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The fluid part of the blood is not less important than the cells which are carried therein. The constituents of the plasma change constantly, as the constituents of living cells change constantly, and, like living cells, the blood plasma maintains always a fairly uniform chemical structure. This uniformity is not, apparently, maintained by any vital activity of the plasma itself. The tissues which are bathed by the fluids derived from the plasma vary their activities according to varying plasma conditions, and the result of such variations in the physiological activities of normal tissue cells is the maintenance of a chemical and physical equilibrium of blood plasma, tissue fluids and lymph. So long as the circulation of the blood remains normal, and the various tissues of the body not too badly injured, the blood plasma and the fluid derived from it retain at nearly the same level of water-content, chemical structure and osmotic tension. The various salts and organic substances vary slightly according to varying diet, exercise and other physiological conditions but even these variations are only slight and transitory, so long as the circulation of the blood is normal and the tissues reasonably normal in structure. The blood plasma serves as a method of transportation. The waste products of katabolism are removed by the blood plasma and are carried to the various emunctories to be eliminated from the body. Katabolites which can be utilized again are carried in the plasma to the tissues which need them. Hormones are katabolites of one tissue which serve a useful purpose in some other tissue; they are carried in the blood plasma from the places of their manufacture to the places of their functional activity. Various gases are transported in solution by the plasma. Food materials are carried from the intestinal tract to the liver and other tissues, to be elaborated into the compounds required by the living cells of the body, and from these various organs to the tissues which need food. The blood cells themselves are fed by the plasma and they give off katabolites to the plasma. The plasma transports the newly formed blood cells from their sites of origin in the bone marrow and the lymphoid tissues over the entire body; the plasma feeds them through their lives within the blood stream, the plasma receives their dead bodies and disposes of them. The plasma is a medium of communication between distant tissues, by means of the hormones and enzymes which it carries and by the manner in which it is affected by varying physiological states. For example, if the blood plasma carries an excess of carbon dioxide certain groups of nerve cells are thereby so affected that they cause increased respiratory activity. Many such reactions occur constantly and the entire body is enabled to act as a unit because the circulating blood plasma as well as the delicate nervous tissues maintain always these systems of inter-communication between distant tissues. The varying states of the blood plasma are best studied
by means of the changes which occur in the blood cells, and by chemical
analysis of the bloods. The latter subject is beyond the scope of
this book. The changes which occur in the blood cells as a result
of changes in the circulating plasma is a matter of much interest.
The importance of determining the total plasma or blood volume is evident, yet at this time there is no known method which is sufficiently accurate and simple to be used in ordinary circumstances. In hospitals with a large and efficient laboratory staff it is possible to determine the total blood volume with reasonable accuracy. From published reports of work in this field it is now known that the total blood plasma per unit of body weight or body surface varies only moderately in nearly all diseases, and that so far as practical clinical experience is concerned the studies made of any given amount of blood are sufficiently accurate for diagnosis in most cases. Much work has been done in an attempt to determine the normal amount of the blood in the entire body. Welcher’s findings were based upon a study of decapitated criminals. The blood was received into vessels, and the veins were then washed out with water. The hemoglobin was determined for the fresh blood and also for the washings mixed with blood. He estimated the total blood weight as 7.7% and 7.2% of the body weight for two different men. Haldane and Smith allowed the patient to inhale a measured amount of carbon monoxide and after a time the amount of carbon monoxide hemoglobin was determined. This method gives figures approximately identical with those secured by the vital red method. The best method now known for the determination of the total amount of blood in the human body is that employed by Rowntree and his associates of the Mayo Clinic. It consists, briefly, of the injection of a known amount of some harmless dye into one cephalic vein, then the withdrawal of a known amount of blood from the opposite cephalic vein three or six minutes later. The total amount of blood in the body can be estimated from the dye present in the withdrawn blood. According to Denny and also to Bock the plasma volume of the blood remains at a definite level per unit of body weight in nearly all normal and abnormal conditions except in those associated with severe dessication of all the tissues. Changes in the total blood volume are due to changes in the corpuscle volume. Blood volume is increased during pregnancy but returns to normal within about a week after delivery. Blood volume is increased in certain anemias; the increase is in the plasma alone. Increased blood volume occurs in chlorosis, polycythemias and a few other diseases. Decreased blood volume occurs in dessication, after very severe hemorrhages and after severe diarrheas and severe sweating. The total blood volume remains remarkably constant
under varying physiological conditions.
Rowntree advises the use of the terms normovolemia, hypovolemia and hypervolemia to express a normal relation between blood volume and body weight, abnormally low blood volume per kilo of body weight and abnormally high blood volume per kilo of body weight. When the blood cells are relatively increased the condition is called polycythemic normovolemia, polycythemic hypovolemia or polycythemic hypervolemia, according to the increase in cells in blood of normal volume (relative to body weight), or in blood of diminished or increased volume. Similarly, when the cells are relatively low and the serum relatively high the condition is called oligocythemic normovolemia, oligocythemic hypovolemia or oligocythemic hypervolemia according as the diminished cell count occurs in blood of normal, increased or decreased volume per body weight. Rowntree has taken the figures which he has derived from an average of normals as a criterion; for blood, 87.7 cubic centimeters per kilogram of body weight; for plasma 51.2 cubi centimeters per kilogram of body weight; for blood cells, 36.5 cubic centimeters per kilogram of body weight. This means that approximately one-eleventh of the body weight of normal individuals is composed of blood. Findings for normal persons vary by 10% or more from these figures, just as some perfectly normal persons may have a basal metabolism rate of 10% more or less than 40 calories per hour per square meter, or a temperature slightly above or below 98.6 degrees F. or a red blood cell count of four million or of five and one-half million, per cubic millimeter, and so for every other condition in which a definite normal figure is generally accepted. Under several abnormal conditions Rowntree found significant variations in plasma volume and in blood volume. In obesity without edema the amount of blood in the body is considerably increased, while the amount of blood per unit of body weight or per unit of body surface is considerably diminished. In pernicious anemia the blood volume per unit of body weight or body surface is diminished. In secondary anemias the blood volume may be increased, decreased or unchanged, according to the causes of the anemias. In polycythemia vera the total volume of blood is increased both actually and per unit of body weight and body surface. In secondary erythrocytosis the total blood volume remains almost or quite unmodified. In edematous states there is little or no variation in the blood volume except in glomerulonephritis. In this renal disease the total blood volume may not be affected, and if it is affected at all it may be increased or diminished. Cardiac edema shows no significant changes in the total blood volume. In Banti’s disease and in splenomegaly without anemia,
with or without cirrhosis of the liver, the blood volume is somewhat increased.
In all forms of leukemia the total blood volume is increased considerably.
Hypertension is associated with a normal blood volume per unit of body
surface and body weight.
