What diseases cause a positive direct Coombs (Direct Antiglobulin) test?

Diseases Causing a Positive Direct Coombs Test

A positive direct Coombs test (Direct Antiglobulin Test) indicates antibody or complement coating on red blood cells and occurs primarily in autoimmune hemolytic anemia, chronic lymphocytic leukemia, non-Hodgkin's lymphoma, autoimmune diseases (especially systemic lupus erythematosus), and drug-induced hemolysis. 1

Hematologic Malignancies

Lymphoproliferative disorders are among the most common causes of positive direct Coombs testing:

• Chronic lymphocytic leukemia (CLL) frequently produces positive DAT even without overt hemolysis, with a reported frequency of 23.3% in untreated patients 1, 2, 3
• Non-Hodgkin's lymphoma commonly causes positive Coombs testing independent of active hemolysis 1, 2
• DAT positivity in CLL correlates with advanced Rai stage III disease and lower hemoglobin levels 3

Autoimmune Diseases

Systemic autoimmune conditions commonly produce red cell antibody sensitization:

• Systemic lupus erythematosus (SLE) is a frequent cause of positive DAT with or without hemolysis 2
• Rheumatoid arthritis and other connective tissue diseases produce positive DCT without necessarily causing overt hemolysis 2
• Patients with a history of any autoimmune disease warrant Coombs testing when anemia develops 1

Drug-Induced Hemolysis

Medications can cause drug-induced positive direct Coombs test through immune-mediated mechanisms:

• Drug exposure should be thoroughly reviewed in any patient with positive DAT 1
• Drug-induced etiology may present with positive DCT without active hemolysis 2
• Discontinuation of offending medications is indicated when drug-induced etiology is identified 2

Autoimmune Hemolytic Anemia (AIHA)

AIHA represents the classic disease associated with positive direct Coombs testing:

• Warm antibody AIHA typically shows IgG positivity on monospecific testing 4, 5
• Cold agglutinin disease may show complement (C3d) positivity, sometimes associated with infectious mononucleosis 5
• Paroxysmal cold hemoglobinuria with Donath-Landsteiner antibodies shows complement positivity 5
• Female gender and presence of autoimmune markers support autoimmune etiology 4

Infectious Causes

Certain infections can trigger positive direct Coombs testing:

• Infectious mononucleosis (EBV) can cause cold agglutinins with complement-positive DAT 5
• Viral studies including CMV, EBV, HHV6, and parvovirus should be considered in the workup 2

Important Clinical Pitfalls

Several critical considerations when interpreting positive direct Coombs tests:

• Low-affinity antibodies may cause false-negative standard DAT but can be detected by cold-washing RBCs at 4°C or using unwashed cells in specialized systems 6, 7
• DAT-negative AIHA exists and may require flow cytometry for detection of low levels of RBC-bound IgG 8, 6
• Positive DAT without hemolysis is common and requires no treatment—only investigation of underlying cause 2
• The monospecific pattern matters: IgG positivity (18.3% in CLL) versus C3d positivity (1.6%) versus dual positivity (3.3%) suggests different etiologies 3

Diagnostic Approach

When encountering a positive direct Coombs test, systematically evaluate:

• Confirm presence or absence of hemolysis with LDH, haptoglobin, indirect bilirubin, and reticulocyte count 4, 2
• Review peripheral blood smear for spherocytes, schistocytes, or other morphologic abnormalities 1
• Obtain autoimmune markers: ANA, RF, HLA-B27 4, 2
• Screen for lymphoproliferative disease with complete blood count and differential 2, 3
• Perform thorough medication review for drug-induced causes 1, 2
• Consider viral studies if infectious etiology suspected 2, 5