Understanding Anemia

by Ed Uthman, MD

University Press of Mississippi

Chapter 1. What Is Anemia?

The word "anemia" is composed of two Greek roots that together mean "without blood," but to use this literal translation as a definition would be a gross exaggeration. Still, the modern definition is simple: anemia is any condition characterized by an abnormal decrease in the body's total red blood cell mass. To understand the definition, one has to understand what red blood cells are and what they do, how the body reacts to an abnormally low red cell mass, and what happens when the mass of red cells falls so low that the body cannot adapt to it. We will discuss these matters in this chapter, but first we will look at the history of anemia and its study.

HISTORICAL PERSPECTIVE

The ancients readily recognized the importance of blood as a life- giving substance, believing it to hold the body's vital force. Hebrews back to the patriarchal age maintained that blood was the seat of the soul and demanded through the Mosaic Laws that it be drained before an animal was prepared as food (a practice still followed by Orthodox Jews today). The Romans drank the blood of their enemies, thinking it would confer on them the courage of their vanquished foes. While today the concept of the circulation of the blood seems obvious, it was not until the relatively recent era of the seventeenth century that William Harvey determined that blood was not just a contained static liquid.

The scientific study of blood had to await the invention of the microscope. While magnifying lenses were known to the monastic scholar and natural historian Roger Bacon (1214-94), lenses of sufficient quality for scientific use were not available for another three centuries. The first compound microscope (the great-granddaddy of the clinical microscope of today) was made in 1590 by the Dutch spectacle maker Zacharias Janssen. No one thought to use this instrument to look at blood until the noted Dutch naturalist Jan Swammerdam (1637-80), turned his instrument on the fluid of life and discovered what he called "ruddy globules," which were presumably red blood cells. The first detailed description of the red cells was produced by the famous (also Dutch) microscopist Antonj van Leeuwenhoek (1632-1723). While these men were great "natural historians," they were not medical researchers in the modern sense of the word. In fact, neither they nor those who immediately followed them thought that red cells were of any importance to the body. This realization had to await the insight of an Englishman, William Hewson (1739-74), whose posthumously published opinion that because red cells were present in such abundance they had to be important earned him the title "the father of hematology."

At the beginning of the nineteenth century, the word "anemia" was a clinical term referring to pallor of the skin and mucous membranes (the thin linings that cover the inside of the mouth, the whites of the eyes, the inner surface of the eyelids, and other surfaces not covered by skin). At the time of the publication of the first textbook of hematology by the French physician Gabriel Andral in 1843, there was no appreciation for the basic concept held today that clinical anemia is due to inadequate numbers of red blood cells. Before this could be determined, it was necessary to develop a technical method by which blood cells could be counted. This was first done in 1852 by Karl Vierordt, but his technique was too tedious to gain widespread use. Vierordt's student, H. Welcher, counted the cells in a patient with chlorosis (an old word for what is probably our modern iron-deficiency anemia) and found in 1854 that an anemic patient had significantly fewer red blood cells than a normal person. Thus, almost two centuries passed after Swammerdam's discovery of red cells in 1658 before it was shown that a deficiency in the number of red cells was behind the clinical diagnosis of anemia.

The clinical and biological science of hematology was given a tremendous boost in the period between 1878 and 1888, when it became possible to examine the microscopic details of blood cells. Interestingly, the event that provided this opportunity was not the development of the microscope, which was already fairly advanced by that time, but of biological stains. Although the human body is opaque and colorful to the naked eye, at the microscopic level almost all cells are nearly transparent. Most cells are completely colorless, and even those that have their own native color, like red blood cells, appear extremely pale and washed-out when viewed individually. Accordingly, few cellular details can be distinguished by looking at unstained specimens with even the best modern microscopes. It is necessary to stain the cells with dyes to obtain much useful information from them. The preeminent figure in the world of biological stains was Paul Ehrlich (1854-1915), the Silesian-born son of affluent Jewish parents and one of the truly great names in the history of biomedical science.