The blood has feeble alkalinity due to the presence of alkaline carbonates and alkaline phosphates. These bases are in feeble combination with the blood proteins, including hemoglobin, under ordinary conditions. With increasing carbon dioxide content the bases are set free, combine with the carbon dioxide and the essential neutrality of the blood is preserved. The presence of these bases in this loose chemical combination provides the “buffer action” which is of such great importance in maintaining the power of the blood to carry oxygen and carbon dioxide to and from the active tissues of the body. The alkalinity of the blood is commonly measured in terms of its ability to carry carbon dioxide, and variations in the carton-dioxide-combining-power of the plasma are identical with variations in the alkalinity of the blood. The average reaction of the blood of a healthy young man, at rest, as reported from several laboratories, is as follows: Arterial
blood plasma . . . . . . .pH 7.443
The average reaction of the blood of a healthy young man, after vigorous exercise lasting for about an hour, is as follows: Arterial
blood plasma . . . . . . .pH 7.375
The alkalinity of the average young healthy woman is somewhat lower, the variation being in harmony with the lower hemoglobin and the lower specific gravity of the blood of women. These variations are not primarily sex characteristics. Women who live active lives show the specific gravity, cell count, hemoglobin content and alkalinity characteristic of the blood of men who live active lives, and men who live sedentary lives show the specific gravity, hemoglobin content, cell count and alkalinity characteristic of the blood of women who live sedentary lives. Since more women than men are inactive, and more men than women live active lives, the proportions given as characteristic of the sex variations in blood are fairly accurate, so far as averages are concerned. It must always be remembered, however, in making blood examinations for women who are athletic, and for men who live quiet and inactive lives, that figures normal for the habits of the patient must be taken as normal without regard to sex. The alkalinity of the blood varies slightly and temporarily as a result of many physiological conditions. Increase in the amount of carbon dioxide of the blood results in increased respiratory activity, the elimination of the carbon dioxide and return to normal resting alkalinity. Increased intake of alkaline substances results in the elimination of the excess, chiefly by the kidneys. Changes in the alkalinity of the blood as a result of disease may be considerable. In diabetic coma there are several organic acids present in the blood plasma. Henderson gives the following figures for a patient in diabetic coma: Arterial
blood serum . . . . . . . . pH 7.140
The alkalinity of the blood is diminished in all diseases in which the aeration or the circulation of the blood is impeded, as in pulmonary tuberculosis, pneumonia, endocarditis and other cardiac diseases. The alkalinity of the blood is also diminished in renal disease. Henderson gives the following figures for a moribund nephritic: Arterial
blood serum . . . . . . . . pH 6.994
The fact that so little difference exists between venous and arterial blood cells and blood serum is of interest in this connection. The alkalinity of the blood is increased by increased atmospheric pressure. Menten gives the following figures: Atmospheric
pressure . . . . . . . . . . . . . mm
Hg 762
or more
Menten gives also the following figures for abnormal states: Malignancy
(60 cases) . . . . . . . . . . . . . .
pH 8.00
to 8.44
Henderson gives the following figures for a patient with myxedema: Arterial
blood serum . . . . . . . . . . . . . . . .
pH 7.506
Henderson gives for a patient with pernicious anemia: Arterial
blood serum . . . . . . . . . . . . . . . .
pH 7.450
Accurate determinations of the reaction of the blood can be made by means of a potentiometer or a voltmeter. These methods do not require an unreasonable amount of blood. Determination of the carbon-dioxide combining power of the blood serum gives results of practical value but this method requires rather more blood than it may be advisable to remove from the veins of a very sick person. Methods based upon the use of reagents are much less accurate but they may give results of clinical value under certain circumstances. The effects produced upon the cells of the blood by variations in the reaction of the blood plasma are of considerable interest. In acidosis due to the presence of abnormal acid substances in the blood stream, such as may be found in diabetes mellitus, the cells show no marked variations in their staining reactions. In acidosis due to renal disease differential staining is difficult because the chemical differences between nucleus and protoplasm, and between the hyaloplasm, deutoplasm and granuloplasm of the dells are less marked than in normal blood. In slides stained with eosin and methylene blue the nuclei take a dull, grayish blue, the neutrophilic granules a grayish lavender, the eosinophiles show a dull, bluish hyaloplasm with grayish, pink granules, the hyaline cells show a dull, bluish protoplasm in which irregularities of staining often cause a semblance of granulation. The various structural changes in the cells due to disturbances in protein katabolism are usually present also. In acidosis due to circulatory disturbances, such as are found when cardiac inefficiency supervenes in other diseases, the changes in staining are similar but are usually less marked. In addition there is considerable gregariousness of the cells, and the neutrophiles and the monocytes show marked irregularities in contour; often they have their edges quite ragged and grayed. Concentration of the cells of the peripheral blood, with red and white cells counts considerably above that normal to the individual are also usually conspicuous factors in the acidosis due to cardiac inefficiency. In the blood of persons with alkalosis the cells show increased avidity for differential stains. In slides stained with eosin and methylene blue the nuclei are a very vivid and brilliant blue. The hyaline cells also show unusual brilliance of staining and they frequently contain azur granules of large size and a royal purplish blue. The neutrophiles are definitely lavender in hue and the eosinophiles shine with even more than their normal brilliance. All the cells of the blood are a trifle smaller than in normal blood and the red cells crenate very quickly on the warm slide. These variations are recognizable only if the methods employed in studying different specimens is uniform, and if the stains can be varied to meet varying conditions of the blood cells. If the conditions usually associated with acidosis are found, the stain should have a crystal or two or three of sodium bicarbonate added to the solution. This should show an approach to normal staining if acidosis is really present. If the conditions characteristic of alkalosis appear,
a stream of carbon dioxide should be passed through the stain before it
is used, or a drop of weak acetic acid may be added to the stain.
This should cause the cells to swell slightly and to give more nearly normal
staining reactions, if the cause of the staining peculiarities is really
alkalosis.
Variations in the color of the plasma or of the serum are often noted in pathological blood. Normally the blood plasma and the serum alike present a rather pale straw color due to the presence of urobilin and other bile derivatives. Abnormally several other pigments are present and these may be of importance in diagnosis under certain conditions. Incorrect readings of hemoglobin may be made as a result of discoloration of the plasma in severe cases of cholemia or carotinemia. Hemoglobin and its derivatives may tint the plasma under those conditions which disintegrate the erythrocytes. Malaria is a common cause of hemoglobinemia; the malarial parasite causes fragmentation and stroma injury of the red cells and laking occurs easily. The hemoglobin is finally excreted in the urine and the bile. The pigment within the parasite is probably a derivative of hemoglobin. The death of the parasite sets this free in the plasma. The kidneys and the liver finally eliminate it from the body. The leucocytes and the cells of the reticulo-endothelial system ingest the fragments of erythrocytes which have been ruined by the malarial parasite, and the iron-free moiety of hemoglobin is finally transformed into bilirubin or some related pigment. This pigment also is set free in the plasma. As a result of these various reactions the plasma often becomes definitely tinged in cases of malaria. Hemoglobin may be set free from the erythrocyte stroma
by several other conditions. Saponins and certain other glucosides,
several types of venom, certain bacterial products and the bile salts all
have the property of laking the blood. Excess of heat and cold, especially
alternating heat and cold, may also cause laking. This may occur,
though rarely after severe frost-bites and after some part of the body
has been frozen. Hemolytic streptococci may cause very severe anemia
which is associated with a dark-colored blood plasma. Infection by
the blastomycetes hemolytica causes hemoglobinemia like that produced by
malaria; both conditions being due to the fragmentation of the erythrocytes
by the organism and the ultimate laking of the fragments with destruction
of the hemoglobin. (Plate IX)
The blood of patients with chronic mild carbon monoxide
poisoning shows some traces of methemoglobin derived from the carbon monoxide
hemoglobin of the erythrocytes injured by the gas. The erythrocytes
whose hemoglobin has been combined with caarbo monoxide remain for a time
in the circulation but are finally destroyed. The pigment derived
from these blood cells includes methemoglobin and some r elated compounds
which tinge the plasma a peculiar brownish color. Such plasma does
not give a reaction for bile pigments by any of the usual tests.
