How to detect hemolytic anemia.

A hemolytic anemia is an anemia in which the red cells are being destroyed more rapidly than they can be replenished. Red cells normally last about 120 days in the circulation after which they become rather tatty and are destroyed, mainly in the spleen. However, the bone marrow can make new ones at up to eight times its normal rate, so hemolysis has to be quite severe before the patient becomes anemic.

The symptoms and signs of hemolytic anemia are similar to those of any other anemia except in two circumstances. If the liver is immature and cannot cope with all the red cell breakdown products, the individual may become severely jaundiced; and if the hemolysis is mainly inside the blood vessels when certain severe systemic effects may occur with back pain, shivering attacks, fever, dark urine, collapse and possibly kidney failure.

Otherwise special tests may be necessary to recognise hemolysis. The blood film may show spherocytes (the red cells no longer have a pale central area and a flat shape, but become like little balls with dark centers), elliptocytes (elliptical cells rather than round ones) or fragmented cells. Staining with certain 'supravital' stains will reveal increased numbers of reticulocytes (large young cells with a network of RNA strands showing up) and perhaps 'Heinz' bodies (tiny dark faceted lumps on the surface membrane of the cells). Reticulocytes are a sign of the bone marrow working overtime to replenish the cells that have been destroyed, and are a usual finding in hemolytic anemia unless the marrow has failed (which it sometimes does in a condition known as paroxysmal nocturnal hemoglobinuria) or run out of folate or is stuffed with things that shouldn't be there not allowing room for the red cell precursors to expand (the best example of this is CLL)

Special tests will also reveal signs of increased red cell destruction. When heme is destroyed it gets changed to bilirubin. This is fat soluble, but it gets changed by the liver to a water soluble form and is excreted in the bile. An immature liver cannot do this and so fat soluble bilirubin accumulates in the blood (sometimes called 'indirect bilirubin') causing jaundice. If it gets too much it dissolves in the white matter of the brain thereby damaging it and causing kernicterus or brain damage. This is really only a problem in babies and was once an important disease (hemolytic disease of the newborn) but with the introduction of anti-D prophylaxis for Rhesus negative mothers, it is now seldom seen.

Another heme breakdown product, urobilinogen is excreted in the urine, so a good test for hemolysis is to test for increased urobilinogen in the urine. This a 'sticks' test but if it is raised it should be confirmed by the biochemistry laboratory. Urobilinogen causes dark urine when it is left to stand. When hemoglobin is first released from the red cells it binds to a protein called haptoglobin and the bound hemoglobin is rapidly cleared from the blood, so a low level of haptoglobin is a sensitive test for hemolysis. Hemolysis taking place in the blood vessels overwhelms the haptoglobin and free hemoglobin then binds to albumin as methemalbumin. This is tested for by the Schumm's test. This is a good test for intravascular hemolysis, but the lab doesn't like doing it because it releases a nasty 'bad eggs' smell. Next free hemoglobin can be detected in the plasma and possibly in the urine, but in the kidney tubules it gets destroyed leaving a deposit of iron in the urine which can be tested for with Perl's stain (hemosiderosis).

Detecting hemolytic anemia in CLL is strewn with hazards and it is often missed. The Coombs test is a good indication that the body is thinking about destroying red cells, but often it stops there. You can't rely on finding reticulocytes because the marrow often has no space to make abundant erythrocytes. Nor is measuring bilirubin a good indication of red cell breakdown since any increase may be very short-lived as the liver metabolises the indirect bilirubin. Reduction in haptoglobin levels is the most useful test along with urinary urobilinogen levels. In teh days when hematologists looked at blood films they would often find spherocytes to clinch the diagnosis. Alas radioactive Chromium-labelled red cell survival studies are no longer done except in specialized laboratories, and sometimes the diagnosis depends on a therapeutic trial of steroids.