Etiology and Pathogenesis of Microangiopathic Hemolytic Anemia (MAHA)

Definition and Clinical Features

Laboratory findings include anemia with microangiopathic changes (schistocytes, burr cells, or helmet cells) on peripheral blood smear, according to the MMWR Recommendations and Reports 1
The characteristic pentad of microangiopathic hemolytic anemia, thrombocytopenia, fever, neurological abnormalities, and renal dysfunction is seen in Thrombotic Thrombocytopenic Purpura (TTP), as reported by MMWR Recommendations and Reports 1

Thrombotic Thrombocytopenic Purpura (TTP) is caused by severe deficiency of ADAMTS13, as stated in Kidney International 2
TTP is characterized by the pentad of microangiopathic hemolytic anemia, thrombocytopenia, fever, neurological abnormalities, and renal dysfunction, according to MMWR Recommendations and Reports 1
Typical Hemolytic Uremic Syndrome (HUS) follows acute gastrointestinal illness, usually diarrheal, as reported by MMWR Recommendations and Reports 1

Systemic Lupus Erythematosus (SLE) and Lupus Nephritis can cause TMA, which may involve monoclonal immunoglobulins acting as autoantibodies against complement regulatory proteins, as stated in Nature Reviews Nephrology 3
Antiphospholipid Syndrome can cause antiphospholipid syndrome nephropathy with features of TMA, as reported in Stroke 4
The mechanism of Antiphospholipid Syndrome involves inhibition of prostacyclin formation or protein C activation, as stated in Stroke 4
Chronic Hemolytic Anemias, such as sickle cell disease, thalassemia, hereditary spherocytosis, and stomatocytosis, can result in TMA due to high rate of nitric oxide consumption leading to resistance to NO bioactivity, as reported in European Heart Journal 5

In Hemolytic Uremic Syndrome (HUS), there is predominant renal involvement with glomerular thrombotic microangiopathy, as reported by MMWR Recommendations and Reports 1

ADAMTS13 activity testing is crucial to identify TTP (activity <10%), as stated in Kidney International 2
Testing for antiphospholipid antibodies helps identify antiphospholipid syndrome-associated TMA, as reported in Kidney International 2
The PLASMIC score can help risk-stratify patients for likelihood of TTP, as stated in Kidney International 2

Treatment should be directed at the underlying etiology of TMA, as reported in Kidney International 2
For TTP, treatment options include plasma exchange, glucocorticoids, rituximab, and possibly caplacizumab, as stated in Kidney International 2
For complement-mediated TMA, consider eculizumab, as reported in Kidney International 2
For antiphospholipid syndrome-associated TMA, anticoagulation with or without plasma exchange is recommended, as stated in Kidney International 2

The European Society of Cardiology suggests that hemolysis in MAHA occurs mainly due to mechanical fragmentation of red blood cells as they pass through damaged small blood vessels with platelet-rich thrombi and fibrin formation, leading to red blood cell trapping and destruction in the fibrin network 6
Endothelial damage and exposure of blood to the subendothelial layer leads to activation of coagulation, platelet activation, and fibrin formation, resulting in two main consequences: (i) formation of platelet-rich thrombi that occlude the microcirculation and (ii) consumption of platelets and intravascular hemolysis due to red blood cell trapping and destruction in the fibrin network 6

Oxidative stress, Ca²⁺ overload, and phospholipid membrane asymmetry can promote eryptosis (red blood cell death) 7
Extracellular histones can induce red blood cell aggregation and lysis in a concentration-dependent manner, while also reducing red blood cell deformability 7

Microangiopathic hemolytic anemia is characterized by non-immune hemolytic anemia (negative direct Coombs test), elevated LDH, decreased haptoglobin, and presence of schistocytes on peripheral blood smear 8

Severe vascular rejection in renal transplant recipients can precipitate thrombotic microangiopathy (TMA) as a direct complication of the rejection episode, representing a secondary TMA rather than a non‑TMA cause of microangiopathic hemolytic anemia. 9