In hemolytic disorders, the normal life span of erythrocytes in the peripheral blood of 120 days is substantially shortened because of red cell destruction. As a compensatory mechanism, there is increased red blood cell (RBC) production by the bone marrow. Under normal conditions, the bone marrow can increase its capacity for RBC generation severalfold in response to anemia. Shortening of RBC life span does not lead to anemia until a relative bone marrow failure follows with an inability of the marrow to keep up with the loss. Proportional increases in both destruction and generation of RBCs can result in compensated hemolysis without significant anemia. Some of the earliest observations of hemolysis have been the visualization of red-pink urine in patients with such rare conditions as paroxysmal cold hemoglobinuria, march hemoglobinuria, or paroxysmal nocturnal hemoglobinuria (PNH).
Hemolytic anemias can be categorized as acute or chronic, inherited or acquired, by the site of hemolysis (intravascular or extravascular), or by the location of the abnormality responsible for the hemolysis (intrinsic or extrinsic to the red cell). The distinction between inherited and acquired is probably the most useful clinically. Most intrinsic defects are inherited, and most extrinsic ones are acquired. Exceptions to this rule are few and include paroxysmal nocturnal hemoglobinuria (acquired intrinsic RBC defect), and G6PD deficiency (inherited intrinsic defect that depends on an extrinsic factor such as drugs to become evident).
Inherited intrinsic RBC disorders can be due to impairments in membrane structure, glycolytic pathway, glutathione metabolism, hemoglobin structure, or other rare enzyme defects. The acquired hemolytic anemias can be divided into antibody induced, physical injury related, or due to infection, physical agents, chemical agents, hypophosphatemia and liver disease.
The site of hemolysis may be intravascular, in which case the erythrocyte is destroyed in the circulation, or extravascular, in which case the red cell destruction occurs within macrophages in the spleen, liver, or bone marrow (see Table 1). Intravascular hemolysis is typically severe and results from mechanical damage to the red cell due to prosthetic valves, the presence of fibrin within the vasculature (microangiopathic hemolytic anemia), or thermal injury to the erythrocytes from serious burns; infections or toxins, such as Clostridium perfringens bacteremia, severe falciparum malaria, or certain snake venoms; or complement-mediated damage to red cells, as with paroxysmal nocturnal hemoglobinuria, ABO-incompatible blood transfusions, and cold agglutinins.
Intravascular hemolysis liberates hemoglobin into the bloodstream, where it binds to haptoglobin. The haptoglobin/hemoglobin complex is then removed by the liver. A reduced serum haptoglobin level is one of many findings in intravascular hemolysis, but it also occurs in extravascular hemolysis. When the amount of free hemoglobin in the circulation exceeds the binding capacity of haptoglobin, it makes the plasma pink and is filtered through the kidneys. The urine may become red, and proves positive for blood upon dipstick testing in the absence of erythrocytes on urine microscopy. The renal tubular cells, which reabsorb some of the hemoglobin and convert it to hemosiderin, are shed into the urine. Iron stains of urinary sediment demonstrate the hemosiderin within these renal tubular cells and confirm ongoing or recent intravascular hemolysis, even when hemoglobin has become undetectable in the plasma or urine.
Most hemolytic disorders are extravascular. The causes of extravascular hemolysis include infections, drugs, or immunologic processes; red cell membrane defects, such as hereditary spherocytosis; erythrocyte metabolic defects, such as deficiencies in pyruvate kinase or G6PD; and hemoglobin structural defects, such as sickle cell anemia or hemoglobin C.
Another classification of hemolytic anemias distinguishes between disorders intrinsic to the red cell, generally hereditary, and those extrinsic to the red cell, generally acquired. The intrinsic disorders include abnormal hemoglobins, such as HbS or HbC; enzyme defects, such as deficiencies in G6PD; and membrane abnormalities, such as hereditary spherocytosis or elliptocytosis. The extrinsic abnormalities are immunologicalloantibodies, such as those associated with ABO incompatibility; autoantibodies, as in warm (IgG) or cold (IgM) antibody hemolytic anemias; drug-induced antibodies; mechanical factors, such as trauma from prosthetic valves or fibrin deposition in small vessels, as in microangiopathic hemolytic anemias; infections and toxins, such as falciparum malaria or certain snake venoms; and severe hypophosphatemia. See Table 2 for the causes of hemolysis broken down by the site of abnormality.
Chronic Congenital Hemolytic Anemias
Even though there are numerous congenital hemolytic disorders, their clinical features are very similar. Chronic congenital hemolytic anemias are usually characterized by anemia, jaundice, periodic crises, splenomegaly, and black pigment gallstones. Other than during a crisis, symptoms are usually mild to moderate because of compensation by several organ systems, including the bone marrow. Chronic symptoms may become severe at times of crisis. Aplastic crisis can be induced by infection with human parvovirus type B19 (fifth disease). The presence of the parvovirus-specific IgM antibody in serum is a marker of recent infection. A single infection results in lifelong immunity (IgG). The virus infects and inhibits proliferation of erythroid progenitors, only in the bone marrow (very low reticulocyte count).
