Unit 4-Circulatory System

Chapter 9

Composition of the Blood and Other Body Fluids

1. Divisions of the Blood:

     A healthy, lean animal, such as a dog, contains about 10% of his weight inside blood vessels. This material, the blood, is made of formed elements--red cells, white cells, and platelets--suspended in a clear protein solution, plasma. Usually, the plasma is about 60% of the blood volume, the formed elements making 40%.

     Adjoining the blood vascular system is a part of the body which separates the blood from the cells of the body. This part, called the interstitium, contains fluids, semisolids, and true solids, such as bone, cartilage and the fibers of connective tissue. It probably makes up 40% of the body weight.

     The remainder of the body weight is contained within cells; that is to say, about 50% of the mass of the body is intracellular. Taken together, the plasma, the fluid, and the semisolid portions of the interstitium make up the extracellular fluid, but that part of the body fluid which is not within cells. It is very difficult to measure this fluid; the best estimates suggest that 20% of the body water is extracellular. Almost all of the remainder of the body water is within cells, making the intracellular fluid. This is usually about 50% of the body water.

     These relationships are illustrated in Figure 191. For simplicity, the values are shown for a l0 kg dog, which is a moderately small dog.

     The bar on the left shows that approximately half of the mass of the animals is in cells. The remaining mass is divided between interstitium--including connective tissue, cartilage, bone, and semi-solids and fluids--40%, and the blood, 10%. The bar in the middle shows the distribution of solids. Blood solids are about 15 kg, the interstitium contains 2.0 kg of solids, and the cells contain 1.0 kg of solids.

     The distribution of water is shown in the bar on the right. 0.8 L of water is within the blood, 0.5 L is in the plasma. The interstitial fluid and semi-solids make up 1.5 L. Extracellular water is the sum of interstitial water and plasma and is about 2 L, or 20% of the body weight. The cells themselves contain 5 L of water, which includes the water of the formed elements of the blood. The total body water is 70% of the body weight.

     Note that the cellular solids are in 20% solution, while plasma solids are about 8%. The solid concentration in the interstitium would appear to be 50%, but this number is basically meaningless, because so many diverse structures are interstitially located.

     Note that these values are for a lean animal. Adipose tissue (fat) changes the mass of the body without influencing any of the components described appreciably. An American or European male is basically like the dog in composition but contains large amounts of fat. For example, an 80 kg man is made much like a 60 kg dog, but 20 kg of fat are added. Such a man would contain 6 kilograms of blood, 9 kilograms of interstitial fluid and 30 kg of cells. If the body fluid volumes were expressed on a weight basis, as they usally are, he would have a blood mass of 7. 5% of his body mass, the interstitial fluids and semi-solids would make up a little more than 11% of his mass, his extracellular fluid would be 15% rather than 20% of his body mass, and his total body water would be 52% rather than 70% of his body mass.

     Since fat is very variable in men and even more variable in women, it is very difficult to determine whether fluid volumes are normal or not. To take an extreme case (though such cases are by no means rare), a fat woman may weigh 100 kg, of which 60 kg are fat. This woman is actually a 40 kg woman with 60 kg of tissue that registers on the scales, but is not truly living tissue. One might expect to find 4 liters of blood in the lean woman; but 4 liters of blood is only 4% of her body weight, substantially less than the 10% of the dog or the 7.5% of the man referred to in the last paragraph. One might ask whether 4% of the body weight is normal for such a woman. The answer is not known conclusively, though the available evidence suggests that it is. It seems possible that the best values for "normal" for any of the fluid volumes will have to be referred to the lean body mass, something which it has only recently become possible to measure.

2. Measurement of Body Fluid Compartments and Concentration Units:

     The volume of a body fluid compartment can be measured by giving an indicator substance homogeneously distributed through that compartment in known quantity and measuring its concentration in the compartment in question after it has become thoroughly mixed. At such a time, the product of volume and "indicator concentration" should be equal to the amount of indicator injected, provided that the indicator has not been lost from the body during its period of mixing. If the indicator has been lost from the body during the mixing period, a correction for its loss must be made. Usually this is accomplished by measuring indicator concentration as a function of time. When the results are plotted as in Figure 192, the mixing period shows up as a period during which the indicator is very concentrated in the blood. When mixing is complete, the concentration of indicator usually falls in a very regular way. This regular fall is often used to "extrapolate to zero time," that is, to determine the concentration of the indicator had all of it been mixed and none lost at the moment of injection.

