich thrombi and fibrin networks, resulting in characteristic schistocytes on peripheral blood smear. 1

Core Pathophysiology

The fundamental mechanism involves endothelial damage that exposes blood to the subendothelial layer, triggering coagulation activation, platelet aggregation, and fibrin formation. 1 This creates two critical consequences:

• Formation of platelet-rich microthrombi that occlude the microcirculation 1
• Red blood cell trapping and destruction within the fibrin network, producing the characteristic fragmented cells (schistocytes, burr cells, helmet cells) 1, 2

Additional contributing factors include oxidative stress, calcium overload, phospholipid membrane asymmetry promoting eryptosis (red blood cell death), and extracellular histones that induce red blood cell aggregation and reduce deformability. 1

Diagnostic Criteria

The diagnosis requires both anemia with microangiopathic changes on peripheral blood smear AND evidence of hemolysis. 2 Specifically:

• Microangiopathic changes: Presence of schistocytes, burr cells, or helmet cells on blood smear 2
• Evidence of hemolysis: Negative direct and indirect Coombs tests (non-immune hemolysis), elevated lactate dehydrogenase (LDH), reduced haptoglobin levels 1, 2
• Associated features: Thrombocytopenia (<150,000/mm³ or 25% reduction from baseline) is commonly present but not required 2

Critical Diagnostic Pitfall

Up to 50% of cases at onset do not show all three classic features (anemia, thrombocytopenia, organ dysfunction) clearly. 2 This incomplete presentation can delay diagnosis, so maintain high suspicion even when the full triad is absent.

Major Etiologies

MAHA is a laboratory finding, not a specific disease. The term "thrombotic microangiopathy (TMA)" describes syndromes characterized by MAHA, thrombocytopenia, and thrombotic lesions in small vessels. 3

Primary Thrombotic Microangiopathies

• Thrombotic Thrombocytopenic Purpura (TTP): Caused by severe ADAMTS13 deficiency (<10% activity), presenting with the classic pentad of MAHA, thrombocytopenia, fever, neurological abnormalities, and renal dysfunction 1
• Typical Hemolytic Uremic Syndrome (HUS): Follows acute gastrointestinal illness (usually diarrheal), with predominant renal involvement and glomerular thrombotic microangiopathy 1
• Atypical HUS: Complement-mediated TMA requiring different therapeutic approach 1

Secondary Causes

• Malignancy-related MAHA: Most commonly associated with gastric, breast, prostate, lung cancers, and lymphoma 4, 5, 6
• Autoimmune diseases: Systemic lupus erythematosus (SLE) and antiphospholipid syndrome can cause TMA through autoantibodies against complement regulatory proteins or inhibition of prostacyclin formation 1
• Drug-induced TMA: Either dose-dependent toxicity or idiosyncratic immune-mediated reactions 7
• Disseminated intravascular coagulation (DIC): RBC fragmentation results from fibrin/platelet deposition within microvasculature 3

Diagnostic Workflow After Confirming MAHA

Once MAHA is confirmed, immediately pursue the following algorithmic approach: 2, 8

1. Exclude DIC: Check PT, PTT, fibrinogen, D-dimer 8
2. Assess for TTP: Send ADAMTS13 activity and inhibitor levels urgently (activity <10% confirms TTP) 1, 8
3. Use PLASMIC score to risk-stratify for TTP likelihood while awaiting ADAMTS13 results 1, 2
4. Evaluate for HUS: Assess renal function, check for diarrheal prodrome, consider Shiga toxin testing 8
5. Screen for malignancy: Particularly if ADAMTS13 is normal and no other cause identified 8, 6
6. Review all medications for potential drug-induced TMA 8, 7
7. Test for complement-mediated disease: Consider complement testing if atypical HUS suspected 1
8. Screen for autoimmune causes: Test for antiphospholipid antibodies, lupus anticoagulant if clinically indicated 1, 8

Treatment Principles

Treatment must be directed at the underlying etiology, as MAHA itself is a manifestation of the primary disease process. 1

TTP Management (ADAMTS13 <10%)

• Initiate plasma exchange immediately without waiting for ADAMTS13 results if TTP is suspected—this is life-saving 8
• High-dose corticosteroids: Methylprednisolone 1 g IV daily for 3 days 8
• Add rituximab early in the treatment course to reduce relapse risk 8
• Consider caplacizumab as adjunctive therapy 1

Complement-Mediated Atypical HUS

• Eculizumab therapy: 900 mg weekly for four doses, then 1,200 mg at week 5, followed by 1,200 mg every 2 weeks 8

Cancer-Related MAHA

• Rapid initiation of chemotherapy targeting the underlying malignancy is essential, as CR-MAHA represents a near-oncologic emergency 5, 7
• Supportive care with blood transfusions as needed 5
• Stop any potentially causative chemotherapy agents if drug-induced TMA is suspected 7

Supportive Care for All MAHA

• RBC transfusions: Only the minimum necessary to relieve symptoms or return to safe hemoglobin range (7-8 g/dL) 8
• Folic acid supplementation: 1 mg daily 8
• Weekly hemoglobin monitoring until treatment is complete 8

Prognostic Considerations

Cancer-related MAHA carries a very poor prognosis but may be controllable for extended periods with rapid chemotherapy initiation. 5 Delay in diagnosis and treatment of TTP significantly increases mortality, making urgent recognition critical. 8