Persons with lesions of the lower thoracic vertebrae and the related ribs suffer somewhat from renal and hepatic disturbances, and such persons are often unable to eliminate the coloring matter of vegetables adequately. These persons are usually somewhat emaciated and anemic, quite nervous and irritable and show other symptoms of mild, chronic toxemia. Unfortunately a diet rich in the colored vegetables is often advised for such patients. Being unable to eliminate the carotin speedily this pigment accumulates in the blood plasma. The plasma and also the serum in such cases presents a peculiar greenish tint which is quite distinctive, and it does not give any reaction for the bile pigments. Carotinemia is not an uncommon condition in those
countries in which colored vegetables are freely eaten. In order
to correct the condition it is necessary that the patient should eat only
colorless vegetables until the blood plasma has returned to its normal
color and the symptoms of toxemia have disappeared. Unless the patient
receives adequate osteopathic treatments he must always refrain from eating
more than a small amount of colored vegetables.
Mr. P. C. This patient was a young man with early pulmonary tuberculosis. He had been advised to go to Southern California and to live largely on vegetables. He earned his living by working in a small roadside lunch room. Being persuaded of the great value of spinach and other colored vegetables as blood-building materials he ate spinach three times each day, and ate other colored vegetables and fruits freely. He ate no cereals or starchy vegetables, no meat, eggs, milk or milk products. The lesions usually present in tubercular subjects were found on osteopathic examination. The blood cell examination showed moderate secondary anemia and the usual evidences of milk toxemia and malnutrition. There was also a greenish tint of the blood serum. The serum did not give any of the ordinary reactions for bile pigments. For three weeks no osteopathic treatments were given,
in order that the dietetic condition might be tested. Mr. P.
C. was given a balanced diet which included all good wholesome foods except
colored vegetables or fruits. He was permitted a reasonable amount
of colorless vegetables and fruits. As a result of this diet alone
the symptoms of vegetables and fruits. As a result of this diet alone
the symptoms of toxemia and malnutrition diminished, the blood serum regained
its normal color and the general condition improved. Some malnutrition
and toxemia persisted, and the symptoms of tuberculosis showed no changes.
After the carotinemia had disappeared the usual osteopathic treatment for
the vertebral lesions was given and ultimately Mr. P. C. recovered.
Blood platelets, or “third corpuscles” are small
masses of protoplasms found in the blood stream. They vary in size
with an average diameter of three microns. They have no recognizable
cell membrane and no true nucleus, though the center of the mass often
takes nuclear stains in a feeble and atypical manner. They are of
varying forms, being roundish, oval, rod-like or spindle-shaped.
They disappear very quickly after the blood has been drawn and special
methods of technique must be employed in order to count them. A few
are still visible in nearly every smear preparation. They have a
peculiar sticky consistency and they adhere to glassware very closely.
They are concerned in the coagulation of the blood.
Views concerning the origin of the platelets are interesting. Engel, Maximow, Preisch and others considered them the extruded nuclei or remnants of the degenerated nuclei of the normoblasts. Hayem thought them immature red cells. Wlassow considered them fragments broken from red cells. Schultze believed them to be fragments of broken down leucocytes. Lowit denied their actual existence and thought them merely artifacts. Bizzozero, Osler and Deetjen considered them truly cells, in the sense that the erythroytes are cells. Cole found that certain agglutinins which affect the platelets do not affect the red blood cells. Kemp found evidences of hemoglobin in the platelets. Marchesini considered erythrocytes grouped into three classes, stable, partly stable and unstable. Platelets are formed from fragments of the third class. De Govaerts and several others described bacteria found within platelets, and supposed this form of phagocytosis of bacteria and other foreign objects to be a factor in immunity. It is now thought that reports of this kind rest upon the presence of fragments of white cells containing bacteria, and that these have been mistaken for platelets. By means of more recent methods of staining, such fragments can be differentiated from platelets, and this source of error eliminated. Platelets arrange themselves in groups in shed blood and these groups may be the center from which radiating threads of fibrin arise. Disintegration occurs rather rapidly unless some methods of preserving them has been employed and during the process of degeneration various peculiar appearances occur, these have been called “mucoid degeneration” and “viscous metamorphosis;” various other terms have been applied to pseudo-structures produced during the degeneration of the platelets. The platelets are now known to be formed by budding
from the protoplasm of the megakaaryocytes in the red bone marrow.
Other sources have been described; none has been definitely proved, but
there may be several other methods of development of platelets than from
the megakaryocytes. The platelets in mammalian blood are analogous
to the thrombocytes in the blood of birds and reptiles.
The normal number of platelets seems to vary between rather wide limits at different times of day for the same person, and for different normal individuals. The normal number of platelets in normal human adult blood has been estimated at from 200,000 to 350,000 per cubic millimeter with variations of 50,000 in either direction for the same person at different times. They are physiologically low in the new-born and in senility. The blood of animals which live in darkness and of young born of such animals is low in platelets Persons whose diet contains little or no vitamin A, and animals kept without vitamin A have low platelet count. In such cases the platelets can be increased by exposure to sunshine or, less efficiently, to radiations from a mercury lamp. Increase of the foods containing vitamin A facilitates the return of the platelets to normal, though these foods are less efficient without sunshine. The sunshine seems to affect the development of platelets from tissues of the body, since platelets are increased during starvation if the animal, previously bred and maintained in darkness, is placed in sunny quarters. They are greatly increased after hemorrhages whether these are due to accident or to the effects of disease. They are increased in all secondary anemias, in chlorosis and in some cases of myelogenous leukemia. They are diminished in typhoid fever, idiopathic purpura , aplastic anemia, pernicious anemia, lymphatic leukemia, and in almost any very severe anemia with inefficient regeneration of blood. In sudden acute fevers the platelets first diminish, then increase; the changes parallel the changes in the leucocyte count. In acute fevers of somewhat longer course the platelets do not follow the leucocyte changes but diminish during the early weeks, then increase as the strength of the patient diminishes. Rapid decrease of platelets is of ominous significance during the course of the slower acute fevers, especially typhoid fever. In most cases of acute, severe, high pyrexia the platelets are very low; in severe pneumonia and in severe malaria it may be difficult to find any platelets at all, even by the most careful methods. After crisis in pneumoia, and after sudden decrease in any fever, the platelets may suddenly rise far above normal, and then within a few days return to normal numbers. In erysipelas, septicemia and acute articular rheumatism, however, the platelets are considerably increased. Platelets are diminished in the circulating blood during the formation of a thrombus; this fact may be useful in the diagnosis of thrombosis in the early stages. In one case of ours the diagnosis made upon this fact, in a case of doubtful nervous disease, was quite important. The platelets remain unchanged in most hemorrhagic
diseases, and in most other forms of secondary anemia the platelets are
considerably increased. This fact is sometimes useful in diagnosis.
These particles of protoplasm seem to undergo dissolution in the circulating plasma, and probably serve as food materials for various tissues. The spleen and other areas of the reticulo-endothelial system, and the monocytes of the circulating blood all ingest and destroy them. Their length of life has not been well studied.
Probably they live only a few days at most. Indeed the term “life”
is scarcely applicable to their feeble activities of the time of their
functional value.
The relations of the fibrinogen of the blood, the phenomena of clotting and the mechanisms by means of which the blood is maintained in a fluid state under ordinary conditions present a group of interesting problems. The functional value of coagulation is evident.
Upon even a slight injury to the blood vessels the blood coagulates and
thus plugs the bleeding vessels. The formation of a coagulum in wounded
areas serves several useful purposes. The injured cells are cemented
together and held in place. The peripheral layer of adult cell protoplasm
is subjected to the tension normally present in embryonic cells and the
pressure thus exerted upon the cell contents initiates cell division, thus
leading to replacement of the cells destroyed by the injury. Further
bleeding is prevented and conditions adapted to rapid repair of the wound
are presented. The repair of wounds by first intention is often surprisingly
rapid and this is due to the fact that the coagulum provides these necessary
conditions for the recovery of injured cells and the replacement of destroyed
cells.
