Chapter LXI: Part 61

(3) Hayem believes that the red corpuscles develop from the small hæmatoblasts, but, so far as I know, his observations have never been confirmed. He states that in normal blood they occur in the proportion of about 1 to 20 red. In all states of blood reparation they increase greatly. He describes a hæmatoblastic crisis as occurring after hemorrhage, fevers, etc., when the number of these elements rapidly augments, and is succeeded by the addition of many small pale-red corpuscles, which he looks upon as intermediate between the hæmatoblasts and the ordinary red forms.

The colorless corpuscles are regarded as the direct offspring of the cells of the follicular cords in the lymph-glands and adenoid tissue, but whether by process of division of existing leucocytes or by sprouting from the endothelial places, or from the protoplasm in the fibres of the reticulum, remains to be settled.

The nucleated red corpuscles are in the healthy adult confined to red marrow, in which they probably develop from colorless cells, and may be regarded, as Neumann originally suggested, as transitional or intermediate forms between white and red cells. In anæmic states they may occur in the spleen and in the lymph-glands.

Of the origin of the hæmatoblasts or blood-plates we know absolutely nothing. They occur most abundantly under two most opposite conditions--in the young growing animal just entering upon life, and in the diseased, cachectic, wornout animal just preparing to abandon it.

Our knowledge of the relation of the cytogenetic organs to blood-formation may be thus briefly stated: The spleen certainly takes part in the development of colorless corpuscles, but its participation in red blood-formation is more doubtful. The nucleated red or embryonal forms do not occur, at least in any numbers, in health, though some observers have noted that after a repeated bleeding the organ was swollen and contained many such cells, as if it was the seat of an active development. Though the opinion prevails widely that the spleen is one of the important organs in the formation of red corpuscles, the evidence for this belief is of an exceedingly scanty nature.

The lymphatic glands and the adenoid tissue in other regions are the seats {885} of constant production of colorless corpuscles, but of their relation to the red corpuscles there is the same lack of information as in the spleen. I do not know of any corroboration of the observation of Johnstone above mentioned, and in any case the number of red cells in the efferent vessels of a lymph-gland is so small--and indeed in the thoracic duct itself--that we cannot believe they are produced as red corpuscles in large numbers within the lymphatic system.

The red bone-marrow, as pointed out by Neumann[10] and Bizzozero,[11] appears to be the seat of blood-formation, and in the adult body is the only region in which the embryonic or nucleated red cells are found. It is a tissue similar in many respects to the spleen, and, though confined to the short and flat bones, the total amount in the body is very considerable. In the young it also fills the long bones. The evidence of the development of red corpuscles in the marrow rests upon the constant presence of nucleated cells infiltrated with hæmoglobin, and of their fission. Forms undergoing the process of karyokinesis can be seen without difficulty. In excessive hemorrhage, natural or induced, it appears to undergo an active proliferation, and in the long bones a red marrow may replace the fatty tissue.

[Footnote 10: _Centralblatt f. d. Med. Wissenschaften_, 1868.]

[Footnote 11: _Ibid._, 1868.]

The liver is doubtless the seat of blood-destruction, for the bile-pigments and leucocytes with red corpuscles in their interior have been found in its tissue. Nicolaides[12] has shown that in the blood of the hepatic vein there may be a reduction of from one million to one million and a half of red corpuscles per c.m. In the embryo Neumann[13] has shown that it may be the seat of the production of corpuscles, but there is no satisfactory evidence that in the adult this ever takes place.

[Footnote 12: _Archives de Physiologie_, 1882.]

[Footnote 13: _Archiv der Heilkunde_, xv.]

The remarkable rapidity with which, after a profuse bleeding, the normal proportion of red corpuscles is reached shows with what activity the development may proceed, and how favorable the conditions must be for their production. After the loss of a large quantity of blood the manufacture of new corpuscles may proceed at the rate of 30,000, 40,000, or even 50,000 a day.

What becomes of the red corpuscles? Here, again, is a question not satisfactorily settled. We do not know the average length of life of corpuscles. They are supposed to be short-lived--three weeks, according to Quincke. The need for their dissolution is assumed to provide pigment for the various secretions and tissues, and we occasionally see a few cells in the blood with a pallor which may be regarded as an indication of senility.

Positive evidence, however, of their destruction is afforded by the occurrence of the so-called corpuscles containing red corpuscles, which occur normally in red marrow and in the spleen, and under some circumstances in the lymphatic glands and liver. The red cells undergo gradual transformation into a yellow granular, and finally black, pigment. In normal spleen and marrow the numbers found are very variable; in fevers and cachectic states they may be in extraordinary numbers. Quincke and his pupil Peters[14] have studied with great care this process of transformation of the red corpuscles and accumulation of the pigment in the cells of the marrow, spleen, liver, and lymph-glands, to which the term siderosis is applied. These pigment-granules are in the form of an iron albuminate, and are used in the development of new corpuscles. Thus, after repeated bleedings in animals, they may disappear completely in the restoration of the blood, while in animals into whose vessels blood has been transfused or injected subcutaneously the iron-containing cells in the various organs are very numerous, and even the cortical cells of the kidney contain numerous granules.

[Footnote 14: _Deutsches Archiv f. klin. Med._, Bds. xxv., xxvii., xxxii., xxxiii.]

