Pathology

Increased destruction of red blood cells in the peripheral blood without evidence of ineffective erythropoiesis is known as hemolytic anemia. Such anemias are generally classified into either inherited or acquired types.

Hemolysis is the premature destruction of RBCs due to intrinsic inherited defects in the RBCs or because of acquired intravascular abnormalities.

RBCs normally live about 120 days following bone marrow release as reticulocytes. When the RBCs become senescent they are removed from the peripheral blood by macrophages in the spleen and liver.

Hemolysis may be either intravascular or extravascular.

In intravascular hemolysis RBCs lyse in the circulation releasing hemoglobin into the plasma. Causes include mechanical trauma, complement fixation, and other toxic damage to the RBC. The fragmented RBCs are called schistocytes.

In extravascular hemolysis RBCs are phagocytized by macrophages in the spleen and liver. Causes include RBC membrane abnormalities such as bound immunoglobulin, or physical abnormalities restricting RBC deformability that prevent egress from the spleen. Extravascular hemolysis is characterized by spherocytes.

Intravascular hemolysis releases hemoglobin which is immediately bound by haptoglobin.

Hemoglobin-haptoglobin is cleared almost immediately from the plasma by hepatic reticuloendothelial cells.

As intravascular hemolysis with binding to haptoglobin generally overwhelms the rate of haptoglobin synthesis, haptoglobin levels decrease.

After haptoglobin is saturated, excess hemoglobin is filtered in the kidney and reabsorbed in the proximal tubules where the iron is recovered and converted into ferritin or hemosiderin.

Hemoglobinuria indicates severe intravascular hemolysis overwhelming the absorptive capacity of the renal tubular cells.

Urine hemosiderin is another indicator that intravascular free hemoglobin is being filtered by the kidneys.

Lactic dehydrogenase (LDH) is greatly elevated in patients with intravascular hemolysis.

Note: Haptoglobin, synthesized by the liver, is decreased in patients with hepatocelIular disease.

In extravascular hemolysis spleen and liver macrophage Fc receptors bind immunoglobulin attached to RBCs and then either ingest small portions of the RBC membrane creating spherocytes or phagocytizing the RBCs.

Amino acids from the globin chains are recycled and the Fe removed from the heme and reused.

The heme is degraded into the tetrapyrrole, bilirubin.

Note: Because little hemoglobin escapes into the plasma in extravascular hemolysis, haptoglobin does not generally decrease.

Free unconjugated bilirubin is transported to the liver where it is conjugated to glucuronic acid.

In extravascular hemolysis plasma levels of unconjugated bilirubin increase because the hepatocytes cannot process the excess bilirubin.

Conjugated bilirubin is excreted into the gastrointestinal tract where it is converted to urobilinogen and eventually excreted in the feces as stercobilinogen.

Conjugated bilirubin levels are usually normal in hemolysis.

Remember unconjugated bilirubin cannot pass the glomerular membrane.

Intravascular

Extravascular

Peripheral smear

schistocytes

spherocytes

Haptoglobin

decrease/absent

mild decrease

Urine hemosiderin

++

negative

Urine hemoglobin

++

negative

Direct DAT

usually negative

++++

LDH

increase

increase

Common hereditary hemolytic anemias include the hemoglobinopathies and abnormalities of RBC membranes and enzymes.

Common acquired abnormalities include mechanical trauma, antibody mediated damage, and other toxic or physical insults.

Transfused normal RBCs will have a shortened survival, no different than the short lifespan of the patient's own RBCs, if, the abnormalities are acquired and extrinsic to the RBC. This is the case in most hemolytic anemias

If the cause of the hemolytic anemia is intrinsic to the red cell (a hemoglobinopathy or a membrane or enzyme abnormality) the normal ransfused RBCs will have a normal ife span.

Normal Red Cell Membrane Review

The RBC membrane is a phospholipid bilayer with varying amounts of membrane cholesterol. A number of transmembrane (band 3 and several glycophorins) and membrane support [actin; ankryn (band2.1); band4.1; spectrin] proteins are present.

The actin - spectrin - 4.1 complexes help maintain the structural strength and stability of the RBC membrane. The spectrin - ankryn - band 3 complexes stabilize the phospholipid bilayer.