The mechanism of coagulation has been studied carefully by many workers but the problems are not yet solved in any satisfactory manner. It seems fairly well demonstrated that coagulation of the blood can occur only when there are present fibrinogen, platelets, calcium salts and extract derived from injured cells, either of the blood itself or of their tissues. The relations between these factors and the steps by which each substance reaches the final clot have been variously described by different students. Howell’s theory is the basis upon which more recent investigators have developed many ingenious descriptions. According to Howell, normal circulating blood contains fibrinogen, prothrombin, alcium salts and anti-thrombin. The function of the last named substance is to hold the prothrombin in combination and to prevent the formation of thrombin within the blood vessels. When blood escapes from the vessels, or when certain abnormal conditions occur within the vessels, the platelets disintegrate and thromboplastin is set free; this combines with the antithrombin, which in turn sets free the prothrombin. The prothrombin becomes thrombin in the presence of calcium salts; this acts upon the fibrinogen and transforms it into fibrin, which is the substance which forms the clot. In the blood of birds and lower vertebrates the thromboplastin cannot be formed from blood alone, which is due to the fact that these animals have no true blood platelets. For coagulation to occur in the blood of nearly all birds there must be some substance derived from tissue cells. Thromboplastin is a substance related to the phosphatids and it an be extracted from injured tissues by means of ordinary fat-solvents. The Morawitz theory assumes that thrombin exists in the circulating blood in an inactive state (prothrombin; thrombogen). Thrombokinase is produced by the action of calcium salts on some tissue extract or some product of injured living cells. Or, by the simultaneous presence of calcium salts and cell products without chemical relationship, the same effect is produced. This thrombokinase acts upon the thrombogen (prothrombin) causing it to become transformed into thrombin. The cell product is called a thromboplastic substance. Soluble calcium salts must be present in order that the thromboplastic substance and the prothrombin may form thrombin, but it is doubtful whether the salts enter into chemical relationship with the thromboplastic substance or not. Several variations of these two theories have been offered, but they are based upon one or the other of the two just described. It will be noticed that they differ only in the points affecting the development of thrombin. Coagulation occurs under several different circumstances
and the essential nature of the process must vary to some extent with these
circumstances. Artificial and experimental methods as well as the
conditions which occur under pathological conditions must be considered.
The coagulation which occurs within the blood vessels, that which occurs
upon the surface of a wound and within the meshes of injured tissue, that
which occurs outside the body in whole blood and that which occurs when
blood is coagulated after various experimental procedures present different
phases of activity.
Intravascular clotting or thrombosis occurs under different circumstances. Extracts from injured cells are always concerned in thrombosis, and it is rare that injured blood cells themselves are the important factors. When the blood vessels are injured, the endothelial cells produce the extract needed for clotting. Such a clot begins at the site of injury, gradually fills the vein and may extend toward the heart until the clot has reached the next branch of the vein; the clot may continue past one or several branches of the veins and these also become filled with the clot. Fragments may be broken from the clot and pass in the blood current as emboli, with further pathogenic influences. Thrombus formation presents several peculiarities. The part of the thrombus first formed contains a great abundance of platelets. These apparently have agglutinated for some reason. In certain cases it seems that some change in the platelets themselves facilitate abnormal agglutination. In other cases it seems that some abnormal current of blood causes mechanical grouping of the platelets with resultant adhesion and agglutination. The grouping of floating elements of like weights and sizes in the eddy of a stream illustrates the method of grouping of platelets at the site of an aneurysm or in vessels which are irregularly dilated. The presence of a foreign substance, an injury to the vessel wall, or an inflammation of the intima may initiate accumulation and agglutination of the blood platelets, and the thrombus follows inevitably. In many cases of thrombosus it is impossible to determine the cause of the intravascular clotting. Blood found in the serous cavities at operation is usually free from clots, though it may have been outside the blood vessels, so far as can be determined from the symptoms for several hours. Absorption of such blood can occur. From experimental evidence it seems that many cells become degenerated, but that some of them may be absorbed by the peritoneal lymphatics. The plasma seems to be absorbed chiefly by the capillaries and veins. In other cases of peritoneal hemorrhage blood clots are found at operation. It is not known whether this is due to some difference in the rate of bleeding, in the quality of the blood or in some condition of thrombokinase, antithrombin or fibrinogen. There is no reason for supposing that there is any difference in the calcium content of the blood which coagulates in the peritoneal cavity and that which does not clot under apparently identical circumstances. Foreign substances in the blood stream may cause
coagulation. It may be that the blood cells injured by the foreign
substance provide the necessary cell extract, but in nearly all cases it
is the injured endothelium which produces this substance. The floating
foreign particle rarely, if ever, forms the nucleus of a clot. It
is quite possible that this is due to the fact that the particle ceases
to float as soon as it is surrounded by coagulum. An embolus derived
from a thrombus serves as the starting point of other thrombi; in this
case the thrombus is itself a foreign substance.
Intravascular coagulation may occur as a result of the injection of solutions containing tissue extract, such as may be derived from testis, thymus, lymph nodes, spleen, liver, and other tissues rich in nuclei. Extracts may be prepared from any of these tissues which cause speedy coagulation of the venous blood when they are injected in a vein. It seems to be nucleoalbumin or some related phosphoprotein which causes the clotting, and its manner of action is not clearly understood. In terms of Howell’s theory, such a substance neutralizes the antithrombin. In terms of the Morawitz theory the extracts provide a thrombokinase. If the animal is poorly nourished the clot is confined to the vein injected. The well-fed animal, under the same circumstances, produces clot through all the veins. If, however, instead of a single mass injection of the tissue substance is made, a series of injections of very small amounts of the same substance are given an animal the coagulation time may be greatly prolonged. By careful manipulation of the extracts and of the nutrition of the animal the coagulability of the blood may be completely destroyed. It is not possible to act upon blood in vitro in such a way as to secure such changes and the repeated injections of small amounts of the cellular extracts must cause a reaction on the part of the living cells of the body somewhat similar to that caused by mild infections or by the absorption of the products of infectious processes within the body. The stroma of mammalian erythrocytes from which the
hemoglobin has been washed facilitates clotting. If any considerable
amount of this stroma is made into a suspension and injected into the veins
of an animal, even of the same animal from which the erythrocytes were
derived, the blood clots within the blood vessels within a few minutes.
This stroma is not related to fibrinogen but is composed chiefly of cholesterin
or some similar lipoid.
