In a patient with intermittent hemoglobinuria, mild transient anemia, normal lactate dehydrogenase and haptoglobin after episodes, no thrombocytopenia, no schistocytes, no renal impairment, low‑normal complement C4, negative direct antiglobulin test, negative paroxysmal nocturnal hemoglobinuria flow cytometry, history of recurrent pregnancy loss, postpartum hypertension, psychiatric decompensation, and family history of kidney disease, is this presentation more suggestive of atypical hemolytic‑uremic syndrome?

This Presentation is NOT Suggestive of aHUS

The clinical picture you describe—intermittent hemoglobinuria with normal LDH and haptoglobin after episodes, absence of thrombocytopenia, no schistocytes, and no renal impairment—does not meet diagnostic criteria for atypical hemolytic uremic syndrome and instead suggests an alternative diagnosis such as paroxysmal nocturnal hemoglobinuria (despite negative flow cytometry) or another episodic hemolytic process. 1

Why aHUS is Excluded

Core Diagnostic Requirements Not Met

• aHUS requires the simultaneous presence of three elements: microangiopathic hemolytic anemia (elevated LDH, reduced/absent haptoglobin, schistocytes), thrombocytopenia (platelets <150,000/mm³ or ≥25% reduction), and acute renal injury (hematuria, proteinuria, or elevated creatinine). 2, 1

• Your patient lacks all three cardinal features during and after episodes: Normal LDH and haptoglobin after hemoglobinuria episodes directly contradict active hemolysis, no thrombocytopenia excludes platelet consumption, and absence of renal impairment rules out the renal component of the diagnostic triad. 2, 1

• Even incomplete presentations of aHUS retain laboratory evidence: While up to 50% of aHUS cases may not show the full triad at onset, some laboratory abnormality (elevated LDH, low haptoglobin, falling platelets, or rising creatinine) is always detectable—complete normalization between episodes is inconsistent with aHUS. 2, 1

Hemolysis Pattern is Incompatible

• Microangiopathic hemolysis in aHUS produces persistent laboratory markers: Elevated LDH and reduced haptoglobin are fundamental to diagnosing the hemolytic component, and their normalization after episodes argues against ongoing complement-mediated endothelial injury. 2, 3

• Absence of schistocytes has low sensitivity early in disease but your patient also lacks other hemolysis markers: The combination of no schistocytes, normal LDH, and normal haptoglobin after episodes makes microangiopathic hemolysis—the hallmark of aHUS—extremely unlikely. 1, 4

• Intermittent hemoglobinuria without sustained hemolysis suggests intravascular hemolysis from a different mechanism: This pattern is more consistent with paroxysmal nocturnal hemoglobinuria, cold agglutinin disease, or episodic complement activation not related to aHUS. 4

Alternative Diagnostic Considerations

Low-Normal C4 is Not Specific for aHUS

• Complement levels (C3, C4, CH50, AP50) are typically normal in aHUS regardless of disease activity: These measurements are useful for monitoring treatment response but not for acute diagnosis, and isolated low-normal C4 does not establish complement dysregulation. 1

• Low C4 suggests classical pathway activation: This finding is more consistent with immune complex disease, lupus-related processes, or acquired angioedema rather than the alternative pathway dysregulation that defines aHUS. 1

Clinical Context Suggests Other Diagnoses

• Recurrent pregnancy loss, postpartum hypertension, and psychiatric decompensation raise concern for antiphospholipid syndrome or systemic lupus erythematosus: These conditions can cause episodic hemolysis, pregnancy complications, and neuropsychiatric manifestations without meeting aHUS criteria. 4

• Family history of kidney disease warrants genetic evaluation for hereditary nephropathies: Alport syndrome, thin basement membrane disease, or other inherited renal disorders should be considered, especially given the absence of acute thrombotic microangiopathy. 2

• Negative PNH flow cytometry does not absolutely exclude PNH: Small PNH clones below detection threshold or technical limitations can yield false-negative results; repeat testing with high-sensitivity assays or alternative methods may be warranted if clinical suspicion remains high. 4

When to Reconsider aHUS

Scenarios That Would Change the Assessment

• Development of the diagnostic triad during an acute episode: If future episodes demonstrate simultaneous thrombocytopenia, elevated LDH with low haptoglobin and schistocytes, plus acute kidney injury, then aHUS should be reconsidered and complement inhibition initiated immediately. 2, 1

• Documented complement pathway mutations in the patient or family members: Genetic testing revealing pathogenic variants in CFH, CFI, C3, CD46, or other complement genes would increase suspicion, but treatment is only indicated when active thrombotic microangiopathy is laboratory-confirmed. 2, 1

• Post-transplant or pregnancy-triggered acute TMA: If the patient undergoes kidney transplantation or future pregnancy and develops acute thrombotic microangiopathy with the full diagnostic triad, aHUS becomes a leading diagnosis requiring urgent eculizumab. 2

Critical Pitfalls to Avoid

• Do not initiate complement inhibition without laboratory-confirmed active TMA: Eculizumab and ravulizumab carry serious risks of meningococcal infection and require lifelong vaccination and prophylaxis; starting therapy based on clinical suspicion alone without the diagnostic triad exposes patients to harm without proven benefit. 1, 5

• Genetic mutations alone do not justify treatment: 40-50% of aHUS patients have no identifiable mutation, and conversely, carrying a pathogenic variant without active disease does not warrant prophylactic complement blockade due to incomplete penetrance. 2, 1

• Recognize that aHUS is a diagnosis of active thrombotic microangiopathy, not a chronic intermittent hemolytic disorder: The episodic nature with complete laboratory normalization between events is fundamentally inconsistent with complement-mediated TMA. 2, 3