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.

Etiology

Hemolysis can result from disorders extrinsic to the RBC or from intrinsic RBC abnormalities (see Table 1: Anemias Caused by Hemolysis: Hemolytic Anemias).

Disorders extrinsic to the RBC

Most extrinsic disorders are acquired; the RBCs are normal and transfused cells as well as autologous cells are destroyed. Disorders extrinsic to the RBC include reticuloendothelial hyperactivity (hypersplenism—see Spleen Disorders: 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).

Intrinsic RBC abnormalities

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.

Table 1
PrintOpen table
Hemolytic Anemias Mechanism Disorder or Agent Disorders Extrinsic to the RBC Reticuloendothelial hyperactivity Hypersplenism Immunologic abnormalities Autoimmune hemolytic anemias: Cold antibody Paroxysmal cold hemoglobinuria Warm antibody Infectious organisms Babesia sp Bartonella bacilliformis Plasmodium falciparum P. malariae P. vivax Toxin production by infectious organisms Clostridium perfringens α- and β-Hemolytic streptococci Meningococci Mechanical trauma March hemoglobinuria Skeletal trauma Thrombotic thrombocytopenic purpura and hemolytic-uremic syndrome Valvular heart disorders Toxins Compounds with oxidant potential (eg, dapsone, phenazopyridine) Copper (Wilson's disease) Lead Insect venom Snake venom Intrinsic RBC abnormalities Congenital RBC membrane disorders Hereditary elliptocytosis Hereditary spherocytosis Acquired RBC membrane disorders Hypophosphatemia Paroxysmal nocturnal hemoglobinuria Stomatocytosis Disorders of RBC metabolism Embden-Meyerhof pathway defects (eg, pyruvate kinase deficiency) Hexose monophosphate shunt defects (eg, G6PD deficiency) Disorders of Hb synthesis Hb C disease Hb S-C disease Hb E disease Sickle cell diseases Thalassemias Hemolytic Anemias Mechanism Disorder or Agent Disorders Extrinsic to the RBC Reticuloendothelial hyperactivity Hypersplenism Immunologic abnormalities Autoimmune hemolytic anemias: Cold antibody Paroxysmal cold hemoglobinuria Warm antibody Infectious organisms Babesia sp Bartonella bacilliformis Plasmodium falciparum P. malariae P. vivax Toxin production by infectious organisms Clostridium perfringens α- and β-Hemolytic streptococci Meningococci Mechanical trauma March hemoglobinuria Skeletal trauma Thrombotic thrombocytopenic purpura and hemolytic-uremic syndrome Valvular heart disorders Toxins Compounds with oxidant potential (eg, dapsone, phenazopyridine) Copper (Wilson's disease) Lead Insect venom Snake venom Intrinsic RBC abnormalities Congenital RBC membrane disorders Hereditary elliptocytosis Hereditary spherocytosis Acquired RBC membrane disorders Hypophosphatemia Paroxysmal nocturnal hemoglobinuria Stomatocytosis Disorders of RBC metabolism Embden-Meyerhof pathway defects (eg, pyruvate kinase deficiency) Hexose monophosphate shunt defects (eg, G6PD deficiency) Disorders of Hb synthesis Hb C disease Hb S-C disease Hb E disease Sickle cell diseases Thalassemias

Pathophysiology

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.

Normal RBC 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. 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.

Extravascular hemolysis

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

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 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.

Consequences of hemolysis

Unconjugated (indirect) hyperbilirubinemia and jaundice occur when the conversion of Hb to bilirubin exceeds the liver's capacity to conjugate and excrete bilirubin (see Gallbladder and Bile Duct Disorders: 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.

Symptoms and Signs

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.

Diagnosis

• Peripheral smear, reticulocyte count, serum bilirubin, LDH, and ALT
• Sometimes, measurement of urinary hemosiderin and serum haptoglobin
• Rarely, measurement of RBC survival using a radioactive label

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.

Spherocytes in Hemolytic Anemia

Abnormalities of RBC morphology are seldom diagnostic but often suggest the presence and cause of hemolysis (see Table 2: Anemias Caused by Hemolysis: 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 consider risk factors (eg, geographic location, genetics, underlying disorder), examine the patient for splenomegaly, and do a direct antiglobulin (Coombs') test and peripheral smear; most hemolytic anemias produce 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:

• Quantitative Hb electrophoresis
• RBC enzyme assays
• Flow cytometry
• Cold agglutinins
• Osmotic fragility

Fig. 1
Direct Coombs' Test. The direct Coombs' test is used to determine whether RBC-binding antibody (IgG) or complement (C3) is present on RBC membranes. The patient's RBCs are incubated with antibodies to human IgG and C3. If IgG or C3 is bound to RBC membranes, agglutination occurs–a positive result. A positive result suggests the presence of autoantibodies to RBCs if the patient has not received a transfusion in the last 3 mo, alloantibodies to transfused RBCs (usually seen in acute or delayed hemolytic reaction), or drug-dependent or drug-induced antibodies against RBCs.

Fig. 2
Indirect Coombs' Test. The indirect Coombs' test is used to detect IgG antibodies against RBCs in a patient's serum. The patient's serum is incubated with reagent RBCs; then Coombs' serum (antibodies to human IgG, or human anti-IgG) is added. If agglutination occurs, IgG antibodies (autoantibodies or alloantibodies) against RBCs are present. This test is also used to determine the specificity of an alloantibody.

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.

Table 2
PrintOpen table
RBC Morphologic Changes in Hemolytic Anemias RBC Morphology Causes Spherocytes Transfused blood Warm antibody hemolytic anemia Hereditary spherocytosis Schistocytes Microangiopathy Intravascular prostheses Target cells Hemoglobinopathies (sickle cell disease, Hb C disease, thalassemias) Liver dysfunction Sickled cells Sickle cell diseases Agglutinated cells Cold agglutinin disease Heinz bodies or bite cells G6PD deficiency Oxidant stress Unstable Hb Nucleated erythroblasts and basophilia Thalassemia major Acanthocytes Spur cell anemia

Treatment

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.

Last full review/revision February 2009 by Alan E. Lichtin, MD