What is microangiopathic hemolytic anemia (MAHA)?

What is Microangiopathic Hemolytic Anemia (MAHA)?

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

Core Pathophysiology

The hemolysis in MAHA occurs through a distinct mechanical process rather than immune-mediated destruction:

• Endothelial damage exposes blood to the subendothelial layer, triggering coagulation activation, platelet aggregation, and fibrin formation 1
• Red blood cells become trapped in the fibrin network within the microcirculation, leading to physical fragmentation and intravascular destruction 1
• Two main consequences result: (1) platelet-rich thrombi that occlude the microcirculation and (2) consumption of platelets with intravascular hemolysis 1
• This process is fundamentally different from autoimmune hemolytic anemia, which is why MAHA typically presents with a negative direct Coombs test 2, 3

Essential Diagnostic Criteria

MAHA requires both anemia with microangiopathic changes on peripheral blood smear AND evidence of hemolysis 2:

Blood Smear Findings

• Schistocytes (helmet cells, burr cells, or fragmented red blood cells) are the hallmark finding 4, 2
• The presence of schistocytes on smear is critical for diagnosis 4

Laboratory Evidence of Hemolysis

• Negative direct and indirect Coombs tests (distinguishes from immune-mediated hemolysis) 2, 3
• Elevated lactate dehydrogenase (LDH) levels 4, 2
• Reduced or undetectable haptoglobin 4, 2
• Elevated indirect bilirubin 3
• Elevated reticulocyte count (if bone marrow can compensate) 4, 3

Commonly Associated Features

• Thrombocytopenia (platelet count <150,000/mm³ or 25% reduction from baseline) is frequently present 2
• Organ dysfunction may occur depending on the underlying cause, including renal injury or neurological symptoms 2

Major Causes of MAHA

MAHA is not a diagnosis itself but rather a manifestation of underlying thrombotic microangiopathy (TMA) or other pathological processes 5:

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
• Hemolytic Uremic Syndrome (HUS): Typical HUS follows acute gastrointestinal illness (often Shiga toxin-producing E. coli), with predominant renal involvement and glomerular TMA 1
• Atypical HUS (aHUS): Related to complement dysregulation 1

Secondary Causes

• Malignancy-associated: Gastric, breast, prostate, lung cancers, and lymphoma can cause MAHA through widespread microvascular metastases or extensive bone marrow involvement 6, 7
• Drug-induced: Tacrolimus, cyclosporine, sirolimus, and immune checkpoint inhibitors can trigger TMA 4, 8
• Autoimmune diseases: Systemic lupus erythematosus and antiphospholipid syndrome can cause TMA through complement activation or inhibition of prostacyclin formation 1
• Disseminated intravascular coagulation (DIC): RBC fragmentation results from fibrin or platelet deposition within the microvasculature 5
• Chronic hemolytic anemias: Sickle cell disease, thalassemia, hereditary spherocytosis can develop TMA due to high nitric oxide consumption 1

Critical Diagnostic Pitfalls

Not all three features of MAHA (anemia, thrombocytopenia, and organ dysfunction) may be present initially—up to 50% of cases at onset do not show all clinical signs clearly 2. This can delay diagnosis and treatment, which directly impacts mortality and morbidity, particularly in TTP where delay in plasma exchange is associated with increased mortality 4.

Immediate Diagnostic Workup

When MAHA is suspected, the following tests should be obtained urgently 4:

• CBC with peripheral blood smear to quantify schistocytes 2, 3
• ADAMTS13 activity level and inhibitor titer (activity <10% confirms TTP) 4, 1
• LDH, haptoglobin, indirect bilirubin, reticulocyte count 4, 3
• Direct Coombs test (should be negative in classic TMA) 4, 3
• Serum creatinine and urinalysis to assess renal involvement 4
• PT, aPTT, fibrinogen to evaluate for DIC 4
• PLASMIC score can help risk-stratify for TTP likelihood while awaiting ADAMTS13 results 1, 2

The distinction between TTP, HUS, DIC, and secondary causes is critical because treatment strategies differ significantly and prompt initiation of appropriate therapy impacts outcome 6. For suspected TTP with severe thrombocytopenia and neurological symptoms, plasma exchange should be initiated immediately while awaiting ADAMTS13 results, as delay in identification is associated with increased mortality and morbidity 4.