Differential Diagnosis

The normal life span of a red blood cell is approximately 120 days, after which the cells are destroyed by the reticuloendothelial system, particularly the spleen. Hemolysis refers to premature RBC destruction, and hemolytic anemia results when bone marrow production cannot compensate for the increased peripheral destruction. There are two general categories of hemolytic anemias, extravascular, which is the more common form, and intravascular. Extravascular hemolysis results when red cells are destroyed by tissue macrophages particularly in the spleen. Intravascular hemolysis results when there is mechanical trauma to the RBCs or when complement induced cell lysis occurs within the bloodstream. Intravascular hemolysis results in hemoglobinemia, hemoglobinuria, methemalbuminemia, and hemosiderinuria whereas splenomegaly is indicative of extravascular hemolysis.

Symptoms of hemolytic anemia are similar to other anemias and include shortness of breath, fatigue, and weakness. Physical findings include orthostatic hypotension, tachycardia, jaundice, icteris, and splenomegaly. The finding of splenomegaly is indicative of extravascular hemolysis and is not a physical finding when intravascular hemolysis is present. Gallstones may develop and their presence in an adolescent or a young adult may be indicative of long-standing hemolytic anemia.

Associated lab abnormalities include a normocytic anemia with an elevated reticulocyte index. Unconjugated hyperbilirubinemia is present along with an elevated LDH. With intravascular hemolysis, hemoglobin spills from the destroyed red cells into the plasma. This free hemoglobin is cleared by combining with haptoglobin, through the oxidation of iron or via the kidneys. The result of renal mediated hemoglobin clearance is the presence of hemoglobin in the urine (hemoglobinuria or hemosiderinuria).

Once hemolytic anemia is diagnosed, the next step in the workup is to differentiate extravascular from intravascular hemolysis. As mentioned above, splenomegaly is a physical finding that points strongly toward extravascular hemolysis. Hemoglobinemia, hemoglobinuria, and hemosiderinuria all indicate intravascular hemolysis and are more sensitive than the serum haptoglobin level. Haptoglobin is a serum protein that binds free serum hemoglobin and is significantly depressed (almost nonexistent) with intravascular hemolysis; however, the finding is not specific and a low haptoglobin may be seen with extravascular hemolysis. Also, haptoglobin is spuriously elevated with many illnesses. Therefore, a patient may have intravascular hemolysis with a concomitant illness, and in that case, the haptoglobin may be normal. Hemosiderinuria may be detected by performing a Prussian blue stain on a spun urine sediment. A pink to red wine appearence of the plasma is indicative of plasma hemoglobin and may be confirmed by the finding of a plasma hemoglobin level of 50 mg/dL or higher. If the urine appears red to brown after centrifugation, then hemoglobinuria is present. Methemalbumin will be detectable in the serum for several days following a hemolytic event.

Severe hypophosphatemia may induce a hemolytic state. RBC pliability is dependent on intracellular ATP, which is in turn dependent on the serum phosphorus level. A depletion of serum phosphorus to levels less than 0.5 mg/dL results in depressed intracellular erythrocyte ATP levels. The RBCs then become rigid and are destroyed in the spleen (extravascular). Other causes of extravascular hemolysis include autoimmune hemolytic anemia (this is the commonest cause of extravascular hemolysis and results from increased phagocytic RBC destruction secondary to autoantibodies), hereditary red cell membrane abnormalities (spherocytosis, elliptocytosis and stomatocytosis), spur cell anemia, pyruvate kinase deficiency, and unstable hemoglobin disease.

Intravascular hemolytic anemia results from enzyme deficiencies (glucose-6-phosphate dehydrogenase and glutathione reductase), immune mediated mechanisms, infections (Clostridium perfringens, Bartonella bacilliformis and malaria), paroxysmal nocturnal hemoglobinuria, and mechanical trauma (microangiopathic hemolytic anemia). Microangiopathic hemolytic anemia occurs when red cell flow is subjected to high velocity turbulent flow (malignant tumors, malignant hypertension, severe aortic stenosis, and prosthetic heart valves), regions of intravascular coagulation (disseminated intravascular coagulation and thrombotic thrombocytopenic purpura), or to small blood vessels in areas of high trauma (march hemoglobinuria). Chronic microangiopathic hemolytic anemia may result in iron deficiency anemia with its associated laboratory abnormalities (inappropriate reticulocytosis, microcytosis, and characteristic abnormal iron studies). After the iron stores have been replenished, the abnormalities consistent with intravascular hemolysis then become apparent. This possible mechanism should be considered in patients with iron deficiency anemia with no apparent etiology (gastrointestinal bleeding, heavy menses, pregnancy, or hookworm infestation).

Autoimmune hemolytic anemias may be diagnosed using the direct antiglobulin test (DAT or Direct Coomb's) and cold agglutinin titer testing.  Polyspecific DAT testing indicates the involvement of IgG or C3 in the hemolytic process. Monospecific serum may be used to detect whether IgG or C3 are involved.  The Donath-Landsteiner test may be used to diagnose paroxysmal cold hemoplobinuria.

Therapy for hemolysis is dependent on the underlying cause. Persons with genetic abnormalities which induce hemolysis should undergo genetic counseling. All attempts should be made to identify which stressors induce hemolysis in an individual patient so that they may be avoided. Folate therapy should be administered to patients with chronic hemolysis as depletion of this vitamin occurs secondary to the increased demand from chronic reticulocytosis. Some patients require iron therapy. In some cases, splenectomy may be therapeutic or at least decrease the need for transfusions.