Fibrinogen is present in the circulating blood and in various tissue fluids, such as lymph, chyle and certain transudates and exudates. Fibrin may be found in the sputum, urine, various inflammatory exudates and occasionally in the contents of cysts. Fibrinogen may occur in these fluids also, in which case coagulation can be produced by the addition of thrombin, calcium or tissue extracts, according to the lacking factor in the fluid being examined. Fibrin in sputum and in certain inflammatory products and certain cyst contents presents a gross resemblance to mucus. The differentiation is made by chemical and staining reactions. Fibrinogen in the circulating blood is not very abundant. It is a globulin which is constantly being utilized as a food by nearly all the cells of the body. It is formed chiefly in the liver but is also formed, to some extent, by the intestinal walls, the spleen, the bone marrow and, possibly, by certain leucocytes of myeloid origin. The lymphocytes seem unable to form any fibrinogen at all, and the endothelial cells of the blood are very inefficient as manufacturers of fibrinogen. The amount of fibrinogen in the circulating blood is greatly diminished in human subjects suffering from any disease of the liver except abscess and cancer. Phosphorous poisoning, acute yellow atrophy and any form of cirrhosis of the liver are associated with extremely small fibrinogen content. In such cases the coagulation time is not greatly increased but the resultant clot is very soft; in some cases the blood may not form a recognizable clot at all. In animals the removal of the liver from the circulation by any operative procedure (or its destruction by poisons) prevents the development of fibrinogen after this substance has been removed from the blood vessels. Both human and animal subjects with bony lesions affecting the circulation through the liver show similar but less marked effects. The clot is formed almost or quite within the normal time but it is soft and the clot does not retract readily. After the correction of the lesion the fibrinogen returns to its normal amount within a few weeks or months, according to the size of the animal and according to the diet and the nutritive condition of the human subject. Under certain physiological conditions the blood varies in coagulability without regard to the fibrinogen content. Increase in the epinephrine content of the blood hastens coagulation. This occurs normally whenever an animal becomes angered or frightened and there is much reason to believe that the same reaction occurs under emotional excitement in man. The place of adrenal secretion in modifying coagulation is of importance. The experiments of Cannon and others are enlightening. As a result of fright or anger the adrenals secrete increasing amounts of epinephrine, and this increases the coagulability of the blood. The biological significance of the reaction is apparent; the speedy closing of the wounds anticipated in battle is thus facilitated. The contraction of the peripheral blood vessels under similar circumstances has also the effect of preventing serious hemorrhage from superficial wounds. Epinephrine added to blood in vitro does not hasten its clotting, and the addition of epinephrine to the blood of animals does not affect its coagulability unless the circulation of the blood through the liver remains unimpeded. The diminished coagulability of the blood of humans with atrophy of the liver or with certain serious degenerations of liver cells is of interest in this connection. Repeated massive doses of epinephrine may delay coagulation
of the blood of dogs, and may even destroy coagulability altogether.
By varying the amounts it is possible to hasten or delay coagulation time
or to cause prolonged or delayed changes in coagulability.
Direct stimulation of the splanchnic nerves increases coagulability. This reaction does not occur in animals whose adrenals have been removed, which suggests that the nervous stimulation of the adrenals might be responsible for the effects of splanchnic stimulation. Human subjects with lesions affecting the splanchnic
spinal centers show diminished coagulability; this more commonly displays
itself in a soft clot with little or no retraction than in increased coagulation
time. Such persons have almost always a low blood pressure, weakened
heart action and some visceroptosis, all of which indicates diminished
activity of the adrenals. However, the presence of bile pigments
in the blood of these persons suggests also diminished hepatic activity,
and since the liver is the chief source of fibrinogen the lack of this
substance may be the most important factor in the effects of splanchnic
vertebral lesions. Further work must be done before these relations
can be explained.
The fibrin can easily be removed by heating and stirring freshly shed blood with any slender rough rods, such as metal wires or wooden sticks. The fibrin is deposited upon the foreign substance and thus can be removed easily, leaving the serum and the cells in a fluid state. The fibrin holds some red cells, many hyaline cells and nearly all the granular cells within its meshes. A differential blood count made of the fluid blood therefore shows an undue proportion of hyaline cells. Normal blood which has been defibrinated is useful for a study of the changes occurring in vitro in the cells of the shed blood. The injection of defibrinated blood into the veins of the person from whom the blood was taken, or into the veins of anemic persons, has been used in therapy. Animals differ somewhat in the coagulability of blood. The vein of a horse can be tied in two places, enclosing any convenient length of vein between the ligatures. The vein then can be severed above the highest and below the lowest ligature and it will then retain the blood in a fluid state for a long time, sometimes for several days. If this bag be kept quiet, the corpuscles sink to the lowest part and the supernatant plasma may be poured off into another vein or into a glass vessel which has been coated thoroughly with paraffin or some other perfectly smooth surface. If the plasma is poured into glass or other vessels, not specially treated, coagulation occurs almost immediately. Horses’ blood received into a prepared vessel at 0 degrees C. and kept at that point does not coagulate. The blood of a bird coagulates very quickly after ordinary wounding. But the blood can be removed from a vein by means of an oiled or paraffined canula, avoiding contamination of the blood by any substance derived from the tissues, and coagulation may not occur for several days, if all dust and foreign matter be kept away. Such blood can be centrifuged and the plasma and cells secured separately. Several salts can be added to the blood which prevent coagulation. Human blood to be used for chemical tests is usually taken from a vein by a sterile syringe and immediately thrown into a vessel containing a few crystals of sodium citrate or sodium oxalate. The oxalate precipitates the calcium. One part of oxalate to 1,000 parts of blood is sufficient. Rabbits, cats, dogs, guinea pigs and other laboratory animals have speedier clotting time. In taking their blood for chemical tests we use a syringe which has been rinsed in oxalate or citrate solution, and put the blood into a vessel also rinsed with the same solution, in order to prevent clotting. The corpuscles settle out of oxalated blood or they may be thrown down more quickly by centrifuging. Oxalated blood or plasma can be made to clot by adding some suitable calcium salt. The citrate has a somewhat different action.
This salt does not precipitate the calcium but it enters into the formation
of a double salt, sodium calcium citrate, in which the calcium is in the
anion; that is, the calcium is associated with the acid radicle while the
sodium is the kation. Coagulation does not occur, even in the presence
of a soluble calcium salt, unless the calcium is ionized past the kation.
This condition is present in calcium chloride and calcium sulphate.
Either of these salts added to either oxalated or citrated plasma or whole
blood is followed by almost immediate clotting.
The addition of one part of a 25% solution of magnesium sulphate to four parts of blood prevents coagulation in the blood of any mammal for an indefinite length of time. Magnesium sulphate precipitates the thrombokinase but this reaction proceeds slowly. If the blood is centrifugated immediately the plasma is clear and fluid, but it coagulates within a short time after it has been diluted to about the normal specific gravity. But if the magnesium salted plasma of whole blood is allowed to remain for one to several days then neither dilution nor the addition of tissue extracts causes clotting; evidently this is due to the precipitation of the thrombokinase by the salt. The addition of one part of a half-saturated solution
of sodium sulphate to one part of blood also prevents coagulation of the
blood of any mammal for an indefinite time. Either the whole blood
or the plasma freed from the cells coagulates at once after dilution with
water to about the original specific gravity of the blood.
Certain animal extracts prevent coagulation in vitro or when injected into the veins of the animal. Hirudin is an extract made from the anterior part of the body of a leech. The prolonged bleeding time of wounds produced by the bites of leeches has long been known. The efficiency of leeches in old-time methods of treatment by bleeding depends upon the fact that a peculiar albumose derived from the buccal glands of the leech was injected into the tissues of the wound, and this prolonged the bleeding time. Blood received into a vessel containing a solution of hirudin does not coagulate. Hirudin injected into the veins of an animal prevents coagulation within the blood vessels after death. Blood drawn either before or after the death of the animal injected with hirudin does not coagulate. Since hirudin is an antithrombin, blood which has
been prevented from clotting by its use needs only to have thrombin added
to it in quantities beyond the efficiency of the hirudin still present.
Clotting then occurs.
A solution of peptone injected into the veins of an animal prevents the coagulation of the blood both within the vessels after death and in vitro whether the blood is removed before or after the death of the animal. Peptone does not prevent coagulation if it is added to the blood in vitro, however. The nature of the physiological relations concerned is puzzling An animal which has received an injection of peptone and has thus the coagulability of its blood diminished or destroyed cannot be used for a second similar test for several weeks. At any time within a few days a second or later injection of peptone solutions has little or no recognizable effect on coagulation. There is no other recognizable change in the physiological condition of the animal under such circumstances. A solution of peptone perfused through an extirpated liver causes the appearance of an anti-coagulating agent in the hepatic veins. This agent seems to act by neutralizing the fibrin ferment but its nature is not yet known. Peptone is much more efficient as an anti-coagulant if the animal to be employed has fasted for a few hours before the experiment is begun, and if the peptone be injected rather slowly. An anticoagulin is formed within the liver and this may be antithrombin. Peptone plasma can be induced to clot by adding an
extract from tissue cells to it, or by passing a stream of carbon dioxide
through the vessel containing it. The addition of ordinary amounts
of fibrin ferment may induce coagulation in peptone plasma or peptone whole
blood.
