What is the most likely diagnosis and appropriate management for a patient with a positive direct Coombs test, anemia (low hematocrit and hemoglobin) and markedly elevated ferritin?

Autoimmune Hemolytic Anemia (AIHA) with Possible Underlying Inflammatory or Lymphoproliferative Disease

The combination of positive direct Coombs test, anemia (low hemoglobin/hematocrit), and high ferritin most likely represents autoimmune hemolytic anemia with an underlying inflammatory condition, lymphoproliferative disorder, or systemic autoimmune disease—requiring immediate assessment of hemolysis markers, reticulocyte count, and peripheral smear to determine disease severity and guide corticosteroid therapy. 1, 2

Immediate Diagnostic Workup

First, confirm active hemolysis by measuring:

• LDH, haptoglobin, and indirect bilirubin to establish whether hemolysis is occurring 1, 3
• Reticulocyte count and calculate reticulocyte index—a low count rules out compensated hemolysis, while elevation confirms active red cell destruction 1, 2
• Peripheral blood smear review for schistocytes, spherocytes, or agglutination 1, 4

The elevated ferritin (>100 µg/L) in this context indicates:

• Anemia of chronic disease coexisting with hemolysis, as ferritin is an acute-phase reactant 5
• Underlying inflammation or malignancy driving both the autoimmune process and ferritin elevation 5
• Measure CRP and ESR to quantify the inflammatory burden 5

Determine the Type of AIHA

Characterize the antibody pattern:

• IgG positivity suggests warm antibody AIHA, the most common form 6, 2
• C3d/complement positivity suggests cold agglutinin disease or mixed-type AIHA 6
• Combined IgG and C3d (3+ for both) indicates mixed warm and cold AIHA, which causes severe hemolysis and requires aggressive corticosteroid therapy 6
• Perform red cell eluate testing to confirm autoantibody specificity and increase diagnostic certainty 4

Identify the Underlying Cause

The positive Coombs test with high ferritin mandates evaluation for:

Lymphoproliferative Disease

• Chronic lymphocytic leukemia (CLL) or non-Hodgkin lymphoma frequently cause positive DCT even without overt hemolysis 1
• Order CBC with differential to assess for lymphocytosis or other cytopenias 1
• Consider CT imaging if lymphadenopathy or splenomegaly is suspected 7, 1

Autoimmune Disorders

• Systemic lupus erythematosus, rheumatoid arthritis, or other connective tissue diseases commonly produce positive DCT 1
• Test ANA, RF, and other autoimmune markers 1

Infectious Triggers

• Cytomegalovirus (CMV) and Epstein-Barr virus (EBV) can induce severe Coombs-positive hemolysis in immunocompetent adults 8
• CMV PCR and EBV VCA IgM should be obtained, as CMV-induced hemolysis may be under-recognized 8
• Consider parvovirus, HHV6, and other viral studies 1

Drug-Induced Hemolysis

• Review all medications for potential drug-induced positive DCT 1
• Discontinue offending agents immediately if identified 1

Management Algorithm Based on Hemolysis Severity

If Active Hemolysis is Confirmed (elevated LDH, low haptoglobin, elevated reticulocyte count):

For severe hemolysis (hemoglobin <7 g/dL or symptomatic):

• Initiate high-dose corticosteroids immediately: prednisone 1-2 mg/kg/day or methylprednisolone 1g IV daily for 3 days 3, 6
• Mixed warm and cold AIHA (IgG + C3d) responds dramatically to corticosteroids, with mean hemoglobin rising from 6.3 to 12.9 g/dL 6
• Transfuse RBCs only to relieve symptoms or achieve hemoglobin 7-8 g/dL in stable patients—do not transfuse more than necessary 3
• Hematology consultation for consideration of IVIG, rituximab, or other immunosuppression if refractory 3, 8

For moderate hemolysis (hemoglobin 7-10 g/dL):

• Start prednisone 0.5-1 mg/kg/day 3
• Monitor hemoglobin weekly during steroid tapering 3
• Folic acid 1 mg daily supplementation 1

If No Active Hemolysis (normal bilirubin, low reticulocyte count, normal smear):

This represents antibody sensitization without clinically significant hemolysis:

• No corticosteroids or immunosuppression are indicated 1
• Focus on identifying and treating the underlying cause (autoimmune disease, lymphoproliferative disorder, drug exposure) 1
• Folic acid 1 mg daily is reasonable given positive DCT 1
• Weekly CBC initially to detect development of hemolysis 1
• Repeat hemolysis markers if hemoglobin drops or symptoms develop 1

Critical Pitfalls to Avoid

Do not perform DAT without clinical indication for hemolysis, as screening without suspicion leads to high false-positive rates and unnecessary workup 4

Do not assume ferritin >100 µg/L rules out iron deficiency—in the presence of inflammation, transferrin saturation <20% confirms functional iron deficiency requiring treatment 5

Do not delay corticosteroids in severe hemolysis while awaiting underlying cause identification, as mortality increases with delayed treatment in severe AIHA 6

Do not overlook CMV and EBV testing, as viral-induced hemolysis may be under-reported and requires specific antiviral therapy in addition to immunosuppression 8

Do not transfuse platelets if thrombotic microangiopathy (TMA) is in the differential—schistocytes on smear would indicate TMA requiring plasma exchange rather than corticosteroids alone 3