The clinical picture can also worsen with increased RBC destruction (splenic crisis) or folate deficiency (megaloblastic crisis). Leg ulcers can be seen with chronic hemolytic disorders, especially with hereditary spherocytosis and sickle cell anemia. When hemolysis is severe during growth and development, as in thalassemia major, marked expansion of the bone marrow may lead to skeletal changes such as tower-shaped skull, thickening of the frontal and parietal bones, dental abnormalities, and other bony distortions.
Acquired Hemolytic Anemias
If hemolytic anemia develops acutely, as in hemolytic transfusion reaction or G6PD deficiency, the symptoms may suggest an acute febrile illness with skeletal pains, headache, malaise, fever, and chills. Symptoms of shock, renal failure, jaundice, and anemia may be evident in severe cases. Usually, however, the symptoms are more gradual and mimic a congenital hemolytic disease. In other patients, symptoms may be more related to the underlying disease, such as lupus, lymphoma, and mycoplasma infection.
Laboratory abnormalities seen with hemolysis can be traced to increased RBC destruction, increased erythropoiesis by the bone marrow, and disease-specific findings.
When RBCs are destroyed at an accelerated rate, bile pigments and carbon monoxide are excreted more than usual. The unconjugated bilirubin is elevated, accounting for more than 80% of the total bilirubin, and is not excreted in the urine. Total bilirubin usually does not exceed 4 to 5 units with hemolysis. Unlike in liver disease, in patients with hemolysis pruritus is usually absent. Fecal urobilinogen excretion increases as an indicator of increased bilirubin metabolism in the liver. When plasma hemoglobin levels exceed haptoglobin binding capacity, the plasma turns pink and is filtered into the urine. The urine becomes red and urine iron levels increase. Other than hemolysis, only in hemochromatosis and nephrotic syndrome can one detect increased urinary iron levels.[7,8]
In hemolytic anemias the reticulocyte count is elevated; this is an indicator of accelerated erythropoiesis. Low reticulocyte count is encountered during aplastic crisis despite hemolysis. The mean corpuscular volume (MCV) may be normal or increased, depending on how many large, immature erythrocytes have prematurely left the bone marrow in response to the anemia. The serum lactate hydrogenase (LDH) level is increased. Of the LDH isozymes, LDH-2 predominates; in megaloblastic conditions LDH-1 is elevated. LDH values lack specificity in hemolysis because many other conditions can result in high levels.
The serum haptoglobin is commonly diminished. Free hemoglobin in the bloodstream binds to haptoglobin. Haptoglobin/hemoglobin complex is then removed by the liver. Haptoglobin is an acute-phase reactant and levels increase in response to inflammation, infection, and malignancy. Haptoglobin levels decrease in association with not only intravascular hemolysis but also with extravascular hemolysis (sickle cell anemia, RBC membrane, and enzyme disorders), and intramedullary hemolysis (megaloblastic anemia). One needs to be aware of nonhemolytic conditions that can result in low haptoglobin levels (liver disease, hereditary haptoglobin deficiency after red cell transfusions), and normalized haptoglobin levels despite hemolysis (acute phase surges) during work-up of such patients. Glycosylated hemoglobin levels are also reduced in response to hemolysis, and usually reflect hemolysis over the past 4 to 8 weeks. Glycosylated hemoglobin levels are not reliable in patients with diabetes mellitus because of high glucose levels and in patients with anemia due to bleeding because of hemoglobin loss.
Blood smear is the single most valuable test in defining the underlying disorder causing hemolysis. Spherocytes are the hallmark of hereditary spherocytosis, sickle cells of sickle cell anemia, target cells of thalassemia, schistocytes of RBC fragmentation, erythrophagocytosis of red cell surface damage by complement-fixing antibodies and infections, auto agglutination of cold agglutinin disease, and elliptocytes of hereditary elliptocytosis. Morphologic findings of hemolysis can be confirmed on a blood smear; this may be very helpful in demonstrating polychromatophilia and nucleated red cells, confirming the early departure of red cells from the bone marrow. Abnormalities in red cell shape, such as fragments, sickle cells, spherocytes, or bite cells, provide clues regarding etiology that may be diagnostic or at least highly suggestive of the cause. Other suggestive findings include red cell agglutination, indicating IgM-mediated disease; organisms such as Plasmodium falciparum or Babesia; and erythrophagocytosis, seen especially with red cell damage from immune mechanisms but also with certain infections or toxins. The bone marrow usually shows erythroid hyperplasia.
Tests useful in suspected intravascular hemolysis include evaluation of the plasma and urine for hemoglobin and an iron stain of the urine sediment to detect hemosiderin. For immune-related hemolytic anemia, the Coombs test to demonstrate IgG and complement on the red cell or in the serum, and the cold agglutinin test looking for IgM are indicated. A positive Coombs test (direct antiglobulin test [DAT]) indicates that RBCs are coated with IgG or complement, hence an immune etiology for hemolysis. Very rarely a DAT will be negative in immune hemolytic anemia if the amount of globulin on the RBC surface is very low.
With suspected hemoglobinopathies, a hemoglobin electrophoresis is appropriate. An osmotic fragility test may help when hereditary spherocytosis is suspected. Special stains on blood smear to identify Heinz body formation (precipitation of hemoglobin to form inclusions) can help identify patients with G6PD deficiency, unstable hemoglobin disease, and thalassemia. Other laboratory evaluations depend on the likely abnormality and may include searching for rare enzyme defects. The following is a brief review of some of the major categories of hemolytic disorders.