At the end of their normal life span (about 120 days), red blood cells (RBCs) are removed from the circulation. Hemolysis is defined as premature destruction and hence a shortened RBC life span (< 120 days). Anemia results when bone marrow production can no longer compensate for the shortened RBC survival; this condition is termed uncompensated hemolytic anemia. If the marrow can compensate, the condition is termed compensated hemolytic anemia.
Etiology
Hemolysis can be classified according to whether the hemolysis is
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Extrinsic: From a source outside the red cell; disorders extrinsic to the RBC are usually acquired.
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Intrinsic: Due to an defect within the red cell; intrinsic RBC abnormalities (see table Hemolytic Anemias) are usually inherited.
Disorders extrinsic to the red blood cell
Causes of disorders extrinsic to the RBC include
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Drugs (eg, quinine, quinidine, penicillins, methyldopa, ticlopidine, clopidogrel)
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Immunologic abnormalities (eg, autoimmune hemolytic anemia, thrombotic thrombocytopenic purpura)
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Infections
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Mechanical injury (eg, microangiopathic hemolytic anemia)
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Reticuloendothelial hyperactivity (hypersplenism)
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Toxins (eg, lead, copper)
Infectious organisms may cause hemolytic anemia through the direct action of toxins (eg, Clostridium perfringens, alpha- or beta-hemolytic streptococci, meningococci), by invasion and destruction of the RBC by the organism (eg, Plasmodium species, Bartonella species,Babesia species) or by antibody production (eg, Epstein-Barr virus, mycoplasma).
Intrinsic red blood cell abnormalities
Defects intrinsic to the RBC that can cause hemolysis involve abnormalities of the RBC membrane, cell metabolism, or hemoglobin structure. Abnormalities include hereditary cell membrane disorders (eg, hereditary spherocytosis), acquired cell membrane disorders (eg, paroxysmal nocturnal hemoglobinuria), disorders of RBC metabolism (eg, glucose-6-phosphate dehydrogenase (G6PD) deficiency), and hemoglobinopathies (eg, sickle cell disease, thalassemias). Quantitative and functional abnormalities of certain RBC membrane proteins (alpha- and beta-spectrin, protein 4.1, F-actin, ankyrin) cause hemolytic anemias.
Hemolytic Anemias
Mechanism |
Disorder or Agent |
Disorders extrinsic to the red blood cell |
|
|
Immunologic abnormalities |
Autoimmune hemolytic anemias: |
|
Infectious organisms |
Babesia Bartonella bacilliformis Plasmodium falciparum P. malariae P. vivax |
|
Mechanical trauma |
March hemoglobinuria |
|
Reticuloendothelial hyperactivity |
Hypersplenism |
|
Toxin production by infectious organisms |
Clostridium perfringens Alpha- and beta-hemolytic streptococci Meningococci |
|
Toxins |
Compounds with oxidant potential (eg, dapsone, phenazopyridine, naphthalene) Copper (Wilson disease) Lead Insect venom Snake venom |
Intrinsic red blood cell abnormalities |
|
|
Acquired red blood cell membrane disorders |
Stomatocytosis |
|
Congenital red blood cell membrane disorders |
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Disorders of hemoglobin synthesis |
|
|
Disorders of red blood cell metabolism |
Glycolytic pathway defects (eg, pyruvate kinase deficiency) Hexose monophosphate shunt defects (eg, glucose-6-phosphate dehydrogenase (G6PD) deficiency) |
Pathophysiology
Hemolysis may be
Hemolysis may also be
Normal red blood cell processing
Senescent RBCs lose membrane and are cleared from the circulation largely by the phagocytic cells of the spleen, liver, bone marrow, and reticuloendothelial system. Hemoglobin is broken down in these cells primarily by the heme oxygenase system. The iron is conserved and reutilized, and heme is degraded to bilirubin, which is conjugated in the liver to bilirubin glucuronide and excreted in the bile.
Extravascular hemolysis
Most pathologic hemolysis is extravascular and occurs when damaged or abnormal RBCs are cleared from the circulation by the spleen and liver. The spleen usually contributes to hemolysis by destroying mildly abnormal RBCs or cells coated with warm antibodies. An enlarged spleen may sequester even normal RBCs. Severely abnormal RBCs or RBCs coated with cold antibodies or complement (C3) are destroyed within the circulation and in the liver, which (because of its large blood flow) can remove damaged cells efficiently. In extravascular hemolysis, the peripheral smear will show microspherocytes or with cold agglutinins, erythrocyte agglutination if the blood is not warmed upon collection.