The amount of hæmoglobin in 100 grammes of healthy blood is {886} 13.45 grm. (Preyer). Malassez estimated the quantity in a cubic millimeter of blood at between 0.125 and 0.134 milligramme, and, taking the corpuscular richness at from 4,000,000 to 4,600,000, he has estimated approximately the amount of hæmoglobin in each corpuscle.

PLETHORA.

General and persistent polyæmia or plethora has scarcely a place in recent pathology. Formerly it was thought that either from over-production or lowered expenditure the total amount of blood accumulated and filled the blood-vessels to an abnormal extent. The amount of blood undergoes, within limits, constant daily alterations, and after a full meal the vessels are in a state of plethora compared with their condition at the end of a ten hours' fast. If a plethysmograph could be devised to record graphically the variations in the total quantity of blood, each ingestion of food or drink into the vessels would be followed by a rise, and each interval by a gradual decline. So long as the organs of secretion and excretion are active the quantitative and qualitative condition of the blood is maintained at a tolerably uniform standard in each individual. At different periods of life the relation of blood-weight to body-weight varies. In the new-born the blood amounts to one-eighteenth part by weight of the body, while in the adult the average is from one-twelfth to one-fourteenth; so that in the infant there is a condition of comparative plethora. There are no reliable observations on the proportion of blood- to body-weight at respective ages, but there appears to be a reduction in old age. In women it is stated that just before each menstrual period there is a state of polyæmia.[15]

[Footnote 15: Mary Putnam Jacobi, _The Question of Rest for Women_, New York.]

Worm-Müller[16] and Cohnheim[17] have made some very interesting experiments on this question of plethora. By transfusion in dogs a state of artificial plethora is readily established, and the animals stand the injection of as much as 10 or 12 per cent. of the body-weight of blood, above which quantity a fatal result ensues. After an injection of 20 or 30 per cent. of the total amount of blood, the superfluous plasma and corpuscles are got rid of in a few days, while with a larger injection of 60 to 80 per cent. it takes two or three weeks before the normal state is again reached. The albuminous and nitrogenous materials are largely got rid of by the urine, which increases rapidly in quantity and also in the amount of urea. The excess of corpuscles gradually disappears, and the hæmoglobin becomes deposited, as Quincke has shown, in the form of small granules in the cells of the liver, spleen, and bone-marrow.

[Footnote 16: _Transfusion and Plethora_, Christiania, 1875.]

[Footnote 17: _Allgemeine Pathologie_, 2te Auflage.]

In a similar way, it is reasonable to think that the body is quite capable of disposing of surplus albuminous materials in over-fed, lazy individuals with active digestion, whose red faces, full vessels, and bounding pulses give the impression of a distended circulatory system, and whom we term plethoric. Their appearance is the result rather of blood-distribution than of actual increase in the total volume, and there is no evidence that under any circumstances a rich and abundant diet without much exercise can permanently increase the amount of blood. It was formerly held that the healing of an old sore or the cessation of an accustomed discharge or loss of blood, by diminishing expenditure while the blood-making power was maintained, could induce plethora if no local disorder was excited "before the vessels {887} in general reached a state of plethoric tension." Of such a condition, and of the plethora apocoptica that was thought to occur after the amputation of a limb, we do not hear much now, and the prevalent opinion of pathologists is expressed by Cohnheim, when he says "that, except as a transitory state, polyæmia does not occur under any circumstances." What, then, is the meaning of the full-blooded, rubicund condition which we see in some men, not necessarily large feeders, but often with vigorous active constitutions and perfect types of health? The appearance of plethora is caused chiefly by the distension of the superficial vessels; the circulation of the skin is remarkably active, particularly in the face, and it is probable that we have here to deal with local peculiarities of the vessels or of their innervation, and not with any general augmentation of the total blood-mass. It may be, however, that in such persons there is a plethora of certain of the constituents of the blood--viz. the red corpuscles--and there may be a state of polycythæmia rubra, as it has been called, in which the percentage of red cells is increased. In several such cases I have found, as has been previously noted, the number of red corpuscles considerably over the average. A relative increase in the number of red corpuscles also occurs in those sudden and excessive losses of fluid, as in cholera, in which the blood may become thick and sticky from the great reduction in the plasma, particularly of the water and salts--anhydræmia--or in cases in which the income of fluid is greatly restricted. Henry (F. P.) has recorded a case[18] of stenosis of the cardia, in which, with great emaciation, the corpuscles per c.m. were 5,525,000.

[Footnote 18: _Archives of Medicine_, New York, vol. vii.]

The condition known as hydræmic plethora develops whenever there is a great reduction in the number of corpuscles, as after a hemorrhage, or when the blood has been impoverished by long-standing suppuration, albuminuria, or in the growth of large tumors. So also when the secretion of urine is diminished, as in some cases of Bright's disease, and at the same time charged with albumen, the blood may become very watery; but in these states there is not an absolute increase in the entire blood, but only a relative excess of the water. Occasionally, this great excess can be noticed in the blood-drop as it comes from the finger-tip; the corpuscles do not fill the entire drop, and consequently leave irregular areas unoccupied by the red disks.

ANÆMIA.

A reduction in the amount of the blood or of its corpuscles occurs under a great variety of circumstances. Broadly speaking, we can recognize two great clinical and pathological groups of cases: I. Those induced by causes acting upon the blood itself; and, II. Those induced by disturbance in the functions of the blood-making organs.

