What is the likely diagnosis and management for a patient presenting with anemia, thrombocytopenia, elevated ferritin, and high Lactate Dehydrogenase (LDH) levels?

Likely Diagnosis: Thrombotic Microangiopathy (TMA)

The combination of anemia, thrombocytopenia, elevated ferritin, and high LDH strongly suggests thrombotic microangiopathy (TMA), which requires immediate diagnostic workup and urgent treatment to prevent mortality and irreversible organ damage. 1, 2

Immediate Diagnostic Workup

The following tests must be ordered urgently to differentiate TMA subtypes and guide life-saving therapy:

• ADAMTS13 activity level and inhibitor titer - this is the single most critical test to distinguish TTP from other TMAs 1, 3
• Peripheral blood smear - to identify schistocytes (fragmented red blood cells), which confirm microangiopathic hemolysis 1, 4
• Complete blood count with differential - to quantify the degree of anemia and thrombocytopenia 1, 3
• Direct antiglobulin test (Coombs) - to exclude immune-mediated hemolytic anemia 1, 3, 5
• Haptoglobin level - will be markedly decreased in hemolysis 2, 4, 5
• Indirect bilirubin - will be elevated due to red cell breakdown 2, 4, 5
• Reticulocyte count - should be elevated as bone marrow compensates for hemolysis 1, 4
• Creatinine and urinalysis - to assess for renal involvement (hematuria/proteinuria), which is typical in TMA 1, 3
• Prothrombin time, aPTT, and fibrinogen - to exclude disseminated intravascular coagulation (DIC) 1, 3

Diagnostic Algorithm Based on ADAMTS13 Results

If ADAMTS13 Activity <10%: Thrombotic Thrombocytopenic Purpura (TTP)

Immediately initiate therapeutic plasma exchange (PEX) without waiting for ADAMTS13 results if TTP is strongly suspected clinically, as mortality increases dramatically with treatment delay. 1, 3

• Administer methylprednisolone 1g IV daily for 3 days, with the first dose given immediately after the first plasma exchange 1, 3
• Continue daily plasma exchange until platelet count exceeds 100-150 × 10⁹/L for 2 consecutive days 1
• Do NOT transfuse platelets unless life-threatening bleeding occurs, as platelet transfusion can worsen thrombosis in TTP 1
• For refractory cases, consider rituximab, intravenous immunoglobulin (IVIg), or cyclosporin A 1

If ADAMTS13 Activity >10%: Atypical Hemolytic Uremic Syndrome (aHUS) or Other TMA

• Begin eculizumab therapy urgently for aHUS with clinical consequences: 900 mg weekly for four doses, 1,200 mg week 5, then 1,200 mg every 2 weeks 1, 3
• Administer meningococcal vaccination and long-term penicillin prophylaxis before or concurrent with eculizumab 1
• Order complement testing (C3, C4, CH50) to confirm complement-mediated aHUS 1, 3
• Review all medications for potential TMA triggers and discontinue if possible 1
• Check for malignant hypertension with blood pressure measurement and funduscopic examination, as severe hypertension with retinopathy can cause TMA that improves within 24-48 hours of controlled blood pressure lowering 1

Critical Pitfalls to Avoid

• Do not delay plasma exchange while awaiting ADAMTS13 results - if clinical suspicion for TTP is high, start PEX immediately as mortality increases with each hour of delay 1, 3
• Do not dismiss TMA based on "rare" or absent schistocytes - schistocyte counts can be low in early or evolving TMA, and the test has poor sensitivity 1
• Do not transfuse platelets in suspected TTP - this can precipitate thrombotic complications 1
• Do not assume elevated ferritin excludes other diagnoses - while ferritin of 5269 ng/mL can suggest hemophagocytic lymphohistiocytosis (HLH), markedly elevated ferritin also occurs in chronic hemolysis and does not exclude TMA 6, 4, 7

Alternative Considerations

Hemophagocytic Lymphohistiocytosis (HLH)

If the patient has persistent fever, organomegaly, and extremely elevated ferritin (>5000 ng/mL), consider HLH as an alternative or concurrent diagnosis 6, 7:

• The combination, extent, and progression of fever, cytopenias, elevated LDH, and hyperferritinemia that are unusual and otherwise unexplained should raise suspicion 6
• Order bone marrow aspirate to look for hemophagocytosis, though this finding is neither sensitive nor specific 6
• In adults, nearly half of HLH cases are triggered by malignancy, particularly lymphoma 6
• HLH can coexist with TMA in rare cases 7

Autoimmune Hemolytic Anemia (AIHA)

If the direct Coombs test is positive and there is no thrombocytopenia or schistocytes:

• Initiate prednisone 1-2 mg/kg/day as first-line therapy 2, 3
• AIHA does not typically cause thrombocytopenia unless Evans' syndrome (AIHA + immune thrombocytopenia) is present 4

Transfusion Strategy

• Transfuse red blood cells only to relieve symptoms or achieve hemoglobin 7-8 g/dL in stable, non-cardiac patients 1, 3
• Do not transfuse more than the 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 feasible, particularly if delayed hemolytic transfusion reaction is suspected 1

Monitoring During Acute Phase

• Daily CBC with differential, LDH, haptoglobin, and creatinine to assess response to therapy 1, 3
• Monitor for neurological symptoms, which occur in 10-20% of aHUS cases and are common in TTP 1, 3
• If neurological symptoms develop, obtain neurology consultation, EEG, and brain MRI with FLAIR and T2-weighted sequences 3