Intravascular hemolysis
Intravascular hemolysis is an important reason for premature RBC destruction and usually occurs when the cell membrane has been severely damaged by any of a number of different mechanisms, including
Intravascular hemolysis results in hemoglobinemia when the amount of hemoglobin released into plasma exceeds the hemoglobin-binding capacity of the plasma-binding protein haptoglobin, a protein normally present in concentrations of about 100 mg/dL (1.0 g/L) in plasma, resulting in the reduction of unbound plasma haptoglobin. With hemoglobinemia, unbound hemoglobin dimers are filtered into the urine and reabsorbed by renal tubular cells; hemoglobinuria results when reabsorptive capacity is exceeded. Iron is released from catabolized hemoglobin and embedded in hemosiderin within the tubular cells; some of the iron is assimilated for reutilization and some reaches the urine when the tubular cells slough.
Consequences of hemolysis
Unconjugated (indirect) hyperbilirubinemia and jaundice occur when the conversion of hemoglobin to bilirubin exceeds the liver’s capacity to conjugate and excrete bilirubin. Bilirubin catabolism causes increased stercobilin in the stool and urobilinogen in the urine and sometimes cholelithiasis.
The bone marrow responds to the excess loss of RBCs by accelerating production and release of RBCs, resulting in a reticulocytosis due to increased production of erythropoietin by the kidneys in response to the ensuing anemia.
Symptoms and Signs
Systemic manifestations of hemolytic anemias resemble those of other anemias and include pallor, fatigue, dizziness, and possible hypotension. Scleral icterus and/or jaundice may occur, and the spleen may enlarge.
Hemolytic crisis (acute, severe hemolysis) is uncommon; it may be accompanied by chills, fever, pain in the back and abdomen, prostration, and shock. Hemoglobinuria causes red or reddish-brown urine.
Diagnosis
Hemolysis is suspected in patients with anemia and reticulocytosis. If hemolysis is suspected, a peripheral smear is examined and serum bilirubin, LDH, haptoglobin, and ALT are measured. The peripheral smear and reticulocyte count are the most important tests to diagnose hemolysis. Antiglobulin testing or hemoglobinopathy screening (eg, high-performance liquid chromatography [HPLC]) can help identify the cause of hemolysis.
Abnormalities of RBC morphology often suggest the presence and cause of hemolysis (see table Red Blood Cell Morphologic Changes in Hemolytic Anemias). The peripheral smear will show schistocytes or other fragmented red cells with mechanical hemolysis. Other suggestive findings include increased levels of serum LDH and indirect bilirubin with a normal ALT, and the presence of urinary urobilinogen.
Intravascular hemolysis is suggested by RBC fragments (schistocytes) on the peripheral smear and by decreased serum haptoglobin levels; however, haptoglobin levels can decrease because of hepatocellular dysfunction and can increase because of systemic inflammation. Intravascular hemolysis is also suggested by urinary hemosiderin. Urinary hemoglobin, like hematuria and myoglobinuria, produces a positive benzidine reaction on dipstick testing; it can be differentiated from hematuria by the absence of RBCs on microscopic urine examination. Free hemoglobin may make plasma reddish brown, noticeable often in centrifuged blood; myoglobin does not.
Once hemolysis has been identified, the etiology is sought. To narrow the differential diagnosis in hemolytic anemias
Most hemolytic anemias cause abnormalities in one of these variables, and so test results can direct further testing.
Other laboratory tests that can help discern the causes of hemolysis include the following:
Direct Antiglobulin (Direct Coombs) Test
Indirect Antiglobulin (Indirect Coombs) Test
Although some tests can help differentiate intravascular from extravascular hemolysis, making the distinction is sometimes difficult. During increased RBC destruction, both types are commonly involved, although to differing degrees.
Red Blood Cell Morphologic Changes in Hemolytic Anemias
RBC Morphology |
Causes |
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Acanthocytes (spur cells) |
Anorexia Liver disease Neuroacanthocytosis |
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Agglutinated cells |
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Echinocytes |
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Heinz bodies (bite or blister cells) |
Oxidant stress Unstable hemoglobin |
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Nucleated erythroblasts and basophilia |
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Schistocytes |
Intravascular prostheses Microangiopathy |
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Sickled cells |
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Spherocytes |
Transfused blood |
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Target cells |
Hemoglobinopathies (eg, sickle cell disease, hemoglobin C disease, thalassemias) Liver dysfunction Post-splenectomy |
Treatment
Treatment depends on the specific mechanism of hemolysis.
Corticosteroids are helpful in the initial treatment of warm antibody autoimmune hemolysis. Transfusions are used in patients with symptomatic anemia, but long-term transfusion therapy may cause excessive iron accumulation, necessitating chelation therapy.
Splenectomy is beneficial in some situations, particularly when splenic sequestration is the major cause of RBC destruction. If possible, splenectomy is delayed until 2 weeks after vaccination with the following:
In cold agglutinin disease, avoidance of cold is recommended, and blood will need to be warmed before transfusion. Folate replacement is needed for patients with ongoing long-term hemolysis.
Drugs Mentioned In This Article
| Drug Name | Select Trade |
|---|---|
phenazopyridine |
No US brand name |
clopidogrel |
PLAVIX |
methyldopa |
No brand name |
quinine |
QUALAQUIN |
dapsone |
ACZONE |
