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Specialty scores for Autoimmune Hemolytic Anemia
Autoimmune diseases in humans have been known to be in existence for almost 100 years. Currently, more than 40 human diseases are attributed to autoimmune pathogenesis. In 1843, Andral described a medical condition of spontaneous anemia, in which no prior blood loss existed. Minkowski was the first one to describe a congenital hemolytic anemia, whereas Hayem described acquired hemolytic anemia. In 1951, Young et al. coined the term autoimmune hemolytic anemia.
Autoimmune hemolytic anemia (AIHA) is a rare medical disorder in which antibodies are formed against the person's own red blood cells (RBCs), causing them to burst and get destroyed, leading to reduction in the number of oxygen-carrying RBCs in the blood circulation. AIHA can reduce the normal life cycle of red blood cell from 120 days to a few days in severe cases.
AIHA is estimated to affect between 1 and 3 persons per 100,000 per year. Overall, the disease is estimated to be present in 17 people per 100,000.
More than 70% of new cases of AIHA are seen in patients above 40 years of age annually. The peak incidence of the disease is present between 60 and 70 years of age and the disorder is usually more commonly seen in females than in males. The male to female disease ratio is 2:3.
In most cases, the exact cause of AIHA is unknown. In warm hemolysis, the RBCs become coated with IgG molecules, which mark the cells for subsequent uptake and destruction by splenic macrophages. In cold AIHA, IgM molecules help fixing the complement to the surface of RBCs. This can lead to activation of the complete complement cascade, resulting in lysis of RBCs. In most cases, complement cascade activation is stopped at the C3 stage, leading to formation of C3-coated RBCs which are then destroyed by hepatic macrophages.
Loss of immunological tolerance to self-antigens of RBCs might originate by different mechanisms that include antigenic mimicry, apoptosis, and other immunoregulatory disorders including cytokine network alteration. The immunologic mechanisms that are involved in the pathogenesis of AIHA include autoantibodies, phagocytes, ADCC, B and T lymphocytes, Tregs, cytokines, and the complement system.
Hemolytic anemia is characterized by the abnormal breakdown of RBCs, either intravascular (in the blood vessels) or extravascular (outside the blood vessels, usually in the spleen). It may be hereditary or acquired in nature.
Hereditary hemolytic anemia can be due to:
-Defective RBC metabolism: Glucose-6-phosphate dehydrogenase deficiency, Pyruvate kinase deficiency
Acquired hemolytic anemia may be caused by immune-mediated conditions, drugs and other miscellaneous causes.
-Immune-mediated causes lead to autoimmune hemolytic anemia (AIHA).
-Non-immune mediated causes include hypersplenism, fragmentation syndrome (grafts, preeclampsia, valves, Thrombotic thrombocytopenic purpura (TTP), Hemolytic-uremic syndrome (HUS), Disseminated intravascular coagulation (DIC), hemangioma, March Hemoglobinuria).
-Drugs may cause acquired hemolytic anemia, for example Cephalosporins, Dapsone, Levodopa, Levofloxacin, Nitrofurantoin, Pyridium & Penicillin and its derivatives
AIHA is a type of hemolytic anemia. In AIHA, destruction of RBCs is due to formation of antibodies in the body that target and destroy own blood cells. In Hemolytic anemia, auto-antibodies are not formed, except in immune-mediated form that is AIHA itself, and the damage is due to structural, metabolic or toxic causes.
About 10% of patients suffering from lupus erythematosus develop an AIHA.
Risk factors include active malignancy, previous DVT, reduced mobility, thrombophilic condition, recent trauma or surgery, age more than 70 years, heart failure, Myocardial Infarction, pulmonary failure, rheumatologic disorder, obesity, ongoing hormone therapy.
