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Overview of Hemolytic Anemia

By Evan M. Braunstein, MD, PhD, Instructor of Medicine, Johns Hopkins School of Medicine

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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 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

  • Extrinsic: From a source outside the red cell; disorders extrinsic to the RBC are usually acquired.

  • Intrinsic: Due to an defect within the red cell; intrinsic RBC abnormalities (see Table: Hemolytic Anemias) are usually inherited.

Disorders extrinsic to the RBC

Causes of disorders extrinsic to the RBC include

Infectious organisms may cause hemolytic anemia through the direct action of toxins (eg, from Clostridium perfringens, alpha- or beta-hemolytic streptococci, meningococci), by invasion and destruction of the RBC by the organism (eg, Plasmodium sp, Bartonella sp), or by antibody production (Epstein-Barr virus, mycoplasma).

Intrinsic RBC abnormalities

Defects intrinsic to the RBC that can cause hemolysis involve abnormalities of the RBC membrane, cell metabolism, or hemoglobin structure. 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 (alpha- and beta-spectrin, protein 4.1, F-actin, ankyrin) cause hemolytic anemias.

Hemolytic Anemias

Mechanism

Disorder or Agent

Disorders Extrinsic to the RBC

Immunologic abnormalities

Autoimmune hemolytic anemias:

  • Cold antibody

  • Drug-induced

  • Epstein-Barr virus

  • Hemolytic uremic syndrome

  • Mycoplasma

  • Paroxysmal cold hemoglobinuria

  • Thrombotic thrombocytopenic purpura

  • Warm antibody

Infectious organisms

Babesia sp

Bartonella bacilliformis

Plasmodium falciparum

P. malariae

P. vivax

Mechanical trauma

March hemoglobinuria

Valvular heart disorders

Reticuloendothelial hyperactivity

Hypersplenism

Toxin production by infectious organisms

Clostridium perfringens

Alpha- and beta-hemolytic streptococci

Meningococci

Toxins

Compounds with oxidant potential (eg, dapsone, phenazopyridine)

Copper (Wilson disease)

Lead

Insect venom

Snake venom

Intrinsic RBC abnormalities

Acquired RBC membrane disorders

Hypophosphatemia

Paroxysmal nocturnal hemoglobinuria

Stomatocytosis

Congenital RBC membrane disorders

Hereditary elliptocytosis

Hereditary spherocytosis

Hereditary stomatocytosis

Disorders of hemoglobin synthesis

Hb C disease

Hb E disease

Hb S-C disease

Sickle cell disease

Thalassemias

Disorders of RBC metabolism

Embden-Meyerhof pathway defects (eg, pyruvate kinase deficiency)

Hexose monophosphate shunt defects (eg, G6PD deficiency)

Pathophysiology

Hemolysis may be acute, chronic, or episodic. 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. 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 may show microspherocytes.

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). The peripheral smear may show schistocytes or other fragmented red cells.

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 protein normally present in concentrations of about 100 mg/dL (1.0 g/L) in plasma. Unbound plasma haptoglobin levels will be low. 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 hemoglobin 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.

Symptoms and Signs

Systemic manifestations resemble those of other anemias and include pallor, fatigue, dizziness, and possible hypotension. Scleral icterus and/or jaundice may occur, and the spleen may be enlarged.

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

  • Peripheral smear and reticulocyte count

  • Serum bilirubin, LDH, haptoglobin, and ALT

  • Coombs test and/or hemoglobinopathy screen

Hemolysis is suspected in patients with anemia and reticulocytosis. If hemolysis is suspected, 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. Coombs testing or hemoglobinopathy screening (eg, HPLC) can help identify the cause of hemolysis.

Abnormalities of RBC morphology are seldom diagnostic but often suggest the presence and cause of hemolysis (see Table: 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.

Once hemolysis has been identified, the etiology is sought. To narrow the differential diagnosis in hemolytic anemias

  • Consider risk factors (eg, geographic location, genetics, underlying disorder)

  • Examine the patient for splenomegaly

  • Do a direct antiglobulin (direct Coombs) test

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:

  • Quantitative hemoglobin electrophoresis

  • RBC enzyme assays

  • Flow cytometry

  • Cold agglutinins

  • Osmotic fragility

Direct Antiglobulin (Direct Coombs) Test.

The direct antiglobulin (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.

Indirect Antiglobulin (Indirect Coombs) Test.

The indirect antiglobulin (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.

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 disease

Agglutinated cells

Cold agglutinin disease

Heinz bodies or bite cells

G6PD deficiency

Oxidant stress

Unstable Hb

Nucleated erythroblasts and basophilia

Thalassemia major

Acanthocytes

Liver disease

Abetalipoproteinemia

Treatment

Treatment depends on the specific mechanism of hemolysis.

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, avoidance of cold is recommended, and sometimes blood is warmed before transfusion. Folate replacement is needed for patients with ongoing long-term hemolysis.

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