Diagnostic Workup When HUS is Suspected
If you suspect HUS, immediately order haptoglobin, indirect bilirubin, LDH, complete blood count with peripheral smear, ADAMTS13 activity, and stool testing for verocytotoxin-producing E. coli (VTEC) while initiating urgent hematology consultation. 1, 2
Immediate Laboratory Testing
First-Level Essential Tests
When anemia plus thrombocytopenia presents in the emergency setting, you must immediately obtain: 1
- Haptoglobin (will be reduced in hemolysis) 1
- LDH (will be elevated) 1
- Indirect bilirubin (will be elevated) 1
- Complete blood count with peripheral blood smear looking for schistocytes >1% 1, 2
- Direct Coombs test (must be negative to confirm non-immune hemolysis) 1
- Creatinine (assess renal involvement, interpret relative to age in children) 2
- Urinalysis (check for hematuria and/or proteinuria) 1
Critical Differential Diagnosis Tests
Order ADAMTS13 activity urgently before initiating any plasma therapy to distinguish thrombotic thrombocytopenic purpura (TTP) from HUS—severely deficient activity <10 IU/dL indicates TTP rather than HUS. 1, 2
Obtain stool testing for VTEC/Shiga toxin to differentiate typical (STEC-HUS) from atypical HUS (aHUS). 1, 2
Key Diagnostic Pitfalls to Avoid
Do Not Exclude HUS Based on:
- Absence of schistocytes: The test has low sensitivity, and their absence should not exclude early TMA diagnosis 1, 2, 3
- Absence of marked thrombocytopenia or anemia: Particularly in post-transplant patients, 13% do not show significant platelet reduction and 38% lack significant anemia or thrombocytopenia 1
- Missing one parameter in children: In pediatric patients, especially newborns, HUS may be present even if one of the three main parameters (thrombocytopenia, anemia, or elevated creatinine) is absent 2, 3
- Normal platelet count if obtained >7 days after symptom onset: Platelets may normalize or increase later in the illness 3
Distinguishing STEC-HUS from Atypical HUS
Timing of Diarrhea is Critical:
- STEC-HUS typically appears 4-5 days after diarrhea onset 1
- Suspect aHUS if: Short period of diarrhea OR simultaneous appearance of diarrhea and HUS symptoms 1, 3
- Typical HUS: Onset within 3 weeks after acute or bloody diarrhea 3
Additional Workup for Suspected Atypical HUS
Second-Level Testing:
- Complement testing: C3, C4, CH50, AP50 2
- Genetic screening for complement pathway mutations (though do NOT delay treatment waiting for results) 2, 4
Special Populations:
In children <1 year old: Consider mutations in complement-unrelated genes (DGKE, WT1) and inborn errors of cobalamin metabolism (MMACHC) 1, 5
In post-transplant patients: Maintain high suspicion even without typical laboratory findings, as diagnosis is particularly challenging in this population 1
Neurological Assessment
If neurological symptoms are present (occurs in 10-20% of aHUS cases), obtain: 1, 5
- Neurological consultation 1, 5
- Electroencephalogram (EEG) 1, 5
- Brain MRI looking for bilateral symmetrical hyperintensities of basal ganglia on FLAIR and T2-weighted sequences, which are suggestive of TMA 1
Common neurological manifestations include motor symptoms, generalized weakness, vision changes, seizures, and encephalopathy. 1
Concurrent Management While Awaiting Results
Do not delay initiating complement inhibitor therapy (eculizumab/ravulizumab) while awaiting genetic testing results, as genetic mutations are found in only 50-60% of aHUS cases and the disease carries high morbidity and mortality when untreated. 2, 4