     There are some theoretical objections to this approach, but it has turned out to be very useful in practice. The major difficulties at present center about the choice of the correct indicators and analytical problems associated with them. Thu the total body water (which includes cellular, interstitial, and plasma water) can be measured by the use of any indicator which follows water whereever it goes. Heavy water and tritiated water appear to do so; both can be analyzed if the proper equipment is available. Unfortunately, such equipment is exceedingly expensive and is ordinarily available only in research hospitals. Antipyrine, an organic compound, follows water very faithfully, but its analysis presents enough difficulties that the determination is usually not carried out routinely. Antipyrine iodinated with radioactive iodine seemed to offer promise as an indicator for total body water at one time, but it does not behave quite like antipyrine, and its use for total body water is not justified.

     The liquid and semi-solid parts of the interstitium, which are very much like the plasma in composition, are usually measured together with the plasma. Both these compartments, which are outside cells, make up the extracellular fluid. This compartment seems to be uniformly penetrated by inulin (a polysaccharide from artichokes), by sucrose, and by mannitol. All of these are excreted quite rapidly by the kidneys; indeed so rapidly that extrapolation to zero time as defined above becomes very difficult. The curve which describes the disappearance of these material is shown in Figure 193. Other substances, such as chloride, bromide and the thiocyanat c ion, which were once believed to measure the extracellular fluid compartment, have been shown to penetrate the intracellular compartment as well. At the present time there is no really satisfactory method for measuring extracellular fluid volume on a routine basis.

     The blood volume can, however, be measured. Red blood cells remain bounded by vascular endothelium. Labelling such red blood cells with a known amount of a radioactive material, such as chromium51 or iron59, is done for blood volume estimation.

     The answer obtained is the ratio mass of label / mass label / ml blood and has the dimensions ml blood. When the same determination is done with plasma protein labelled with iodine, the answer is usually 15% to 20% larger. The obvious interpretation of this, that plasma proteins cross endothelium, is usually overlooked, though it has long been known that large molecules introduced into the blood stream can be collected from the tissue spaces. This question will be considered further in Part 7 of this chapter. For the moment, it will be sufficient to recognize that the blood volume should always be characterized in terms of the measuring agent: if the agent is cellular, the blood volume will be less than if the agent is associated with the plasma.

     The units for expressing concentrations of various materials in the compartments of the body follow. A molar solution contains one mole, meaning molecular weight of the substance in grams per one liter. For example, glucose has a molecular weight of l80 g / mole, so molar glucose solution contains 180 g / liter of solution. Similarly, urea has a molecular weight of 60, so a molar solution of urea contains 60 grams in a liter of solution. Usually, solutions found in the body are much weaker than 1 molar, so in most laboratories a solution is described in terms of the number of millimoles per liter, where a millimole is one-thousandth of a mole. In this unit, one molar glucose is the same as 1000 milimolar glucose; conversely, a glucose solution containing three hundred millimoles per liter is the same as one which is 0.3 molar. These terms are usually expressed by the following conventions: M = Molar, meaning 1 mole per liter. The number preceding the M designates how many moles are to be found per liter, so a 2.5 M solution contains two and a half moles per liter. When concentrations are described in millimoles per liter, the convention is to designate the number of millimoles per liter as mM/L. Thus a solution which was designated as 250 mM/L would contain 250 / 1000, or one quarter of a mole, of the dissolved substance in a liter of solution.

     In the case of a material which ionizes, such as sodium chloride, which breaks up into a sodium and a chloride ion in solution, the term equivalent is used. A 1 molar sodium chloride solution contains one equivalent of sodium and one equivalent of chloride ion. Such a solution is said to be N, normal. The same convention used in the last paragraph permits us to state that this solution contains 1000 mEq/L of sodium and 1000 mEq/L of chloride ions. In general, whenever the material in question breaks up into ions, the equivalent concentration of the ion being considered is given as the product of its molarity and its valence. For example, a 1 Molar solution of magnesium, which breaks up into a divalent magnesium ion and a dlvalent sulfate ion, is said to be 2 Normal or to contain 2000 mEq/L of both the magnesium and the sulfate ions.

