What are the diagnostic criteria and treatment options for Evan Syndrome?

Diagnosis of Evans Syndrome

Evans syndrome is diagnosed by demonstrating the simultaneous or sequential occurrence of immune thrombocytopenia (ITP) and autoimmune hemolytic anemia (AIHA) with a positive direct antiglobulin test (DAT), after excluding other known underlying etiologies. 1, 2

Diagnostic Criteria

The diagnosis requires three essential components:

• Immune thrombocytopenia: Platelet count typically <100,000/μL with evidence of immune-mediated platelet destruction 3
• Autoimmune hemolytic anemia: Hemolytic anemia with elevated reticulocyte count, elevated indirect bilirubin, decreased haptoglobin, and positive DAT 4, 1
• Exclusion of other causes: No identifiable underlying disease process at diagnosis that could explain both cytopenias 5, 2

The syndrome can present with simultaneous cytopenias or sequential development over time, making longitudinal monitoring essential in patients with isolated ITP or AIHA 6.

Required Diagnostic Workup

Initial Laboratory Evaluation

Complete blood count with differential, peripheral blood smear, and reticulocyte count are mandatory first steps 3, 4:

• CBC typically reveals thrombocytopenia, anemia, and may show leukopenia
• Peripheral smear demonstrates spherocytes, polychromasia, and reduced platelets
• Elevated reticulocyte count confirms hemolysis (though may be inappropriately low in some cases) 4

Direct antiglobulin test (DAT/Coombs test) must be positive to confirm the autoimmune hemolytic component 4, 1, 2. This distinguishes Evans syndrome from other causes of combined cytopenias.

Hemolysis Markers

Document active hemolysis with 4, 1:

• Elevated indirect (unconjugated) bilirubin
• Decreased or absent haptoglobin
• Elevated lactate dehydrogenase (LDH)
• Peripheral smear showing spherocytes and polychromasia

Exclusion of Secondary Causes

Extensive testing is required to exclude secondary Evans syndrome, as this significantly impacts treatment approach 4, 1:

• Infectious screening: HIV, hepatitis B virus, hepatitis C virus, CMV, H. pylori 3, 4
• Autoimmune evaluation: Antinuclear antibodies (ANA), antiphospholipid antibodies, lupus anticoagulant for systemic lupus erythematosus and antiphospholipid syndrome 4, 1
• Lymphoproliferative assessment: Flow cytometry on peripheral blood, serum protein electrophoresis, immunoglobulin levels 1

Bone Marrow Evaluation

Bone marrow examination is strongly recommended in the diagnostic workup of Evans syndrome 1:

• Evaluates for underlying lymphoproliferative disorders, myelodysplastic syndromes, or aplastic anemia
• Demonstrates adequate megakaryocytes (confirming peripheral platelet destruction rather than production failure)
• Shows erythroid hyperplasia (confirming compensatory response to hemolysis)
• Required if other cell lines are affected or if there are atypical features 3, 4

Imaging Studies

CT scan is recommended as part of the comprehensive evaluation 1:

• Assesses for lymphadenopathy suggesting lymphoproliferative disease
• Evaluates spleen size (splenomegaly may suggest underlying disorder)
• Identifies occult malignancies

Clinical Presentation Clues

Look for specific bleeding manifestations 3, 2:

• Petechiae and purpura (thrombocytopenia component)
• Ecchymoses and mucosal bleeding
• Epistaxis or gingival bleeding
• Heavy menstrual bleeding in women

Hemolysis symptoms include 5, 2:

• Jaundice or scleral icterus
• Dark urine (hemoglobinuria)
• Fatigue and dyspnea from anemia
• Pallor

Obtain detailed personal and family history of autoimmunity, as Evans syndrome may be associated with other autoimmune conditions or primary immunodeficiencies 3, 1.

Common Diagnostic Pitfalls

Do not diagnose Evans syndrome if DAT is negative—this excludes autoimmune hemolytic anemia and suggests alternative diagnoses like thrombotic thrombocytopenic purpura or disseminated intravascular coagulation 2, 7.

Reticulocyte count may be inappropriately low despite hemolysis in some Evans syndrome patients, requiring recombinant erythropoietin consideration 1. This does not exclude the diagnosis if other hemolysis markers are present.

The presence of DIC can complicate diagnosis and make Evans syndrome more challenging to recognize 7. Look for prolonged PT/PTT, decreased fibrinogen, and elevated D-dimer to identify concurrent DIC, which requires urgent intervention.

Nutritional deficiencies (B12, folate, iron) should be evaluated and corrected, as these can confound the hemolytic picture 3.

Treatment Implications Based on Diagnosis

First-Line Therapy

Prednisone 1-2 mg/kg/day orally is the recommended first-line treatment 4, 1:

• Continue for 2-4 weeks until platelet count increases to 30-50 × 10⁹/L
• Taper over 4-6 weeks to lowest effective dose
• Different tapering schedules may be needed for ITP versus AIHA components 1

Intravenous immunoglobulin (IVIG) 1 g/kg should be added when rapid platelet increase is required 3, 4:

• Particularly important for severe bleeding or platelet count <25,000/μL
• Can be repeated if necessary
• Use in conjunction with corticosteroids, not as monotherapy

Second-Line Options

Rituximab is strongly recommended as second-line treatment in specific scenarios 1:

• First-line for cold-type AIHA
• Second-line for warm-type AIHA
• Second-line for patients with antiphospholipid antibodies or previous thrombotic events
• Contraindicated in patients with immunodeficiency or severe infections 1

Thrombopoietin receptor agonists (eltrombopag, romiplostim) are recommended for chronic ITP component 4, 8:

• Response rates: 70-81% for eltrombopag, 79-88% for romiplostim
• Particularly useful in patients with previous grade 4 infections where immunosuppression should be avoided

Monitoring Response

Evaluate response based on 4:

• Platelet count improvement to >30 × 10⁹/L with at least 2-fold increase from baseline
• Resolution of hemolysis: improved hemoglobin, decreased reticulocyte count, normalized bilirubin
• Negative or decreasing DAT titer (though may remain positive despite clinical remission)