Venoms from snakes and other lower animals produce different effects on coagulation. The venom of the cobra inhibits coagulation whether it is injected into the blood in minute amounts during life or is placed in a vessel into which the blood is to be received. Other snakes (for example the pseudechis porphytacrous) produce a venom which causes abundant coagulation within the vessels of a living body, such as might follow the injection of tissue extracts into the blood stream. It is not known to what constituents of the venom this effect is due. Certain intestinal parasites produce a substance which prevents coagulation. Wounds made by them in the intestinal wall continue to bleed for a long time and the entire blood may show greatly diminished coagulability because of the absorption of this substance. The severe anemia due to the hook worm, the dibothriocephalus latus and other intestinal worms is thus explained. There is little change from birth to senility in the coagulability of normal blood. The coagulation time has been determined for newly born infants by many authors. The figures vary slightly from four to ten minutes, with an average of seven minutes; this is longer than the average coagulation time of adults. Newly born infants with hemorrhages show greatly prolonged clotting time and increased coagulation time. Intramuscular or intravenous injection of paternal or other whole blood frequently provides the necessary substances and after coagulation of the blood has been established the hemorrhages may cease. For a day or two before menstruation begins the coagulability of the blood is slightly diminished for about two-thirds of the women examined. The old idea that menstrual blood does not coagulate is untrue; any blood mixed with mucus coagulates with difficulty or not at all. The presence of mucus and of degenerated endometrial cells prevents coagulation to some extent. Pure menstrual blood coagulates as quickly as does blood derived form the veins of any part of the body. During pregnancy the coagulability of the blood is somewhat diminished; possibly the developing embryo or fetus needs the serum albumins and globulins. Before labor an increased coagulability of the blood is occasionally noted. The biological relations of these facts are self-evident. The blood from embryos shows low coagulability. In pig embryos from 100 to 250 millimeters in length the average coagulation time was found by Emmel and others to be twenty-three minutes. The adult pig’s blood coagulates within about three minutes. Addition of adult pig platelets or of extracts of adult cells to the embryonic pig’s blood caused coagulation to occur within three to four minutes. Calcium is higher in the blood of embryonic pigs than in the blood of adult pigs. In normal old persons the coagulability of the blood is normal or only slightly hastened. Various diseases affect senile blood rather more seriously than younger blood but there is no quantitative variation in the effects after adult life has been reached, so far as coagulation is concerned. Variations in the coagulability of the blood in certain diseases present even more puzzling problems. The abnormal conditions of coagulation include (a) delayed clotting (b) imperfect nature of the clot (c) hastened clotting The causes of these different abnormal conditions of coagulability may differ considerably. There may be a lack of fibrinogen in the circulating blood. This causes the formation of a soft and imperfect clot which permits prolonged bleeding from wounds which may be almost negligible. Lack of fibrinogen is known to occur when the liver is seriously injured, as in cases of poisoning by phosphorous or chloroform, or in cases of hepatic cirrhosis or acute atrophy, or in fulminating cases of certain infectious diseases. There is not any delay in coagulation in uncomplicated cases of deficiency of fibrinogen. Morawitz considers lack of thromboplastin (prothrombin) an important factor in cases of delayed coagulation. It is difficult to see how there could be a lack of a substance derived from injured cells, especially as injured blood cells may produce it. It is possible that a disturbance in the metabolism of the cells, necessarily of developmental and constitutional nature, may so affect the end-products of katabolism that the thromboplastic substances are inefficient in the transformation of prothrombin to thrombin. Deficiency of calcium salts was at one time considered important in the etiology of delayed coagulation. That the blood always contains enough of the soluble calcium to provide for coagulation seems definitely proved. Increased calcium intake does not hasten coagulation in any useful degree, though certain cases of delayed coagulation in obstructive jaundice seems to be somewhat improved by increased calcium intake. Deficiency of prothrombin is present in cases of melena neonatorum. In these cases intramuscular infusions of whole blood or intravenous injection of blood serum or of whole blood are usually efficient in relieving the condition, by adding the necessary prothrombin to the blood of the infant. Excess of antithrombin may prolong coagulation. Certain chemical agents, such as hirudin, act as antithrombins and coagulability may be completely destroyed by such substances injected into the blood stream. Lack of blood platelets diminishes coagulability,
since these structures are the chief source of prothrombin, probably also
of thromboplastin.
Increased rapidity of coagulation may occur as a result of increased amounts of epinephrine, as already noted, under experimental conditions. It does not seem to occur as a result of disease. Increased amounts of antithrombin occur in pneumonia and this fact is useful in diagnosis. In septicemia and in miliary tuberculosis there may be excess of antithrombin. The biological significance of increased coagulability in these diseases is evident. Hemophilia is a puzzling disease which is characterized by a marked tendency to continued bleeding from wounds apparently insignificant. The blood coagulates in vitro within a normal time, but the clot is soft and fails to show retraction present in a normal clot. In this disease the platelets are normal in number but they do not agglutinate properly, and it seems that they lack the ability to form prothrombin. The nature of this functional defect is not known, but the hereditary character of the disease indicates that the defect is inherent in the germ plasm. The blood of a hemophiliac contains normal amounts of fibrinogen, calcium, salts, and platelets; the blood cells are normal in both actual and differential counts. A normal clot is formed in vitro from the blood of hemophiliacs if kephalin is added to it. If the tissue of the bleeder is bruised or if the blood flows over injured tissues after leaving the vessels, the blood clots and the clot retracts as in normal blood. These various observations indicate that the platelets defect is essential in the disease Another peculiarity of the blood platelets of hemophiliacs is their failure to agglutinate at the site of bleeding points, as do the platelets of normal blood. Deficiency of platelets may prevent normal coagulation.
Excess of platelets does not cause abnormally rapid coagulation nor the
formation of an abnormal clot. In certain hemorrhagic diseases such
as the leukemias, and in certain infectious diseases, such as “black” smallpox
and “black” diphtheria, the platelets are tremendously diminished.
As a result of leukemia the leucocytopoietic centers crowd out the megakaryocytes,
thus preventing normal replacement of the platelets. As a result
of the exhaustion of the bone marrow, in extremely malignant infections,
the megakaryocytes share in the atrophic changes. In these cases
it is occasionally impossible to find even one platelet by the most careful
methods of taking the blood. In these diseases the coagulation time
remains almost or quite normal but the clot is very soft. The bleeding
time may be prolonged almost indefinitely.
The diminished coagulability of the blood in persons with hepatic disease has long been recognized. Several factors are concerned in this relationship. The place of diminished fibrinogen formation as a result of hepatic disease has already been mentioned. The mixture of bile pigments, and especially of bile salts, with blood in vitro diminishes coagulability. With hepatic diseases cholemia is very common; the diminished coagulability may be, in part, due to the cholemia. The bile interferes with the conversion of fibrinogen into fibrin, but the amount of thrombin is not affected. Carbon monoxide poisoning delays coagulation.
In lethal cases the blood may not coagulate at all within the vessels.
In the chronic mild carbon monoxide poisoning which is so common in large
cities the coagulation time is usually prolonged to ten minutes or more
(normal by our methods, four to six minutes).