Ehrlich had done poorly in school as a boy, but he had shown great aptitude for and interest in biology and chemistry. His first major discovery was a good method for staining the bacterium that causes tuberculosis, which made the microscopic diagnosis of that important disease much easier. Unfortunately, he caught a mild case of it and had to take time off to recover. Ehrlich later worked out the details of preparing an antitoxin for another dreaded disease, diphtheria, which represented the first use of immunotherapy to specifically treat an infection (vaccines are also immunotherapy and had been around for much longer, but they prevent infections rather than treating them). Ehrlich's contribution won for his boss, Emil von Behring, the first Nobel Prize for physiology or medicine in 1901. Although Ehrlich had probably done most of the actual work, von Behring was given full credit for the discovery (Ehrlich eventually did get a Nobel in 1908 for other work).

Continuing to be interested in dyes, Ehrlich realized that something about their chemical makeup allowed them to attach themselves to specific parts of a cell. Combining this property with a poisonous one, he reasoned, should make it possible to create a dye-like substance that would attach itself to a specific infection-causing microorganism and kill it. This concept led Ehrlich to develop trypan red, a dye used in the treatment of trypanosomiasis (a class of parasitic infestations that includes African sleeping sickness), and arsphenamine, which was the first effective treatment for syphilis, another major public health problem of Victorian times.

Ehrlich's contribution to routine hematology was his development of the triacid stain, which allowed him to properly classify white blood cells into a scheme similar to the one used today. In 1891, the triacid stain was replaced by the eosin methylene blue stain invented by D. L. Romanowsky of St. Petersburg, Russia. The "Romanowsky stain" was further modified by Richard May of Munich in I902, Gustav Giemsa of Hamburg in 1905, and J. H. Wright of Boston in 1906. All of these modifications were direct descendants of Ehrlich's original ideas. Over ninety years later, we still use two of these, the May-Gruenwald-Giemsa stain and the Wright stain, for the examination of the myriad blood smears routinely prepared in clinical laboratories every day.

Standing on the broad shoulders of nineteenth century giants like Ehrlich, twentieth century hematologists led their science at an ever- accelerating rate into the modern age, providing scientific explanations for the various types of anemia discussed in this book. Ever easier, faster, and cheaper ways to diagnose and classify anemias were developed, and techniques for treating them, from nutritional therapy to blood transfusion to bone marrow transplants, were devised. The era of modern hematology is considered to have begun at Harvard Medical School with the work of George Richards Minot (1885-1950) and his assistant, William Parry Murphy (1892-1987), who, between 1924 and 1926, found that patients who suffered from pernicious anemia could be successfully treated with large quantities of raw liver in their diets. Minot and Murphy shared the 1934 Nobel Prize for their discovery. From this point on, the investigation of anemia revolved around phenomena at the molecular level, which is where we are today.

BLOOD

Given the amount that flows from even a trivial cut, it is tempting to assume that the body is literally full of blood. Actually, blood makes up a small fraction of the body's volume. Consider an "average" man weighing 70 kilograms, or 154 pounds. Since the human body has just about the same density as water, and 1 liter of water weighs 1 kilogram, the total volume of his body is about 70 liters. Of this, only about 5 liters represents the total volume of blood. Therefore, blood accounts for only 7 percent of the total body volume. In the normal state, blood must stay confined to several anatomic structures meant to hold it. The first of these is the circulatory system, which consists of the heart and blood vessels. The heart's main function is to be a pump for the blood (although it has a lesser-known function in the endocrine system concerning the regulation of body water content and blood volume). The blood vessels consist of (1) arteries, thick- walled elastic structures that withstand the high pressures generated by the pumping action of the heart, (2) veins, thin-walled low- pressure vessels that conduct blood back to the heart, and (3) capillaries, microscopic tubes that ramify throughout all the tissues of the body (except the cartilage of the skeletal system and cornea of the eye, which are able to live without a direct blood supply). Arteries conduct blood from the heart to innumerable beds of capillaries, which have such thin walls that exchange of nutrients, hormones, and waste products between the blood and tissues is easily accomplished. The capillaries converge into small veins, which converge into larger veins to conduct the blood back to the heart under very low pressure, where the pumping cycle begins again. The heart actually consists of two separate pumps in series; these just happen to be stuck to each other side by side. The right heart collects oxygen-poor blood, which has a dark purple color, from veins arriving from all the tissues of the body and pumps it into the lungs, where inhaled oxygen is picked up and carbon dioxide is dropped off to be exhaled. The oxygen-rich blood, which is bright red, is returned to the left heart and pumped out to the periphery of the body to complete the cycle.

