Classification of Anemia
Anemias can be classified as :-
1) Cytometric schemes (i.e., those that depend on cell size and hemoglobin-content parameters, such as MCV and MCHC)
2) Erythrokinetic schemes (those that take into account the rates of rbc production and destruction)
3) Biochemical/molecular schemes (those that consider the etiology of the anemia at the molecular level).
An example: sickle cell anemia:
- Cytometric classification: normochromic, normocytic
- Erythrokinetic classification: hemolytic
- Biochemical/molecular classification: DNA point mutation producing amino acid substitution in hemoglobin beta chain
A. Cytometric classification :- Because cytometric parameters are more easily and less expensively measured than are erythrokinetic and biochemical ones, it is most practical to work from the cytometric classification, to the erythrokinetic, and then (hopefully) to the biochemical. Your first job in working up a patient with anemia is to place the case in one of three major cytometric categories
1) Normochromic, normocytic anemia (normal MCHC, normal MCV)
These include:
2) Hypochromic, microcytic anemia (low MCHC, low MCV).
These include:
1) Reticulocyte count :- A sample of blood is stained with a supravital dye that marks reticulocytes. An increased number of reticulocytes is seen when the marrow is churning out rbc's at excessive speed (presumably to make up for those lost to hemolysis or hemorrhage). Most labs will report the result of the reticulocyte count in percent of all rbc's counted. A typical normal range is 0.5-1.5 %. Making clinical decisions based on this raw count is somewhat fallacious.
2) Serum unconjugated bilirubin and urine urobilinogen concentration:-
When red cells, at the end of their 120-day life-span, go to the great spleen in the sky, they are systematically dismantled. Through a series of biochemical steps too boring to go into even here, the heme is changed into bilirubin. The bilirubin is greedily scarfed up by the liver, conjugated with glucuronide, squirted into the alimentary tract in the bile, and converted to urobilinogen by evangelical colonic bacteria. The urobilinogen is excreted in the stool (most of it) or reabsorbed and excreted in the urine (very little of it). This is summarized in the next diagram.
In cases of accelerated rbc destruction, the capacity of the liver to capture bilirubin is saturated, and the concentration of unconjugated bilirubin in serum increases, occasionally to the point of producing clinical jaundice. Moreover, the increased production of urobilinogen that results is reflected by increased urobilinogen concentration in the urine. Unconjugated bilirubin is not water soluble and therefore will not be excreted in the urine, despite its elevation in the serum.
3) Serum haptoglobin concentration :-
When an rbc is destroyed, the liberated hemoglobin binds mole-for-mole with a serum protein, haptoglobin. The "purpose" of this reaction is to keep the kidneys from squandering iron (free hemoglobin is freely filtered by the glomerulus, but hemoglobin-haptoglobin complexes are too big to muscle their way through, so that they are safe to bumble their way back to the reticuloendothelial system where they can be properly disassembled). The serum haptoglobin concentration then decreases. Laboratory measurement of haptoglobin is fairly easy and yields useful information to assist in documenting decreased rbc life span.
In the case of hemolysis which takes place in the bloodstream (rather than in the RES), so-called intravascular hemolysis, additional biochemical phenomena are observed (see diagram, below). Free hemoglobin in excess of that which binds haptoglobin is rapidly filtered into the urine. What remains in the plasma spontaneously degrades into metheme and globin. A portion of metheme binds albumin to produce a measurable compound, methemalbumin, while the remainder binds to a measurable serum protein, hemopexin, which then decreases in serum concentration. All of the substances whose names are boxed in the diagram are those whose laboratory measurement is feasible and helpful in documenting hemolysis.
4) Bone marrow biopsy:- This can be used to directly observe any accelerated production of rbc's. The ratio of the number of myeloid to erythroid precursors (the M:E ratio) tends to decrease in high-production states, and the marrow becomes hypercellular. Marrow biopsy is not usually performed just to measure the M:E ratio, but to answer other hematologic questions that have been raised.
The normoregenerative anemias are in contrast to those characterized by inadequate marrow response to the degree of anemia. These are the hyporegenerative anemias. In such cases, the reticulocyte production index is decreased. The classic example is aplastic anemia, in which there is primary marrow failure to produce enough erythrocyte mass. As you have probably come to expect, the distinction of these categories is not always absolute. For instance, in thalassemia major there is a degree of hemolysis (generally associated with the normoregenerative states) and inadequate marrow response to the degree of anemia.
C. Biochemical classification
Finally, one should attempt to determine the etiology of the anemia as specifically as possible. In some cases (e.g., iron deficiency), etiologic classification is easily attained; in others (e.g.. aplastic anemia) the biochemical mechanism of disease may be hopelessly elusive. Generally, biochemical tests are aimed at identifying a depleted cofactor necessary for normal hematopoiesis (iron, ferritin, folate, B12), an abnormally functioning enzyme (glucose-6-phosphate dehydrogenase, pyruvate kinase), or abnormal function of the immune system (the direct antiglobulin [Coombs'] test).
