What is the most likely diagnosis for a patient with anemia, normocytic red blood cells, and schistocytes noted on peripheral smear?

Thrombotic Microangiopathy (TMA)

The most likely diagnosis is a thrombotic microangiopathy (TMA), specifically thrombotic thrombocytopenic purpura (TTP), hemolytic uremic syndrome (HUS), or another form of microangiopathic hemolytic anemia (MAHA). The combination of anemia (hemoglobin 10.2), normocytic red blood cells (MCV 90), and schistocytes on peripheral smear is pathognomonic for intravascular red blood cell fragmentation occurring in TMA 1, 2, 3.

Immediate Diagnostic Workup Required

Order ADAMTS13 activity level and inhibitor titer immediately—this single test differentiates TTP from other TMAs and determines treatment urgency 1, 2. Do not delay empiric treatment if TTP is strongly suspected clinically, as mortality increases with delayed plasma exchange 1, 2.

Critical First-Line Laboratory Tests

• ADAMTS13 activity: <10% confirms TTP; >10% suggests atypical HUS or secondary TMA 2, 4
• Complete blood count with platelet count: Expect thrombocytopenia (<150,000/mm³) in TTP/HUS 2, 3
• Lactate dehydrogenase (LDH): Markedly elevated in hemolysis 1, 2, 3
• Haptoglobin: Decreased or undetectable in intravascular hemolysis 1, 3
• Direct Coombs test (DAT): Must be negative to confirm non-immune hemolytic anemia 2, 3
• Reticulocyte count: Should be elevated as appropriate marrow response 1, 2
• Serum creatinine and urinalysis: Elevated creatinine indicates renal involvement consistent with HUS 1, 2

Additional Testing to Exclude Mimics

• Prothrombin time, aPTT, fibrinogen: To exclude disseminated intravascular coagulation (DIC) 1
• Complement testing (C3, C4, CH50): For suspected complement-mediated atypical HUS 5, 1
• Vitamin B12 and folate levels: Severe B12 deficiency can rarely present with schistocytes and thrombocytopenia, mimicking TTP 6

Differential Diagnosis Framework

The triad defining TMA consists of non-immune microangiopathic hemolysis, thrombocytopenia, and organ involvement (typically renal) 1.

Primary TMA Etiologies Based on ADAMTS13

• TTP: ADAMTS13 activity <10% with or without inhibitory autoantibodies 2, 4
• Atypical HUS: ADAMTS13 activity >10% with complement dysregulation 2, 4
• Secondary TMA causes: Malignancy (gastric, breast, lung, prostate), drugs (calcineurin inhibitors, chemotherapy), malignant hypertension, infections 1, 2, 7

Important Clinical Context

• Approximately 50% of TMA cases at onset do not present with all three classic findings (hemolytic anemia, thrombocytopenia, renal involvement) 3
• Schistocytes >1% strongly support TMA diagnosis, but their absence does not exclude early TMA due to low test sensitivity 1, 3
• Neurological symptoms are common in TTP but not required for diagnosis 1

Management Algorithm

If ADAMTS13 <10% (TTP Confirmed)

Immediately initiate therapeutic plasma exchange (PEX) before ADAMTS13 results return if TTP is clinically suspected—delay increases mortality 1, 2, 4.

• Administer methylprednisolone 1g IV daily for 3 days, with first dose typically given immediately after first PEX 5, 1
• Continue daily PEX until platelet count exceeds 100-150 × 10⁹/L for 2 consecutive days 4, 8
• Consider rituximab, IVIg, or other immunosuppression for refractory cases 1
• Platelet transfusion is contraindicated unless life-threatening bleeding 1

If ADAMTS13 >10% (Atypical HUS or Secondary TMA)

Begin eculizumab therapy urgently for atypical HUS with clinical consequences: 900 mg weekly for four doses, 1,200 mg week 5, then 1,200 mg every 2 weeks 5, 1.

• Administer meningococcal vaccination and long-term penicillin prophylaxis with eculizumab 1
• Review all medications for potential TMA triggers (tacrolimus, cyclosporine, sirolimus, chemotherapy agents) and discontinue if possible 5, 2
• Evaluate for malignant hypertension: Measure blood pressure and perform funduscopic examination; if severely elevated with advanced retinopathy, initiate controlled blood pressure lowering and monitor for TMA improvement within 24-48 hours 1

Supportive Care and Transfusion Guidelines

• RBC transfusion only to relieve symptoms or achieve hemoglobin 7-8 g/dL in stable, non-cardiac patients—do not transfuse more than minimum necessary 1
• Use extended antigen-matched red cells (C/c, E/e, K, Jk^a^/Jk^b^, Fy^a^/Fy^b^, S/s) if patient has sickle cell disease 1
• Monitor daily CBC with differential, LDH, haptoglobin, and creatinine during acute phase 1

Critical Pitfalls to Avoid

• Do not dismiss the diagnosis based on "rare" schistocytes alone—low schistocyte counts can occur in early or evolving TMA 1
• Do not wait for ADAMTS13 results to initiate plasma exchange if TTP is strongly suspected—mortality increases with treatment delay 1, 2
• Do not assume anemia is solely from bleeding—it should be disproportionate to any bleeding if TMA is present 3
• Do not overlook malignancy-associated MAHA—gastric, breast, prostate, lung cancers and lymphoma can present with identical laboratory findings 7
• Residual schistocytosis at discontinuation of plasma exchange (present in 35.6% of cases) is not predictive of relapse—do not unnecessarily prolong treatment 8