The other anatomic structure for containing the blood is the reticuloendothelial system (RES), which consists of cavern-like structures called sinusoids lying within the spleen, liver, and bone marrow. The function of the sinusoids is to facilitate the exposure of blood to certain cells that are involved in the immune response to foreign invaders. Sinusoids in the bone marrow also serve as embarkation areas for newly born blood cells beginning their journey in the circulation. Blood flow through the sinusoids is very slow, so as to allow the blood maximum contact time with the tissues charged with these complex interactions.

Blood in a test tube would appear to be an inert liquid, but it is in fact no less a living, breathing tissue than is the heart, brain, or any other body part. Physically, blood consists of cells suspended in a liquid medium. The liquid medium, accounting for about 6o percent of the volume of blood, is called plasma. Of the plasma, about 93 percent is water. The remainder consists of suspended and dissolved solids, the most abundant of which is a protein called albumin. Other proteins in the plasma are called globulins. Both types of proteins have a variety of functions, some of which will be discussed later. There is also a set of important proteins in the plasma involved in the coagulation of the blood; these are called, appropriately enough, coagulation factors. If you take plasma from the blood and allow it to coagulate (form a clot), the resulting fluid left after the clot is removed is called serum. Several of the important laboratory measurements employed in the evaluation of anemias involve the determination of the quantity of nutrients and other substances in serum. These will also be discussed later.

BLOOD CELLS

The cells of the blood constitute about 40 percent of its volume. Of this volume, the overwhelming proportion is represented by the red blood cells (RBCs), or erythrocytes. There are about 5 million RBCs in every microliter of blood. Since there are about 5 million microliters of blood in the body (5 liters times 1 million microliters per liter), there are approximately 5 million times 5 million, or 25 trillion, red cells present. The whole body has an estimated 50 trillion cells of all types; thus, red blood cells account for about half the cells in the body. It may seem surprising that half of the body's cells are confined to 7 percent of its volume, until one considers how small and packed together the red cells are compared to the others. In fact, the red cell is smaller than just about any cell in the body, the sperm being a rather memorable exception.

Red cells, like most blood cells, are made in the bone marrow, the spongy internal core of most bones. In children the entire skeleton contains hematopoietic (blood cell-producing) marrow, but, as we age, marrow cell production becomes confined to bones in the central portion of the body, namely those of the spinal column, pelvis, skull, sternum (breastbone), hip and shoulder. In the adult, the weight of active marrow is about 4 1/2 pounds, making the marrow the second largest organ in the body (after the skin). Red cells begin their existence as marrow cells called erythroblasts (in biological parlance, a "blast" is a primitive cell from which other, more mature, cells form). These cells have nuclei with DNA and can reproduce themselves like the many other self-replicating cells in the body. Some of the erythroblasts reach a point at which they stop reproducing themselves and instead go out into the wide world of the bloodstream as erythrocytes. To do this they have to spend several days in the marrow undergoing a sequence of events called maturation, by which they (1) become progressively more filled with hemoglobin, and (2) eventually lose their nuclei. The resulting cell is essentially a sac containing hemoglobin and the biochemical minifactory necessary to maintain the chemical integrity of hemoglobin. The shape of the red cell is referred to as a biconcave disc. (A donut with its hole partially filled in is a good analogy.) It is essential that the red cell maintain its normal biconcave disc shape; otherwise, it is quickly destroyed by various police cells in the reticuloendothelial system.

