Evans Syndrome

A rare chronic hematologic disorder characterized by the simultaneous or sequential association of autoimmune hemolytic anemia (AIHA; a disorder in which auto-antibodies are directed against red blood cells causing anemia of varying degrees of severity) with immune thrombocytopenic purpura (ITP; a coagulation disorder in which auto-antibodies are directed against platelets causing hemorrhagic episodes) and occasionally autoimmune neutropenia, in the absence of a known underlying etiology.

Epidemiology

The prevalence in Europe is estimated at 1/1,000,000 but there are no robust epidemiological data available.

Clinical description

The syndrome can manifest both in childhood or adulthood. Episodes of thrombocytopenia may precede, occur concurrently with (50% of cases), or follow episodes of AIHA. The severity of symptoms and the delay between episodes of AIHA and/or ITP is variable. In non simultaneous cases in adults, the delay between the episodes is on average of 4 years. ITP is often revealed by mucocutaneous hemorrhage with epistaxis, petechiae, purpura, and ecchymoses. In case of severe thrombocytopenia, hematuria, gastrointestinal and/or cerebromeningeal hemorrhage may be observed in rare cases. AIHA manifests as an unusual weakness, pallor, fatigue with tachycardia and exertional dyspnea, and also in some cases jaundice, dark urine and/or splenomegaly.

Etiology

Evans syndrome is an autoimmune disorder in which non-cross-reacting autoantibodies are targeted towards different antigenic determinants on red cells, platelets, sometimes neutrophils; however, the exact pathophysiologic mechanism is unknown. Because of the observation of a decrease in T-helper and an increase in T-suppressor lymphocyte population, it is suggested that the cytopenia may be related to T-cell abnormalities. Evans syndrome is frequently associated with other diseases, such as systemic lupus erythematosus, antiphospholipid syndrome, autoimmune lymphoproliferative syndrome, and common variable immunodeficiency (see these terms), which could point to a common cellular and humoral abnormality.

Diagnostic methods

Diagnosis is based on a complete blood count showing anemia (hemoglobin level <12g/dL) and thrombocytopenia (platelet count <100,000/microL), associated or not with neutropenia (neutrophil count <1500/microL). A raised lactate dehydrogenase (LDH) and/or direct bilirubin level, and a decreased haptoglobin level indicate hemolysis. A positive direct antiglobulin test (Coombs test) confirms the presence of antibodies targeting red blood cells (RBCs) antigens. The presence of autoantibodies targeting both platelets and neutrophils cans also be observed.

Differential diagnosis

Differential diagnosis mainly includes microangiopathies such as thrombotic thrombocytopenic purpura, and typical or atypical hemolytic uremic syndrome (see these terms).

Genetic counseling

Most of the cases are sporadic. Familial cases have exceptionally been observed, mainly in the setting of an underlying primary immunodeficiency.

Management and treatment

Immunosuppressive therapy combined or not with intravenous immunoglobulin for ITP constitutes the first-line treatment. Administration of corticosteroids (prednisone) is the mainstay of treatment but other drugs can be prescribed for refractory cases such as rituximab, cyclosporine, azathioprine, cyclophosphamide, and danazol. Splenectomy is performed as a third-line treatment; however long-term remission is less frequent and patients show a high risk of sepsis. In severe cases, hematopoietic stem cell transplantation may be required.

Prognosis

Evans syndrome is a chronic disease with alternating periods of remission and relapse of AIHA and/or ITP despite treatment, which can be associated with significant morbidity and mortality due to severe hemorrhage and infections in case of severe thrombocytopenia and neutropenia.