Evans syndrome is a rare disease represented by a combination of hemolytic anemia and thrombocytopenia. Pathology has an idiopathic character, among the provoking factors are viral infections, autoimmune diseases. The syndrome is manifested by spontaneous bleeding, hemorrhages in the skin and mucous membranes, shortness of breath during exercise. For diagnosis, clinical, immunological and biochemical blood tests, bone marrow puncture, genetic testing are prescribed. Treatment includes glucocorticoids, cytostatics, monoclonal antibodies, splenectomy, hematopoietic stem cell transplantation (HSCT) are indicated in severe cases.
D69.3 Idiopathic thrombocytopenic purpura (Evans syndrome)
Evans syndrome (ES) is a rare pathology that occurs with a frequency of 4.5—20 cases per 100 thousand population, children get sick more often than adults, women – more often than men. The peak of diagnosis occurs at the age of 5, and the median incidence is 58.5 years according to Danish studies. Up to 82% of cases of the syndrome are associated with various autoimmune disorders. The disease was first described in 1947 by Fischer, who suggested its autoimmune nature. Evans and his colleagues in 1951 studied the clinic of the disease, confirmed the immune mechanisms of its occurrence.
In the idiopathic form of ES, it is not possible to identify the connection of hemolysis, thrombocytopenia with other pathological processes in the body. The symptomatic form of Evans syndrome is characterized by a combination with primary and secondary immunodeficiency, viral or bacterial infections. The provoking factor is autoimmune pathologies (SLE, antiphospholipid syndrome, rheumatoid arthritis), lymphoproliferative processes.
Evans syndrome occurs in violation of immune regulation, decreased tolerance to the body’s own antigens. The main role in the pathogenesis of the syndrome is played by plasma cells that produce antiplatelet antibodies directed against membrane glycoproteins. At the same time, platelets begin to be intensively destroyed in the spleen. Destruction of erythrocytes occurs under the influence of autoreactive IgG (extravascular hemolysis), IgA and IgM (intravascular hemolysis).
In the mechanism of development of Evans syndrome, a violation of the balance between T-suppressors and T-helpers with the predominance of the latter is important, which activates pathological immune reactions. ES is also characterized by an increase in the levels of interleukin-10 and gamma interferon, which stimulate B-lymphocytes and enhance the production of immunoglobulins. An important link in pathogenesis is the overexpression of the APO-1 antigen, which indicates apoptosis of blood cells.
More than half of patients suffer from simultaneous signs of thrombocytopenia and anemia, in 30% of cases, a lack of platelets first appears, and in 16-25% of cases, red blood cells begin to break down first. With the sequential development of cytopenia, the interval between them averages 4.2 years, but can stretch up to 16 years. ES has a chronic progressive course. A typical manifestation after a viral infection.
Thrombocytopenia is characterized by spot hemorrhages (petechiae), large bruises (ecchymoses). Spontaneous nasal, gastrointestinal, uterine, and pulmonary hemorrhages are also typical. Anemia is clinically manifested by pallor or jaundice of the skin, signs of shortness of breath during exercise. Rare signs of the disease include an increase in lymph nodes, abdominal discomfort due to an increase in the liver, spleen.
Evans syndrome in 55% of cases is associated with neutropenia and a sharp decrease in immunity, which leads to recurrent infections of the respiratory and urinary systems, severe bacterial processes, and a tendency to generalize inflammation. In 6-14% of patients with ES suffer from pancytopenia — a deficiency of all blood cells.
Autoimmune anemia in Evans syndrome is usually complicated by hemolytic crises, and the development of intravascular hemolysis is fraught with venous thrombosis with the risk of embolism. In the chronic course of the disease, secondary hemosiderosis is observed. Severe thrombocytopenia is dangerous by spontaneous bleeding, which, without emergency medical treatment, ends in the death of the patient from blood loss.
Examination of a patient with typical symptoms of anemia, thrombocytopenia is carried out by a hematologist. During the examination, the doctor identifies external signs of a deficiency of cellular elements of the blood, palpates the abdomen, studies the condition of the external lymph nodes. Since Evans’ disease is considered an exception diagnosis, a specialist needs complete information about the state of the blood system and the entire body, so he prescribes the following studies:
- Hemogram. The results of the analysis determine moderate or deep thrombocytopenia, normochromic anemia. The hemolytic nature of the destruction of erythrocytes is indicated by an increased level of young cells (reticulocytes). With a prolonged course of the syndrome, neutropenia is usually detected in the hemogram.
- The Coombs test. The study is considered the most informative to confirm the immune origin of hemolysis. In 90% of patients, the test shows a positive result. However, false negative indicators are possible, which are caused by excessive fixation of antibodies on red blood cells.