After release into the bloodstream, red cells circulate for an average lifespan of 120 days. Therefore, every day, 1/120 of the total erythrocyte mass must be replaced. This comes out to 200 billion red cells per day, or over 2 million per second. If that's not enough of a task, the marrow must also produce most of the other types of cells in the blood.

The other cellular constituents of the blood are the white cells (leukocytes) and the platelets. These make up only a tiny volume of the blood; all the body's circulating white cells would not even fill a bartender's jigger, and all its platelets could easily fit into a teaspoon. In contrast, all the body's red cells would overflow a half-gallon milk carton. Leukocytes are involved in the immune response to foreign substances, and platelets are necessary for proper clotting of the blood. While these cells are not directly germane to our discussion of anemia, they will be discussed briefly in later chapters.

HEMOGLOBIN

The only function of the red blood cell is to keep hemoglobin healthy and happy. With no DNA-containing nucleus, the erythrocyte cannot reproduce itself or program itself to adapt to various challenges by synthesizing new proteins. With no mitochondria (tiny sacs in the cytoplasm filled with sugar-burning enzymes) it cannot generate the large amount of energy enjoyed by almost all other cells of the body. By allowing for the relatively limited role it performs in physiology, the red cell has its work cut out for it in caring for hemoglobin, a most fastidious customer. Hemoglobin is a protein that serves as a carrier for oxygen from the lungs to the tissues. To work properly, the hemoglobin has to hold on to oxygen molecules with just the right amount of force. If the hemoglobin molecule binds the oxygen molecules too loosely, then it will not be capable of picking them up at the lungs. If it binds the oxygen too tightly, then when it gets out to the tissues it will not release the oxygen to the tissues that need it. To perform such a delicate balancing act, the hemoglobin molecule takes advantage of its unusual physical structure (fig. 1.1). Each hemoglobin molecule consists of 4 smaller protein molecules, called globin subunits. There are 2 alpha and 2 beta subunits in each molecule. Each subunit partially encloses an unusual molecule called heme. Heme is similar to a class of compounds called porphyrins, which are widely found in nature in various roles. Chlorophyll, the light-capturing component of green plants, is an example of a porphyrin-based molecule. One peculiar property of porphyrins is their willingness to bind atoms of heavy metals. In the case of heme, that heavy metal is iron. Each heme molecule (4 per hemoglobin molecule) contains 1 atom of iron. Although 4 atoms of iron may seem a trivial amount in an enormous protein molecule (the protein part of hemoglobin weighs almost 300 times more than the iron it contains), iron is an absolutely essential component of hemoglobin. Without iron, there is no hemoglobin. Since without hemoglobin there is no blood, iron is an essential component of vertebrate life. (Iron will be discussed in detail in chapter 3.)

When an oxygen molecule binds to a hemoglobin molecule, the latter changes shape very slightly, which causes the next oxygen molecule to bind to the hemoglobin molecule even more avidly. This again causes a change in shape and again increases the willingness of the hemoglobin molecule to bind with oxygen. The process continues until the hemoglobin molecule has bound a total of 4 oxygen molecules, at which time the hemoglobin is full; it can bind no more oxygen. When the oxygen-laden hemoglobin gets out to the tissues of the body, it begins to drop off its oxygen load. The first oxygen molecule is given up reluctantly, but each subsequent one is released more easily than the last. What is the physiological advantage of this phenomenon?