I. Of causes acting directly upon the blood, we shall consider--

1st. Hemorrhage, traumatic or spontaneous. A high grade of anæmia may be quickly produced by loss of a large quantity of blood, and the reduction is in all the constituents; there is a true oligæmia. If the amount lost be excessive, death results from the diminution in the total volume of blood and general lowering of the arterial pressure. If the hemorrhage is sudden and profuse, as from a large vessel, the loss of four or five pounds of blood, or even less, may be sufficient to induce fatal syncope. In hemorrhage into the pleura or peritoneum from rupture of aneurisms, etc., it is rare to meet with more than three or four pounds of clot and serum; seven and a half {888} pounds is the largest amount I know of shed into one of the cavities (pleura) by rupture of an aneurism. When the bleeding extends over several days, the amount lost may be very much greater. In cases of hæmophilia extraordinary accounts are given of the amount collected in the course of a few days. In a case of hæmoptysis a patient lost over ten pounds by measurement in one week, and then recovered from the immediate effects. After the most severe hemorrhages the reduction in the number of red corpuscles is not nearly so great as in forms of idiopathic anæmia. Thus in the case just mentioned at the termination of the week of bleeding there were 1,390,000 red corpuscles to the cubic millimeter. In any single bleeding a fatal result follows the loss of one-third or one-half of the total blood-volume. The process of regeneration of the blood goes on with astonishing rapidity, and in some bleeders a week or ten days will suffice to re-establish the normal amount. The restitution begins even during a hemorrhage by the absorption of lymph from the tissues under the lowered pressure in the vessels. The dryness and stickiness of the serous membranes after death from a profuse hemorrhage is usually very marked. The water and saline constituents of the blood are readily restored by absorption from the gastro-intestinal tract. The albuminous elements are also quickly renewed, but it may take weeks or months before the number of corpuscles reaches the normal standard. Indeed, this condition of oligocythæmia, as it is called, may persist, grow worse, and ultimately prove fatal. The microscopical characters of the blood after severe hemorrhage are not much changed, except as regards the white corpuscles, which are relatively increased, and the fibrin network, which is much less marked than in health. The white corpuscles may be very slightly reduced in number per cubic millimeter--a fact to be accounted for either by a relatively diminished loss during the bleeding, owing to their adhesiveness and wall-loving properties, or to a quick restitution from the lymph which is poured into the blood-stream. It has been observed both in dogs and men by Lyon[19] that after a severe hemorrhage the number of red per cubic millimeter diminished for several days after the bleeding had been checked. How and where does the regeneration of red corpuscles take place after a severe hemorrhage? One would think that under these circumstances, if any, we should be able to get information which might be of service in determining the problem of blood-development; but, in spite of the numerous experiments on the subject, we are still far from a knowledge of full details. The observations of Neumann,[20] Litten and Orth,[21] Bizzozero,[22] Lepine,[23] and others appear to prove conclusively that the bone-marrow plays an important part in the formation of the new red disks, becoming lymphoid, losing its fat, and the nucleated red cells increase enormously. The same process has been observed in many cases in man. In a case of profuse metrorrhagia with profound anæmia Neumann[24] found the marrow in all the bones of a rich raspberry red, full of the nucleated forms, which were also very abundant in the blood, and more in the vena azygos than in the aorta. The evidence in favor of the active participation of the spleen is not so conclusive. Neumann[25] concludes that the spleen takes no share in the process, and holds that the nucleated red cells found in it are probably derived from the bone-marrow. Bizzozero, on the other hand, has found the spleen swollen and showing signs of lively blood-formation. He states that after removal of the spleen the restitution of the red corpuscles takes place much more slowly. Pouchet, on the contrary, says the regeneration goes on just as rapidly without the spleen. {889} Of the action of the lymph-glands there is even less evidence. They have been found swollen, but in traumatic anæmia I do not know of any observations on their swelling and conversion into a red spleen-like tissue, such as have been found in some cases of idiopathic anæmia.

[Footnote 19: Of Norwich, Conn.: _Virchow's Archiv_, lxxxiv.]

[Footnote 20: _Archiv der Heilkunde_, Bd. x.; _Frerichs and Leyden's Archiv_, Bd. iii.]

[Footnote 21: _Berliner klin. Wochenschrift_, 1877, li.]

[Footnote 22: _Centralblatt f. d. Med. Wissenschaften_, 1879, xvi.]

[Footnote 23: _Revue Mensuelle de Méd. et de Chirurg._, 1877.]

[Footnote 24: _Loc. cit._]

[Footnote 25: _Loc. cit._]

The microcytes which occur in numbers in blood in some cases of traumatic anæmia have been regarded as young developmental forms, but there is a great diversity of opinion as to their real nature, and their connection with productive blood-processes is somewhat doubtful.

Cohnheim suggests[26] that after a profuse hemorrhage the rapid consumption of red corpuscles may be reduced, in which case we need not suppose such an active development; but the fact noted by Lyon[27] and others of the increased reduction after a bleeding is against the view. In any case, if Quincke is right in assuming that the average life of a red corpuscle is only three or four weeks, what is the restitution of a couple of millions of corpuscles per cubic millimeter in comparison with the monthly renovation of the entire mass?

[Footnote 26: _Loc. cit._]

[Footnote 27: _Loc. cit._]

In the regeneration of the blood the development of the hæmoglobin does not keep pace with that of the corpuscles, so that they may, even when normal in amount, have a lowered hæmoglobin percentage, indicated under the microscope by a paleness in the cells.

