What are the non‑thrombotic microangiopathy causes of microangiopathic hemolytic anemia?

Non-TMA Causes of Microangiopathic Hemolytic Anemia

MAHA can occur without thrombotic microangiopathy through several distinct mechanisms, most notably mechanical hemolysis from prosthetic heart valves or cardiac devices, disseminated intravascular coagulation (DIC), widespread metastatic cancer with microvascular involvement, and severe hemolytic anemias like sickle cell disease. 1, 2, 3

Primary Non-TMA Mechanisms of MAHA

Mechanical Hemolysis from Cardiac Devices

• Prosthetic heart valves and intravascular assistive devices cause direct mechanical fragmentation of red blood cells through acute mechanical stress, producing schistocytes without the microvascular thrombosis characteristic of TMA 4
• This represents pure mechanical trauma to erythrocytes rather than endothelial damage and platelet-rich thrombi formation 1

Disseminated Intravascular Coagulation (DIC)

• DIC produces MAHA through consumption coagulopathy with fibrin deposition in vessels, but the pathophysiology differs fundamentally from primary TMA 2, 3
• DIC may be precipitated by sepsis or driven by malignancy itself, creating a distinct clinical picture with coagulation factor consumption and bleeding diathesis 2
• The coagulation abnormalities in DIC (prolonged PT/PTT, low fibrinogen, elevated D-dimer) distinguish it from primary TMA syndromes 3

Cancer-Associated MAHA (Non-TMA Mechanism)

• Widespread microvascular metastases cause mechanical red blood cell fragmentation without the complement or ADAMTS13 abnormalities of primary TMA 2, 3
• Extensive bone marrow involvement by malignancy produces MAHA and thrombocytopenia through direct marrow infiltration rather than microvascular thrombosis 2, 3
• This occurs most commonly in metastatic adenocarcinomas (gastric, breast, prostate) and may be the presenting feature of undiagnosed cancer 3

Chronic Hemolytic Anemias with Secondary Vascular Damage

• Sickle cell disease, thalassemia, hereditary spherocytosis, and stomatocytosis can produce TMA-like features through high rates of nitric oxide consumption leading to resistance to NO bioactivity and subsequent vascular damage 1
• The primary pathology is the inherited red blood cell disorder, with vascular complications occurring secondarily rather than primary endothelial injury 1

Critical Distinction: Allograft Rejection-Associated MAHA

• Severe vascular rejection in renal transplant recipients causes thrombotic microangiopathy as a complication of the rejection episode itself 5
• This represents a secondary TMA triggered by rejection rather than a non-TMA cause of MAHA 5

Clinical Pitfall to Avoid

• The key distinction is that non-TMA MAHA lacks the primary endothelial injury and microvascular platelet-rich thrombi that define TMA, even though schistocytes are present in both conditions 1, 2
• DIC will show coagulation factor consumption (low fibrinogen, prolonged clotting times) that is absent in primary TMA 3
• Mechanical hemolysis from cardiac devices typically shows less severe thrombocytopenia compared to TTP or HUS 6
• Cancer-associated MAHA usually occurs in patients with known metastatic disease, though it can be the presenting feature 3

Diagnostic Approach to Differentiate Non-TMA MAHA

• Assess for DIC with PT/PTT, fibrinogen, and D-dimer—abnormalities suggest DIC rather than primary TMA 3
• Evaluate for prosthetic valves or intravascular devices on history and imaging 4
• Screen for metastatic malignancy with imaging and bone marrow biopsy if clinically indicated 2, 3
• Check ADAMTS13 activity to exclude TTP (activity <10% indicates TTP, a true TMA) 1, 6

Treatment Implications

• Plasma exchange has no known benefit for cancer-induced or drug-induced TMA, and should be avoided in non-TMA MAHA to prevent unnecessary complications 3
• Treatment of the underlying malignancy is essential for controlling cancer-associated MAHA 2
• DIC management focuses on treating the precipitating cause (sepsis, malignancy) rather than plasma exchange 2
• Mechanical hemolysis may require valve replacement or device removal if severe 4