Overview.
Autoimmune hemolytic anemia and immune thrombocytopenia occur simultaneously or sequentially.
The main manifestations are anemia, jaundice, hepatosplenomegaly, and skin and mucous membrane bleeding.
The cause of the disease is unknown and may be related to immune dysfunction and secondary to systemic lupus erythematosus and lymphoma.
Lack of specific treatment, commonly used drugs include glucocorticoids, immunoglobulin, rituximab, immunosuppressants, etc.
Definition
Evans syndrome is an autoimmune disease characterized by simultaneous or sequential occurrence of autoimmune hemolytic anemia (AIHA) and immune thrombocytopenia (ITP), and in some patients, neutropenia.
The main manifestations are anemia, jaundice, hepatosplenomegaly, cutaneous and mucosal bleeding, and visceral bleeding, with or without recurrent infections.
The disease was named after Dr. Evans and colleagues who first reported it in 1951 [1-2].
Staging
Evans syndrome can be categorized as primary or secondary based on the cause leading to it:
Primary Evans syndrome: the etiology is unknown, and it is thought to be caused by abnormal immune function leading to B-cell antibodies against own red blood cells, platelets, and neutrophils.
Secondary Evans syndrome: It can be secondary to systemic lupus erythematosus, autoimmune lymphoid tissue proliferation syndrome, pregnancy, proliferative disorders of the lymphatic system such as chronic lymphocytic leukemia, lymphoma, multiple myeloma, etc., and can also occur after allogeneic hematopoietic stem cell transplantation.
Pathogenesis
Evans syndrome is clinically very rare.
Some studies have reported an incidence of about 5% to 20% of all patients with AIHA or ITP.
The annual incidence of AIHA is approximately (0.8 to 3.0)/100,000, which means that 8 to 30 out of every 1 million people may develop the disease each year.The incidence of ITP is (5 to 10)/100,000
Epidemiologic data in the United States show that fewer than 5,000 people in the United States have Evans syndrome.
Evans syndrome can be seen in children or adults and is more common in females than males [3-5].
Causes
Causes
The exact cause of Evans syndrome is unknown.
Some studies have found that mutations in genes associated with immunodeficiency may be associated with the development of the disease, such as mutations in TNFRSF6, CTLA4, STAT3, PIK3CD, CBL, ADAR1, LRBA, RAG1, and KRAS.
Imbalance in immune function causes B cells to produce antibodies against their own tissues and cells, e.g. antibodies against red blood cells, platelets and white blood cells attack their own cells, causing a range of clinical symptoms.
Autoimmune diseases such as systemic lupus erythematosus, dry syndrome, autoimmune lymphohistoproliferative syndrome; pregnancy; proliferative diseases of the lymphatic system such as chronic lymphocytic leukemia, lymphoma, and multiple myeloma, etc., and Evans syndrome may also be caused after allogeneic hematopoietic stem cell transplantation [6-7].
Symptoms
Main Symptoms
Symptoms of Evans syndrome vary widely among individuals, and most often present as a chronic course that gradually worsens as the disease progresses. In severe cases, it can be life-threatening.
Hemolysis-related symptoms
Anemia manifestations: weakness, dizziness, nausea, palpitations, etc.
Change of urine color. When hemolytic crisis occurs, it also manifests as low back pain, chills, high fever, fainting, hemoglobinuria, etc.
Skin changes: there may be skin pallor and/or jaundice.
Enlarged liver and spleen/lymph nodes
There may be mild or moderate hepatosplenomegaly, mostly without pain.
Some patients also have painless lymph node enlargement.
Bleeding
Bleeding from the skin and mucous membranes, such as petechiae, ecchymosis, and difficulty in stopping bleeding after trauma.
Nosebleed, bleeding gums, excessive menstrual flow, dribbling, etc.
Gastrointestinal bleeding: black stool, blood in stool, vomiting blood.
In severe cases, there may also be intracranial hemorrhage.
Neurological symptoms
Some patients may have hemorrhagic shock, headache, irritability, fainting, coma, etc.
Recurrent infections
Commonly found in patients with neutropenia, patients with long-term use of immunosuppressants are also prone to secondary infections.
