This young girl has presented with fever, abdominal pain, and vomiting; examination reveals the presence of icterus, severe pallor, and splenomegaly. The above constellation of clinical findings is strongly suspicious of a hematological disorder; this is corroborated by the presence of severe anemia, and a marked reticulocytosis in the complete blood count. Note also the presence of indirect hyperbilirubinemia; in the context of this specific patient, this is suggestive of underlying hemolysis. A peripheral blood film, and assessment of lactate dehydrogenase (LDH) and urine urobilinogen levels are good next steps; all of these show changes compatible with hemolysis. Note in particular the presence of microspherocytosis in the blood film; this distinctive finding is encountered in only a few conditions, with autoimmune hemolytic anemia (AIHA), and hereditary spherocytosis (HS) being the most notable of these. That said, HS is clinically less likely in this patient, given the absence of a family history (which is present in over 75% of such individuals). Therefore, a direct antibody test (DAT) is a logical next step; this turns out to be positive for IgG, but negative for the complement factor C3d; in other words, IgG autoantibodies are present. Note that when considered along with the evidence of hemolysis, the above finding is sufficient to diagnose the presence of AIHA. An indirect antibody test (IAT) should also be performed, aiming to determine if the antibodies are 'warm' or 'cold'; the results seen here indicate the former. Most cases of warm AIHA are primary (idiopathic) in origin; however, the condition can also occur secondary to lymphoproliferative disorders and certain autoimmune conditions, mandating further evaluation in this regard. Given the severity of the anemia, blood transfusion is probably advisable; note that antibody screening studies should be performed beforehand. Folic acid supplementation should also commence, as active hemolysis can rapidly deplete body stores of the nutrient. Azathioprine and Rituximab are second line agents in the management of AIHA, and are not indicated right now.
Autoimmune hemolytic anemia (AIHA) is a rare hematological disease characterized by the production of autoantibodies against one's own erythrocytes. The condition can be divided into several subtypes, depending on the nature of the antibodies present; these include "warm", "cold", "mixed", and "biphasic" disease, which are defined based on the optimal temperature at which mediator antibodies bind to erythrocytes. AIHA can also be classified based on the underlying etiology; in over half of patients a causative disease can be identified, with this being termed "secondary" AIHA; in contrast, "primary" or "idiopathic" AIHA occurs in the absence of any distinct underlying cause. The overall incidence of AIHA is estimated to be between 0.6 to 3 per 100,000 persons; warm AIHA is the most common subtype, with an incidence of 1 in 100,000 individuals; cold AIHA is the rarest, with an incidence of only 1 in 1,000,000 persons. While the pathogenesis of AIHA is not fully understood, it is hypothesized that an initial immune response to a foreign antigen leads to cross reaction with autoantigens on erythrocytes, ultimately resulting in hemolysis; this can occur with or without complement activation. In warm AIHA, the autoantibodies target the Rhesus (Rh) antigen; the antibody coated erythrocytes are then engulfed and destroyed by the cells of the reticuloendothelial system. On the other hand, erythrocyte destruction in cold AIHA takes place via antibody mediated complement activation. Note also that the autoantibodies can be of various isotypes; this plays a significant role in the pathogenesis. Most, if not all, cases of warm AIHA are mediated by IgG antibodies; these maximally bind to erythrocytes at normal body temperatures (37°C / 98.6 °F). Conversely, cold AIHA is mostly mediated by IgM antibodies, which bind best at temperatures below 30°C (86 °F). Biphasic AIHA is also due to IgG autoantibodies; however, these show optimal binding below 30 °C (86 °F), but cause complement fixation at 37 °C (98.6 °F). An example is the Donath-Landsteiner autoantibodies seen in paroxysmal cold haemoglobinuria (PCH). Affected patients typically present with symptoms and signs of anemia (such as pallor, fatigue, headache, dizziness, shortness of breath and palpitations); discoloration of the urine (due to hemoglobinuria) may rarely be seen. Individuals with cold AIHA may also develop acrocyanosis in cold weather, or rarely, abdominal pain precipitated by eating cold food; as these changes are brought about by agglutination of erythrocytes secondary to exposure to cold, they quickly disappear once the patient warms up. Physical examination often reveals icterus, and mild splenomegaly. Note that massive splenomegaly is unlikely in AIHA, and if present, should raise suspicions of other blood dyscrasias. The diagnosis of AIHA requires demonstration of hemolysis, and confirmation of the presence of autoantibodies directed against erythrocytes. In this respect, the presence of indirect hyperbilirubinemia and increased lactate dehydrogenase (LDH) levels provide evidence for increased red blood cell breakdown. In addition, if rapid hemolysis has taken place, visual inspection of the plasma may reveal discoloration due to the binding capacity of haptoglobin being temporarily exceeded; this may range from a slight pinkish tinge (if only miniscule amounts of free hemoglobin are present), to a cola color in severe hemolysis. Note also that hemoglobinuria and hemosiderinuria are frequently present following intravascular haemolysis; the latter can potentially be detected in the urine for up to several days after an episode. A complete blood count will demonstrate anemia, and may also reveal a reticulocytosis; note that the latter is not a universal finding, and may be absent if there is a coexistent decrease in bone marrow function; a peripheral blood film will often reveal the presence of microspherocytes. The direct antibody test (DAT), also known as the direct Coombs test, is the first line investigation for the detection of autoantibodies; in this, the patient's anticoagulated erythrocytes are mixed with polyspecific anti-human globulin (AHG) directed against IgG and complement factor C3. A positive DAT indicates the presence of antibodies which bind in-vivo to the patient's erythrocytes; in patients with other clinical and biochemical findings suggestive of hemolytic anemia, this can be considered diagnostic of AIHA. However, a negative DAT does not necessarily rule out the disease, as polyspecific AHG does not contain much anti-IgA, and can thus be negative in individuals with this type of antibodies; if this is suspected, the test should be repeated with monospecific AHG. Note also that the DAT may be falsely positive in some normal persons, as well as in a variety of other hematological conditions. Classification of the antibodies into warm or cold types can be performed via the indirect antibody test (IAT), also known as indirect Coombs test. If blood transfusion becomes necessary, red blood cell (RBC) antibody panels should be performed beforehand; these use red cells coated with a number of antigens (e.g. Rh, Duffy, Lutheran, Kell, Kidd, Lewis, P, MNS and Xg) to determine which autoantibodies are present. The treatment of AIHA depends on the exact form, and underlying etiology. In both warm and mixed-type disease, corticosteroids are the first-line therapy; splenectomy and Rituximab are second-line options, if there is an inadequate response to glucocorticoids. In cases of cold AIHA, the first line therapy essentially comprises warming the patient and avoidance of further cold exposure; Rituximab and Chlorambucil are second-line agents. Note that glucocorticoids and splenectomy are usually ineffective in this group. Note also that plasmapheresis or administration of immunoglobulins is considered to be transiently beneficial in fulminant hemolysis due to any cause, until other therapies take effect. Correction of the anemia seen in AIHA should be based on clinical symptoms; unnecessary blood transfusions should be avoided at all costs, as there is a high risk of autoantibodies cross reacting with the transfused erythrocytes, leading to an exacerbation of the existing hemolysis. Thus, transfusion is indicated in patients with life threatening anemia or significant cardiovascular or cerebrovascular disease; even then, this is should performed carefully, with immaculate monitoring of vital parameters. Similar to other forms of hemolytic anemia, folic acid supplementation is also beneficial in these patients.