A patient experienced a transient hemolytic episode during a viral upper‑respiratory infection with resolved hemolysis, persistent thrombocytopenia, and borderline low complement C3; what is the most appropriate next step in management?

Management of Transient Viral-Associated Hemolysis with Persistent Thrombocytopenia

The most appropriate next step is to obtain a peripheral blood smear to evaluate for schistocytes, perform complement workup (including CH50 and complement regulatory protein testing), and obtain hematology consultation to evaluate for atypical hemolytic uremic syndrome (aHUS) or complement-mediated thrombotic microangiopathy, given the borderline low C3, resolved hemolysis, and persistent thrombocytopenia following viral illness.

Diagnostic Evaluation Priority

Immediate Blood Smear Analysis

• Examine peripheral smear for schistocytes to determine if this represents a thrombotic microangiopathy (TMA) process, even though hemolysis markers normalized at 24 hours 1
• The presence of schistocytes would be critical for diagnosis of TMA conditions including aHUS, even with transient hemolysis 2
• Note that hemolysis can resolve while the underlying TMA process continues, particularly in complement-mediated disease 3

Complement System Evaluation

• The borderline low C3 (89) with normal C4 (21) suggests possible alternative complement pathway activation, which is the hallmark of aHUS 1
• Obtain CH50, factor H, factor I, and membrane cofactor protein (MCP/CD46) levels to evaluate for complement dysregulation 1
• Consider genetic testing for complement regulatory protein mutations if aHUS is suspected, as this has major implications for recurrence risk and treatment 3, 4

Additional Laboratory Assessment

• Measure ADAMTS13 activity level and inhibitor titer to definitively exclude thrombotic thrombocytopenic purpura (TTP), though the normal LDH and haptoglobin at 24 hours make this less likely 1
• Obtain direct antiglobulin test (DAT/Coombs) and blood group antibody screen to exclude immune-mediated hemolysis 1, 2
• Repeat PT ratio (not INR alone), aPTT, and fibrinogen to assess for consumptive coagulopathy 5

Clinical Reasoning for aHUS Suspicion

Key Features Supporting aHUS

• Viral infection is a well-recognized trigger for aHUS in patients with underlying complement dysregulation 4
• The transient hemolysis with rapid normalization of LDH/haptoglobin does not exclude aHUS, as complement-mediated TMA can have variable presentations 3
• Persistent and progressive thrombocytopenia (326→271→222) despite hemoglobin recovery is concerning for ongoing endothelial injury 1
• Borderline low C3 with normal C4 indicates alternative pathway consumption 1

Differentiating from Simple Viral-Associated Thrombocytopenia

• In uncomplicated viral thrombocytopenia, platelet counts typically recover within 1-2 weeks parallel to clinical improvement 6
• The continued decline in platelets 2 weeks post-illness is atypical and warrants investigation for TMA 1
• The presence of nucleated RBCs (0.05 nRBC) suggests bone marrow stress response 2

Monitoring Strategy

Serial Laboratory Surveillance

• Monitor platelet count every 2-3 days until trend is established 7, 5
• Watch for 25% or greater decline in platelets from peak, which would indicate TMA complication 8
• Monitor serum creatinine closely, as 25% increase from baseline suggests TMA progression requiring urgent intervention 8
• Track LDH and haptoglobin weekly to detect recurrent hemolysis 1, 2

Clinical Warning Signs

• Immediately escalate care if any of the following develop: new neurologic symptoms, worsening renal function, recurrent hemolysis, or platelet count <50,000/μL 1
• Monitor for hypertension, as malignant hypertension can trigger or indicate TMA 4

Hematology Consultation Urgency

Immediate Consultation Indicated If:

• Schistocytes are present on peripheral smear, regardless of current hemolysis markers 1
• Platelet count drops below 100,000/μL or continues declining 1
• Any evidence of organ dysfunction (rising creatinine, neurologic changes) develops 1
• C3 continues to decline on repeat testing 1

Rationale for Specialist Involvement

• Delay in identification of TMA is associated with increased mortality and morbidity, particularly for aHUS 1
• Complement-mediated TMA may require specific therapy with eculizumab (anti-C5 antibody), which has shown efficacy in case reports of complement-mediated microangiopathy 8, 3
• Early plasmapheresis may be necessary if TTP cannot be excluded or if aHUS is confirmed 1

Common Pitfalls to Avoid

Do Not Assume Simple Viral Recovery

• Normal LDH and haptoglobin at 24 hours do not exclude ongoing TMA, as endothelial injury can persist without active intravascular hemolysis 3, 2
• The iron studies showing recent hemolysis (ferritin 36, transferrin saturation 44%) confirm significant RBC destruction occurred 2

Avoid Premature Reassurance

• Persistent hematuria (1+ blood, no RBCs on microscopy) over 6 months suggests glomerular pathology, possibly related to complement deposition 1
• This finding combined with borderline C3 and thrombocytopenia creates a concerning pattern for complement-mediated disease 1, 3

Do Not Use INR Alone

• If coagulopathy develops, monitor PT ratio rather than INR, as INR is calibrated for warfarin monitoring and may miss subtle changes 5

Therapeutic Considerations if aHUS Confirmed

Complement Inhibition

• Eculizumab may be indicated for confirmed aHUS with evidence of ongoing TMA 8, 3
• Meningococcal vaccination is mandatory at least 2 weeks before eculizumab, or prophylactic antibiotics must be given if urgent treatment needed 8

Supportive Management

• Avoid platelet transfusion unless active bleeding or platelet count <10,000-20,000/μL, as transfusion may worsen TMA 1, 7
• Maintain adequate hydration to support renal perfusion 4
• Avoid NSAIDs given thrombocytopenia and potential renal involvement 5