What is the appropriate management for a patient with hemolytic anemia (HA) and hematuria?

Management of Hemolytic Anemia with Hematuria

The immediate priority is to obtain a peripheral blood smear, direct antiglobulin test (Coombs), complete blood count with platelets, LDH, haptoglobin, indirect bilirubin, reticulocyte count, creatinine, and urinalysis to distinguish between immune-mediated hemolytic anemia requiring corticosteroids versus thrombotic microangiopathy (particularly atypical hemolytic uremic syndrome) requiring urgent complement inhibition or plasma exchange. 1, 2

Critical Initial Diagnostic Algorithm

The combination of hemolytic anemia and hematuria demands urgent differentiation between three life-threatening conditions:

First-Line Laboratory Tests (Order Immediately)

• Complete blood count with differential to assess for thrombocytopenia, which when combined with hemolysis suggests thrombotic microangiopathy rather than isolated autoimmune hemolytic anemia 1, 3
• Peripheral blood smear to identify schistocytes (>1% supports microangiopathic hemolysis), though their absence does not exclude early thrombotic microangiopathy 1, 2
• Direct antiglobulin test (Coombs) to distinguish immune-mediated from non-immune mechanical hemolysis, as this fundamentally changes management 1, 2
• Hemolysis markers: LDH (elevated), haptoglobin (reduced), indirect bilirubin (elevated), and reticulocyte count (elevated) to confirm active hemolysis 1, 4
• ADAMTS13 activity level to exclude thrombotic thrombocytopenic purpura (TTP), as levels <10% indicate TTP requiring immediate plasma exchange 1, 3
• Renal function tests (creatinine) and urinalysis to quantify hematuria and proteinuria, which define renal involvement in hemolytic uremic syndrome 3
• Stool testing for verocytotoxin-producing E. coli (VTEC/STEC) to distinguish typical STEC-HUS from atypical HUS 3

Decision Tree Based on Coombs Test Result

If Direct Coombs Test is POSITIVE:

• Diagnosis is autoimmune hemolytic anemia 1, 2
• Initiate prednisone 0.5-1 mg/kg/day orally for grade 2 or higher hemolysis 1, 5
• For grade 3 or higher severity, obtain urgent hematology consultation 1
• Review medication history for drug-induced hemolysis 1

If Direct Coombs Test is NEGATIVE with schistocytes present:

• Diagnosis is thrombotic microangiopathy (non-immune microangiopathic hemolysis) 1, 2
• Proceed immediately to thrombotic microangiopathy subtype differentiation below

Thrombotic Microangiopathy Subtype Differentiation

If ADAMTS13 Activity <10%:

• Diagnosis is thrombotic thrombocytopenic purpura (TTP) 1, 3
• Do not delay plasma exchange while awaiting ADAMTS13 results if TTP is strongly suspected clinically 1
• Initiate therapeutic plasma exchange immediately 1
• Administer methylprednisolone 1g IV daily for 3 days starting after first plasma exchange 1

If ADAMTS13 Activity Normal AND Thrombocytopenia Present:

Assess timing of diarrhea (if present):

• STEC-HUS: Positive stool VTEC testing AND diarrhea onset 4-5 days before HUS symptoms 3
• Atypical HUS (aHUS): Negative VTEC testing OR short diarrhea period OR simultaneous onset of diarrhea and HUS 3

For suspected atypical HUS:

• Begin eculizumab therapy urgently without waiting for genetic confirmation 3, 2
• Administer meningococcal vaccination (MenACWY and MenB) and initiate long-term penicillin prophylaxis before eculizumab 6
• Obtain complement levels and genetic testing for complement pathway mutations 2
• In infants <1 year old, test for complement-unrelated genes (DGKE, WT1) and consider methylmalonic acidemia with homocystinuria (MMACHC) causing cobalamin deficiency 3, 7

Immune-Mediated Hemolytic Anemia Management

For confirmed autoimmune hemolytic anemia (positive Coombs):

Corticosteroid Therapy

• Prednisone 0.5-1 mg/kg/day orally is first-line therapy 1, 5
• The FDA label supports prednisone use for acquired (autoimmune) hemolytic anemia 5
• For severe cases, consider methylprednisolone 1-4 mg/kg/day 6

Second-Line Immunosuppression

If corticosteroids are insufficient or in severe hyperhemolysis:

• IVIG 0.4-1 g/kg/day for 3-5 days (up to total dose of 2 g/kg) 6
• Note: Plasmapheresis immediately after IVIG will remove immunoglobulin 6
• For refractory cases, consider eculizumab for patients experiencing clinical deterioration despite first-line agents 6
• Rituximab is indicated for potential prevention of additional alloantibody formation in patients requiring future transfusions 6

Transfusion Strategy

Critical transfusion principles:

• Transfuse red blood cells only to relieve symptoms or achieve hemoglobin 7-8 g/dL in stable, non-cardiac patients 1
• Do not transfuse more than the minimum necessary units 1
• Discuss with blood bank if thrombotic microangiopathy is suspected before transfusing 1
• If transfusion is required for life-threatening anemia in suspected delayed hemolytic transfusion reaction, use extended antigen-matched red cells (C/c, E/e, K, Jka/Jkb, Fya/Fyb, S/s) if feasible 6

Supportive Care Measures

• Initiate erythropoietin with or without IV iron for patients experiencing hyperhemolysis 6
• Serial monitoring of hemoglobin, hematocrit, quantification of HbA and HbS fractions (if applicable), reticulocyte count, bilirubin, LDH, and urinalysis for hemoglobinuria 6

Neurological Assessment (If Symptoms Present)

Neurological involvement occurs in 10-20% of aHUS cases 3, 2:

• Obtain neurology consultation 3
• Perform electroencephalogram (EEG) and brain MRI with FLAIR and T2-weighted sequences 3
• Assess for motor symptoms, generalized weakness, vision changes, seizures, or encephalopathy 3

Common Pitfalls to Avoid

• Do not dismiss thrombotic microangiopathy based on "rare" schistocytes alone, as schistocyte counts >1% support diagnosis, but their absence does not exclude early disease 1
• Do not wait for complete workup before initiating plasma exchange if TTP is strongly suspected clinically 1
• Do not assume adequate reticulocyte response in all hemolytic cases; reticulocytopenia occurs in 20-40% of autoimmune hemolytic anemia cases and is a poor prognostic factor 4
• In pediatric patients, particularly newborns, HUS may be present even if one of the three parameters (hemolysis, thrombocytopenia, renal involvement) is absent in up to 50% of cases at disease onset 3

When to Obtain Urgent Hematology Consultation

• Any grade 3 or higher hemolytic anemia 1
• Suspected thrombotic microangiopathy with thrombocytopenia 1
• Unclear etiology after initial workup 1
• Reticulocytopenia despite active hemolysis 4