2d. There is a large group of cases in which the anæmia is induced by a long-continued drain on the albuminous material of the blood--pus in a chronic suppuration, albumen in Bright's disease, prolonged lactation, etc. Rapidly-growing tumors act in the same way.

3d. The anæmia of inanition, brought about by defective food-supply or by conditions of the digestive organs which interfere with the proper reception and preparation of nourishment, as cancer of the gullet, chronic dyspepsia, etc. The reduction in the blood-mass may be extreme, but the plasma suffers proportionately more than the corpuscles, which even in the extreme wasting of cancer of the oesophagus may not be reduced more than one-half or three-fourths.

4th. Toxic anæmia, induced by the action of certain poisons in the blood, such as lead, mercury, and arsenic among inorganic substances, and the virus of syphilis and malaria among organic poisons. They act by increasing the rate of consumption of the red corpuscles, and the reduction may be considerable. The gradual impoverishment of the blood in pyrexia may be in part due to the toxic action of the fever-producing agent on the blood itself; but in this there is probably also disturbance of function in the blood-making organs.

The last three groups comprise what are known as secondary anæmias, and the condition of the blood is characterized by an increase in the water and diminution in the albuminous elements; the fibrin is often increased, and the network which separates, as seen under the microscope, is unusually dense; the white corpuscles are not much increased; there is rarely microcytosis or poikilocytosis; the reduction in the number of red corpuscles is not so great; hemorrhages do not often occur; when fever is present it is due to the disease or some complication, and is not the pyrexia of anæmia; and, lastly, they are more or less amenable to the action of iron and other remedies.

II. A consideration of the anæmias induced by disturbance in the blood-making organs themselves presents difficulties proportionate to our ignorance of the details of hæmatogenesis. We may regard, as above stated, the spleen, the general lymphatic tissue, and the marrow as the sites of production of corpuscles which are passed into the circulation fully formed. Certain of these organs--the spleen and marrow particularly--are also concerned with blood-destruction as well as blood-elaboration; but there is evidence to show[28] that {890} they, to use an ordinary simile, consume their own smoke, using the waste products for the purpose of further manufacture. Looking now upon the hæmatogenetic tissues as a single organ scattered through the body, let us consider what general disturbances of function it may suffer comparable to those met with in other structures. We can evidently suppose the physiological activity to be diminished or increased, and we should expect to find corresponding to these changes equivalent alterations in the character of the blood. Unfortunately, our knowledge of the normal processes as they go on in these tissues is so scanty that it amounts to a discussion upon the disturbances of a function itself imperfectly understood.

[Footnote 28: Quincke, quoted above.]

With diminished functional activity in an organ we commonly meet with reduction in volume, the one depending on the other: now, the only instance in the blood-making organs in which a decrease in size and diminished functional activity go together is in the senile atrophy in which the spleen becomes small, the marrow more fatty, and the lymph-glands sclerotic, and in consequence the blood also is reduced in amount; but this is only a part of the general failure of nutrition in old age. Pathologically, there is no such well-recognized condition of uniform atrophy of spleen, lymph-gland, and bone-marrow, with a corresponding general reduction in the elements of the blood. Certain cases of idiopathic anæmia come close to it, in which these parts are wasted, but there are other differences which make the two conditions scarcely comparable. In fact, as we shall see, diminished activity in blood-making is usually associated with an increase in what we call hæmatogenetic tissues. Of increased functional activity in these parts we know very little, apart from the changes met with in cases of traumatic anæmia, in which the hyperplasia of the spleen and bone-marrow may be regarded as intimately connected with the rapid development of red corpuscles.

One fact is evident: that a progressive increase in the cytogenic tissues, local or general, is associated with disturbance in the process of blood-formation, and sooner or later induces anæmia. Thus, progressive enlargement of the spleen or of the lymph-glands or marked hyperplasia of the marrow, either singly or combined, is invariably accompanied with alteration in the characters of the blood. Even in those rare instances in which the lymphoid elements of the tonsils and fauces or of the gastro-intestinal canal are chiefly involved the same change may take place.

The nature of the process in the organs is of a hyperplastic character. In the spleen the pulp at first increases and the Malpighian bodies enlarge, but ultimately there is such a development of the fibrous reticulum that the consistence is greatly augmented and the organ becomes indurated. Histologically, there is very little distinction to be made between forms of chronic enlargement of this organ. In the lymph-glands there is increase in the cells; the tissue becomes more succulent, and is in a state of hyperplasia which may terminate in a great development of the fibrous elements, with induration. So also with the bone-marrow: in the short and flat bones, where in the adult a reddish or slightly fatty tissue exists, the fat disappears entirely, and the long bones, normally filled with yellow marrow, become occupied with a red-gray or greenish-gray cytogenous tissue not unlike spleen-pulp, and in many instances more consistent than the red marrow of early life.

A reduction in the number of red corpuscles is the chief and most constant change in the blood; anæmia seems to be the invariable result, whether the spleen, marrow, or lymph-glands are affected singly or together, and is the central feature in the entire group of cases. This diminution in the red cells may or may not be accompanied by an increase in the white corpuscles, which in some cases may be so striking as to be regarded as the special blood-change, and is, as a rule, permanent, though it may be a variable or even a transitory state.