The answer lies in a basic observation, well known to chemists and physicists, called the law of mass action. Essentially, this law states that chemical substances move spontaneously from areas of greater concentration to areas of lesser concentration. In the lungs, oxygen moves from its high concentration in the inhaled air toward the red blood cells, which have a low concentration. The problem is that, as oxygen moves into the red cells, its concentration becomes greater in the blood, and, because of the law of mass action, it is progressively more difficult to get oxygen to move from the lung to the blood. Accordingly, evolution has provided all vertebrates with the gift of hemoglobin. As the hemoglobin picks up oxygen from the lungs and gets more saturated, the changes in the hemoglobin molecule's shape force it to chemically bind oxygen more tightly, so that, despite the law of mass action, oxygen continues rapidly crossing over into the blood.

Out in the peripheral tissues, the reverse situation takes place. With the high concentration of oxygen in the blood initially assuring transfer of oxygen from blood to tissues, the law of mass action tries to slow this transfer down as the concentration of oxygen in the blood decreases. Once again hemoglobin saves the day, as it increasingly unbinds and delivers oxygen molecules with each of the oxygens that is stripped from it.

So it is clear that hemoglobin has to have its peculiar structure for proper oxygen transport, even if that structure turns out to be very delicate. Just as schoolyard bullies like to pick on the weakest classmate, almost any type of natural or artificial toxic substance can cause the hemoglobin molecule to denature (be permanently altered so that it does not work). The task of the red cell is to protect hemoglobin from these assailants. It has to continually synthesize certain molecules that destroy the toxins, and also has to maintain the correct pH (the degree of acidity or alkalinity of a liquid). It even has to keep the iron atoms happy. If an iron atom loses even one electron (which it likes to do if left to its own delinquent devices), the hemoglobin in which it resides turns into something called methemoglobin, which is totally worthless as an oxygen carrier.

HOW THE BODY ADAPTS TO ANEMIA

The various causes of different types of anemia will be discussed in later chapters, but first it is important to consider what all anemias and people with anemia have in common. As stated earlier, anemia is the condition characterized by an abnormal decrease in the body's total red blood cell mass. There are two possibilities as to what happens then to the blood's physical properties. The first is that, as the mass of red cells goes down, so does the total volume of blood. In fact, this is exactly what happens whenever there is heavy bleeding over a short period of time, whether from a wound or a disease (such as a bleeding ulcer). When this happens, the blood is just as thick and concentrated as it is in the normal state, but there is less of it left in the body. This is referred to as anemia of acute blood loss. While this does strictly fit our definition of anemia, it is in something of a category of its own, mostly because the loss in red cell mass plays second fiddle to the loss of total blood volume. When acute bleeding occurs, the most important thing for doctors to do is to maintain blood volume, even if they have to use fluids other than blood. This does not replace the lost red cell mass, to be sure, but it does keep the patient from going into shock, which can be irreversible. This is why the first thing that is done for severely injured patients, such as at the scene of an accident, is to get an IV going. The IV (intravenous) fluids can replenish the circulating fluid volume long enough for the patient to get to a hospital, where a blood transfusion can be given.

The second possibility surrounding the loss of total red cell mass is the one that is typically associated with all anemias except anemia of acute blood loss. In this scenario, the loss of red cells is gradual over weeks or months, so that the body has time to adapt to it. In this case, the body starts its own "IV" and adds water to the circulating blood volume. It does this by causing the kidneys to hold on to the water that is taken in by normal drinking. As more water is added to the plasma, and as the mass of red cells continues to decrease, the blood becomes thinner, i.e., less syrupy and more watery. To a point this is a favorable adaptation. Because thinner blood can travel through the tiny capillaries faster than thick blood, in the early stages of anemia the blood actually becomes more efficient at delivering oxygen to the tissues. However, as with many quick fixes the body employs to deal with problems, things eventually go awry. As the blood continues to thin out, less and less oxygen-laden hemoglobin is presented to the tissues per unit time. The result is oxygen starvation at the cellular level. But the body, not ready to give up yet, has several tricks up its sleeve:

  1. Increased cardiac output. The volume of blood the heart pumps through itself per unit time is called the cardiac output. In the normal resting state, the heart pumps about 5 liters of blood every minute, abbreviated 5 L/min. This means that the heart is easily capable of pumping the body's total blood volume through its chambers in one minute. Actually it is capable of much more than that. When there is a greater demand for oxygen, as during vigorous exercise, the heart can increase its output manyfold, to as much as 30 L/min. It does this by increasing not only the number of beats per minute (the heart rate) but also the volume of blood pumped with each stroke (the stroke volume). Mathematically, the cardiac output can be calculated by multiplying the heart rate times the stroke volume. In anemia, the cardiac output increases, and that allows more hemoglobin to be exposed to the peripheral tissues, making up for the decreased hemoglobin concentration. Accordingly, the heart rate increases, which gives us one of the cardinal clinical manifestations of anemia, tachycardia, or fast heart rate.

    The heart does not act alone to increase the cardiac output. It has to have cooperation from the peripheral tissues and the blood itself. If nothing changes in the body but the heart rate and stroke volume, the heart will be trying to pump blood faster into a fixed, unchanging bed of blood vessels. This is like trying to squeeze thick dishwasher detergent gel out of its container by pushing harder. The only way to make the gel dribble out faster is to increase the pressure. Analogously, in the body, to push more blood through an ungiving vascular bed would require a higher blood pressure. Higher blood pressure would cause the heart to work harder, because it would have to pump against a high pressure head, just like a muscle has to work harder to lift a heavier weight. Clearly this is not in the best interest of the body. Fortunately, the blood pressure is kept from going up by two factors. The first is the viscosity of anemic blood. Viscosity is the quality of a fluid which tends to cause it to resist being propelled through a tube or opening. Thin, anemic blood is less viscous than normal blood and can be pushed through the vascular bed with less pressure. The second factor is the blood vessels themselves. The wall of each small artery or vein contains one or more layers of muscle capable of responding to nerve signals by contracting. This causes the vessel to close down to a smaller caliber and be more resistant to the flow of blood. Other nerve impulses cause the muscles to relax, letting the vessels expand to a wider caliber and allowing more blood to flow with less resistance. In the anemic patient, the brain sends signals to the muscles around the small vessels telling them to relax and open up. The result is less impediment to the flow of blood. Therefore, because of less peripheral vessel resistance and thinnet, less viscous blood, the cardiac output can rise without causing the blood pressure to go up.

  2. Redistribution of blood flow. The various organs of the body are quite capable of cutting deals among themselves when times are bad. In the case of anemia, all the organs conjoin to protect the two most oxygen-demanding organs in the body, the brain and the heart. If these organs don't get enough oxygen, the rest of the body is in real trouble. Fortunately, two other organs can get by without nearly as much blood as they normally enjoy in good times. The first of these is the skin. As a response to anemia, small blood vessels in the skin contract, causing a greater resistance to the flow of blood than is present in more vital organs. Since the blood being pumped out of the heart will preferentially follow the path of least resistance, it will go through the more vital organs faster than it will through skin with contracted vessels. The result is a partial diversion of blood from the skin to other organs. The second organ which sacrifices its right to blood supply is the kidney. Now the kidney is a very vital organ, to be sure, but it is normally endowed with much more blood flow than it needs to stay alive and function properly. Both kidneys, taken together, weight about 350 grams (or about 1/2 of 1 percent of the total body weight), but they receive 20 percent of the cardiac output, or about 1 liter per minute. Gram for gram, then, the kidneys receive 50 times the cardiac output of the body as a whole. Clearly they could give up some of that for the benefit of their fellow organs, and as part of the adaptation to anemia, they do so.

    The diversion of blood flow from the skin causes one of the cardinal clinical features of anemia--pallor. Pallor is the pale color observed in the skin of a light-skinned anemic individual, and in the mucous membranes and nailbeds of all anemic individuals, light-skinned or otherwise. It should be noted that anemic patients are pale not because their blood is thin (anemic blood is just as opaque and highly colored as normal blood), but because the diversion of blood means that there is less of it in the skin, and more of the pale color of bloodless human tissue shows through.