     In the case of a substance like sodium sulfate, one mole is 142 g. In this 142 grams, there are two moles of sodium, which each weigh 23 g. In total, the mole of sodium sulfate, NaSO4, contains 23 (Na) x 2 + 32 (S) x 1 + 16 (0) x 4, or 142 grams. Thus a one molar solution of sodium sulfate is 2N with respect to sodium (2 moles x 1 valence) and is also 2N with respect to sulfate, because sulfate does not break up In a solution (1 mole x 2 valences). This solution contains sodium at a concentration of 2000 mEq/L and sulfate at the same concentration. The description of biological concentrations as mEq/L is exceptionally useful, for in any solution the number of positive milliequivalents per liter, cations, is identical with the number of negative milliequivalents per liter, anions. An example of the usefulness of this designation follows: the cations of most biological fluids can be determined quite easily because most of the anions can also be measured, but some cannot. It is customary in such a case to say that the unmeasured anions contribute as many milliequivalents per liter to the fluid as are necessary to make equivalence between cations and anions

     Another unit of concentration which is coming more and more into use is osmolarity. An osmolar solution is the same as a molar solution if it does not dissociate in solution. If it does and by dissociating makes two particles (for example NaCl --> Na+ + Cl-), the solution is said to be 2 osmolar. If three particles are made (for example Na2SO4 --> 2Na+ + SO4-), the osmolarity is three times the molarity. Since one osmolar solutions are much stronger than those found in the body, these solutions are described in terms of a unit 1000 times smaller, the milliosmol, and concentrations are recorded as milliosmolar per liter, or mosm/L. In this terminology, body fluids are approximately 305 mosm/L. With the exception of certain parts of the kidney, osmolarity is quite constant in the plasma, interstitium, intracellular fluid, and the blood cells. The reason for this has to do with the high mobility of water. Water crosses almost every cell membrane; it moves from reasons of low osmolarity, where the vapor pressure of water is high, to areas of high osmolarity, where the vapor pressure of water is low.

     Milliosrnols per liter and milliequivalents per liter do not necessarily have the same value. 9 g/L of sodium chloride makes a solution which contains 154 mEq/L of sodium and chloride ion, but whose osmolarity is 308 mosm/L. Proteins, which act as polyvalent anions, are of such immense molecular weight that they contribute almost nothing to the osmolar concentration. For example a cellular protein which binds, say, 100 potassium ions and has a weight of, say, 250,000 may be written K100Prot. A solution of such a protein, breaking up into 101 particles for each molecule (100 K, 1 protein) would have 101 times the osmolar concentrations of the same protein if it were not dissociated. Since very slight variations in the acidity or alkalinity of the body fluids have enormous effects on the dissociation of proteins-ion complexes, the same protein might in slightly different circumstances break up into 2 or 20 particles. The osmolar concentration would change correspondingly, and water movement would occur.

     Because of custom and usage, many contituents of the body fluids are measured in such units as mg / ml or mg/l00 ml. There is a strong tendency to describe gas concentrations as ml gas/100 ml. For example, most laboratories report the glucose concentration of plasma as mg glucose/100 ml blood; the oxygen content of blood is usually described as ml O2 / 100 ml blood. The diligent reader can usually make the transformation to the more standard units (millimoles per liter, milliequivalents per liter, milliosmols per liter) when such transformations are indicated. Sometimes the customary unit is so deeply entrenched, as in the case of examples cited above, that it is best to accept it.

     Cells are about 20% solid by weight, the greatest part of the weight being protein. The fluid which dissolves these solids contains potassium and magnesium as its chief cations: sodium and calcium, are quite low. Phosphate is the most important inorganic anion; there is a little dicarbonate and a little chloride orgainic anions including proteins predominate.



     The values tabulated above give a general picture of the intracellular contents. There is considerable variability from cell to cell, but all show a high potassium, magnesium, protein and phosphate concentration and all, except the red blood cells of cats, dogs, oxen, and sheep, are low in sodium. Almost all cells, again excepting the red blood cells, are low in chloride.

4. Composition and Volume of the Interstitiuim:

     The interstitium is often called the interstitial fluid, which is quite misleading. Rigorously defined, the interstitium is that part of the body which is neither within cells nor within blood vessels, so most of the connective tissues are interstitial. Much of bone and cartilage, no longer cellular, belongs to this compartment as do the fibers of loose and dense connective tissue.

     Even apart from these obviously solid bodies, the interstitium is primarily a gelatinous solid, called the ground substance, which is most weakly gelied near the capillaries and most strongly gelied near the cells. It is quite probable that the ground substance gels and solates intermittently in different areas, so that every portion of it is at some time in a liquid phase. It is this portion of the interstitium which one attempts to measure when "interstitial fluid" is measured. At the present time, there are no methods for measuring the solid parts of the interstitium; they are probably composed of materials more like those of the interstitial fluid than those of the intracellular fluid, but the exact composition is not known.