{891} The general and histological differences between forms of hypertrophy of these blood-making organs are exceedingly slight, and in their clinical features they present a large number of symptoms in common; indeed, we may say that all the important symptoms are present, whether the spleen is affected alone or with the lymph-glands and bone-marrow, or whether these parts are independently involved, and whether there is simple reduction in the red or with it an increase in the white corpuscles. Such common features are--the progressive anæmia with its group of circulatory symptoms; the irregular febrile reaction, essential fever of anæmia; the absence of marked emaciation; the tendency to effusions of serum; the progressive debility; the occurrence of hemorrhages; gastric and intestinal disturbances; and resistance to treatment.

The affections characterized pathologically and clinically by so many similar features are known and recognized as distinct diseases under the names leukæmia, Hodgkin's disease or pseudo-leukæmia, splenic anæmia, and idiopathic anæmia (some cases); and we shall now consider these a little more closely.

First, of the hyperplasias of the cytogenic tissues associated with simple anæmia. The various groups, spleen, lymph-glands, and marrow, may be involved singly or together; usually one is first affected, and the others, if at all, subsequently. Progressive enlargement of the spleen induces sooner or later anæmia, the anæmia splenica of Griesinger. These cases are by no means rare: certain of them represent the final stage of a malarial intoxication, but there are others in which the enlargement seems causeless. There may also be hyperplasia of the bone-marrow, less often of the lymph-glands. The anæmia may be profound, and the clinical picture is that mentioned above. Two cases of it under my care died of hæmatemesis. The diagnosis of this affection from splenic leukæmia rests solely on the microscopical examination of the blood. It is also classed as the splenic form of Hodgkin's disease or pseudo-leukæmia.

Primary enlargement of the lymph-glands with anæmia constitutes Hodgkin's disease or pseudo-leukæmia, in which there may be general hyperplasia of the lymphatic elements throughout the body, with nodular growths of adenoid tissue in other organs. The spleen and marrow are not often affected. Here, too, the diagnosis from lymphatic leukæmia rests with the microscope.

Is there a form of anæmia dependent upon hyperplasia of the bone-marrow--an anæmia medullaris? In 1875, Pepper and Tyson[29] found affection of the marrow in idiopathic anæmia, and Pepper suggested that this might be the starting-point of the disease, which could thus be regarded as a medullary form of pseudo-leukæmia. Cohnheim in 1876[30] described the same condition, and I had an opportunity of examining several cases.[31] Granting that the marrow is a tissue which shares in the blood-making functions, it seemed reasonable to suppose that a general hyperplasia of its elements might disturb the processes of hæmatosis and produce anæmia, just as in hyperplasia of the spleen and lymph-glands. Two facts soon came to light which seem opposed to this explanation of the pathology of idiopathic anæmia. A hyperplasia of the marrow was found in cases of chronic disease with wasting, and cases of idiopathic anæmia were described in which the marrow was normal. The numerous observations of the past five or six years have not brought us nearer to a solution of the problem. The observations of Neumann,[32] and those of Litten and Orth,[33] on the changes in the marrow in chronic diseases have been abundantly confirmed, and a red lymphoid marrow may be met with in various cachectic states. This, too, I have frequently seen, {892} yet it is in my experience rare to find such marked, rich hyperplasia of the marrow, such an entire absence of fat, as in some cases of idiopathic anæmia. In 9 autopsies in typical cases at Montreal, not parturition cases, the marrow of the long bones was lymphoid and red in 6; in 1 it was not examined; in 1, which I did not see, the marrow was stated to be normal; and in 1, an old woman over sixty years of age, the marrow of the short bones was rich in lymphoid cells and nucleated red corpuscles, and the long bones contained a grayish gelatinoid--atrophic--marrow. It does not appear possible with our present knowledge to arrive at a satisfactory conclusion on this question. Some regard the marrow-change as the consequence, others as the cause, of the anæmia. Both Cohnheim[34] and Pye-Smith[35] regard those cases of idiopathic anæmia in which the marrow-changes are pronounced as cases of anæmia medullaris.

[Footnote 29: _American Journal Med. Sciences_, 1875, ii.]

[Footnote 30: _Virchow's Archiv_, Bd. lxviii.]

[Footnote 31: _Centralblatt f. d. Med. Wissenschaften_, 1877, Nos. 15 and 28; 1878, No. 26.]

[Footnote 32: _Berl. klin. Wochenschrift_, 1877, xlvii.]

[Footnote 33: _Ibid._, 1877, li.]

[Footnote 34: _Loc. cit._, Bd. i. S. 467.]

[Footnote 35: _Loc cit._]

Next of the parallel series of hyperplasias of the blood-forming organs with anæmia, plus an increase of the colorless corpuscles--leukæmia. Here, too, we have the three forms--splenic, lymphatic, and medullary.

The splenic leukæmia is the most common, and in its general features is identical with splenic anæmia, the excess of white corpuscles being the only distinguishing feature. It is almost invariably associated with changes in the marrow.

The lymphatic leukæmia may arise in connection with hyperplasia of the lymph-glands or of the adenoid elements in the alimentary tract--tonsils and Peyer's glands. It is much less common than lymphatic anæmia or Hodgkin's disease, and there are not many uncomplicated cases on record. Apparently, a very limited bunch of glands--cervical--may induce the change in the blood.[36] Medullary changes are almost invariably associated with a great increase of colorless corpuscles in the blood, and a myelogenous form of leukæmia is now, owing chiefly to the investigations of Neumann, well established. Indeed, he would regard the change in this tissue as the primary and important, and those in the lymph-glands and spleen as secondary.

