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Overview of Hemolytic Anemia
At the end of their normal life span (about 120 days), RBCs are removed from the circulation. Hemolysis involves 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 hemolytic anemia. If the marrow can compensate, the condition is termed compensated hemolytic anemia.
Hemolysis can result from
Disorders extrinsic to the RBC
Intrinsic RBC abnormalities (see Hemolytic Anemias)
Most extrinsic disorders are acquired; RBCs are normal, and transfused cells as well as autologous cells are destroyed. Disorders extrinsic to the RBC include reticuloendothelial hyperactivity (hypersplenism—see Hypersplenism), immunologic abnormalities (eg, autoimmune hemolytic anemia, isoimmune hemolytic anemia), mechanical injury (traumatic hemolytic anemia), and certain infections. Infectious organisms may cause hemolytic anemia through the direct action of toxins (eg, from Clostridium perfringens, α- or β-hemolytic streptococci, meningococci) or by invasion and destruction of the RBC by the organism (eg, Plasmodium sp, Bartonella sp).
Defects intrinsic to the RBC that can cause hemolysis involve one or more components or functions of the RBC: the membrane, cell metabolism, and the Hb. Abnormalities include hereditary and acquired cell membrane disorders (eg, spherocytosis), disorders of RBC metabolism (eg, G6PD deficiency), and hemoglobinopathies (eg, sickle cell diseases, thalassemias). Quantitative and functional abnormalities of certain RBC membrane proteins (α- and β-spectrin, protein 4.1, F-actin, ankyrin) cause hemolytic anemias.
Hemolysis may be acute, chronic, or episodic. Chronic hemolysis may be complicated by aplastic crisis (temporary failure of erythropoiesis), usually caused by an infection, often parvovirus. Hemolysis can be extravascular, intravascular, or both.
Senescent RBCs lose membrane and are cleared from the circulation largely by the phagocytic cells of the spleen, liver, bone marrow, and reticuloendothelial system. Hb 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.
Most pathologic hemolysis is extravascular and occurs when damaged or abnormal RBCs are cleared from the circulation by cells of the spleen, liver, and bone marrow similar to the process by which senescent RBCs are removed. 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.
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 autoimmune phenomena, direct trauma (eg, march hemoglobinuria), shear stress (eg, defective mechanical heart valves), and toxins (eg, clostridial toxins, venomous snake bite).
Intravascular hemolysis results in hemoglobinemia when the amount of Hb released into plasma exceeds the Hb-binding capacity of the plasma-binding protein haptoglobin, a globulin normally present in concentrations of about 100 mg/dL (1.0 g/L) in plasma. With hemoglobinemia, unbound Hb dimers are filtered into the urine and reabsorbed by renal tubular cells; hemoglobinuria results when reabsorptive capacity is exceeded. Iron is 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.
Unconjugated (indirect) hyperbilirubinemia and jaundice occur when the conversion of Hb to bilirubin exceeds the liver’s capacity to conjugate and excrete bilirubin (see Overview of Biliary Function). 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.
Systemic manifestations resemble those of other anemias and include pallor, fatigue, dizziness, and possible hypotension. Hemolytic crisis (acute, severe hemolysis) is uncommon; it may be accompanied by chills, fever, pain in the back and abdomen, prostration, and shock. Severe hemolysis can cause jaundice and splenomegaly. Hemoglobinuria causes red or reddish-brown urine.
Hemolysis is suspected in patients with anemia and reticulocytosis, particularly if splenomegaly or another possible cause is recognized. If hemolysis is suspected, peripheral smear is examined and serum bilirubin, LDH, and ALT are measured. If results of these tests are inconclusive, urinary hemosiderin and serum haptoglobin are measured.
Abnormalities of RBC morphology are seldom diagnostic but often suggest the presence and cause of hemolysis (see RBC Morphologic Changes in Hemolytic Anemias). 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 Hb, 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 Hb may make plasma reddish brown, noticeable often in centrifuged blood; myoglobin does not.
Although hemolysis can usually be identified by these simple criteria, the definitive diagnosis is demonstration of decreased RBC survival, preferably with a radioactive label, such as radiochromium (51Cr). The measured survival of radiolabeled RBCs can establish hemolysis and also identify the sites of sequestration by using body surface counting. This procedure is rarely required, however.
Once hemolysis has been identified, the specific disorder is sought. One approach to narrowing the differential diagnosis in hemolytic anemias is to
Most hemolytic anemias cause abnormalities in one of these variables that can direct further testing.
Other laboratory tests that can help discern the causes of hemolysis include the following:
Direct Antiglobulin (Coombs) Test.
Indirect Antiglobulin (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.
RBC Morphologic Changes in Hemolytic Anemias
Treatment depends on the specific mechanism of hemolysis.
Hemoglobinuria and hemosiderinuria may necessitate iron-replacement therapy. Corticosteroids are helpful in the initial treatment of warm antibody autoimmune hemolysis. 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 wk after vaccination with pneumococcal, Haemophilus influenzae, and meningococcal vaccines. In cold agglutinin disease, the patient is kept warm. Folate replacement is needed for patients with ongoing long-term hemolysis.
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