5. Composition and Mass of the Interstitial Fluid:

     This fluid is like plasma in its composition. Its volume is usually measured by indicators which do not penetrate cells and therefore measure the entire extracellular fluid at once. A separate measurement of the plasma volume makes it possible to determine the tnterstitial fluid volume by difference.

     Unfortunately, as noted in Part 2 of this chapter, the substances which are distributed in the interstitial fluids are eliminated by the kidney while they are mixing in the interstitial fluid. Time concentration curves like those of Figure 193 are obtained, and the analysis of these curves is exceedingly difficult. When this analysis is performed, it indicates that the extracellular fluid forms one fifth of the lean body mass (20%), and that the plasma is one quarter of it, so that the interstitial fluid is 15% of the body mass.

     The composition of the interstitial fluid is almost identical with that of the plasma, but it is deficient in protein, except near the blood vessels (See also Part 7). Essentially, it is a solution in which sodium and chloride are the predominant ions. Potassium, which is so high in the cellular fluid, is almost absent, as are phosphates.

     The table which follows describes the composition of the interstitial fluid.

Table 2

6. ComposItion and Mass of the Plasma:

     Plasma is easily accessible. One need only take a blood sample from any blood vessel and separate out the cellular elements by centrifuging. Its composition is, therefore, well known. See Table.

Table 3

     There are no major differences between the composition of the plasma and the interstitial fluid. The slight differences in the major cations and anions are attributable to protein binding on the plasma side. The protein acts as an anion which, by binding sodium and other cations, weakly releases chloride and bicarbonate and the other anions.

     The volume of the plasma can be measured by determining the dilution of substances which are associated with the plasma proteins. One such, often used, is the blue dye, Evans Blue. Its concentration is plotted as a function of time as shown in Figure 192 and its extrapolated zero concentration determined. Dividing the amount of dye by its concentration at this time gives the volume of distribution of the plasma proteins. This value is ordinarily about 7% of the lean body mass.

7. Relationship between Plasma and the Interstitial Fluids:

     As noted in Part 2 of this Chapter, the plasma volume measured by the use of plasma protein indicators is a little larger than that measured by the use of red cell labels. This suggests that the plasma proteins cross a barrier which is impermeable to blood cells, the capillary endotheliurn. Nevertheless, the distribution volume of the plasma proteins is not as great as the volume of the entire extracellular fluid, suggesting that the interstitial fluid may be divided into two parts, that close to the capillaries, which is entered freely by proteins, and that part which is converted as "ground substance." This arrangement is shown in Figure 194. In this Figure, the area closest to the capillary, penetrated easily by protein labels, is called the "pericapillary lymph". The ground substance is shown as the true barrier to protein movements, though the movement of cells is restricted at the level of the capillary.

8. Lymph:

     In Chapter 13, the relationships between the forces which move fluid across the capillary wall will be more fully described. For the present, it will only be said that when more fluid moves out of the capillary than is returned to it, it crosses the ground substance and finds its way to a true lymph capillary. Lymph capillaries that collect excess fluid has crossed capillary walls, are blind-ended. They fuse to make up the larger lymph vessels which eventually return these fluids to the blood system.

     The composition of lymph is quite like that of the plasma with respect to everything except proteins. In general, the concentration of proteins is lower in lymph channels than in plasma. The volume of the lymphatic system is not known with certainty, but it probably does not exceed a few hundred cm3.

9. Formed Elements of the Blood--Red Cells:

     In health, 40-48% of the volume of the blood is contained within its cellular elements. The red blood cells, or erythrocytes, account for almost all of this volume. In man, erthrocytes are 7-8 micra in diameter. Their thickness is about 1.5u except at their borders where they may be 2u thick. The appearance of the erythrocyte is shown in Figure 195.

     The erythrocytes have, as their major function, the transportation of oxygen from lungs to tissues, and to a lesser extent, they act in transportation of carbon dioxide from tissues to lungs. Unlike most cells, erythrocytes have no nucleus; many cellular organelles commonly seen in other cells are absent from the erythrocyte.

     The chief of the solid components of the erythrocyte is the pigment hemoglobin, which makes up 33% by weight of the cell. A few other substances are also present, but these are not important to the primary function of the cell.

     The total number of red blood cells in man of average size (80 kg) is 2 x 1013, that is to say 20 million million. Customarily, the number of red blood cells per cubic millimeter of blood is measured. This value, the red cell count, ranges from five to six million per cubic millimeter in the normal healthy person. There are two other ways to describe the erythrocyte concentration: one is the determination of the packed cell volume, and the other is the measurement of hemoglobin concentration. The first of these packed cell volumes is usually given as the percentage of the blood volume occupied by red blood cells, the quantity called the hematocrit.This value, normally about 40%, may fall as low as 10% in anemia and rarely rises as high as 70% in polycythemia.

