What is the recommended work‑up and immediate management for a patient presenting with microangiopathic hemolytic anemia, acute kidney injury, and thrombocytopenic purpura suggestive of hemolytic‑uremic syndrome or thrombotic thrombocytopenic purpura?

Immediate Management of Suspected HUS/TTP

When a patient presents with microangiopathic hemolytic anemia, thrombocytopenia, and acute kidney injury, immediately send ADAMTS13 activity and begin plasma exchange with glucocorticoids while awaiting results if the PLASMIC score is ≥5 points, because delays in treating TTP are associated with increased mortality. 1

Initial Emergency Laboratory Work-Up

Obtain the following tests immediately upon presentation:

• Complete blood count with platelet count to document thrombocytopenia (<150,000/mm³ or ≥25% reduction from baseline) 2, 3
• Peripheral blood smear for schistocytes, burr cells, or helmet cells indicating microangiopathic hemolysis 2, 3
• Hemolysis markers: elevated LDH, reduced or absent haptoglobin, and elevated indirect bilirubin 2, 3
• Direct Coombs test (must be negative to confirm non-immune hemolysis) 2, 3
• Comprehensive metabolic panel with creatinine to assess acute kidney injury 2, 3
• Urinalysis for hematuria and/or proteinuria 2, 3
• ADAMTS13 activity and anti-ADAMTS13 antibodies sent urgently, as severely deficient activity (<10%) indicates TTP requiring immediate plasmapheresis 1, 2, 3

Critical Diagnostic Caveat

• The absence of schistocytes should not exclude early diagnosis due to low sensitivity of this finding; other hemolysis markers (elevated LDH, low haptoglobin) remain essential 2
• Up to 50% of atypical HUS cases may not present with the full triad at onset, though at least one laboratory abnormality is always detectable 2

Etiologic Testing to Distinguish HUS from TTP

For Typical (STEC) HUS:

• Stool culture and Shiga toxin testing to identify Shiga toxin-producing E. coli (most commonly O157:H7) 2, 3
• If stool testing is negative but HUS is present, serologic testing for STEC (CDC-validated testing for serogroups O157 and O111) may aid diagnosis 2, 3
• Clinical history is essential: typical STEC-HUS appears 4-5 days after diarrhea onset 3

For Atypical HUS:

• Complement testing: C3, C4, CH50 (classical pathway), and AP50 (alternative pathway) 2
• Genetic testing for complement pathway mutations (CFH, CFHR1-5, C3, CD46, CFI, THBD, DGKE, CFB) should be performed in all suspected aHUS cases, though results may take weeks to months 2
• Antiphospholipid antibodies if lupus or antiphospholipid syndrome is suspected 1

Immediate Treatment Algorithm

Step 1: Calculate PLASMIC Score While Awaiting ADAMTS13

The PLASMIC score stratifies TTP risk based on: Platelet count, hemolysis variables, absence of active cancer, absence of transplant, MCV, INR, and creatinine 1

• PLASMIC score ≥5 points (moderate/high risk): Start plasma exchange and glucocorticoids immediately in adults while awaiting ADAMTS13 results 1
• PLASMIC score 0-4 points (low risk): Consider alternative diagnoses but still await ADAMTS13 results 1

Step 2: Treatment Based on ADAMTS13 Results

If ADAMTS13 Activity <10% (Confirmed TTP):

• Continue plasma exchange as the essential treatment 1, 4
• High-dose glucocorticoids 1
• Rituximab for acquired TTP 1
• Caplacizumab (von Willebrand factor inhibitor) may be added 1

If ADAMTS13 Activity Normal and Positive Antiphospholipid Antibodies:

• Anticoagulation ± plasma exchange for antiphospholipid syndrome nephropathy 1

If ADAMTS13 Activity Normal and Negative Antiphospholipid Antibodies:

For Typical (STEC) HUS:

• Supportive care only with IV fluid resuscitation during the diarrhea phase to reduce risk of oligoanuric renal failure 3
• Avoid antibiotics, as they may worsen outcomes and potentially increase HUS risk 3
• Avoid antimotility agents, narcotics, and NSAIDs during the acute phase 5
• Daily monitoring of hemoglobin, platelet counts, electrolytes, BUN, and creatinine during days 1-14 2

For Atypical HUS:

• Initiate eculizumab within 4-8 hours of suspected aHUS diagnosis, as delays are associated with increased morbidity and mortality 3
• Before eculizumab administration: Give quadrivalent A, C, W, Y meningococcal conjugate vaccine and B meningococcal vaccine 3
• Long-term antimicrobial prophylaxis with penicillin (or macrolides for penicillin-allergic patients) for the duration of treatment 3
• Consider eculizumab or ravulizumab for complement-mediated TMA 1

Step 3: Pediatric Considerations

• In children, TTP is less common, and plasma exchange has considerable morbidity; it is acceptable to defer plasma exchange for 24-48 hours until ADAMTS13 results are available 1
• For children <1 year old with aHUS, test for mutations in complement-unrelated genes (DGKE, WT1) and inborn errors of cobalamin metabolism (MMACHC) 2

Common Pitfalls to Avoid

• Do not delay plasma exchange in adults with high PLASMIC scores while awaiting ADAMTS13 results, as TTP mortality increases with treatment delays 1
• Do not use plasma exchange for typical STEC-HUS or drug-induced TMA, as it has no known benefit and is associated with major complications 4
• Do not start eculizumab without laboratory-confirmed active TMA (the full triad), as it carries serious meningococcal infection risk and requires lifelong vaccination and prophylaxis 2
• Do not give antibiotics for typical STEC-HUS, as they may increase HUS risk 3, 5
• Do not assume absence of schistocytes rules out TMA, as sensitivity is low in early disease 2

Monitoring During Acute Phase

• Daily monitoring of hemoglobin, platelet counts, electrolytes, BUN, and creatinine during the at-risk period (days 1-14) 2
• Monitoring can stop when platelet count begins to increase or stabilize with resolved/resolving symptoms 2
• Patients with increasing creatinine, elevated blood pressure, and volume overload require close monitoring in centers capable of managing acute renal failure 2