Deficiency of fibrinogen may prevent the formation of a normal clot. The coagulation time is not modified, if coagulation occurs at all, but the resultant clot is soft, does not retract and serves little useful purpose in closing wounds. Deficiency in prothrombin is apparently the cause of melena neonatorum. Intravenous transfusions or intramuscular infusions of normal blood usually result in supplying the lacking factor to the infant’s blood and recovery usually follows promptly. Deficiency in thromboplastin has been emphasized by Morawitz. Since this substance is derived from injured cells of blood or tissues its presence would seem almost inevitable. Possibly there is some developmental defect in the cells of bleeders of this group. Excess of antithrombin occurs under experimental
conditions such as the injection of hirudin or peptone into laboratory
animals. An excess of antithrombin is said to occur during the course
of septic diseases, especially those affecting the lungs.
The manner in which the fibrin threads appear on the warm slide which is practically a vital phenomenon, gives much useful information. The slide is kept at 99 degrees F., to 100 degrees F. usually by means of an electric appliance made for the purpose. The blood is placed on this slide directly from the exuding drop, is immediately covered with a warm cover-glass and examined immediately. Hence the blood is under physiological conditions, except for the lack of circulation and the recurring variations of oxygenation, nutrition and so on. Vital phenomena occur under such circumstances almost normally. The presence of the foreign bodies, the slide and cover-glass, initiate reactions similar to those occurring within the body around a foreign body, if not identical with them. The manner in which fibrin is formed under such circumstances presents variations which are often very useful in diagnosis. Normal blood placed on the warm slide begins to show fibrin threads after about ten minutes. If the slide is warmed to 103 degrees F. fibrin threads may appear within five minutes. The threads are very fine, so that accurate measurements have not yet been found practicable under the circumstances of the warm slide preparations. When threads of fibrin fail to appear upon the warm slide within about ten minutes, the condition is distinctly abnormal. In persons whose diet fails to include a proper amount of protein foods, but who are not utilizing their own muscles as a source of energy, the amount of fibrin may be extremely scanty and may appear only after fifteen minutes or more. The greatest delay and the greatest lack of fibrin upon the warm stage occurs in persons with serious hepatic disease, but not in cancer of the liver, either primary or metastatic, nor in abscess of the liver. The even caliber of the normal threads is noticeable. The threads vary in length. When first visible, they are from three to six microns long. During the fifteen minutes following their first appearance they increase in length, at first visibly, then more and more slowly. By careful watching it is usually possible to say that the fibrin formation ceases at a definite minute. Abnormally fibrin may be present as soon as the slide is seen under the microscope, or it may not appear at all, or only after half an hour or more on the warm slide. In normal blood the fibrin threads appear to have no relationship with one another, and rarely to any other blood structures. Occasionally they seem to originate from a group of platelets; this is in normal blood at correct temperature. The threads are straight and they may or may not lie across one another. Abnormally many fibrin threads radiate from groups of platelets or from white cells; they form net-like arrangements which may be quite complicated in structure; they may be so related with phagocytes as to appear to be merely continuations of abnormally long and slender pseudopodia; they may be abnormally long and abnormally heavy, or they may present marked irregularities in contour or they may even have sharp variations in thickness so that they present a definitely beaded appearance. The significance of these variations is not yet clearly understood. Much further work must be done before the problems presented by these most interesting reactions are solved in any satisfactory manner. But there are useful indications of diagnosis and prognosis to be gained from a study of fibrin formation as it occurs on the warm slide. Fibrin develops very speedily under several conditions,
and in many cases this is of great value in early diagnosis.
In lobar pneumonia fibrin develops immediately and abundantly. The threads are long, heavy, fairly even in content, not arranged in nets but often so abundant as to present a felted appearance. The fibrin is completely formed within a very few minutes or, occasionally, is completely formed at once, so that no increase in the length of the threads is visible. By the time the slide is placed under the microscope, very often, the abundant heavy threads are easily visible. This reaction is present in such degree in no other acute disease, and it occurs so early that a diagnosis of lobar pneumonia can often be made twenty hours before any other pathognomonic finding can be secured. During the course of the disease and for several weeks after recovery this rapid fibrin formation is present. It disappears gradually and the blood returns to the normal condition after some weeks,--the exact time for recovery of normal fibrin relations has not yet been studied. In aborted cases of pneumonia this fibrin reaction also occurs and it is possible to determine whether or not an actual pneumonia has been aborted by a study of the fibrin at any time within a week after the initial symptoms have disappeared. In ordinary colds, in cases of influences without
pulmonary involvement, in bronchitis without alveolar involvement and in
other infections without lung disease but presenting symptoms that might
be confused with early pneumonia, the fibrin formation is either normal
or only feebly modified.
In active carcinoma the fibrin formation is very rapid, and in some cases is as rapid as in pneumonia. In malignancy the threads are uneven in contour and there may be so many and such marked inequalities that the threads present a definitely beaded appearance. The threads often radiate from a small group of platelets or from a white blood cell, usually a lymphocyte. In cases in which there is some difficulty of diagnosis, the presence of these irregular fibrin threads, appearing quickly and in great abundance, suggests carcinoma. In sarcoma the fibrin threads present less marked modifications, and the reactions are of much less significance. In malnutrition the fibrin threads are extremely fine, delicate and scanty. If the malnutrition is associated with any marked toxemia, the threads are apt to be uneven in contour. If there is little or no toxemia, the threads are even and regular, but are so very fine that it may be difficult to see them at all, except when the field is darkened or a dark-stage illuminator is used. The fibrin formation is considerably delayed in malnutrition, often to twenty or thirty minutes after the blood is placed on the warm slide. When malnutrition is associated with malignancy or
with early pneumonia, the fibrin threads become heavy, abundant, irregular
and are formed very speedily, as in ordinary malignancy and pneumonia.
In other diseases associated with moderate increase in the fibrin threads,
the presence of severe malnutrition modifies the fibrin reactions, so that
it may often be difficult to determine the relationships of the fibrin
studies. Fortunately most of the conditions in which there are complicating
factors are those in which some other laboratory findings or some symptom
complex helps in differentiation.