[Footnote 36: Gowers, _Reynolds's System of Medicine_, art. "Leucocythæmia."]

The hyperplasia, either lymphadenoid in character or pyoid, may result in the expansion and softening of the bones, with the production of irregular tumor-like masses.

We have, then, the following group of anæmias induced by a primary disturbance of function in the blood-making organs:

PRIMARY OR | Leucocytic | Splenic, |
CYTOGENIC | | Lymphatic, | Leukæmia.
ANÆMIA. | | Medullary, |
|
| Non-leucocytic | Splenic, Anæmia splenica.
| Lymphatic, Hodgkin's disease.
| Medullary, Idiopathic anæmia
(certain cases).

There remain for consideration the relation of the tissue-change to the anæmia and the nature of the leucocytosis; but until the chief facts in the development of the corpuscles are thoroughly known we cannot expect a satisfactory solution of these problems.

The anæmia may be explained on the view of diminished production (anæmatosis) or increased consumption of the red corpuscles (hæmophthisis). We know nothing of the intimate processes connected with lessened production, but as anæmia so constantly accompanies the hyperplasia, we assume they are intimately connected with each other, and the diminution in the number of corpuscles in some way the result of disturbed functional activity in the blood-making organs. An increased consumption of corpuscles in anæmia is {893} indicated by the presence in large numbers of cells containing red blood-corpuscles in the spleen and marrow, and occasionally in the lymph-glands; by the increased amount of iron which has been found in the liver; and in some cases by the deep color of the muscles and an intensification of the color of the urine. Either a failing production with normal rate of consumption, or a normal output with heightened destruction, would produce anæmia. Possibly, in some instances, both factors may prevail. Quincke's interesting observations[37] may enable us to determine the cases in which one or other has been dominant. Where there is great destruction we shall expect to find the granules of iron albuminate in the spleen, bone marrow, and liver-cells, possibly in the cells of the cortex of the kidneys, and the iron reaction should be present.

[Footnote 37: _Loc. cit._]

The relation of the hyperplasia of the cytogenic tissues to the increase in the colorless corpuscles is even more obscure. A prime difficulty is the circumstance that apparently identical tissue-changes may be associated with either a leucocytic or non-leucocytic anæmia. The splenic hyperplasia of leukæmia and of anæmia splenica are histologically identical. The excess of white corpuscles may be due either to over-production or to failure in their transformation into red. That they develop in the hyperplastic spleen, marrow, and lymph-glands is not to be doubted, and it seems reasonable to attribute the excess to the hyperplasia. Their variable size, as spleen or lymph-glands are chiefly affected, was early observed by Virchow, and when the marrow is involved there may be many large leucocytes similar to the larger marrow-cells. Virchow's original explanation, that the excess of colorless cells was due to a failure in their transformation into red corpuscles, rests upon the presumption that such a transformation is the normal process--a view not fully established. If this is the case, we should expect to find some relation between the increase of the white and the decrease in the red, but this is not always constant; as a general rule, with a diminution of the white there is an increase in the red, but the red and the white cells may increase or diminish in numbers simultaneously, or, again, the leucocytes may be greatly reduced while the red corpuscles remain about stationary. Griesinger,[38] Biesiadecki,[39] and others regard the increase in leucocytes as a primary blood-change. Several recent French writers support this view, as Renant,[40] who believes that the unequal size of the leucocytes indicates their division in the blood, and Variot.[41] One of the most interesting features in connection with an increase in the colorless cells is that it may be only transitory, and a case which clinically and pathologically may present the features of idiopathic anæmia to-day may to-morrow present the characters of leukæmia; a case of splenic anæmia may become one of splenic leukæmia, or vice versâ. Thus, in Litten's oft-quoted case--about which there can be no doubt[42]--of acute anæmia of three weeks' duration, an enormous increase of colorless corpuscles took place, and finally a ratio of one white to four red was reached. Quite as interesting is the case of Fleischer and Penzoldt,[43] in which for eight months the patient presented the ordinary symptoms of anæmia lymphatica or Hodgkin's disease, and then, before death, the blood became intensely leukæmic, the ratio 1:9. Still more so as the case of Goodhart's,[44] in which, with an enlarged spleen and lymphoid growths in liver and kidneys, there were variations in the number of corpuscles every few days--at one time great excess of white, at another no increase whatever. Again, a case may early come under observation as one of leukæmia, with a ratio of 1:20 or 1:30, and in the course of a few months, with persistence or even aggravation of {894} the general symptoms, the normal ratio of white to red may be reached. This was the history in one of the Montreal cases.[45]

[Footnote 38: _Virch. Archiv_, Bd. v.]

[Footnote 39: _Wien. Med. Jahrbuch._, 1876.]

[Footnote 40: _Archives de Physiologie_, 1881.]

[Footnote 41: _Thèse de Paris_, 1882.]

[Footnote 42: _Berl. klin. Wochenschrift_, 1877.]

[Footnote 43: _Deutsches Archiv f. klin. Medicin_, Bd. xxvi.]

[Footnote 44: _Clin. Society's Transactions_, London, 1877.]

