What is the cause of Microangiopathic Hemolytic Anemia (MAHA) and thrombocytopenia?

From the Guidelines

Microangiopathic Hemolytic Anemia (MAHA) with thrombocytopenia is most commonly caused by thrombotic microangiopathies (TMAs) such as thrombotic thrombocytopenic purpura (TTP) and hemolytic uremic syndrome (HUS), as well as other conditions like heparin-induced thrombocytopenia (HIT) and immune-related adverse events associated with immune checkpoint inhibitor therapy. When encountering a patient with MAHA and thrombocytopenia, immediate evaluation and treatment are essential as these conditions can be life-threatening. The initial management should include urgent plasma exchange (PLEX) for suspected TTP while awaiting ADAMTS13 activity results, as well as evaluation for other potential causes of thrombocytopenia, including HIT and immune-related adverse events 1.

Key Considerations

• The pathophysiology of MAHA and thrombocytopenia involves microthrombi formation, mechanical hemolysis, and platelet consumption, which can be caused by various factors, including ADAMTS13 deficiency, complement dysregulation, and immune-related adverse events 1.
• HIT is a clinical-biological syndrome induced by IgG isotype antibodies, which recognize heparin-modified platelet factor 4 (PF4/H), leading to intense platelet activation and thrombin generation 1.
• Immune-related adverse events associated with immune checkpoint inhibitor therapy can cause hematologic toxicities, including hemolytic anemia and thrombocytopenia, which can be managed with corticosteroids, IVIG, and growth factor support 1.

Management

• The initial management of MAHA and thrombocytopenia should include urgent evaluation and treatment, with consideration of PLEX for suspected TTP, as well as evaluation for other potential causes of thrombocytopenia, including HIT and immune-related adverse events.
• Concurrent corticosteroids and supportive care, including blood product transfusions and renal support, may be necessary.
• For refractory or relapsing TTP, rituximab may be added, and in cases of complement-mediated HUS, eculizumab is the treatment of choice 1.

From the FDA Drug Label

Patients with sepsis, infection with E. coli 0157, atypical hemolytic uremic syndrome, disseminated intravascular coagulation or congenital thrombotic thrombocytopenic purpura were not eligible for enrollment The cause of Microangiopathic Hemolytic Anemia (MAHA) and thrombocytopenia is not directly stated in the provided drug label. However, it can be inferred that these conditions are related to underlying diseases such as:

• Thrombotic thrombocytopenic purpura (TTP)
• Atypical hemolytic uremic syndrome
• Disseminated intravascular coagulation The drug label discusses the treatment of TTP with caplacizumab, but does not provide a direct cause of MAHA and thrombocytopenia 2.

From the Research

Causes of Microangiopathic Hemolytic Anemia (MAHA) and Thrombocytopenia

• Microangiopathic Hemolytic Anemia (MAHA) and thrombocytopenia are characteristics of thrombotic microangiopathies (TMAs), which include thrombotic thrombocytopenic purpura (TTP) and atypical hemolytic uremic syndrome (aHUS) 3, 4, 5.
• In TTP, MAHA and thrombocytopenia are caused by decreased activity of ADAMTS13, a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13, which leads to the accumulation of ultra-large von Willebrand factor (vWF) multimers 3, 4, 6.
• The accumulation of ultra-large vWF multimers activates platelets and endothelium, initiating microvascular thrombosis and resulting in MAHA and thrombocytopenia 3, 4.
• Autoantibody-mediated ADAMTS13 inhibition is a common cause of TTP, leading to the accumulation of ultra-large vWF multimers and subsequent microvascular thrombosis 3, 4.
• Other causes of TTP include certain chemotherapies, bone marrow transplantation, and progression of underlying disease, such as multiple myeloma 5.

Triggers of TTP

• COVID-19 infection has been reported as a trigger for TTP, although the association between COVID-19 and TTP is not well understood 4.
• Other triggers of TTP include certain medications, such as rituximab, and underlying medical conditions, such as autoimmune disorders 3, 6.

Pathophysiology of MAHA and Thrombocytopenia

• The pathophysiology of MAHA and thrombocytopenia in TTP involves the formation of platelet-rich thrombi in small vessels, leading to fragmentation of red blood cells and subsequent hemolysis 4, 6.
• The accumulation of ultra-large vWF multimers and the activation of platelets and endothelium play a crucial role in the development of microvascular thrombosis and MAHA 3, 4.