These include:
· anemias of chronic disease
· hemolytic anemias (those characterized by accelerated destruction of rbc's)
· anemia of acute hemorrhage
· aplastic anemias (those characterized by disappearance of rbc precursors from the marrow)
2) Hypochromic, microcytic anemia (low MCHC, low MCV).
These include:
· iron deficiency anemia
· thalassemias
· anemia of chronic disease (rare cases)
3) Normochromic, macrocytic anemia (normal MCHC, high MCV)
These include:
3) Normochromic, macrocytic anemia (normal MCHC, high MCV)
These include:
· vitamin B12 deficiency
· folate deficiency
B. Erythrokineti classification
You would now want to proceed with classifying your case based on the rate of rbc turnover. If this is high, a normoregenerative anemia exists. Such anemias are seen in hemolysis (excess destruction of rbc's) or hemorrhage (loss of rbc's from the vascular compartment. In these cases, the marrow responds appropriately to anemia by briskly stepping up the production of rbc's and releasing them into the bloodstream prematurely. There are several lab tests that allow you to determine if increased rbc turnover exists:
1) Reticulocyte count :- A sample of blood is stained with a supravital dye that marks reticulocytes. An increased number of reticulocytes is seen when the marrow is churning out rbc's at excessive speed (presumably to make up for those lost to hemolysis or hemorrhage). Most labs will report the result of the reticulocyte count in percent of all rbc's counted. A typical normal range is 0.5-1.5 %. Making clinical decisions based on this raw count is somewhat fallacious.
For instance: A normal person with an rbc count of 5,000,000 /microliter and an absolute reticulocyte count of 50,000 /microliter would have a relative retic count of 1.0%. An anemic person with 2,000,000 rbc's/microliter and the same 50,000 retics/microliter would have an apparently "abnormal" relative retic count of 2.5 % and could be misdiagnosed as having high turnover.
Clearly, one needs to find some way to correct the raw retic count so as to avoid this problem. One can easily calculate the absolute retic count (in cells/microliter) by multiplying the rbc count by the relative retic count. The normal range for the absolute retic count is 50,000-90,000 /microliter.2) Serum unconjugated bilirubin and urine urobilinogen concentration:-
When red cells, at the end of their 120-day life-span, go to the great spleen in the sky, they are systematically dismantled. Through a series of biochemical steps too boring to go into even here, the heme is changed into bilirubin. The bilirubin is greedily scarfed up by the liver, conjugated with glucuronide, squirted into the alimentary tract in the bile, and converted to urobilinogen by evangelical colonic bacteria. The urobilinogen is excreted in the stool (most of it) or reabsorbed and excreted in the urine (very little of it). This is summarized in the next diagram.
3) Serum haptoglobin concentration :-
When an rbc is destroyed, the liberated hemoglobin binds mole-for-mole with a serum protein, haptoglobin. The "purpose" of this reaction is to keep the kidneys from squandering iron (free hemoglobin is freely filtered by the glomerulus, but hemoglobin-haptoglobin complexes are too big to muscle their way through, so that they are safe to bumble their way back to the reticuloendothelial system where they can be properly disassembled). The serum haptoglobin concentration then decreases. Laboratory measurement of haptoglobin is fairly easy and yields useful information to assist in documenting decreased rbc life span.
In the case of hemolysis which takes place in the bloodstream (rather than in the RES), so-called intravascular hemolysis, additional biochemical phenomena are observed (see diagram, below). Free hemoglobin in excess of that which binds haptoglobin is rapidly filtered into the urine. What remains in the plasma spontaneously degrades into metheme and globin. A portion of metheme binds albumin to produce a measurable compound, methemalbumin, while the remainder binds to a measurable serum protein, hemopexin, which then decreases in serum concentration. All of the substances whose names are boxed in the diagram are those whose laboratory measurement is feasible and helpful in documenting hemolysis.
4) Bone marrow biopsy:- This can be used to directly observe any accelerated production of rbc's. The ratio of the number of myeloid to erythroid precursors (the M:E ratio) tends to decrease in high-production states, and the marrow becomes hypercellular. Marrow biopsy is not usually performed just to measure the M:E ratio, but to answer other hematologic questions that have been raised.
The normoregenerative anemias are in contrast to those characterized by inadequate marrow response to the degree of anemia. These are the hyporegenerative anemias. In such cases, the reticulocyte production index is decreased. The classic example is aplastic anemia, in which there is primary marrow failure to produce enough erythrocyte mass. As you have probably come to expect, the distinction of these categories is not always absolute. For instance, in thalassemia major there is a degree of hemolysis (generally associated with the normoregenerative states) and inadequate marrow response to the degree of anemia.
Finally, one should attempt to determine the etiology of the anemia as specifically as possible. In some cases (e.g., iron deficiency), etiologic classification is easily attained; in others (e.g.. aplastic anemia) the biochemical mechanism of disease may be hopelessly elusive. Generally, biochemical tests are aimed at identifying a depleted cofactor necessary for normal hematopoiesis (iron, ferritin, folate, B12), an abnormally functioning enzyme (glucose-6-phosphate dehydrogenase, pyruvate kinase), or abnormal function of the immune system (the direct antiglobulin [Coombs'] test).
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