     The unit used for hemoglobin measurement is concentration in g/100 ml blood. The normal value of 16 g/100 ml blood may fall in anemia to 2-3 g/100 ml blood or rise in polycythemia to 20-25 g/100 ml blood.

     The student should bear in mind that each of these measurements describes a different property of the erythrocyte. The red blood cell count describes the concentration of erythrocytes in numbers, hematocrit gives the concentration of erythrocytes in volume, and hemoglobin gives the concentration of the respiratory pigment of the erythrocyte. It will be seen in Part 14 of this chapter that these values do not necessarily vary together. Important information can be gained by proper combinations of the values.

     Erythrocytes in the mature adult are formed in the marrow of the bones of the chest. In children and young adults, the marrow of the long bones is also involved, but their contribution has usually become insignificant by the age of 18. Erythrocytes ordinarily live 110 to 120 days. A little less than 1% of them must therefore be replaced per day. This is an enormous growth rate, and for it to occur properly there must be an adequate supply of the material from which erythrocytes are made as well as of the growth factors which influence their development. The materials required for the production of red cells are iron and protein. Maturation depends on the presence of vitamin B12 and folic acid.

     In the maturation process of the erythrocyte, a stem cell in the bone marrow goes through a number of stages. These stem cells, hemocytoblasts, contain nuclear material but no hemoglobin. Hemoglobin is gradually synthesized and the cell nucleus degenerates. At this stage, the cell is called a normoblast. The degenerated nucleus is ejected from the cell, though usually a few strands of nuclear material remain in a loose network. At this point, the nuclear material, is condensed and ejected in turn, leading to the formation of the true erythrocyte, a process shown in Figure 196. The exact stimulus for the beginning of the erythropoietic process is not known with certainity, but there is some evidence that it may be initiated by a substance produced in the kidney named erythropoietin. This cannot be the only factor involved, for persons who survive with artificial kidneys have relatively little difficulty in regulating red cell formation.

     In some way, then, the rate formation of red cells appears to depend on the oxygen available and the rate of its utilization. Thus, persons living at very high altitudes show accelerated erythropoiesis resulting in very high blood counts. Even higher counts are seen in persons doing heavy labor at high altitudes. Conversely, bed rest, which diminishes the need for oxygen, also reduces the rate of erthropoiesis, and the blood volume falls. This may become a serious problem for astronauts. In the weightless state, the astronaut is almost perfectly at rest. This reduces erythropoiesis and blood volume. Upon reentry, the reduced blood volume may be inadequate to support the suddenly increased needs for oxygen.

10. Formed Elements of the Blood--White Cells:

     When blood is centrifuged for the determination of the hematocrit, there is usually a thin white layer which separates red cells from the plasma. This layer, rather less than 5% of the blood volume, contains the white cells, or leucocytes.

     The leucocytes are generally much larger than the erythrocytes, though they are only one one-thousandth as numerous. Thus, a white cell count of 6000 cells per cubic millimeter is about normal.

     Unlike the erythrocytes, the white cells have nuclei and are much more complicated in structure. There are five major types of white cells easily distinguishable in the blood, monocytes, lymphocytes, basophiles, eosinophiles, and neutrophiles.

     Monocytes are large cells with a kidney bean shape nucleus. They appear to be important in the body's defences against small foreign bodies, which they may engulf or surround. Lymphocytes, which may be the carriers of defensive antibodies, are usually smaller than monocytes. Basophiles are relatively rare, about one white cell in 200 belonging to this classification. They have dark granules in their cytoplasm. It has been suspected that they carry an anticoagulant substance, heparin, but the exact way in which the cell functions is not known. Eosinophiles have large granules stained by the dye eosin in the plasma, but their function is not known at all.

     The neutrophiles ordinarily make up 60% to 70% of all the leukocytes. These cells appear to be capable of engulfing certain bacteria and some products of tissue destruction. Their circulation numbers increase in certain infections as if they were summoned by the infecting agent. In addition, these cells can travel through capillary walls, so that they are, in fact, concentrated at the infection site.

     The various forms of leucocytes are illustrated in Figure 197. Figure 198 shows several views of a neutrophile passing through a capillary wall.

