In a 9‑year‑old boy with acute lymphoblastic leukemia who is 36 days post‑haploidentical hematopoietic stem‑cell transplant and now has decreasing hemoglobin and platelet counts, schistocytes on peripheral smear, elevated lactate dehydrogenase, and a urine protein‑creatinine ratio of 0.2 mg/mg, what is the most likely diagnosis?

Transplant-Associated Thrombotic Microangiopathy (TA-TMA)

The most likely diagnosis is transplant-associated thrombotic microangiopathy (TA-TMA), a life-threatening complication occurring in 10-30% of allogeneic hematopoietic stem cell transplant recipients, particularly after haploidentical transplants. 1

Clinical Presentation Consistent with TA-TMA

Your patient presents with the classic triad defining TMA: 1

• Non-immune microangiopathic hemolysis (dropping hemoglobin with schistocytes and elevated LDH)
• Thrombocytopenia (dropping platelets)
• Organ involvement (proteinuria at 0.2 mg/mg, though this is relatively mild)

The timing at day +36 post-haploidentical transplant is highly characteristic, as TA-TMA typically manifests between day +30 to +100 post-transplant. 1

Immediate Diagnostic Workup Required

Order these tests urgently: 1, 2

• ADAMTS13 activity level and inhibitor titer (to differentiate TTP from other TMA causes)
• Complement levels (C3, C4, CH50) to evaluate for complement-mediated atypical HUS
• Direct antiglobulin test (DAT/Coombs) to exclude immune-mediated hemolysis
• Haptoglobin level (expect decreased or undetectable <25 mg/dL)
• Indirect bilirubin (expect elevated >1.2 mg/dL)
• Reticulocyte count to confirm appropriate bone marrow response
• Comprehensive metabolic panel with creatinine to assess renal function
• Urinalysis for hematuria and quantify proteinuria

Critical Diagnostic Considerations

Do not dismiss this diagnosis based on the relatively low proteinuria (0.2 mg/mg). 1 Early or evolving TMA can present with minimal proteinuria, and the absence of abundant schistocytes does not exclude TMA due to low test sensitivity. 1, 3

The presence of schistocytes >1% on peripheral smear strongly supports TMA diagnosis, even if they appear "rare" on initial review. 1, 4 Request expert hematopathology review of the peripheral smear to confirm schistocyte identification. 4

Differential Diagnosis to Exclude

While TA-TMA is most likely, consider: 1

• Thrombotic thrombocytopenic purpura (TTP): If ADAMTS13 activity <10%, this becomes the diagnosis requiring immediate plasma exchange
• Atypical hemolytic uremic syndrome (aHUS): If ADAMTS13 >10% with complement activation
• Malignant hypertension-associated TMA: Check blood pressure and perform funduscopic examination (typically shows only moderate thrombocytopenia and fewer schistocytes) 1
• Drug-induced TMA: Review all medications, particularly calcineurin inhibitors (tacrolimus/cyclosporine) commonly used post-transplant 1

Management Algorithm Based on Severity

If ADAMTS13 <10% (TTP diagnosed): 1, 2

• Immediately initiate therapeutic plasma exchange (do not delay while awaiting results if TTP strongly suspected clinically, as mortality increases with delayed treatment)
• Administer methylprednisolone 1g IV daily for 3 days, with first dose immediately after first plasma exchange
• Continue daily plasma exchange until platelet count exceeds 100-150 × 10⁹/L for 2 consecutive days

If ADAMTS13 >10% with clinical consequences (TA-TMA or aHUS): 1

• Begin eculizumab therapy urgently (900 mg weekly for four doses, 1,200 mg week 5, then 1,200 mg every 2 weeks)
• Administer meningococcal vaccination and long-term penicillin prophylaxis
• Review and discontinue all potentially causative medications (especially calcineurin inhibitors if possible)

For Grade 2 severity (moderate symptoms): 1

• Hematology consultation
• Prednisone 0.5-1 mg/kg/day
• Monitor hemoglobin weekly during steroid tapering

For Grade 3 severity (severe symptoms requiring hospitalization): 1

• Hospital admission
• Hematology consultation
• Prednisone 1-2 mg/kg/day
• Consider plasma exchange if deteriorating

Transfusion Management

RBC transfusion: Only transfuse to relieve symptoms or achieve hemoglobin 7-8 g/dL in this stable patient—do not transfuse more than the minimum necessary. 1, 2

Platelet transfusion: Generally contraindicated in TTP unless life-threatening bleeding occurs. 1, 2 For TA-TMA, use clinical judgment based on bleeding risk.

Monitoring During Acute Phase

Perform daily monitoring of: 1, 2

• CBC with differential
• LDH
• Haptoglobin
• Creatinine
• Platelet count

Critical Pitfalls to Avoid

Do not delay plasma exchange while awaiting ADAMTS13 results if TTP is strongly suspected clinically. 1 Mortality increases significantly with delayed treatment, and empiric plasma exchange should be initiated based on clinical presentation alone.

Do not dismiss the diagnosis based on "rare" schistocytes alone. 1, 4 Low schistocyte counts can occur in early or evolving TMA, and the sensitivity of schistocyte detection is only 80%. 4

Do not transfuse aggressively. 1, 2 Excessive transfusion, particularly platelets in TTP, can worsen microvascular thrombosis.