In a 27‑year‑old man with known aplastic anemia presenting with abdominal pain, marked weakness, pallor, severe pancytopenia, rapidly worsening azotemic renal failure unresponsive to antibiotics and dialysis, metabolic acidosis, elevated transaminases, indirect hyperbilirubinemia indicating hemolysis, hypertension, and normal‑size kidneys on ultrasound, what is the most likely diagnosis and appropriate management?

Diagnosis: Atypical Hemolytic Uremic Syndrome (aHUS) / Complement-Mediated TMA

This patient most likely has atypical hemolytic uremic syndrome (aHUS) or complement-mediated thrombotic microangiopathy (TMA) complicating his aplastic anemia, and requires urgent ADAMTS13 testing, peripheral blood smear evaluation, and immediate initiation of complement blockade therapy with eculizumab or ravulizumab to prevent irreversible organ damage and death. 1

Clinical Reasoning

The Diagnostic Triad is Present

This patient demonstrates the classic triad of TMA that mandates urgent evaluation 1:

• Microangiopathic hemolytic anemia: Indirect hyperbilirubinemia indicates hemolysis, and the elevated AST likely reflects hemolysis rather than hepatocellular injury 1
• Thrombocytopenia: Severe pancytopenia with platelet consumption 1
• Acute kidney injury: Progressive azotemia (creatinine 484.5→698.66 µmol/L despite hemodialysis) with normal-sized kidneys and no obstruction, indicating intrinsic renal TMA 1

Why aHUS Over Other Diagnoses

The presentation of anemia plus thrombocytopenia should always prompt immediate measurement of haptoglobin, indirect bilirubin, and LDH levels 1. In this case, the indirect hyperbilirubinemia confirms hemolysis.

The key distinguishing features pointing to aHUS include 1:

• Renal-predominant TMA: Severe, dialysis-resistant AKI with hypertension
• No diarrheal prodrome: Leptospirosis was considered but ruled out; STEC-HUS typically follows 4-5 days of bloody diarrhea 1
• Underlying aplastic anemia: Patients with bone marrow failure syndromes have increased risk of complement-mediated TMA
• Generalized weakness: This is a recognized neurological manifestation of aHUS (occurs in 10-20% of patients) 1

Critical Pitfall: Don't Be Misled by Pancytopenia

A common pitfall is that the absence of marked thrombocytopenia or significant anemia should NOT exclude a TMA diagnosis, especially in patients with pre-existing bone marrow disorders 1. In fact, 13% of TMA patients do not show significant platelet reduction, and 38% lack significant anemia or thrombocytopenia 1. This patient's baseline aplastic anemia makes the thrombocytopenia less obvious but no less significant.

Immediate Diagnostic Workup

Urgent First-Line Tests (Within Hours)

1. ADAMTS13 activity level: Must be performed urgently to distinguish TTP (activity <10 IU/dL) from aHUS 1
2. Peripheral blood smear: Look for schistocytes, though their absence does NOT exclude TMA due to low test sensitivity 1
3. Direct Coombs test: Should be negative to confirm non-immune hemolytic anemia 1
4. LDH and haptoglobin: To confirm microangiopathic hemolysis 1
5. Stool culture for VTEC/Shiga toxin: To exclude STEC-HUS 1

Additional Confirmatory Tests

• Complement studies: C3, C4, factor H, factor I levels
• Genetic testing: For complement pathway mutations (especially given young age and aplastic anemia history)
• Flow cytometry for PNH clone: Aplastic anemia patients require PNH screening, and PNH can cause hemolysis and renal TMA 2, 3, 4

Management Algorithm

Immediate Management (Do Not Wait for Test Results)

Given the high mortality risk and potential for irreversible renal damage, treatment should be initiated immediately when TMA is suspected, before confirmatory test results return 1:

1. Initiate complement blockade therapy:

   • Eculizumab (loading dose 900 mg IV weekly × 4 weeks, then 1200 mg at week 5, then 1200 mg every 2 weeks) OR
   • Ravulizumab (weight-based dosing, longer half-life allows less frequent administration)

2. Meningococcal vaccination: Must be given before or concurrent with complement blockade (or provide antibiotic prophylaxis if vaccination delayed) 1

3. Continue hemodialysis: For metabolic acidosis and severe azotemia, but recognize that dialysis alone will not reverse the underlying TMA 1

4. Avoid platelet transfusions: Unless life-threatening bleeding occurs, as transfusions may worsen microvascular thrombosis

5. Blood pressure control: Manage hypertensive episodes aggressively

If ADAMTS13 Returns Severely Deficient (<10%)

• Diagnosis is TTP, not aHUS
• Switch to plasma exchange therapy immediately
• Add corticosteroids and consider rituximab or caplacizumab 1

If ADAMTS13 is Normal or Mildly Reduced

• Continue complement blockade for aHUS
• Monitor response with platelet count, LDH, creatinine, and hemolysis markers
• Most patients show hematologic response within 1-2 weeks

Addressing the Underlying Aplastic Anemia

Once the acute TMA is controlled, the patient's aplastic anemia requires definitive management 3, 4:

• Age 27 years: Allogeneic hematopoietic stem cell transplant (HSCT) from a matched sibling donor is the treatment of choice and potential cure 3, 4
• If no matched sibling donor: Immunosuppressive therapy with horse antithymocyte globulin, cyclosporine A, and eltrombopag is first-line treatment 3, 4
• Supportive care: Transfusion support, antimicrobial prophylaxis, and infection management throughout 4

Prognosis and Monitoring

• Without treatment: aHUS has extremely high mortality and morbidity, with progression to end-stage renal disease 1
• With complement blockade: Most patients achieve hematologic remission and renal function stabilization or improvement
• Long-term: This patient will likely require indefinite complement blockade therapy and management of both aHUS and aplastic anemia, ideally at an expert center 4