11. Formed Elements of Blood--Platelets:

     Normal blood contains about 200,000 tiny cell fragments per cubic millimeter. The fragments are actually pieces of the cytoplasm of giant bone marrow cells, megakaryocytes. Normally, platelets do not touch each other, other blood cells, or the lining of the blood vessels. When they do touch something else and are wetted by it, they tend to become sticky and they may adhere to each other, to blood vessel walls, or to other cells, forming large aggregates. These may obstruct the flow of blood in small vessels or prevent leaking through the wall of an injured blood vessel.

12. Coagulation of the Blood:

     This process is involved in the sealing of small defects in vessel walls. Larger defects usually involve the clotting mechanism, which is most clearly seen when shed blood is allowed to coagulate. This process involves the conversion of a plasma protein called fibrinogen to another form which is insoluble, fiber-shaped and sticky, and called fibrin. Fibrin fibers tangled together trap the cellular elements between them, and the blood is suddenly converted into a solid.

     The conversion of fibrinogen to fibrin and the clot is the end stage of a number of previous stages which ordinarily begin when blood is brought into contact with foreign bodies. Such contact leads to the formation of thromboplastin. This is a generic name given to substances which increase the conversion of prothrombin to thrombin. Platelets release a thromboplastin when they are touched, tissues also have thrombopiastic factors, and the plasma itself may have a thromboplastic factor. Any or all of these thromboplastins may act in a plasma protein called prothrombin, causing its conversion to thrombin. Calcium ions are usually required for this conversion. A number of factors accelerate the process, while a few reduce its rate.

     Once thrombin has been formed, the conversion of fibrinogen to fibrin proceeds automatically. The quality of the clot which results may be modified slightly by chemical circumstances. Viewed overall, the thromboplastic process begins as the result of the shedding of blood, which leads to the conversion of prothrombin to thrombin, which leads in turn to the conversion of fibrinogen to fibrin and the formation of a clot.

13. Regulation of Fluid Volumes:

     Regulation of blood volume is a complex process involving the synthesis of red cells and plasma proteins at a rate corresponding to their loss from the circulation. It is far from certain what "receptors" measure the blood volume or any of its components. Many such receptors have been suggested, among others, the veins of the head, the right heart and pulmonary circulation, and the juxtaglomerular apparatus in the kidney. The failure to identify any one of these areas as the prime receptor suggest that there may be others, or perhaps that all of them act together. Presumably, in the last analysis, the organs which respond to the signal that there is altered blood volume are the bone marrow, changing its production of erythrocytes, and the liver, changing its production of proteins.

     Investigations in this field are of particular interest because of the number of diseases in which the blood volume is disorded (see Part l4 of this Chapter). Nonetheless, there is remarkably little useful information concerning the normal control mechanisms.

     The volume of the extracellular fluid, like that of the blood, is somehow regulated. Again, most of the mechanisms of regulation are unknown despite extensive investigation. There is, however, one, well-explored mechanism which adjusts the volume of the extracellular to the amount of extracellular solutes in such a way that the osmolar concentration of the extracellular solutes is 305 mosm/L. This mechanism has its receptors in the hypothalamus. It operates by signalling the posterior lobe of the pituitary to produce more or less of a circulating hormone, antidiuretic hormone, which controls the excretion of water by the kidney. The mechanism will be further considered in Chapters 22 and 23.

     The total body water is, within relatively narrow limits, fixed at 70-72% of the lean body mass. Its osmolarity, like that of the extracellular fluid, is 305 mosm/L. Presumably, living mammalian cells contain 305 mosm/L of osmotically active agents, a quantity which includes proteins, nucleic acids, organic compounds, etc.

     If, in fact, it is in the nature of living cells to be 305 mosmolar, it is not remarkable that the extracellular fluid has the same osmolarity. What is remarkable is that the volumes of extracellular and intracellular are usually closely adjusted to each other. An example will illustrate this:

     Assume that a normal man with 27 liters of intracellular fluid and 12 liters of extracellular fluid, both at 305 mosm/L, drinks a liter of water. Water crosses cell boundaries, and if evenly distributed, will change the osmolarity of the body fluids to 293 mosm/L. This lowering of osmolarity, acting via the hypothalamus on the posterior lobe of the pituitary causes suppression of antidiuretic hormone release and elimination of water by the kidney, which quickly corrects the water excess. Conversely, a normal man drinking a liter of 2% salt solution will elevate his body fluid osmolarity to about 312 mosm/L. Urinary retention of fluids and increased drinking of water will bring about a correction of this hyperosmolar state. If, however, the same man were to drink 1 liter of 0.89% salt, which is 305 mosm/L, the volume of the extracellular fluids would be increased 1 liter and there would be no change in osmolarity at all. Total body water would be increased 2.5%, yet cellular water would be quite normal. From this example, it would appear that the total body water is very dependent on the regulation of the extracellular fluid volume. As has already been stated, the mechanism for regulation of volume of the latter is not well understood, but at least in man, it is a very sluggish mechanism. Men can gain weight simply by drinking isosmolar salt solutions, and they can lose weight very quickly by abstaining from salt and water for a short time. The changes are entirely in the extracellular fluid, so the real cell weight is altered little, if at all, yet these changes may persist for days, sometimes even weeks.

