What is microangiopathic hemolytic anemia?

Microangiopathic Hemolytic Anemia (MAHA)

Microangiopathic hemolytic anemia is a form of intravascular hemolysis characterized by red blood cell fragmentation (schistocytes) due to mechanical damage in small blood vessels, often presenting with thrombocytopenia and evidence of organ dysfunction. 1

Definition and Pathophysiology

MAHA is defined by:

• Presence of schistocytes (fragmented red blood cells) on peripheral blood smear
• Evidence of hemolysis (elevated LDH, decreased haptoglobin, elevated indirect bilirubin)
• Often accompanied by thrombocytopenia
• Organ dysfunction (particularly renal, neurological)

The condition results from mechanical destruction of red blood cells as they pass through abnormal microvasculature with fibrin deposits or platelet thrombi 1, 2.

Clinical Presentation

Common clinical manifestations include:

• Pallor and fatigue due to anemia
• Petechiae or purpura due to thrombocytopenia
• Neurological symptoms (confusion, seizures, focal deficits)
• Renal dysfunction (proteinuria, hematuria, oliguria)
• Fever in some cases
• Jaundice from hemolysis

Laboratory Findings

Key diagnostic findings:

• Schistocytes on peripheral blood smear (1-5% is significant) 2
• Decreased hemoglobin
• Thrombocytopenia
• Elevated LDH
• Decreased or absent haptoglobin
• Elevated reticulocyte count
• Normal direct antiglobulin test (Coombs)
• Elevated creatinine (in renal involvement)

Differential Diagnosis and Classification

MAHA is primarily seen in thrombotic microangiopathies (TMAs), which include:

1. Thrombotic Thrombocytopenic Purpura (TTP)

   • Severe ADAMTS13 deficiency (<10%)
   • Prominent neurological symptoms
   • Pentad: fever, MAHA, thrombocytopenia, neurological symptoms, renal dysfunction

2. Hemolytic Uremic Syndrome (HUS)

   • Typical: associated with Shiga toxin-producing E. coli (STEC)
   • Atypical: complement dysregulation
   • Predominant renal involvement
   • Normal ADAMTS13 activity

3. Cancer-associated MAHA

   • Due to microvascular metastases or bone marrow involvement
   • Common in gastric, breast, prostate, lung cancers 3
   • May be the presenting feature of undiagnosed malignancy

4. Drug-induced MAHA

   • Common culprits: chemotherapeutic agents, immunosuppressants (tacrolimus, cyclosporine), quinine/quinidine 1, 4
   • Can be dose-dependent or immune-mediated

5. Other causes

   • Disseminated intravascular coagulation (DIC)
   • Malignant hypertension
   • Pregnancy complications (HELLP syndrome, preeclampsia)
   • Post-transplantation

Diagnostic Approach

When MAHA is suspected:

1. Initial workup:

   • Complete blood count with peripheral smear review
   • Reticulocyte count
   • LDH, haptoglobin
   • Direct antiglobulin test
   • Renal function tests
   • Coagulation studies (PT, aPTT, fibrinogen)

2. Specialized testing:

   • ADAMTS13 activity and inhibitor (to diagnose TTP)
   • Stool testing for Shiga toxin/E. coli O157 (for typical HUS)
   • Complement studies (C3, C4, CH50) for atypical HUS
   • Genetic testing when appropriate

Management

Treatment depends on the underlying cause:

1. TTP:

   • Medical emergency requiring immediate intervention
   • Plasma exchange (PEX) is first-line therapy
   • Corticosteroids (methylprednisolone 1g IV daily for 3 days)
   • Consider rituximab in refractory cases 1

2. Typical HUS:

   • Supportive care
   • Fluid and electrolyte management
   • Renal replacement therapy if needed

3. Atypical HUS:

   • Complement inhibition therapy (eculizumab)
   • Begin therapy within 4-8 hours of diagnosis 2
   • Meningococcal vaccination prior to or concurrent with therapy

4. Cancer-associated MAHA:

   • Treatment of the underlying malignancy
   • Plasma exchange is generally not beneficial 5, 6
   • Supportive care with transfusions as needed

5. Drug-induced MAHA:

   • Discontinuation of the offending agent
   • Supportive care
   • Consider switching to alternative medication

Prognosis

Prognosis varies significantly based on the underlying cause:

• TTP: Historically fatal without treatment; >80% survival with prompt plasma exchange
• Typical HUS: Generally good with supportive care
• Atypical HUS: Improved with complement inhibitors
• Cancer-associated MAHA: Poor, reflects advanced disease
• Drug-induced MAHA: Generally resolves with drug discontinuation

Important Clinical Pearls

• MAHA with severe ADAMTS13 deficiency (<10%) defines TTP and requires immediate plasma exchange 1
• The presence of schistocytes on peripheral smear is the hallmark finding in MAHA
• Early recognition and prompt initiation of appropriate therapy significantly impacts outcomes 2
• Serial monitoring of schistocyte counts is more valuable than a single measurement 2
• Plasma exchange has no proven benefit in cancer-associated or drug-induced MAHA 5, 6
• In patients with unexplained MAHA, consider occult malignancy, particularly in older adults 3