  3. Decrease of hemoglobin-oxygen affinity. Earlier we discussed how the affinity (or the "willingness" to bind) between oxygen and hemoglobin changed with the number of oxygen molecules gained or lost by hemoglobin. It turns out that hemoglobin-oxygen affinity can be accomplished by other chemical means as well. There is a simple organic acid, called 2,3-diphosphoglycerate (2,3-DPG) that is elaborated within the red cell under anemic conditions. This 2,3-DPG causes hemoglobin to bind oxygen less avidly and to give up as much to the starved tissues as possible. Of course, the other side of the coin is that oxygen is more difficult to pick up in the lungs, but, since the respiratory system is not the main concern in an anemic patient, something has to give, and the healthy system ends up taking up the slack for the sick one.

WHEN COMPENSATION FALLS: THE CLINICALLY ANEMIC PERSON

A recurring theme in the study of disease is the sequence of events by which the body withstands some sort of insult (in the case of anemia, the decrease of red cell mass) by engineering various physiological workarounds to compensate for the damage done. Fortunately the body's various systems have a tremendous amount of reserve function to draw on to support these schemes. The down side is that when the insult becomes so great that the healthy systems, which are stretched to their limits, cannot overcome it, then the whole physiology comes crashing down like a house of cards. The result is a sick person in need of medical attention. In anemia, such a person appears with a characteristic constellation of symptoms and signs. These are listed below, along with the physiologic phenomenon responsible for each.

  1. Pallor is due to the shunting of blood flow away from the skin, as discussed above.
  2. Tachycardia, or fast heart rate, results from the increased cardiac output, also discussed above.
  3. Dyspnea (shortness of breath) occurs on exertion. Although the respiratory system in the anemic person is healthy, the tissues out in the body are starved for oxygen, because there is not enough hemoglobin to get it to them. When they need even more oxygen, as in a period of strenuous exercise, they send signals to the respiratory system asking it to deliver more. The respiratory system responds by increasing the depth and rate of breathing, which the anemic person experiences as shortness of breath.
  4. Easy fatigability is an effect of oxygen starvation at the tissue level.
  5. Dizziness and fainting are due to relative lack of oxygen in the brain.
  6. Tinnitus means the perception of noises which do not exist, or "ringing in the ears." In the anemic patient, this may actually be more of a buzzing or roaring. One possible explanation for this is that the cardiac output is so increased that the rushing of the blood through the vessels in the region of the ear is perceived as sound. Oxygen starvation of the brain cells is an alternative explanation.
  7. Headaches can be a symptom of anemia, although the exact cause is unknown.
  8. Miscellaneous symptoms include dimmed vision (which suggests oxygen starvation of the brain), loss of appetite, nausea, and constipation.
  9. Heart failure may occur. The cardiac output can increase only up to a certain point. After that, if the heart is called on to deliver even more blood per minute, it fails. When this happens the heart is unable to pump through all the blood presented to it by the veins, causing a buildup in pressure there; the blood then backs up into the capillaries. In this high-pressure environment, fluid from the plasma of the blood begins to seep out of the capillaries into the tissues. When this happens in the peripheral tissues of the body, swelling occurs, a condition referred to as edema. This swelling is seen particularly around the ankles (pedal edema) and over the lower back (sacral edema). When edema occurs in the lungs, the fluid not only causes the thin walls of the alveoli to swell, thus stiffening the lung and making inhaling more difficult, but it also fills up the alveolar sacs themselves, interfering with the exchange of oxygen and carbon dioxide. This is called pulmonary edema, and it is a dire event in the clinical course of the severely anemic patient. Without treatment (or with unskillful treatment) such a condition will quickly lead to the patient's demise.

Now that we have a person with clinically full-blown anemia in need of medical care, we will look at how doctors make a diagnosis and how they classify each person's case for proper management.

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