What is microangiopathic anemia?

Microangiopathic Hemolytic Anemia (MAHA)

Microangiopathic hemolytic anemia (MAHA) is a non-immune hemolytic anemia caused by intravascular fragmentation of red blood cells as they pass through damaged or obstructed small blood vessels, resulting in the characteristic finding of schistocytes (fragmented red blood cells) on peripheral blood smear. 1, 2, 3

Pathophysiology

• MAHA results from mechanical destruction of red blood cells as they encounter abnormalities in the microvasculature, including small arterioles and capillaries 3
• The fragmentation occurs when red blood cells are sheared by:
  • Fibrin strands deposited in small vessels (as in DIC) 2
  • Platelet-rich thrombi in the microvasculature 2
  • Intravascular devices such as prosthetic heart valves 3
• Poor red blood cell deformability leads to entrapment, fragmentation from microthrombi, or acute mechanical stress, resulting in hemolysis 3

Clinical Presentation

MAHA manifests with signs and symptoms of acute hemolysis, including:

• Acute anemia with associated fatigue, dyspnea, and tachycardia 3
• Jaundice from elevated indirect bilirubin 3
• Hematuria from intravascular hemolysis 3
• Potential hypotension in severe cases 3
• Fever, thrombocytopenia, and fluctuating neurological signs when associated with thrombotic thrombocytopenic purpura (TTP) 4

Diagnostic Features

The diagnosis of MAHA requires demonstration of hemolytic anemia with characteristic red blood cell fragmentation:

• Schistocytes (helmet cells, tear-drop cells) on peripheral blood smear 1, 2, 5
• Evidence of hemolysis:
  • Elevated lactate dehydrogenase (LDH) 4, 1, 5
  • Decreased haptoglobin 4, 1
  • Elevated indirect bilirubin 1, 6
  • Elevated reticulocyte count (when bone marrow compensation is intact) 1, 5
• Negative direct antiglobulin test (Coombs test), distinguishing it from immune-mediated hemolysis 4, 1, 6
• Thrombocytopenia (platelets <150,000/mm³ or 25% reduction from baseline) is often present 4

Relationship to Thrombotic Microangiopathy (TMA)

MAHA is the hematologic hallmark of thrombotic microangiopathy (TMA), a syndrome characterized by MAHA, thrombocytopenia, and thrombotic lesions in small blood vessels 2:

• The most prominent TMA diagnoses are thrombotic thrombocytopenic purpura (TTP) and hemolytic uremic syndrome (HUS) 2
• ADAMTS13 activity testing is essential to distinguish TTP (activity <10%) from other forms of TMA 1, 6
• Atypical HUS is complement-mediated and requires different treatment than TTP 1, 6

Common Etiologies

MAHA occurs in diverse clinical contexts:

Primary TMA Syndromes

• TTP (ADAMTS13 deficiency) 6, 2
• Hemolytic uremic syndrome (typical Shiga toxin-producing E. coli and atypical complement-mediated) 4, 2

Secondary Causes

• Disseminated intravascular coagulation (DIC) 2, 7
• Malignancy-associated: gastric, breast, prostate, lung cancers, lymphoma, and signet-ring cell carcinoma 7, 8
• Drug-induced TMA: chemotherapy agents, calcineurin inhibitors (tacrolimus, cyclosporine), sirolimus, quinine, antibiotics 4, 6, 7
• Transplant-associated: hematopoietic stem cell transplantation, solid organ transplantation 4, 2
• Pregnancy-related: preeclampsia, HELLP syndrome 2
• Autoimmune diseases: systemic lupus erythematosus, antiphospholipid antibody syndrome 4, 2
• Infections: sepsis, cytomegalovirus 2, 7
• Hematologic disorders: chronic granulocytic leukemia, chronic myelofibrosis, polycythemia vera 5

Critical Diagnostic Pitfalls

• In cancer patients presenting with MAHA, consider widespread microvascular metastases, extensive bone marrow involvement, or cancer therapy-induced TMA 7
• Approximately 50% of patients with monoclonal gammopathy and thrombotic microangiopathy may have concurrent MAHA 4
• Some patients may lack compensatory reticulocytosis due to bone marrow involvement or suppression, distinguishing them from typical TMA presentations 5
• Drug-induced TMA requires a detailed medication history, as it can occur with commonly used immunosuppressants and antimicrobials 4, 6

Treatment Principles

Treatment of MAHA is directed at the underlying cause:

• For TTP: immediate plasma exchange, high-dose corticosteroids, and early rituximab 1, 6
• For atypical HUS: eculizumab (complement inhibitor) 1, 6
• For drug-induced TMA: discontinue the offending agent 6, 7
• For malignancy-associated MAHA: treatment of the underlying cancer is essential 7
• Supportive care includes RBC transfusions to maintain hemoglobin 7-8 g/dL and folic acid supplementation 1
• Platelet transfusion is contraindicated in TTP unless life-threatening bleeding occurs 6