What is the comparison between Thrombotic Microangiopathy (TMA) and Maha for a patient with a history of renal issues, cancer, or autoimmune diseases?

TMA vs MAHA: Understanding the Relationship

TMA (Thrombotic Microangiopathy) is the underlying pathological disease process, while MAHA (Microangiopathic Hemolytic Anemia) is one of the key clinical manifestations of TMA—they are not competing diagnoses but rather disease and symptom. 1, 2

Defining the Relationship

TMA is a clinicopathological syndrome characterized by endothelial injury leading to platelet activation, formation of platelet-rich thrombi in the microcirculation, and organ damage from microcirculation obstruction. 1 MAHA represents the hemolytic component of this syndrome, manifesting as schistocytes on blood smear, elevated LDH, and unmeasurable haptoglobin. 3, 2

Key Diagnostic Features

The diagnostic triad of TMA includes:

• MAHA with schistocytosis (the hemolytic anemia component) 2, 4
• Thrombocytopenia (consumptive, from platelet activation) 2, 4
• End-organ dysfunction (kidney, brain, or other organs from microvascular thrombosis) 1, 4

Clinical Context for Patients with Renal Issues, Cancer, or Autoimmune Disease

Renal Disease Context

In patients with renal involvement, TMA can present as:

• Malignant hypertension-associated TMA: Severe BP elevation with advanced retinopathy (Grade III/IV) triggers endothelial injury and MAHA, typically showing only moderate thrombocytopenia and few schistocytes compared to primary TMA forms. 5 BP control within 24-48 hours usually improves the TMA. 5
• Antiphospholipid syndrome nephropathy: TMA lesions in lupus nephritis biopsies (up to 25% of cases) should prompt antiphospholipid antibody testing, as this carries distinct prognostic and therapeutic implications. 5
• Monoclonal gammopathy-related TMA: Can occur with multiple myeloma or Waldenström macroglobulinemia, where the monoclonal immunoglobulin may act as an autoantibody against complement regulatory proteins. 5

Cancer Context

Chemotherapy-associated TMA occurs with:

• Mitomycin-C, gemcitabine, platinum-based drugs, antiangiogenesis agents, and proteasome inhibitors as the primary offending agents. 6
• Treatment requires immediate withdrawal of the offending agent plus supportive care targeting blood pressure and proteinuria reduction. 6
• Plasma exchange and immunosuppression have not shown clear benefit in drug-induced TMA, unlike primary forms. 6
• Eculizumab shows promise in some chemotherapy-associated TMA cases, including for drug re-exposure, though data remain limited. 6

Autoimmune Disease Context

In systemic lupus erythematosus:

• TMA lesions on kidney biopsy should trigger antiphospholipid antibody retesting even if previously negative, as this indicates antiphospholipid syndrome nephropathy. 5
• The prognostic implications of TMA in lupus nephritis remain unclear despite its frequency (up to 25% of biopsies). 5

Critical Diagnostic Algorithm

Step 1: Confirm TMA syndrome is present by documenting all three components: MAHA with schistocytes, thrombocytopenia, and organ dysfunction. 1, 2, 4

Step 2: Immediately measure ADAMTS13 activity to distinguish TTP from other TMA forms:

• ADAMTS13 <10% confirms TTP and requires immediate plasma exchange, high-dose glucocorticoids, and rituximab ± caplacizumab. 1, 3
• ADAMTS13 >10% rules out TTP and directs evaluation toward secondary TMA causes. 1, 2

Step 3: For ADAMTS13 >10%, systematically evaluate:

• Blood pressure: Severe hypertension with Grade III/IV retinopathy indicates malignant hypertension-associated TMA requiring aggressive BP control. 5, 3
• Medication history: Recent chemotherapy, immunosuppressants (tacrolimus + everolimus combination particularly high-risk), or other drugs suggests drug-induced TMA requiring immediate discontinuation. 6, 7
• Antiphospholipid antibodies: Positive testing indicates antiphospholipid syndrome-associated TMA requiring long-term anticoagulation with warfarin. 1
• Complement studies: Consider complement-mediated TMA if other causes excluded; eculizumab may be effective. 1

Common Pitfalls

Do not confuse TMA with isolated MAHA: MAHA can occur without TMA in conditions like mechanical heart valves or severe burns—the presence of thrombocytopenia and organ dysfunction distinguishes true TMA syndrome. 2, 4

Do not delay ADAMTS13 testing while awaiting results: Use the PLASMIC score to risk-stratify; intermediate-to-high risk patients should receive empiric plasma exchange and glucocorticoids immediately. 1

Do not assume all TMA in cancer patients is chemotherapy-related: Cancer itself can cause TMA through multiple mechanisms including widespread inflammation and endothelial damage. 2

Do not use plasma exchange for all TMA forms: It is life-saving in TTP but ineffective in drug-induced TMA and malignant hypertension-associated TMA, where removing the offending agent or controlling BP is the primary intervention. 5, 6