The common ones are recurrent infections of respiratory tract, digestive tract, skin mucosa and genitourinary tract, which are manifested as fever, cough, sputum, dyspnea; abdominal pain, diarrhea, vomiting; frequent urination, urinary urgency, painful urination, perianal abscess and so on.
Other symptoms
Evans syndrome secondary to other diseases may also have symptoms associated with the primary disease, examples of which are given below:
Patients with secondary SLE may have butterfly-shaped red spots on the bridge of the nose and both cheeks, mostly without significant itching.
Patients secondary to dry syndrome may have decreased tearing and salivation.
Patients secondary to chronic lymphocytic leukemia mainly have painless lymph node enlargement, with night sweats and weight loss in the advanced stage.
Complications
Renal failure
Acute hemolytic crisis occurs, and hemolysis products lead to necrosis of renal tubular cells and tubular lumen blockage, resulting in acute renal failure.
Thromboembolism
After the red blood cells are destroyed and dissolved, a large amount of pro-coagulant mediators are released, causing the blood to be hypercoagulable, and thrombus can be formed in some patients, leading to embolism of the intracranial venous system, with headache, irritability, and even loss of consciousness, which can be life-threatening in severe cases [1,8-11].
Medical treatment
Department of Medicine
Hematology
Anemia, fatigue, low back pain, large liver and spleen, enlarged lymph nodes, petechiae and ecchymosis of skin and mucous membranes, and difficulty in stopping bleeding after trauma, etc. should be consulted in the Department of Hematology in a timely manner.
Rheumatology
If Evans syndrome is suspected to be secondary to immune diseases such as systemic lupus erythematosus, dry syndrome, etc., the rheumatology and immunology department should also be consulted.
Emergency Medicine
In the event of hemolytic crisis, hemorrhage or vital organ thrombosis symptoms, such as dizziness, headache, and confusion, it is recommended to call the 120 emergency number or the Emergency Department.
Preparation for medical treatment
Preparation for medical consultation: registration, preparation of information, common problems
Tips for medical consultation
Doctors will usually conduct a detailed physical examination of the whole body and advise patients to choose loose-fitting clothes.
Record the time of onset and duration of symptoms, and whether there is any aggravation or alleviation.
If there are bruises and petechiae on the skin, jaundice, deepening of urine color, etc., you can take photos to provide more information for the doctor.
Preparation Checklist for Doctor’s Visit
Symptom Checklist
Particular attention needs to be paid to the time of onset of symptoms, special manifestations, etc.
How long has anemia been found?
Is there any change in skin rash, jaundice, urine color?
Are there skin petechiae and ecchymosis, nosebleeds, gum bleeds, bleeding after trauma that cannot be easily stopped? Does the female patient have increased menstrual flow and prolonged menstrual period?
Is there joint swelling and pain?
Are there fever and chills?
Is there dizziness, headache, irritability, coma?
List of medical history
Is there any history of lymphatic malignancy, autoimmune disease, immunodeficiency disease, etc.?
Is there any history of food and drug allergy, blood transfusion?
Any history of organ transplantation, allogeneic hematopoietic stem cell transplantation, etc.?
Checklist
Test results in the last six months, which can be brought to the doctor’s office
Hematology results: routine blood test, routine biochemistry, coagulation function, human immunodeficiency virus (HIV) test, immunoglobulin quantification, immunofixation electrophoresis, red blood cell autoantibody test such as direct anti-human globulin test, indirect anti-human globulin test, etc.
Urine routine, stool routine, fecal occult blood, blood smear test, etc.
Imaging examination: abdominal ultrasound, cranial CT, etc.
Pathological examination: bone marrow smear, biopsy, immunophenotyping and other comprehensive examinations, pathological findings of enlarged lymph nodes and other tissues.
List of medications used
Medication use in the last 3 months, if available, bring the box or package to the doctor’s office
Any use of medications such as hormones, immunosuppressants, etc.