[Footnote 45: Howard, _Montreal General Hospital Reports_, vol. i. p. 39.]

It seems questionable whether such a variable feature as increase in the colorless corpuscles should be permitted to separate diseases which have all essential characters in common. We shall probably, however, continue for a long time to speak of these conditions as separate and distinct, but it is evident that as time goes on, and our knowledge of the diseases and of blood-development increases, the identity of many of them will be acknowledged, and we shall find that here, as so often the case in natural history, the multiplication of species has been the result of imperfect information, and that as points of resemblance in essential characters and development are studied minor differences disappear.

With reference to the general tissue-changes in anæmia there are two points of interest: The metabolism of the proteids is increased, as shown by the increased excretion of urea, and owing to defective exudation the decomposition of the fats is lessened; hence the retention of fat, or even increase, in anæmic persons. The influence of repeated small bleedings in hastening the fattening of cattle has been known since the time of Aristotle, and horse-dealers still affirm that there is nothing like bloodletting to put an animal into good condition.

CHLOROSIS

is a special form of anæmia distinguished by certain etiological and anatomical peculiarities. In the first place, it is a disease of the female sex; cases in the male are of extreme rarity. In the majority of instances it is associated with disturbed menstrual function or with the evolution of the reproductive organs at the period of puberty. Occasionally it occurs in pregnant women and in children. It is a common disease among the ill-fed, overworked young girls in large towns who are confined all day in close, badly-lighted rooms or who have to do much stair-climbing. Girls of the better classes are by no means exempt; indeed, some writers speak of it as specially prone to affect the higher ranks of life. Lack of proper exercise, good food, and fresh air, the mental stimulation of unhealthy literature, and masturbation, are important factors. Emotional and nervous symptoms may be prominent--so much so that the disease is regarded by some as a neurosis.

The anatomical peculiarities relate to the blood and circulatory system. There is anæmia, but the impoverishment is less in the number than in the corpuscular richness in hæmoglobin. This fact, first pointed out by Duncan,[46] has been abundantly confirmed. Thus, for example, in one case, with a globular richness of 85 per cent., the hæmoglobin was only 52 per cent., and in another, with 92 per cent. of red, the hæmoglobin percentage was as low as 64. The numerous investigations of the past few years[47] have, among other points, fully established this as perhaps one of the most striking features in chlorosis. The color-value of the individual corpuscle is very much reduced. Of 22 observations of Hayem, the average number of red corpuscles was {895} 3,740,000, and the hæmoglobin reduced to about 50 per cent. In Laache's 13 cases the average percentage of corpuscles was 72, and of hæmoglobin 45. This author has pointed out that in certain cases with all the clinical symptoms of chlorosis well marked there may be very slight reduction in the corpuscles or hæmoglobin; and such he terms pseudo-chlorosis. The red corpuscles in chlorosis vary much in size. Very large forms--giant red cells--are common, and microcytes are sometimes to be seen; but there is not the extreme irregularity in size and outline of the blood in idiopathic anæmia. The presence of a large number of young, imperfectly-formed corpuscles, especially as regards the hæmoglobin, is the distinguishing feature of chlorotic blood. Hayem and Willcocks both regard the average corpuscular diameter to be lower than normal, though many large forms occur. The color of the red corpuscles is noticeably pale, and the marked deficiency in hæmoglobin can be observed in individual corpuscles as well as in the blood-mixture prepared for counting. Quinquaud found the serum normal in quality, but the solids were slightly reduced in amount. Hunt[48] has shown that there are peculiar inter-menstrual oscillations in the blood in chlorotics. There is usually a fall in numbers just before the flow, but the individual value remains good; subsequently the number rises, but the color-value is not maintained (Willcocks). Virchow[49] pointed out that in many cases of chlorosis there was a defective development of the circulatory system, either congenital or resulting in failure of the normal rate of growth; the parts remained infantile. The heart and arteries were small, the walls of the latter thin, and the calibre of the aorta narrowed. In some instances there was found a compensatory hypertrophy of the heart. Defective development of the uterus and ovaries has also been noted, but these changes on the part of the circulatory and generative organs are not constant features in chlorosis.

[Footnote 46: _Sitzungsbericht d. Kais. Akad. d. Wissenschaften zu Wien_, 1867.]

[Footnote 47: Leichtenstern, _Hæmoglobingehalt des Blutes_, Leipzig, 1878; Hayem, _Recherches sur l'Anatomie, etc. du Sang_, 1878; Malassez, _Archives de Physiologie_, 1877; Moriez, _La Chlorose_, Paris, 1880; Laache, _Die Anämie_, Christiania, 1883; Willcocks, _Practitioner_, 1883.]

[Footnote 48: _Lancet_, ii., 1880.]

[Footnote 49: _Ueber die Chlorose_, etc., Berlin, 1872.]