The disease may be primary (idiopathic), or secondary to another underlying disorder. The primary AIHA accounts for about 50% of cases. Secondary AIHA can result from lymphoproliferative disorders (chronic lymphocytic leukemia, lymphoma), autoimmune disorders (systemic lupus erythematosus, crohn's disease, ulcerative colitis, rheumatoid arthritis, scleroderma) and solid malignancies (ovarian cancer). Drug-induced AIHA, though rare, can be caused by a number of drugs, including alpha-methyldopa and penicillin.
Primary cold AIHA is without an underlying disorder. Secondary cold AIHA may be associated with bacterial infections, such as syphilis, listeriosis, legionnaires’ disease or mycoplasma infections. Viral causes include infections due to Epstein-Barr virus, cytomegalovirus, adenovirus, HIV, influenza, mumps, varicella, rubella, or hepatitis C. Parasitic infections such as malaria or trypanosomiasis may also lead to cold AIHA. Certain types of cancers such as lymphoma, chronic lymphocytic leukemia, Waldenstrom macroglobulinemia, multiple myeloma, and Kaposi sarcoma may give rise to cold AIHA.
Severe, aggressive and fatal AIHA may be a complication of hematopoietic stem cell transplantation. A recent large study described this incidence to be 3.6% and showed disease association with hematopoietic stem cell transplantation from donors who are unrelated to the patient.
Depending on the temperature range at which the auto-antibodies are most active, AIHA is classified as warm, cold, or mixed.
Autoimmune hemolytic anemia is caused due to role of auto-antibodies. Warm type of AIHA is mediated by immunglobulin (Ig) G and IgG antibodies bind maximally at body temperature (37°C). Cold type of AIHA is mediated by IgM antibodies, which bind best at temperatures below 37°C.
Between 50-90% of AIHA cases are due to warm antibodies.
More than 80% patients suffer with headaches, muscle weakness, palpitations, fatigue, dizziness, shortness of breath and paleness.
About 50% patients suffer with signs and symptoms suggestive of immunodeficiency and frequent infections.
Less than 30% patients suffer with abdominal pain, abnormal urinary color, jaundice (yellow discoloration of eye white and skin), congestive heart failure, edema, fever, splenomegaly and cardiac arrhythmias.
Patients with acute-onset, rapidly progressive hemolysis may complain of lumbar back pain. Patients with cold AIHA may present with symptoms related to agglutination of red cells in the peripheral circulation, such as evidence of acrocyanosis in cold weather seen in toes, fingers, ears and nose.
In rare cases, abdominal pain is noticed when eating cold food. It is primarily due to ischemia related to agglutination of red cells in the stomach.
Physical examination generally shows tachycardia, pallor, petechiae, purpura and peripheral edema.
Sudden drop of red blood cell count along with supportive medical history and clinical findings raise the clinical suspicion of the disease. Definitive diagnosis requires certain clinical laboratory tests that may demonstrate evidence of (1) hemolysis, and (2) presence of autoimmune component.
Evidence of Hemolysis:
Hemolysis is diagnosed by finding conclusive evidence of red cell breakdown and the compensatory raise in red cell production.
Lactate dehydrogenase: When RBCs undergo hemolysis, they release LDH enzyme, making it a sensitive test.
Serum bilirubin: Hemolysis of RBCs leads to breaking down of the heme moiety of hemoglobin to bilirubin.
Serum haptoglobin: Haptoglobin is responsible for binding free serum hemoglobin and it usually falls to very low levels in hemolysis.
Serum hemoglobin: In case the hemolysis is rapid, all the free hemoglobin is not bound by haptoglobin and leads to free hemoglobin in the plasma.
Reticulocyte count: Hemolysis is accompanied by an increase in the reticulocyte count. Reticulocyte count is a marker of red blood cells that are 24 hours old or less in age. Reticulocytosis might be absent in case of decreased functional activity of the bone marrow, as seen after chemotherapy.
Blood smear: Presence of spherocytes on the blood smear is the hallmark laboratory parameter of AIHA.
