In a patient with normal complete blood count, no evidence of hemolysis, normal platelet count, and normal renal function, what do the guidelines recommend regarding initiation of complement‑inhibiting therapy for atypical hemolytic uremic syndrome?

Management of Suspected aHUS in Patients with Normal CBC and Renal Function

Direct Answer

Do not initiate complement-inhibiting therapy in a patient with normal complete blood count, no hemolysis, normal platelets, and normal renal function, as these findings are incompatible with an active aHUS diagnosis requiring treatment. 1, 2

Diagnostic Requirements for aHUS

The diagnosis of aHUS fundamentally requires the presence of the diagnostic triad, which cannot be met if laboratory parameters are normal:

• Microangiopathic hemolytic anemia with evidence of hemolysis (elevated LDH, reduced/absent haptoglobin, elevated indirect bilirubin, schistocytes on peripheral smear) 1, 2, 3
• Thrombocytopenia defined as platelets <150,000/mm³ or ≥25% reduction from baseline 1, 2
• Acute kidney injury evidenced by hematuria, proteinuria, or elevated creatinine (≥1.0 mg/dL in children <13 years; ≥1.5 mg/dL in individuals ≥13 years; or ≥50% increase over baseline) 2

Critical Diagnostic Considerations

When Laboratory Findings May Be Misleading

• Up to 50% of aHUS cases may not clearly present with all three clinical signs at disease onset, but this refers to incomplete manifestations (e.g., mild thrombocytopenia or early hemolysis), not completely normal values 1, 2
• Absence of schistocytes (>1%) should not exclude early TMA diagnosis due to low test sensitivity, but other hemolysis markers must still be present 1
• Post-transplant patients may have less pronounced thrombocytopenia (13% lack significant platelet reduction) or anemia (38% lack significant findings), but abnormalities are still present, not completely normal 1, 2

Serial Monitoring Strategy

If clinical suspicion for aHUS remains high despite normal initial laboratories:

• Obtain serial monitoring of hemoglobin, platelet counts, LDH, haptoglobin, and creatinine rather than relying on a single CBC, as a single measurement is insufficient to define risk 2, 3
• Daily monitoring during the at-risk period is recommended when aHUS is suspected, as laboratory abnormalities may evolve 2
• Near-normal hemoglobin may indicate dehydration masking anemia, requiring assessment of volume status 2

When to Pursue aHUS Workup Despite Normal Labs

Proceed with complement testing and genetic evaluation in specific scenarios:

• Family history of thrombotic microangiopathy suggesting hereditary complement dysregulation 1, 4
• Previous documented aHUS episodes now in remission, where genetic counseling and family screening are indicated 1
• Pre-transplant evaluation in patients with history of unexplained renal failure or suspected complement-mediated disease 1

Appropriate Testing in Remission

• Genetic testing through next-generation sequencing of complement genes (CFH, CFHR1-5, C3, CD46, CFI, THBD, DGKE, CFB) for prognostic and family planning purposes 1, 2
• Baseline complement levels (C3, C4, CH50, AP50) are typically normal in aHUS regardless of disease activity state, so these do not aid in diagnosis but establish baseline for future monitoring 1, 5, 6
• Anti-complement factor H antibodies in appropriate clinical contexts 7

Treatment Initiation Criteria

Eculizumab or ravulizumab should only be initiated when there is active TMA with laboratory evidence of the diagnostic triad, as treatment decisions are based on disease activity, not genetic risk alone:

• Initiate complement inhibition within 4-8 hours of confirmed aHUS diagnosis with active TMA, as delays increase morbidity and mortality 3, 7
• Treatment requires documented thrombocytopenia, hemolysis, and renal injury to justify the risks of lifelong immunosuppression and meningococcal infection 1, 3
• Prophylactic treatment is not recommended in genetically at-risk but asymptomatic individuals 1

Common Pitfalls to Avoid

• Do not confuse genetic risk with active disease: Having a pathogenic complement mutation does not equal active aHUS requiring treatment 1
• Do not initiate eculizumab based solely on clinical suspicion without laboratory confirmation of TMA, as this exposes patients to significant infection risk without clear benefit 1, 3
• Do not overlook alternative diagnoses: Normal CBC and renal function should prompt consideration of other conditions if TMA was initially suspected 7
• Remember that 40-50% of aHUS patients have no identifiable mutation, so genetic testing cannot rule out future risk, but treatment still requires active disease 1, 2