Diagnosis
Diagnostic basis
The diagnosis of Evans syndrome lacks specific tests and is based on history, clinical manifestations and laboratory and imaging tests. The diagnosis is often made after other diseases have been ruled out. Usually, the diagnosis of Evans syndrome can be made after the diagnosis of autoimmune hemolytic anemia (AIHA) and immune thrombocytopenia (ITP) is confirmed, and AIHA and ITP may occur at the same time or sequentially.
Medical History
Past history of systemic lupus erythematosus, autoimmune lymphoproliferative syndrome, chronic lymphocytic leukemia, lymphoma, and multiple myeloma.
History of previous allogeneic hematopoietic stem cell transplantation therapy.
Clinical manifestations
Mainly hemolysis, anemia, bleeding and other clinical manifestations.
Some patients may also have recurrent infections.
Laboratory examination
Blood routine can see different degrees of erythrocyte decline, hemoglobin reduction, mostly normocytic and normochromic anemia, reticulocytosis, thrombocytopenia, with or without neutropenia.
Bone marrow cytology may show hyperplasia of young erythrocytes and megakaryocytosis, and immunophenotyping may help to detect proliferative disorders of the lymphatic system.
Biochemical tests suggest elevated serum total bilirubin, predominantly indirect bilirubin, and elevated lactate dehydrogenase.
A positive direct anti-human globulin test and/or indirect anti-human globulin is important to confirm the diagnosis of AIHA.
Imaging
Ultrasonography reveals hepatosplenomegaly and enlarged lymph nodes and may also be used to visualize renal lesions.
Lung and cranial CT is also required when lung infection and intracranial hemorrhage are suspected [1-3,8].
Differential diagnosis
Autoimmune lymphoproliferative syndrome (ALPS)
Similarities: both may present with enlarged lymph nodes, hepatosplenomegaly and autoimmune hematopenia such as thrombocytopenia and hemolytic anemia. In addition, autoimmune lymphoid hyperplasia syndrome can be secondary to Evans syndrome.
Differences: α/β-DNT cell expansion is present in the peripheral blood and tissues of patients with ALPS, which expresses the α/β-T cell receptor-CD3 complex, but not the CD4 and CD8 co-receptors.
Thrombotic thrombocytopenic purpura
Similarities: both have hemolytic anemia, neurologic symptoms, and renal impairment.
Differences: Thrombotic thrombocytopenic purpura is a microangiopathic hemolysis, mainly due to a severe reduction in vascular hemophilic factor cleaving enzyme activity, and it has a negative anti-human globulin test.
Treatment
Aim of treatment: symptomatic treatment, as far as possible to control the condition in a stable state, to prolong the survival time of patients.
Treatment principle: There is no specific treatment for primary Evans syndrome, and secondary Evans syndrome should be treated mainly for the primary disease. Usually, a multidisciplinary team of experts from hematology, rheumatology and immunology, and surgery is needed to formulate an individualized treatment plan based on a comprehensive assessment of the severity of anemia and bleeding, the general state of the patient’s body and age, and whether the patient has any primary diseases.
General Treatment
Minimize or avoid blood transfusion. Cross-matching is difficult due to the presence of autoantibodies, which may lead to hemolytic transfusion reaction caused by homologous antibodies. Filtered red blood cell transfusion is an option in cases of severe anemia. Add glucocorticoid before transfusion to reduce and mitigate the occurrence of transfusion reaction. Pay attention to the speed of transfusion and drip slowly.
Those with severe bleeding should pay attention to rest. Patients with platelets lower than 20×109/L should be properly bedridden and avoid trauma such as bumping. When bleeding is not stopping, localized pressure bandage is needed, or ask vascular surgeon to assist in treatment. Platelet transfusion is needed when necessary.
Pay attention to fluid replenishment to maintain water-electrolyte balance.
Medication
Glucocorticoid
Glucocorticosteroids are the first line of treatment for Evans syndrome.
Contraindications to glucocorticoids should be excluded before use. Commonly used drugs are: prednisone, methylprednisolone, dexamethasone.
Platelet counts, hemoglobin levels, and absolute reticulocyte values should be closely monitored during treatment.
Immunoglobulin
Immunoglobulins are primarily used for emergency treatment of severe Evans syndrome and are not usually used as long-term maintenance therapy.