Urinary hemosiderin: Hemosiderinuria is a late finding of hemolysis. It takes around one week for iron-laden tubule cells to be excreted in the urine.
Urinary hemoglobin: Presence of hemoglobin in the urine is a sign of hemolysis. In hemolysis, the dipstick will detect the presence of blood, while the microscopic exam will not detect red blood cells.
Expected laboratory findings in AIHA include positive direct antiglobulin test (DAT), decreased haptoglobin, increased indirect bilirubin, increased lactate dehydrogenase (LDH), increased reticulocyte count (reticulocytosis) and positive urine hemosiderin test.
Evidence of autoimmune component:
The autoimmune component of AIHA is shown by demonstrating the presence of either IgG molecules or complement on the surface of RBCs. This is done by the direct antiglobulin test (DAT) or Coombs test. DAT can have false positive and false negative results. Positive DAT may be seen in patients with liver disease & HIV infection. The antiglobulin test, used to detect nonagglutinating antierythrocyte antibodies, was brought into clinical medicine by Coombs in 1945 and within 1 year, this test was used in clinical medicine to diagnose autoimmune hemolytic anemia.
If the DAT is positive when using a polyspecific antihuman globulin reagent, further specification is obtained with a monospecific reagent order to detect whether RBC are coated with IgG, IgM, IgA, and C3C or/and C3d.
-First line Treatment: It consists of Prednisone 1 mg/kg/day, Folic acid 1 mg/day
-Second line Treatment consists of: Rituximab 375 mg/m2 weekly for 4 weeks or Splenectomy
-Third line Treatment consists of: Azathioprine 125 mg/day, Cyclophosphamide 1 g/m2, IV every 28 days, Mycophenolate 500-100 mg twice daily, Cyclosporine, Danazol 200 mg 4 times daily, Alemtuzumab
(1) Steroids: Steroids are very effective in the treatment of AIHA. They work by decreasing the production of autoantibodies by B-cells and by reducing the density of Fc gamma receptors on phagocytes in the spleen.
Prednisolone, the most commpnly used steroid in AIHA, is usually started with 1mg/kg/day dose and tapered as per the clinical response. In about 2-3 weeks' time, as the hemoglobin is stabilized a bit, the dose is narrowed down to 20mg/day. It is essential to keep a check on hemoglobin level and keep on tapering the steroid dose till the hemoglobin level is totally stable. The patients must be given calcium supplements throughout the steroid therapy and blood glucose should be monitored in order to diagnose steroid-induced diabetes mellitus early.
(2) Cytotoxic drugs: Cytotoxic drugs work by suppressing the immune system leading to a reduction in production of autoantibodies. These drugs are added to the treatment regime of AIHA when steroid therapy alone does not yield sufficient results, when daily maintenance dose of steroid is more than 20 mg, or when it becomes mandatory to taper the steroid dose due to development of side effects.
Cyclophosphamide and azatioprine are most commonly used cytotoxic drugs, either in monotherapy or in combination with steroids. Other agents include cyclosporine or mycophenolate-mofetil, found to effective in some cases. Cytotoxid drugs cause bone marrow suppression so strict monitoring of peripheral blood count is needed during the treatment.
Steroids are known to induce partial remission in 60-70% patients, and complete remission in 10-15%.
(3) Splenectomy: Splenectomy helps halt the process of RBCs destruction and decrease the production of autoantibodies. About 20% patients reach eventual cure or a long term remission after splenectomy. About 50% patients experience clinical and hematological stability in about 2 weeks. In 50% patients, steroids can be further tapered following splenectomy. In about one-third patients, a substantial disease remission is not obtained even after splenectomy.
Post-splenectomy patients have a higher risk of infections and pre-surgery vaccination against N. menigitidis, S. pneumoniae, H. influenzae significantly decreases the risk for infection in these patients.
Splenectomy is considered the most effective conventional second-line treatment of warm AIHA as spleen is a major organ for immune destruction of IgG-coated erythrocytes. Splenectomy is ineffective in about 30% of cases, because of elevated synthesis of autoantibodies in other lymphoid organs, and replacement the spleen's function of RBC destruction by the liver.