14. Disorders of the Body Fluids:

     Red cells may make up an unduly large portion of the blood in polycythemia or an unusually small fraction in anemia. They may contain too much hemoglobin per cell when hyperchromic or too little when hypochromic. They may come into the blood stream in minature form in reticulocytosis. Their size and hemoglobin content may be irregular from cell to cell in poikilocytosls, and polychromatosis, respectively. Examples of each of these will be given, but for more detailed accounts, the reader is referred to textbooks of medicine and hematology.

     Polycythemia is normal in persons who live at high altitudes. It occasionaly occurs in persons who live at sea level and may then be considered a disease, polycythemia Vera. In this condition, the hematocrit is very hig--more than 50%--and the blood is quite viscous. The treatment is suppression of red cell formation or the elimination of existing red cells. Polycythemia patients benefit from blood donation at frequent intervals.

     Anemia includes a constellation of diseases which can be classified easily:

     Disorders in the production, breakdown, or loss of red cells can sometimes be detected by blood counts, sometimes the hematocrit is altered, and in many cases the hemoglobin concentration of blood is changed. Immature red cells may appear in the blood, which is a normal reaction to blood loss.

     Any abnormal increase in the white cell count is called leukocytosis. A decrease is called leukopenia. Leukopenia may result from over-destruction or underproduction of leukocytes. It is commonly seen in persons who have undergone extensive radiation treatment or who have received immuno-suppressive drugs. A rarer form of leukopenia corresponds to a plastic anemia and may occur together with it. In the condition, white cells may disappear almost altogether from the circulating blood. Since these cells are one of the bodies first protections against infection, persons with leukopenia are easily susceptible to infectious agents.

Leukocytosis is quite normal in some infectious diseases, but its absence should never be taken to indicate that no disease is present. The type of leukocytosis produced varies with the disease. The form most familiar to college students is infectious mononucleosis. The fact that it affects mostly young people, some of whom are believed to kiss each other, has resulted in its being named the kissing disease. This appears to be a misnomer since the disease, though infectious, is not transmitted by saliva.

     The most common leukocytosis results from damage to tissue, usually through streptococci or staphylococci. The leukocytes which increase in number are the neutrophiles. Such increases to, say, 10,000 to 15,000 per cubic millimeter of blood are often seen in appendicitis. They assist in the diagnosis, but their absence does not rule it out, and their presence does not make the diagnosis certain.

Lymphocytosis may be observed in whooping cough and some other relatively obscure diseases of children. The white cell count may reach extraordinarily high levels--100,000 cells / mm3 is not rare. Any lymphocytosis, in fact, any leukocytosis, should suggest leukemia (See below).

     An increase in the number of eosinophiles occurs in certain infections with worms and often in allergy. The cause is quite unknown.

Leukemia is a disease of overproduction of leukocytes. Extraordinary levels may be reached in the blood. The cell types in the leukemias are very variable. The normal forms may be seen in increased numbers, but immature cells also appear. In general leukemias can be classified as lymphocytic, where the lymphocytes predominate, or myeloaenous, where basophiles, eosinophiles and neutrophiles predominate. They may be subclassified further: Both lympocytic and myelogenous leukemias have acute and chronic forms, the former having a life expectancy measured in terms of weeks or months, the latter having life expectancy measured in terms of years. It is beyond the scope of this text to consider the methods used in diagnosis and treatment of these diseases, but it should be emphasized that they must be considered fatal conditions and that treatment makes the victims feel better rather than just prolonging life. It may also be mention that the anemia characteristically seen in the myelocytic leukemias results from encroachment on the erythrocyte-forming elements by the leukemic cells not, as is popularly held, from red cell destruction by the white cells.

     These may take two forms: The blood may coagulate less readily than usual, but the opposite, hypercoagulability, is probably more common, though less dramatic.