- Immunological studies. Analyses are carried out to assess the number of serum immunoglobulins and their subclasses, the ratio of different types of lymphocytes. Be sure to examine the blood for autoantibodies (antinuclear, anti-DNA, antiphospholipid) to exclude other autoimmune diseases.
- Genetic tests. Molecular genetic tests are necessary for the differential diagnosis of Evans disease with lymphoproliferative syndrome. In 76% of ES, mutations of the FAS, CASP8, and CASP10 genes are detected. According to the indications, a multigenic panel of immunodeficiency states is performed.
- Bone marrow puncture. Cytology of bone marrow biopsies is necessary to exclude malignant neoplasms of the blood system, which often manifest cytopenia. In patients with Evans syndrome, normal or increased cellularity is found without signs of atypical growth.
Instrumental diagnostics is not used to verify the diagnosis, but it is informative to establish the root cause of the syndrome in the symptomatic variant of ES. To study lymphoid tissues, the doctor prescribes a referral for ultrasound of the lymph nodes and spleen, radiography or CT of the chest. To clarify the diagnosis, the hematologist directs the patient to consult an immunologist, rheumatologist, oncologist.
Etiotropic treatment of the syndrome has not been developed, therefore, the efforts of doctors are aimed at correcting pathological changes in the hemogram. Prescribed medications are divided into first- and second-line medications. First-line therapy is recommended for rapid correction of cytopenia, prevention of life-threatening complications, and line 2 medications are used to maintain remission.
The treatment regimen for Evans syndrome begins with the administration of glucocorticoids in standard doses or in pulse therapy mode for rapid relief of autoimmune processes. If the effect of GCS is insufficient, the scheme is supplemented with intravenous immunoglobulins. To correct the consequences of massive bleeding, transfusions of erythrocyte suspension, platelet concentrate are prescribed.
As part of the second line of therapy, monoclonal antibody preparations (ritusuximab, alemtuzumab) are actively used, which regulate autoimmune mechanisms and reduce the destruction of blood components. In refractory cases of the syndrome, cytostatics with the maximum immunosuppressive effect are indicated. Plasmapheresis is effective for removing part of serum antiplatelet immunoglobulins.
Splenectomy is recommended for patients who do not respond to drug therapy. Removal of the spleen increases the chances of achieving long-term remission, and also reduces the frequency of relapses, allows you to reduce the dosage of glucocorticoids. With a refractory and continuously recurrent course of the syndrome, hematologists conduct HSCT.
In recent years, therapy of Evans syndrome with drugs from the group of thrombopoietin receptor agonists (eltrombopag, romiplostim) has been proposed. Medications stop severe thrombocytopenia, reduce the risk of spontaneous hemorrhages. They are especially effective in combination with corticosteroids. To correct neutropenia, it is proposed to use colony-stimulating factors.
Prognosis and prevention
Evans syndrome is characterized by a chronic relapsing course, however, with the right selection of drugs, remission can be achieved. The prognosis for the patient depends on the severity of cytopenia and the timeliness of the start of treatment. Concerns are caused by clinical cases when 1st and 2nd line medications do not give a positive hematological response. Given the unclear etiology of the syndrome, preventive measures have not been developed.
- The spectrum of Evans syndrome in adults: new insight into the disease based on the analysis of 68 cases. – Michel M, Chanet V, Dechartres A, Morin AS, Piette JC, Cirasino L, Emilia G, Zaja F, Ruggeri M, Andrès E, Bierling P, Godeau B, Rodeghiero F. – Blood. 2009 Oct 08;114(15):3167-72. – link
- Sdentifying autoimmune lymphoproliferative syndrome in children with Evans syndrome: a multi-institutional study. – Manno CS, Sheen C, Grupp SA, Teachey DT. I Blood. 2010 Mar 18;115(11):2142-5 link
- Neonatal familial Evans syndrome associated with joint hypermobility and mitral valve regurgitation in three siblings in a Saudi Arab family. Ahmed FE, Albakrah MS. – Ann Saudi Med. 2009 May-Jun;29(3):227-30. – link
- Hereditary spastic paraplegia and Evans’s syndrome. Ahmed FE, Qureshi IM, Wooldridge MA, Pejaver RK. – Acta Paediatr. 1996 Jul;85(7):879-81.
- Evidence-based focused review of the treatment of idiopathic warm immune hemolytic anemia in adults. – Crowther M, Chan YL, Garbett IK, Lim W, Vickers MA, Crowther MA. – Blood. 2011 Oct 13;118(15):4036-40. – link