Considered to be a safer procedure, splenectomy is associated with 1% mortality by laparotomy and 0.5% by laparoscopic approach.
(4) Anti-C20 antibody: Rituximab ia a monoclonal antibody that targets C20 present on all B-cells except plasma cells. It is well tolerated and occasional instances of general side effects, e.g. urticaria, hypotension are reported. After rituximab therapy, patients suffering with SLE (systemic lupus erythematosus) are rarely reported to develop a rare but life-threatening complication, progressive multifocal leucoencephalopathy.
If splenectomy is considered after rituximab therapy failure, it must be weighed in that pre-surgery vaccination to encapsulated bacteria might be ineffective after Rituximab therapy.
(5) Immunoglobulins: Administration of immunoglobulins improves anaemia temporarily in about 40% of cases. This is mainly due to a decrease of RBC destruction in the spleen & immunomodulatory effects. Immunoglobulins might be considered in acute fatal situations to reduce breakdown of patients or donor RBCs.
(6) Transfusion: The blood product must be compatible with respect to alloantibodies present in patient’s serum. Studies indicate that 15-30% of patients will have underlying alloantibodies, which can lead to transfusion reactions. However, patients who have never been transfused or pregnant patients will rarely have alloantibodies. Also, a patient who received transfusion in the remote past may have an anamnestic antibody response, unlikely to cause an immediate hemolytic reaction.
In case of a conflict in making the right choice while transfusion, it should be remembered that alloantibodies are more important than auto-antibodies. In case of urgent transfusion requirement, chances of alloantibody formation must be prevented by matching patient and donor for the most important RBC antigens, such as Rhesus, Kell, Kidd, and Duffy.
The short-term prognosis of warm-antibody hemolysis depends upon the severity of the anemia. If not treated quickly and effectively, anemia can worsen rapidly and turn fatal. The long-term prognosis of warm AIHA depends upon the nature and severity of underlying disease and upon the risks of chronic immunosuppression, which is required to control the disease.
First line Treatment: Rituximab 375 mg/m2 weekly for 4 weeks, Folic acid 1 mg/day. Keep patients and infusion products warm.
Second line Treatment: Rituximab 375 mg/m2 days 1, 29, 57, 85 with Fludarabine 40 mg/m2 given orally days 1-5, 29-34, 57-61, and 85-89
Third line Treatment: Bortezomib, Eculizumab
Anemia in cold AIHA is usually mild and mainstay of the treatment is to 'keep the patient warm’. Patients avoid getting cold by wearing gloves, woolen clothes, a hat and warm shoes. If necessary, transfusion must be performed at 37°C by a controlled heating system. Also during surgery, body temperature must be maintained at 37°C.
Steroids have proven to be less effective than in warm AIHA. Also, cytotoxic agents, such as cyclophosphamide and azathioprine show less beneficial effects than in warm AIHA. Splenectomy also has no role in cold AIHA. Rituximab is demonstrated to induce a response in 40-50% PATIENTS, but achievement of total remission is rare and relapses are commonly seen. Plasmapheresis brings a quick reduction of IgM levels and may contribute to a short-term stabilization of the clinical condition.
In young patients, cold AIHA often occurs following an infection, especially viral and mycoplasma infections, and the disease course is usually self-limited. Destruction of RBCs usually starts 2-3 weeks after the illness and last for 4-6 weeks.
AIHA in children generally has a good prognosis and is self-limiting in nature.
About 20% patients suffer with potentially lethal complication of venous thromboembolism.
Pulmonary embolism is the most common cause of death in AIHA patients.
Reported mortality in the cases of AIHA has been shown to be 11% in older series, and 4% in more recent studies.
About 18% of patients with primary AIHA develop lymphoma at a later date.
Immune complex hemolytic anemia