     Abnormally low coagulability is seen in persons lacking thromboplastic factor or with low plasma prothrombia. The best known of the former group, though very rare, is hemophilia. This disease appears to be due to a lack of one of the thromboplastic proteins, anti-hemophiliac globulin, and has a predictable hereditary pattern. The great interest in the disease is more probably due to the prominence of the victims than to the prevalence of the disease.

     Low plasma prothrombin is a much more frequent cause of low blood coagulability, which sometimes results from obstruction to the flow of bile. The synthesis of prothrombin requires vitamin K, whose intestinal absorption requires bile. Nowadays, low plasma prothrombin is often induced deliberately by physicians to prevent diseases associated with high coagulability. This is most commonly done by administration of the drug dicumarol, which antagonizes vitamin K. Anticoagulant treatment of this sort is of proved of value in persons who have had certain kinds of heart attacks (See Chapter 16).

     Hypercoagulability of the blood has not excited as much attention as low coagulability. It seems quite possible that there are at least two forms of hypercoagulability, one affecting blood in arteries, one in veins. Arterial hypercoagulahility appears to begin with the adherence of platelets to each other rather than disorder of the whole clotting mechanism. Such adherence may result in the formation of a so-called "white clot" which, if dislodged from its site of formation, may produce an obstruction in an arterial branch downstream. This may have the most serious consequences if the obstructed blood vessel is in the heart muscle or the brain.

     In the venous system, where blood moves more slowly, "red clots" can form at the site of vessel wall damage. Such clots, when they become dislodged, tend to produce obstructions in the branches of the pulmonary arteries. These are usually dissolved within a few hours, leaving no detectable residue, but very large ones may produce death through sudden obstruction of a major pulmonary vessel.

     A liter of blood plasma contains about 45 grams of albumins, 25 grams of globulins and 5 grams or so of fibrinogen. For reasons which are not well understood, the globulins and fibrinogen increase in most chronic diseases so that the normal ratio of albumins to globulin (9:5) is reversed, and fibrinogen increases. The larger molecules, fibrinogen and globulin, do not serve as well to suspend the red cells as the albumins. When blood is removed from a normal person and made incoagulable, the rate of settling of the erythrocytes, the sedimentation rate, can be measured under standard conditions. Usually in a tube called a Wintrobe tube, 10 cm in length and 3 mm in internal diameter, the sedimentation rate is less than 10 mm / hour in men and less than 20 mm / hour in women; in some chronic diseases, the sedimentation rate may reach 40-50 mm / hour (Figure 199). An abnormally high sedimentation rate should be considered evidence of disease unless proved otherwise, but a low sedimentation rate, unfortunately, does not rule out the possibility that disease exists.

     In starvation and in certain diseases of the liver and kidneys, the plasma proteins are at low concentration. This results in disturbed relationships between the body fluids which will be described in the next part of this chapter and in Chapter 13.

     In some diseases, the normal value of solutes in cells, 305 mosm/L, is unaccountably lower. This is particularly true in debilitating and pre-terminal illnesses, where fluid volumes may be normal in relation to each other, but the fluid of content of the whole person may be quite high.

     It is much more common for the relationship between intracellular and extracellular fluid to be distorted, forming an excessive intake of salt. When the extracellular volume is abnormally high, an extracellular edema is said to exist, and conversely, when it is low, there is said to be an extracellular dehydration. These conditions are usual corrected by the kidneys, adrenals, cortex, sweat glands, hypothalamus, and the lining membranes of the mouth, each acting in concert. Extracellular edema, for example, may lead to increased excretion of sodium by the kidney (Chapter 23).

     This makes the extracellular fluid hypoosmolar, so that antidiuretic hormone is no longer produced, leading to water excretion. Conversely, increased anti-diuretic hormone production conserves water. (Chapter 23). At the same time, dehydration leads to dryness of the mouth and thirst which, if recognized, further corrects the defect (the role of the adrenal glands will be considered in more detail in Chapter 25). Circulatory disability may disable the kidneys, leading to inability to excrete sodium. This leads to an extracellular edema, which will be discussed in more detail in Chapter 16, under heart failure.

     Heart failure is usually associated with increased blood volume. It is not clear whether this increase occurs independently of the extracellular fluid volume or is secondary to it.

     Failure to regulate blood volume is also seen when plasma protein synthesis is changed. Increases in plasma protein synthesis lead to increased blood volume, often at the expense of interstitial fluid, while decreased plasma protein synthesis is associated with losses of fluid to the interstitial space. In the same way, plasma proteins may be lost to the outside, leading to hypoproteinemia and expansion of the interstitial space. These and related matters will be considered in Chapter 13.

Continue to Chapter 10.