This is a document in a five-part series|
on blood cells and anemia:
|1. Blood cells and the CBC|
2. Anemia: Pathophysiologic
Classification, and Clinical Investigation
3. Nutritional Anemias
Anemia of Chronic Disease
|4. Hemolytic Anemias|
|5. Hemoglobinopathies and Thalassemias|
Free oxygen, the plant kingdom's unique gift to this planet, is a highly reactive, dangerous substance capable of laying waste the delicate molecules that form the basis of life. How peculiar that we, as aerobes, have traded the security of a languid existence in a reducing milieu for the high-stakes, fast-lane life of free-flowing ATP, the dear currency that gives us the strength, speed, and mental facility to profoundly alter our world. Aerobic respiration, for all the complexity of the chemical reactions of intermediary metabolism, simply boils down to the body's need to find something to do with the spare electron left over from the destruction of the glucose molecule. This orphaned lepton, bereft of binding energy by its repeated violation at the hands of the cytochrome gantlet, finds no comfort in the carbon dioxide rubble of its former hexose home. Should it not find the succor of oxygen, it would escape to a feral existence of unsavory chemical reactions, where it would find itself in the company of the opprobrious Free Radicals, miscreants whose only purpose is the steric vandalism of the macromolecular cathedrals of life.
It has been said that all damage to the body from any pathologic state in the end is caused by hypoxia at some level. If this is true, the story of pathology is the story of hypoxia. Preventing or correcting hypoxia is then the ultimate goal of all medical specialties. Pulmonologists and cardiologists deal with hypoxia at the gross mechanical level, but hematologists do so at the finer cellular and molecular levels. The physicochemical properties of hemoglobin and biochemical housekeeping in the erythrocyte are both in their purview, but what hematologists contend with at the grossest level is anemia.
Anemia may be defined as any condition resulting from a significant decrease in the total body erythrocyte mass. Measurement of total body rbc mass requires special radiolabeling techniques that are not amenable to general medical diagnostic work. Measurements typically substituted for rbc mass determination take advantage of the body's tendency to maintain normal total blood volume by dilution of the depleted rbc component with plasma. This adjustment results in decrease of the total blood hemoglobin concentration, the rbc count, and the hematocrit. Therefore, a pragmatic definition of anemia is a state which exists when the hemoglobin is less than 12 g/dL or the hematocrit is less than 37 cL/L. Anemia may exist as a laboratory finding in a subjectively healthy individual, because the body can, within limits, compensate for the decreased red cell mass.
One must be careful in blindly applying this practical definition of anemia in every case. As the following diagram shows, it is possible to be severely anemic and have a normal hematocrit (and hemoglobin). This occurs when there is rapid hemorrhage, with red cells and plasma being rapidly lost simultaneously, before the body can respond by hiking up the plasma volume.
The final example in the above diagram illustrates that a person can have a low hematocrit and not be anemic. This occurs when a patient is overhydrated, typically as a result of overenthusiastic intravenous fluid therapy.
Each physiologic mechanism will be discussed below. It should be noted that, although there are many adjustments that can be made, one that cannot is decrease in the tissue requirement for oxygen. Actually, overall body oxidative metabolism increases in anemia because of the energy requirement of the compensatory activities.
Decreased hemoglobin oxygen affinity
Increased oxygen extraction of anemic blood by the tissues produces increased concentration of deoxyhemoglobin in the rbc, which stimulates the production of 2,3-diphosphoglycerate (2,3-DPG). 2,3-DPG shifts the hemoglobin-oxygen dissociation curve to the right, thus allowing the tissues to more easily strip the hemoglobin of its precious electron-accepting cargo:
In anemia selective vasoconstriction of blood vessels subserving certain nonvital areas allows more blood to flow into critical areas. The main donor sites who sacrifice their aerobic lifestyle are the skin and kidneys. Shunting of blood away from cutaneous sites is the mechanism behind the clinical finding of pallor, a cardinal sign of anemia. Although the kidney can hardly be thought of as a nonvital area, it receives (in the normal state) much more blood flow than is needed to meet its metabolic requirements. Although (by definition) total body red cell mass is decreased in anemia, in the chronically anemic patient the total blood volume paradoxically is increased, due to increased plasma volume. It is as if the body were trying to make up in blood quantity what it lacks in quality.
The heart can respond to tissue hypoxia by increased cardiac output. The increased output is matched by decreased peripheral vascular resistance and decreased blood viscosity (thinner blood flows more freely than thick blood), so that cardiac output can rise without an increase in blood pressure. Generally, anemia must be fairly severe (hemoglobin < 7 g/dL) before cardiac output rises.
When the above mechanisms are overwhelmed by the increasing magnitude of the anemia, or when the demands of physical activity or intercurrent illness overwhelm them, a clinical disease state becomes apparent to the physician and to the patient. The severity of clinical symptoms bears less relationship to the severity of the anemia than to the length of time over which the condition develops. An acute hemorrhagic condition may produce symptoms with loss of as little as 20% of the total blood volume (or 20% of the total red cell mass). Conversely, anemias developing over periods long enough to allow compensatory mechanisms to operate will allow much greater loss of rbc mass before producing symptoms. It is not terribly uncommon to see a patient with a hemoglobin of 4 g/dL (hematocrit 12 cL/L), representing a loss of 70% of the rbc mass, being reluctantly dragged into a clinic by relatives concerned that he or she is looking a bit washed out.
When symptoms do develop, they are pretty much what you would expect given the precarious state of oxygen delivery to the tissues: dyspnea on exertion, easy fatigability, fainting, lightheadedness, tinnitus, and headache. In addition, the hyperdynamic state of the circulatory system can produce palpitations and roaring in the ears. Pre-existing cardiovascular pathologic conditions are, as you would expect, exacerbated by the anemia. Angina pectoris, intermittent claudication, and night muscle cramps speak to the effect of anemia on already compromised perfusion.
Clinical signs of a slowly developed anemia are pallor, tachycardia, and a systolic ejection murmur. In rapidly developing anemia (as from hemorrhage and certain catastrophic hemolytic anemias), additional symptoms and signs are noted: syncope on rising from bed, orthostatic hypotension (i.e., the blood pressure falls when the patient is raised from the supine to the sitting or standing positions) and orthostatic tachycardia. Keep in mind that if anemia develops through rapid enough bleeding, the hematocrit and hemoglobin will be normal (since in hemorrhage the rbc's and plasma are lost in proportion). Because of this, your appreciation of these clinical signs will serve you better in diagnosing this type of anemia than will the laboratory.
Anemias can be classified by cytometric schemes (i.e., those that depend on cell size and hemoglobin-content parameters, such as MCV and MCHC), erythrokinetic schemes (those that take into account the rates of rbc production and destruction), and 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
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:
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:
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.
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.
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.
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).