The patient’s immune function is regulated by infusion of immunoglobulin.
Immunotargeted therapy
Rituximab is a second-line drug.
It is mainly indicated for: glucocorticoid resistance; intolerance to glucocorticoid therapy or contraindication to glucocorticoid; relapsed, refractory patients.
B-lymphocyte levels may be monitored during treatment as appropriate.
Attention needs to be paid to the prevention and treatment of viral activation or exacerbation in patients with hepatitis B virus infection.
Immunosuppressive therapy
Mainly used in the second-line treatment of Evans syndrome.
Commonly used drugs include: cyclophosphamide, azathioprine, cyclosporine A, vincristine, etc., which can be combined with glucocorticoids.
Androgen inhibitors
Danazol is commonly used in patients with immune thrombocytopenia.
Attention should be paid to the monitoring of liver and kidney function, etc.
Other treatments
Recombinant human thrombopoietin or thrombopoietin receptor agonist therapy may be considered as appropriate for thrombocytopenia.
Splenectomy: mainly used for patients who have not been treated with glucocorticoids and rituximab.
Plasma exchange is also indicated when conventional therapy is ineffective and the condition is urgent.
Infected patients are treated with empirical antibiotics as soon as possible, and can be adjusted to sensitive antibiotics when the results of drug sensitivity tests are available.
Some studies have shown that hematopoietic stem cell transplantation can be used in the treatment of patients with Evans syndrome.
Patients with secondary Evans syndrome need to be treated aggressively for the primary disease [1-2,12-14].
Prognosis
Cure
Compared with autoimmune hemolytic anemia (AIHA) alone, patients with Evans syndrome have a worse prognosis, are incurable, and tend to have chronic recurrence.
Some patients can remain seizure-free for longer periods of time and be in a stable state with aggressive treatment.
The occurrence of fatal bleeding or thromboembolism may be life-threatening.
Secondary Evans syndrome in which the primary disease is difficult to control has an even worse prognosis [1,15].
Daily
Daily management
Dietary management
Attention to protein and vitamin intake, diet should be easy to digest food.
Balanced nutrition, meat and vegetable combination, consume more food rich in folic acid, iron, vitamin B12, such as fresh vegetables and fruits, animal offal.
Choose soft food as much as possible and avoid eating food with hard texture, bones and thorns, so as not to scratch the digestive tract and cause bleeding, etc.
Life management
Quit smoking and drinking, pay attention to rest, ensure sufficient sleep, avoid exertion and staying up late.
Avoid strenuous exercise and bumping, and stay in bed appropriately when platelet count <20×109/L.
Keep the bowel movement smooth, avoid straining the bowels to increase the risk of anal bleeding.
Adopt good hygienic habits, minimize access to crowded public places, and take protective measures when necessary.
Psychological support
The treatment of Evans syndrome is a long-term process, which requires adjusting the mindset and actively cooperating with the doctor’s examination and treatment.
Communicate with family members or friends more often, and take positive treatment with the comfort and encouragement of family members.
Disease monitoring
Pay attention to the color of the face, lips, whether there is jaundice and the color of urine.
If there is weakness, palpitation, bleeding, chills, high fever, dizziness, headache, back pain, etc., timely medical attention is needed.
Follow-up and review
Evans syndrome is often chronic and recurrent, and even after it is effectively controlled and in remission, regular follow-up is needed.
Regular blood tests, reticulocyte counts, liver function, urine tests, etc. are usually required.
The frequency of follow-up is related to the primary disease, the degree of hemolysis, anemia, bleeding, and the mode of treatment. Follow-ups should be ordered by the doctor. Once symptoms of hemolysis, anemia, or bleeding appear, you should seek medical attention without being bound by the time of review.
Prevention
There is a lack of specific preventive measures for this disease:
Pay attention to whether you have food and drug allergies in daily life, and avoid accidental consumption of allergenic food and drugs.
Adopt a good lifestyle and dietary habits, appropriate exercise, enhance their own immunity, and avoid infections.
Actively treat primary diseases.
Have regular medical checkups and seek medical advice when abnormalities are detected.