What is the etiology and pathogenesis of Microangiopathic Hemolytic Anemia (MAHA)?

Etiology and Pathogenesis of Microangiopathic Hemolytic Anemia (MAHA)

Microangiopathic hemolytic anemia (MAHA) is characterized by red blood cell fragmentation occurring in association with small vessel disease, resulting from endothelial damage and vascular occlusion that leads to mechanical destruction of erythrocytes as they pass through damaged microvasculature. 1

Definition and Clinical Features

• MAHA is defined by the presence of intravascular fragmentation of red blood cells, leading to characteristic schistocytes on peripheral blood smear 2
• It typically presents with the clinical triad of microangiopathic hemolytic anemia, consumptive thrombocytopenia, and organ injury 3
• Laboratory findings include anemia with microangiopathic changes (schistocytes, burr cells, or helmet cells) on peripheral blood smear 4

Pathophysiological Mechanisms

• Injury to the endothelial cell is the central and inciting factor in the sequence of events leading to thrombotic microangiopathy (TMA) 5
• The damaged endothelium loses its physiological thromboresistance, leading to:
  • Leukocyte adhesion to damaged endothelium
  • Complement consumption
  • Abnormal von Willebrand factor release and fragmentation
  • Increased vascular shear stress that sustains and amplifies the microangiopathic process 5

Major Etiologies of MAHA

1. Primary Thrombotic Microangiopathies

• Thrombotic Thrombocytopenic Purpura (TTP)

  • Caused by severe deficiency of ADAMTS13 (a disintegrin and metalloproteinase with thrombospondin type 1 motif, member 13) 4
  • ADAMTS13 deficiency can be:
    • Genetic (congenital TTP)
    • Acquired (autoimmune production of inhibitory anti-ADAMTS13 antibodies) 5
  • Characterized by pentad of microangiopathic hemolytic anemia, thrombocytopenia, fever, neurological abnormalities, and renal dysfunction 4

• Hemolytic Uremic Syndrome (HUS)

  • Typical HUS (Shiga toxin-associated)

    • Follows acute gastrointestinal illness, usually diarrheal 4
    • Caused by Shiga toxin-producing bacteria (E. coli, Shigella dysenteriae) 5
    • Renal endothelial damage is mediated by Shiga toxin 5

  • Atypical HUS (aHUS)

    • Disorder of complement alternative pathway dysregulation 5
    • Approximately 60% of aHUS patients have mutations in genes encoding complement regulatory proteins:
      • Loss-of-function mutations in complement factor H (CFH), factor I (CFI), membrane cofactor protein (MCP)
      • Gain-of-function mutations in complement factor B or C3 5
    • About 10% have functional CFH deficiency due to anti-CFH antibodies 5

2. Secondary Causes of MAHA/TMA

• Systemic Lupus Erythematosus (SLE) and Lupus Nephritis

  • TMA can occur concurrently with lupus nephritis 4
  • Pathophysiology may involve:
    • Monoclonal immunoglobulins acting as autoantibodies against complement regulatory proteins 4
    • Antiphospholipid antibodies causing endothelial damage 4

• Antiphospholipid Syndrome

  • Can cause antiphospholipid syndrome nephropathy with features of TMA 4
  • Mechanism involves inhibition of prostacyclin formation or protein C activation 4

• Malignancy-Associated MAHA

  • Can be directly related to underlying malignancy (initial presentation or progressive disease) 6
  • Caused by widespread microvascular metastases or extensive bone marrow involvement 6
  • Common malignancies associated with MAHA include gastric, breast, prostate, lung, and lymphoma 2

• Drug-Induced TMA

  • Can be dose-dependent toxicity or idiosyncratic immune-mediated reaction due to drug-dependent antibodies 6

• Pregnancy-Related TMA

  • Includes preeclampsia and HELLP syndrome 5

• Hematopoietic Stem Cell Transplantation-Associated TMA 1

• Chronic Hemolytic Anemias

  • Sickle cell disease, thalassemia, hereditary spherocytosis, stomatocytosis can result in TMA 4
  • Mechanism related to high rate of nitric oxide consumption leading to resistance to NO bioactivity 4

• Disseminated Intravascular Coagulation (DIC)

  • RBC fragmentation results from deposition of fibrin or platelets within the microvasculature 1
  • Can be precipitated by sepsis or driven by cancer itself 6

Pathological Features

• Histopathologically characterized by generalized microvascular occlusion by platelet thrombi 5
• Vascular endothelial injury is the fundamental pathological process 3
• In TTP, there is formation of platelet-rich thrombi in the microcirculation due to unusually large von Willebrand factor multimers that are not cleaved due to ADAMTS13 deficiency 5
• In HUS, there is predominant renal involvement with glomerular thrombotic microangiopathy 4

Diagnostic Approach

• Peripheral blood smear showing schistocytes is essential for diagnosis 2
• ADAMTS13 activity testing is crucial to identify TTP (activity <10%) 4
• Testing for antiphospholipid antibodies helps identify antiphospholipid syndrome-associated TMA 4
• PLASMIC score can help risk-stratify patients for likelihood of TTP 4
• Evaluation for complement dysregulation in suspected aHUS 5

Treatment Considerations

• Treatment should be directed at the underlying etiology of TMA 4
• For TTP: Plasma exchange, glucocorticoids, rituximab, and possibly caplacizumab 4
• For complement-mediated TMA: Consider eculizumab 4
• For antiphospholipid syndrome-associated TMA: Anticoagulation with or without plasma exchange 4
• For malignancy-associated MAHA: Treatment of the underlying malignancy is important 6
• Platelet transfusions are contraindicated in most forms of TMA 5