The fibrinolytic ferment was first studied in the laboratory of The A. T. Still Research Institute in Chicago. Since that time it has been studied in other laboratories of the Institute and in several other laboratories, though the subject has not yet received the attention to which its importance entitles it. Normal blood usually contains an enzyme which digests the fibrin of the blood clot but which does not digest the cells of the blood or the tissues of the body. The blood of approximately one-fourth of all persons, healthy or ill, fails to contain this ferment. The fibrinolytic ferment is destroyed by heat above 108 degrees F., and its activity is diminished at 104 degrees F. and by temperatures below 96 degrees F. Tests have not yet been made determining the low point at which the enzyme is destroyed. Fibrinolysis is decreased by the use of distilled water in the tests and by the presence of any appreciable excess of the salts present in tap water or spring water. Roseman was able to precipitate a fibrinolytic substance from fibrin autolysate. A similar substance was extracted from the pressed juice of pneumonic lung. This substance differs from leucocytic trypsin in its greater thermolability and by the fact that it is not related to the leucocytic content of clot. The exudates from tubercular scrositis markedly retards fibrinolysis. Roseman also later reported that the fibrinolytic substance of horses’ blood serum is precipitable by alcohol, ammonium sulphate and zinc chloride. It is not dialyzable. Temperatures of 46 degrees to 48 degrees C. are destructive. Tubercular exudates inhibit fibrinolysis by this enzyme also. Human material gives the same findings, according to Roseman. The function of this ferment in normal life is not known. Inasmuch as persons who lack the ferment show no evil effects referable to its lack, except as shown later in this chapter, its function may be altogether protective. Possibly other ferments may perform similar or identical functions under ordinary circumstances. The function of fibrinolysis is most easily recognizable after the repair of wounds. When any tissue is injured, the blood vessels of the immediate vicinity are dilated. An increased amount of fluid passes into the tissue spaces. Usually the capillaries of the part are also injured so that there is some extravasation of blood (hemorrhage per rhexin of the older pathologists). If there is no frank bleeding the dilatation of the blood vessels permits some escape of blood from the capillaries (hemorrhage per diapedesin). The fluid derived from the blood plasma as well as the blood itself undergoes coagulation throughout the areas involved. The clot contracts very slightly and this reaction forms a fairly firm substance which exerts pressure upon the periphery of every living cell within the area. This pressure exerts the same influence upon the cellular contents as that which is exerted by a cell wall. The mature cells of animal bodies do not have a cell wall, and their surfaces offer no resistance to the growth or the swelling of the cell. Mature animal cells continue to grow until the metabolic control of the nucleus is reached but they do not undergo division unless the cell contents are subjected to pressure. The coagulum exerts such pressure. The cells imbibe some fluid from the surrounding edematous fluids which, in turn, are due to the vaso-dilatation. With increasing intercellular pressure the phenomena of karyokinesis are initiated in some of the cells and they divide. This division of the cells is necessary to the repair of the wounds. Not only the tissue cells themselves but also the various hyaline cells of the blood and of the tissue spaces begin to divide in the same way (plasma cells, macrophages, lymphocytes, monocytes and others). These processes follow a definite series of events which differ slightly according to the histological characters of the tissue which has been wounded but which always include the multiplication of several types of cells after a preliminary pressure due to the clotting and the swelling due to the edema. The ingestion, digestion and removal of the debris left by the injured tissues is also an essential part of the phenomena of repair. When cell division is no longer required the clot must be removed. In persons whose blood contains the fibrinolytic ferment the digestion of the fibrin of the clot begins within about twenty-four hours and is complete within about fifty hours. If the wound is simple, without any serious bruising of the tissues and no infection; that is, if the wound is repaired by first intention, there is little or no need for further cell division after the first day or so. The digestion of the fibrin thus removes the impulse to karyokinesis and no further multiplication of the cells occurs. If the fibrinolytic ferment is absent the various microphages and macrophages must destroy the coagulum; this is a slower process and there is some reason to believe it less efficient than normal fibrinolysis. After inflammations of any ordinary type, the presence of normal fibrinolysis facilitates the removal of the remaining coagulum. Persons recovering from pneumonia may show rapid and complete resolution if their blood contains normal fibrinolysis, or resolution delayed with a greater amount of cirrhosis if the blood lacks fibrinolytic ferment. During high fever and under certain other conditions there is produced a non-specific proteolytic ferment in marked degree. This ferment is present in the blood of all persons in a very slight amount, and it may be very greatly increased during high temperatures. This non-specific proteolytic ferment facilitates the digestion and removal of coagulum even in persons without fibrin ferment, so that the lack of fibrinolysis is not a serious matter in those cases characterized by hyperpyrexia. Low grade inflammations do not initiate any great increase in the non-specific proteolytic ferment (or ferments), and persons whose blood lacks the fibrinolytic ferment show delayed resolution, a greater amount of connective tissue hyperplasia and more serious adhesions after recovery from inflammations with mild pyrexia than do persons with normal fibrinolysis. For example, of many patients with severe acute inflammatory rheumatism with high temperatures about one-fourth have no fibrinolysis while about three-fourths have normal fibrinolysis. All of these patients develop an abundant supply of the non-specific proteolytic ferment during the high fever. The coagula of the inflamed areas are digested and absorbed, and there is no recognizable difference between the two groups of persons so far as recovery is concerned. On the other hand, of a considerable number of persons with some low-grade arthritis characterized by little or no fever, about one-fourth have no fibrinolytic ferment while about three-fourths have normal fibrinolytic ferment. As a rule (not without exceptions) those persons without fibrinolytic ferments have greater hypertrophy of the affected joints with denser adhesions than do the persons with normal fibrinolysis. Of all persons with any type of chronic articular rheumatism about eight-tenths have no efficient fibrinolytic ferment. That is, persons with normal fibrinolysis have a partial immunity or else they recover more speedily. The place of fibrinolysis in protection against malignant neoplasms has been studied with some care. Animals which have about the same cancer-incidence as human beings have about the same fibrinolysis incidence, that is, about one-fourth of all individuals lack the ferment while about three-fourths show its presence in the blood serum. Animal families which seem to be immune to cancer all show normal fibrinolysis. Animal families which have no immunity to cancer have no fibrinolysis. In human families in which cancer never occurs, all members have blood with normal fibrinolysis. In human families in which there are many cancers both in the paternal and maternal line of inheritance, the fibrinolytic ferment is absent in nearly all individuals. That is, many persons of the human race inherit an important factor of protection against cancer. Persons who do not have this factor of protection against cancer may still fail to develop cancer. For the development of certain kinds of cancer repeated
irritation seems to be necessary; for other kinds some chronic inflammatory
processes seem to be necessary. Other types of cancers arise from
some developmental defect. For all kinds of cancer the cooperative
activity of two or several pathogenic processes seems to be necessary.
The lack of the fibrinolytic ferment is one factor which is common to many
cancer-producing conditions, among animals and human subjects alike.
PLATE IV Neutrophiles in severe cholemia. From patient
with cancer of the liver, a few days before death. The protoplasm
is eroded, leaving the nuclear masses.
Persistent vegetable diet does not lead to its development. This test was repeated in human beings because of the rather common idea that vegetarianism tends to diminish cancer development. In this connection it may be said that certain gramnivorous animals are very prone to cancer, and that other gramnivorous animals are almost or quite immune; that certain carnivorous animals are prone to cancer and other carnivorous animals are immune; that of any animal group certain strains or families may be immune while other strains or families may be unusually susceptible. The animals most thoroughly studied in this connection are all laboratory animals, kept under conditions as nearly normal as is practicable for animals in confinement. Persons known to have cancer, and in whose blood no fibrinolysis can be shown, have been treated by giving them infusions of the blood of persons whose blood is known to be well-provided with the fibrinolytic ferment. The number of cases so treated is too few to warrant definite statements. The patients so treated were those for whom recovery could not be expected under ordinary methods of treatment, and a few of these have recovered from the cancer and have lived without recurrence for ten years or more. Such persons have shown normal fibrinolysis for six years or more after the last administration of blood. Normal blood has been given to patients whose blood contained no fibrinolysis and who suffered from arthritis deformans with unusually dense adhesions; normal fibrinolysis was established in these cases and further adhesions did not occur in the joints. About two cubic centimeters of blood were taken from the
vein of a donor known to be in excellent health and free from any infection,
and injected into a muscle of the recipient. Usually two or three such
infusions at three to five day intervals resulted in the development of normal
fibrinolysis on the part of the recipient. This method presents certain
possibilities for cases otherwise hopeless but is not to be commended as a routine
practice. Tests have been made in an attempt to find that some especial organ or tissue produced the fibrinolytic ferment, in the hope of finding some cause for its absence other than heredity. No tissue has been found to be solely or especially capable of producing it. Persons lacking this ferment do not show any particular lesions. Persons lacking it do not develop it after the most persistent osteopathic treatments, no matter what lesions were present before the treatments were begun. Persons normally provided with this ferment do not lose it, though the activity of the ferment is delayed or subnormal during the course of several abnormal conditions. Much more study is necessary before definite reports can be made as to the relations between abnormal conditions and the delay or inhibition of fibrinolysis in persons normally provided with the ferment. It is not now possible to say that there is any lesion or any disease which exerts a specific action upon fibrinolysis. |