By Dr.AMEER E. AL-AASAM

MECHANISM DRUG ADSORPTION (HAPTEN) TERNARY (IMMUNE) COMPLEX AUTOANTIBODY INDUCTION Direct antiglobulin testPositive (anti-IgG)Positive (anti-C3)Positive (anti-IgG) Site of hemolysisExtravascularIntravascularExtravascular Medications PenicillinQuinidineα-Methyldopa AmpicillinPhenacetinMefenamic acid MethicillinHydrochlorothiazide(Ponstel) CarbenicillinRifampin (Rifadin)l-Dopa Cephalothin (Keflin)* SulfonamidesProcainamide Cephaloridine (Loridine) IsoniazidIbuprofen Quinine Diclofenac (Voltaren) Insulin Interferon alfa Tetracycline Melphalan (Alkeran) Acetaminophen Hydralazine (Apresoline) Probenecid Chlorpromazine (Thorazine) Streptomycin Fluorouracil (Adrucil) Sulindac (Clinoril Table SELECTED DRUGS THAT CAUSE IMMUNE-MEDIATED HEMOLYSIS

Drugs (penicillin or sometimes cephalosporins) that cause hemolysis via the “hapten” mechanism (immune but not autoimmune) bind tightly to the RBC membrane (see Table 458-1). Antibodies to the drug, either newly or previously formed, bind to the drug molecules on RBCs, mediating their destruction in the spleen. In other cases, certain drugs, such as quinine and quinidine, do not bind to RBCs but, rather, form part of a “ternary complex,” consisting of the drug, an RBC membrane antigen, and an antibody that recognizes both (see Table 458-1). Methyldopa and sometimes cephalosporins may, by unknown mechanisms, incite true autoantibodies to RBC membrane antigens, so that the presence of the drug is not required to cause hemolysis.

Clinical Manifestations Autoimmune hemolytic anemias may occur in either of 2 general clinical patterns. The first, an acute transient type lasting 3-6 mo and occurring predominantly in children ages 2-12 yr, accounts for 70-80% of patients. It is frequently preceded by an infection, usually respiratory. Onset may be acute, with prostration, pallor, jaundice, fever, and hemoglobinuria, or more gradual, with primarily fatigue and pallor. The spleen is usually enlarged and is the primary site of destruction of immunoglobulin G (IgG)– coated RBCs. Underlying systemic disorders are unusual. A consistent response to glucocorticoid therapy, a low mortality rate, and full recovery are characteristic of the acute form. The other clinical pattern involves a prolonged and chronic course, which is more frequent in infants and in children >12 yr old. Hemolysis may continue for many months or years. Abnormalities involving other blood elements are common, and the response to glucocorticoids is variable and inconsistent. The mortality rate is approximately 10%, and death is often attributable to an underlying systemic disease.

Laboratory Findings In many cases, anemia is profound, with hemoglobin levels <6 g/dL. Considerable spherocytosis and polychromasia (reflecting the reticulocyte response) are present. More than 50% of the circulating RBCs may be reticulocytes, and nucleated RBCs usually are present. In some cases, a low reticulocyte count may be found, particularly early in the episode. Leukocytosis is common. The platelet count is usually normal, but concomitant immune thrombocytopenic purpura sometimes occurs (Evans syndrome). The prognosis for patients with Evans syndrome is guarded, because many have or eventually have a chronic disease, including SLE, an immunodeficiency syndrome, or an autoimmune lymphoproliferative disorder. Results of the direct antiglobulin test are strongly positive, and free antibody can sometimes be demonstrated in the serum (indirect Coombs test). These antibodies are active at 35-40?C (“warm” antibodies) and most often belong to the IgG class.

They do not require complement for activity and are usually incomplete antibodies that do not produce agglutination in vitro. Antibodies from the serum and those eluted from the RBCs react with the RBCs of many persons in addition to those of the patient. They often have been regarded as nonspecific panagglutinins, but careful studies have revealed specificity for RBC antigens of the Rh system in 70% of patients (≈50% of adult patients). Complement, particularly fragments of C3b, may be detected on the RBCs in conjunction with IgG. The Coombs test result is rarely negative because of the limited sensitivity of the Coombs reaction. A minimum of molecules of IgG per cell is necessary on the RBC membrane to produce a positive reaction. Special tests are required to detect the antibody in cases of “Coombs-negative” autoimmune hemolytic anemia. In warm antibody hemolytic anemia, the direct Coombs test may detect IgG alone, both IgG− and complement fragments, or solely complement fragments if the level of RBC-bound IgG is below the detection limit of the anti-IgG Coombs reagent

Treatment Transfusions may provide only transient benefit but may be lifesaving in cases of severe anemia by providing delivery of oxygen until the effect of other treatment is observed. In general, all tested units for transfusion are serologically incompatible. It is important to identify the patient's ABO blood group in order to avoid a hemolytic transfusion reaction mediated by anti-A or anti-B. The blood bank should also test for the presence of an underlying allo-antibody, which could cause rapid hemolysis of transfused red cells. Patients who have neither been previously transfused nor pregnant are unlikely to harbor an alloantibody. Early consultation between the clinician and the blood bank physician is essential. Failure to transfuse a profoundly anemic infant or child may lead to serious morbidity and even death.

Patients with mild disease and compensated hemolysis may not require any treatment. If the hemolysis is severe and results in significant anemia or symptoms, treatment with glucocorticoids is initiated. Glucocorticoids decrease the rate of hemolysis by blocking macrophage function by down regulating Fcγ receptor expression, decreasing the production of the autoantibody, and perhaps enhancing the elution of antibody from the RBCs. Prednisone or its equivalent is administered at a dose of 2 mg/kg/24 hr. In some patients with severe hemolysis, doses of prednisone of up to 6 mg/kg/24 hr may be required to reduce the rate of hemolysis. Treatment should be continued until the rate of hemolysis decreases, and then the dose gradually reduced. If relapse occurs, resumption of the full dosage may be necessary. The disease tends to remit spontaneously within a few weeks or months. The Coombs test result may remain positive even after the hemoglobin level returns to normal,

it is safe to discontinue prednisone once the direct Coombs test result becomes negative. When hemolytic anemia remains severe despite glucocorticoid therapy, or if very large doses are necessary to maintain a reasonable hemoglobin level, IV immunoglobulin may be tried. Rituximab, a monoclonal antibody that targets B lymphocytes, the source of antibody production, has been useful in chronic cases refractory to conventional therapy. Plasmapheresis has been used in refractory cases but generally is not helpful. Splenectomy may be beneficial but is complicated by a heightened risk of infection with encapsulated organisms, particularly in patients <6 yr. Prophylaxis is indicated with appropriate vaccines (pneumococcal, meningococcal, and Haemophilus influenzae type b) before splenectomy and with oral penicillin after splenectomy. In general

Course and Prognosis Acute idiopathic autoimmune hemolytic disease in childhood varies in severity but is self-limited; death from untreatable anemia is rare. Approximately 30% of patients have chronic hemolysis, often associated with an underlying disease, such as SLE, lymphoma, or leukemia. The presence of antiphospholipid antibodies in adult patients with immune hemolysis predisposes to thrombosis. Mortality in chronic cases depends on the primary disorder.