HEMOLYTIC ANEMIAS

The hemolytic anemias are a group of disorders in which red blood cell survival is reduced, either episodically or continuously. The bone marrow has the ability to increase erythroid production up to eightfold in response to reduced red cell survival, so anemia will be present only when the ability of the bone marrow to compensate is outstripped. This will occur when red cell survival is extremely short or when the ability of the bone marrow to compensate is impaired for some second reason.
Since red blood cell survival is normally 120 days, in the absence of red cell production the hematocrit will fall at the rate of approximately 1/100 of the hematocrit per day, which translates to a decrease in the hematocrit reading of approximately 3% per week. For example, a fall of hematocrit from 45% to 36% over 3 weeks need not indicate hemolysis, since this rate of fall would result simply from cessation of red blood cell production. If the hematocrit is falling at a rate faster than that due to decreased production, blood loss or hemolysis is the cause.
Reticulocytosis is an important clue to the presence of hemolysis, since in most hemolytic disorders the bone marrow will respond with increased red blood cell production. However, hemolysis can be present without reticulocytosis when a second disorder (infection, folate deficiency) is superimposed on hemolysis; in these circumstances, the hematocrit will fall rapidly. However, reticulocytosis also occurs during recovery from hypoproliferative anemia or bleeding. Hemolysis is correctly diagnosed (when bleeding is excluded) if the hematocrit is either falling or stable despite reticulocytosis.
Hemolytic disorders are generally classified according to whether the defect is intrinsic to the red cell or due to some external factor . Intrinsic defects have been described in all components of the red blood cell, including the membrane, enzyme systems, and hemoglobin; most of these disorders are hereditary. Hemolytic anemias due to external factors are the immune and microangiopathic hemolytic anemias.

Classification of hemolytic anemias.

Intrinsic
Membrane defects: hereditary spherocytosis, hereditary elliptocytosis, paroxysmal nocturnal hemoglobinuria
Glycolytic defects: pyruvate kinase deficiency, severe hypophosphatemia
Oxidation vulnerability: glucose-6-phosphate dehydrogenase deficiency, methemoglobinemia
Hemoglobinopathies: sickle cell syndromes, unstable hemoglobins, methemoglobinemia
Extrinsic
Immune: autoimmune, lymphoproliferative disease, drug toxicity
Microangiopathic: thrombotic thrombocytopenic purpura, hemolytic-uremic syndrome, disseminated intravascular coagulation, valve hemolysis, metastatic adenocarcinoma, vasculitis
Infection: Plasmodium, Clostridium, Borrelia
Hypersplenism
Burns

Certain laboratory features are common to all the hemolytic anemias. Haptoglobin, a normal plasma protein that binds and clears hemoglobin released into plasma, may be depressed in hemolytic disorders. However, haptoglobin levels are influenced by many factors and, by themselves, are not a reliable indicator of hemolysis. When intravascular hemolysis occurs, transient hemoglobinemia occurs. Hemoglobin is filtered through the glomerulus and is usually reabsorbed by tubular cells. Hemoglobinuria will be present only when the capacity for reabsorption of hemoglobin by these cells is exceeded. In its absence, evidence for prior intravascular hemolysis is the presence of hemosiderin in shed renal tubular cells (positive urine hemosiderin). With severe intravascular hemolysis, hemoglobinemia and methemalbuminemia may be present. Hemolysis increases the indirect bilirubin, and the total bilirubin may rise to 4 mg/dL. Bilirubin levels higher than this may indicate some degree of hepatic dysfunction. Serum LDH levels are strikingly elevated in cases of microangiopathic hemolysis (thrombotic thrombocytopenic purpura, hemolytic-uremic syndrome) and may be elevated in other hemolytic anemias.