What is Microangiopathic Hemolytic Anemia (MAHA)?

What is Microangiopathic Hemolytic Anemia (MAHA)?

MAHA is a non-immune hemolytic anemia caused by mechanical fragmentation of red blood cells as they pass through damaged small blood vessels, characterized by the presence of schistocytes (fragmented red cells) on peripheral blood smear, elevated LDH, decreased haptoglobin, and a negative direct Coombs test. 1, 2

Core Pathophysiology

The hemolysis in MAHA occurs through mechanical destruction rather than immune-mediated mechanisms 1, 2:

• Endothelial damage in small arterioles and capillaries exposes blood to the subendothelial layer, activating coagulation and platelet aggregation 1
• Fibrin network formation traps red blood cells, causing them to fragment as they attempt to pass through narrowed vessels 1
• Platelet-rich thrombi occlude the microcirculation, creating shear stress that physically tears red blood cells apart 1

Essential Diagnostic Features

Laboratory hallmarks that distinguish MAHA from other anemias 1, 2:

• Schistocytes, burr cells, or helmet cells on peripheral blood smear (this is the critical diagnostic finding) 1, 3
• Elevated LDH and decreased/absent haptoglobin indicating intravascular hemolysis 1, 2, 3
• Negative direct Coombs test (distinguishes from autoimmune hemolytic anemia) 1, 2, 3
• Elevated indirect bilirubin and reticulocytosis reflecting hemolysis and compensatory bone marrow response 2
• Thrombocytopenia is typically present due to platelet consumption in microthrombi 4, 3

Major Clinical Entities Causing MAHA

Primary Thrombotic Microangiopathies

Thrombotic Thrombocytopenic Purpura (TTP) 4, 1:

• Caused by severe ADAMTS13 deficiency (activity <10%) 4, 1
• Classic pentad: MAHA, thrombocytopenia, fever, neurological abnormalities, and renal dysfunction 1
• ADAMTS13 activity testing is crucial for diagnosis 1
• Requires immediate plasma exchange therapy 4

Hemolytic Uremic Syndrome (HUS) 1, 3:

• Typical (post-diarrheal) HUS follows acute gastrointestinal illness, usually from Shiga toxin-producing E. coli 1, 3
• Atypical HUS (aHUS) involves complement dysregulation without preceding diarrhea 3
• Predominant renal involvement with glomerular thrombotic microangiopathy 1, 3
• Diagnostic criteria require acute renal injury (creatinine ≥1.0 mg/dL in children <13 years; ≥1.5 mg/dL in ≥13 years) 3

Secondary Causes of MAHA

Autoimmune conditions 1:

• Systemic Lupus Erythematosus (SLE) and lupus nephritis can cause TMA through monoclonal immunoglobulins acting as autoantibodies against complement regulatory proteins 1
• Antiphospholipid syndrome causes TMA by inhibiting prostacyclin formation or protein C activation 1

Malignancy-associated MAHA 5, 6, 7:

• Widespread microvascular metastases or extensive bone marrow involvement can cause MAHA 6
• Most commonly associated with gastric, breast, prostate, lung cancers, and lymphoma 5
• May present as initial manifestation of metastatic disease 5, 7
• Treatment of underlying malignancy is critical for controlling cancer-related MAHA 6

Disseminated Intravascular Coagulation (DIC) 8, 6:

• RBC fragmentation results from fibrin or platelet deposition within microvasculature 8
• May be precipitated by sepsis or driven by cancer itself 6

Drug-induced TMA 4, 6:

• Can occur as dose-dependent toxicity or idiosyncratic immune-mediated reaction 6
• Common culprits include tacrolimus, cyclosporine, sirolimus, and immune checkpoint inhibitors 4
• Any suspected causative agent must be stopped immediately 6

Critical Diagnostic Pitfall

A positive direct Coombs test with schistocytes is an unusual combination that requires immediate hematology consultation 2:

• Classic MAHA/TMA typically presents with a negative Coombs test 1, 2, 3
• Positive Coombs suggests concurrent autoimmune hemolytic anemia or a hybrid presentation 2
• This combination mandates urgent evaluation to distinguish between overlapping processes 2

Initial Diagnostic Workup

When MAHA is suspected, obtain 4, 1, 2:

• Peripheral blood smear to quantify schistocytes (mandatory for diagnosis) 2, 3
• CBC with differential and platelet count 4, 2
• LDH, haptoglobin, indirect bilirubin, reticulocyte count to confirm hemolysis 4, 1, 2
• Direct Coombs test to exclude immune-mediated hemolysis 1, 2, 3
• ADAMTS13 activity level and inhibitor titer to identify TTP 4, 1
• Serum creatinine and urinalysis to assess renal involvement 4, 3
• PT, aPTT, fibrinogen to evaluate for DIC 4
• PLASMIC score can help risk-stratify for likelihood of TTP 1

Management Principles

Treatment must be directed at the underlying etiology 1:

• For TTP: Immediate plasma exchange, glucocorticoids, rituximab, and possibly caplacizumab 1
• For complement-mediated TMA/aHUS: Eculizumab 4, 1
• For antiphospholipid syndrome-associated TMA: Anticoagulation with or without plasma exchange 1
• For drug-induced TMA: Discontinue offending agent immediately 6
• For malignancy-associated MAHA: Treat underlying cancer with chemotherapy and provide supportive transfusions 6, 7