What are the differential diagnoses and initial management strategies for a patient presenting with symptoms similar to Hemolytic Uremic Syndrome (HUS)?

HUS Mimics: Differential Diagnosis and Management

Primary Differential Diagnoses

The key conditions that mimic HUS include thrombotic thrombocytopenic purpura (TTP), disseminated intravascular coagulation (DIC), systemic lupus erythematosus with lupus nephritis, antiphospholipid syndrome, and secondary causes of thrombotic microangiopathy (TMA). 1

Critical First Step: Confirm TMA

Before differentiating among HUS mimics, document the presence of TMA by confirming:

• Microangiopathic hemolytic anemia with schistocytes, burr cells, or helmet cells on peripheral blood smear 2
• Thrombocytopenia (platelet count <150,000/mm³) 2
• Elevated LDH and reduced haptoglobin indicating hemolysis 2
• Negative direct Coombs test to exclude immune-mediated hemolysis 2

Algorithmic Approach to Differentiation

Step 1: Rule Out DIC First

DIC must be recognized and treated before discriminating among other TMAs 3. Look for:

• Prolonged PT/PTT and decreased fibrinogen (unlike HUS/TTP where coagulation studies are typically normal) 4, 3
• Elevated D-dimer and fibrin degradation products
• Clinical context of sepsis, trauma, or malignancy

Step 2: Distinguish TTP from HUS

ADAMTS13 activity is the definitive test: severely deficient activity (<10 IU/dL) confirms TTP 1, 4

Order ADAMTS13 activity and inhibitor assays before initiating plasma therapy in any patient presenting with TMA 3

Clinical predictors favoring TTP over aHUS:

• Predominant neurological involvement with minimal renal impairment 4, 5
• Lower platelet counts and higher serum creatinine predict ADAMTS13 deficiency 4

Step 3: Differentiate STEC-HUS from Atypical HUS

STEC-HUS characteristics:

• Bloody diarrhea preceding HUS by 4-5 days 1, 6
• Positive stool culture or Shiga toxin testing (PCR or EIA) 1, 2
• Serologic testing for STEC (O157 and O111 serogroups) if stool testing negative 2
• Primarily affects children under 5 years 6

Atypical HUS characteristics:

• No preceding diarrhea, OR simultaneous onset of diarrhea and HUS suggests aHUS rather than STEC-HUS 2, 6
• Evidence of complement dysregulation 2
• Can occur at any age but represents majority of adult HUS cases 7

Critical caveat: In pediatric patients, both aHUS and STEC-HUS may present with diarrhea; timing is key 2

Step 4: Identify Secondary Causes of TMA

Systemic lupus erythematosus/lupus nephritis:

• Monoclonal immunoglobulins acting as autoantibodies against complement regulatory proteins 1, 6
• Check ANA, anti-dsDNA, complement levels (C3, C4)

Antiphospholipid syndrome:

• Inhibition of prostacyclin formation or protein C activation 1, 6
• Test for anticardiolipin antibodies, anti-β2-glycoprotein I, lupus anticoagulant

Chronic hemolytic anemias:

• Sickle cell disease, thalassemia, hereditary spherocytosis causing TMA through high nitric oxide consumption 6

Essential Diagnostic Workup

Immediate Laboratory Testing

Core TMA confirmation panel (obtain simultaneously):

• Complete blood count with platelet count 1
• Peripheral blood smear for schistocytes 1, 2
• LDH, haptoglobin, indirect bilirubin 1
• Direct Coombs test 1
• BUN and creatinine 2

Etiologic differentiation panel (order before plasma therapy):

• ADAMTS13 activity and inhibitor assays 1, 3
• Stool culture and Shiga toxin testing (PCR or EIA for stx1 and stx2 genes) 1, 2
• Complement studies: C3, C4, CH50, AP50 2
• Coagulation studies: PT, PTT, fibrinogen, D-dimer to exclude DIC 3

Additional testing for aHUS:

• Anti-factor H antibodies 1, 2
• Genetic screening for complement pathway mutations (CFH, CFI, CD46, C3, CFB, THBD, CFHR1-5) 2, 7

Monitoring Protocol

For suspected STEC infection, perform daily monitoring (days 1-14):

• Hemoglobin and platelet counts 2
• Electrolytes, BUN, creatinine 2
• Blood pressure and volume status 2

Monitoring can stop when platelet count begins to increase or stabilize with resolved symptoms 2

Initial Management Strategies

Immediate Supportive Care

IV fluid resuscitation is critical:

• Administer IV fluids during diarrhea phase to reduce risk of oligoanuric renal failure 1, 6
• Dehydration at admission increases need for dialysis 6

Monitor for complications:

• Neurological involvement occurs in 10-20% and is the first cause of death 6
• Blood pressure control and management of volume overload 1

Specific Treatment Based on Diagnosis

For suspected aHUS:

• Initiate eculizumab within 4-8 hours of suspected diagnosis, as delays worsen outcomes 1
• Dosing for adults: 900 mg weekly × 4 weeks, then 1200 mg at week 5, then 1200 mg every 2 weeks 8
• Meningococcal vaccination required at least 2 weeks prior, or provide antibiotic prophylaxis if urgent therapy needed 8
• Plasma exchange is much less effective in aHUS compared to eculizumab 1, 4

For TTP:

• Plasma exchange is treatment of choice 1, 4

For STEC-HUS:

• Supportive care only; eculizumab is NOT indicated 8
• Avoid antibiotics as they may worsen outcomes and increase HUS risk 6

Critical Pitfalls to Avoid

Do not delay eculizumab in suspected aHUS while awaiting complement studies or genetic testing 1 - these results take weeks to months but treatment decisions must be made within hours

Do not use platelet count alone to exclude HUS: up to 50% of aHUS cases may not have all three clinical signs clearly present at disease onset 2

Do not assume absence of schistocytes excludes early TMA: peripheral smear has low sensitivity early in disease course 2

If platelet count obtained within 7 days after gastrointestinal illness onset is not below 150,000/mm³, strongly consider alternative diagnoses 2, 6