Can the Coombs Test Yield False Positive Results?
Yes, the direct antiglobulin test (Coombs test) can produce false positive results through multiple mechanisms, and clinicians must be aware of these pitfalls to avoid misdiagnosis and inappropriate treatment.
Mechanisms of False Positivity
The Coombs test is prone to false positive results despite its widespread use in clinical practice 1. Several distinct mechanisms can produce spurious positive results:
Drug-Induced False Positivity
Certain medications can cause positive Coombs tests through non-immunological mechanisms without actual hemolysis. Cephalosporin antibiotics, particularly cephalexin, produce positive direct antiglobulin tests in approximately 4% of treated patients through drug adsorption to red blood cells rather than true antibody formation 2. Importantly, these patients do not develop immunohemolytic anemia despite the positive test 2.
Monoclonal Antibody Interference
Daratumumab, a therapeutic monoclonal antibody used in multiple myeloma treatment, causes false positive indirect Coombs tests by interfering with serological testing 3. This represents a significant clinical pitfall when evaluating patients receiving this therapy, as the positive result does not indicate autoimmune hemolysis.
Technical and Specimen-Related Causes
False positive results can occur due to 1:
- Presence of fibrin strands in the specimen that interact with immunoassays
- Heterophile antibodies interfering with the test reagents
- Hemolysis in the sample
- Rheumatoid factor presence 3
Disease-Associated False Positivity
In COVID-19 patients, positive Coombs tests occur in approximately 20% of hospitalized cases without evidence of actual hemolysis 4. When these patients were evaluated for hemolysis using indirect bilirubin, haptoglobin consumption, and peripheral smear examination, no hemolytic process was identified 4. The mechanism likely involves cytokine storm-induced complement activation and SARS-CoV-2 protein binding to red blood cells rather than true autoantibody-mediated destruction 4.
Clinical Implications and Diagnostic Approach
Confirming True Positivity
When a positive Coombs test is obtained, clinicians must actively seek evidence of actual hemolysis before diagnosing autoimmune hemolytic anemia 3, 1. The diagnostic workup should include:
- Hemolysis markers: Elevated indirect bilirubin, decreased haptoglobin, elevated lactate dehydrogenase 4
- Peripheral blood smear: Presence of schistocytes or spherocytes indicating red cell destruction 3
- Reticulocyte count: Elevated in active hemolysis
- Serial hemoglobin measurements: Declining values suggesting ongoing destruction
Medication History
Always obtain a detailed medication history, particularly focusing on cephalosporins, penicillins, and monoclonal antibodies before interpreting a positive Coombs test 3, 2. The temporal relationship between drug administration and test positivity provides crucial diagnostic information.
Repeat Testing Considerations
A single positive Coombs test without clinical or laboratory evidence of hemolysis should prompt repeat testing and comprehensive evaluation rather than immediate treatment 1. This approach prevents unnecessary immunosuppressive therapy in patients with false positive results.
Common Pitfalls to Avoid
Do not diagnose autoimmune hemolytic anemia based solely on a positive Coombs test without corroborating evidence of hemolysis 1, 4. The test's susceptibility to false positivity means that clinical context, hemolysis markers, and medication history are essential for accurate interpretation.
In patients with advanced malignancies like Hodgkin's disease, a positive Coombs test may indicate disease activity rather than clinically significant hemolysis 5. Only 3 of 7 Coombs-positive Hodgkin's patients in one series had overt hemolysis despite all being anemic 5.
For patients receiving daratumumab or other therapeutic monoclonal antibodies, document the interference potential and interpret subsequent Coombs testing with extreme caution 3.