The SYMPTOMS of chlorosis are those of anæmia of moderate grade. As in idiopathic anæmia, the subcutaneous fat is in full, or even extra, amount. The complexion is most peculiar, neither the blanched aspect of hemorrhage nor the muddy pallor of grave anæmia; but there is a curious yellow-green tinge in marked cases which has given the name to the disease ([Greek: chlôros]), and also its popular designation, the green sickness. Breathlessness, palpitation, and tendency to fainting are due to the anæmia. Digestive troubles are also common, and the appetite is often depraved. There are venous and cardiac murmurs. The menstrual functions are almost always deranged, and there may be hysterical and nervous manifestations. Relapses are not uncommon. The intimate pathology of the disease is unknown. In its insidious onset, sometimes causeless, and in certain features of the blood-state, it resembles pernicious anæmia, but it differs from it in many essential particulars. The association with menstrual disorders, the hypoplasia of the circulatory and generative organs in some cases, the favorable course and response to suitable treatment, as well as the sex and period of life, are features peculiar to chlorosis. Then, again, the anæmia is not so intense, and the relation of the hæmoglobin is just the reverse; in chlorosis the individual corpuscles are deficient in hæmoglobin, while in idiopathic anæmia the reverse appears to be the case.

Some regard the blood circulatory and uterine condition as the expression of a congenital defect leading to the formation of a diathesis--and in certain cases this may be so--but some of the most marked cases I have seen have been in girls of healthy families, who after a healthy childhood developed chlorosis at puberty, from which, under suitable treatment, they recovered to become robust and vigorous women. The almost specific action of iron suggests failure of the digestion or assimilation of the minute traces of this substance which are contained in our ordinary foods, and from which {896} the iron of the corpuscles must be derived. Zander[50] holds that it is largely due to a defect in the hydrochloric acid of the gastric juice, by which the iron-holding compounds are dissolved, and claims that in chlorosis the administration of this remedy after eating fulfils every indication and enables the iron in the foods to be converted into an absorbable compound.

[Footnote 50: _Virchow's Archiv_, lxxxiv.]

The condition of the blood-making organs themselves throw no light on the PATHOLOGY of the disease.

The TREATMENT of chlorosis requires special mention. Iron may be regarded as a specific when given in sufficient doses. I have found Blaud's formula, as given in Niemeyer's textbook (ferri sulph. potass. carb. et tart. aa ounce ss; tragacanth q. s. Make ninety-six pills. Two or three pills to be taken three times a day), the most satisfactory method of administering the drug. Under their use I have repeatedly seen the number of the red corpuscles per cubic millimeter double in a fortnight; and it is one of the most interesting therapeutic phenomena to watch with the hæmacytometer the progressive development and increase of red corpuscles under the influence of fifteen or twenty grains of iron daily. Other forms may be used--reduced iron, dialyzed, the lactate, the tinct. of the perchloride--and it does not really make much difference which form is employed so long as enough is administered. Dilute hydrochloric acids or the vegetable acids may be given, and special attention should be devoted to dietetic and hygienic regulations.

MELANÆMIA

is a condition characterized by an accumulation of granular pigment in the blood and various organs, particularly the spleen, liver, marrow, and brain. It is almost invariably associated with prolonged malarial infection, and the pigment results from the transformation of the hæmoglobin of the corpuscles, many of which undergo destruction as a direct consequence of the influence of marsh miasm. Very exceptionally, however, the dark particles are extraneous, and result from the passage of carbon-granules into the circulation in cases of intense anthracosis. Soyka[51] met with a case of this kind in which the coal particles were distributed throughout the spleen, liver, and kidneys. In blood the pigment occurs either free in the form of fine granules or in cloud-like collections of various sizes and shapes, often surrounded by a hyaline margin, or it occurs enclosed in cells. The free pigment, not often met with, is either molecular or in the form of irregular particles which may equal a red corpuscle in size. Aggregations of the granules are not uncommon, forming various-sized masses which may be imbedded in a hyaline substance. More commonly the pigment is contained in cells, ordinary leucocytes or large flattened--endothelial--cells derived from the spleen or liver. The color varies from yellowish-brown to a deep black. Except during periods of intense malarial infection and in the most severe and chronic cases melanæmia is rarely observed. In most ordinary cases of intermittent one may seek in vain for the pigment-granules, and I have examined many chronic cases with well-marked ague-cake with negative results. In other instances the pigment is found during or after a paroxysm; and this is the period when an examination of the blood should be made. The greatest care and cleanliness should be exercised in obtaining the blood-drop; and it should be remembered that in some of the glass slips used for microscopic purposes {897} irregular brownish flakes may occur which I have known to be mistaken for pigment.

[Footnote 51: Quoted by Hindenlang, _Virchow's Archiv_, lxxix.]

The melanæmia is but the expression of extensive destruction of corpuscles and accumulation of pigment in the spleen, liver, and bone-marrow; and these organs in cases of fatal intermittent or remittent fevers may present important changes. In the spleen, which is usually enlarged and indurated, the pigment is chiefly in the vicinity of the arteries and veins, the tissues about which may be absolutely black, and in both stroma and pulp innumerable cells are found filled with blood-corpuscles and blood-pigment in all stages of transformation to melanin. The color of the organ may be of a deep reddish-brown, or in very chronic states gray or even a dark olive. In the liver the dark granules are chiefly at the periphery of the lobules, fixed within the connective-tissue elements and leucocytes, not in the liver-cells themselves. It may be abundant about the portal branches, staining the connective tissue of Glisson's sheath, and it is also met with in the vicinity of the hepatic veins. When much affected the liver may have a deep bronze tint. As Arnstein has shown,[52] the bone-marrow may present similar changes and have a grayish-brown color. There may be deep pigmentation of peritoneum and omentum. The deposition of the granules in and about the vessels of the cortex cerebri may give a slate-gray color to the brain, or even a graphite tint in very severe cases. The capillaries have been found occluded with cells filled with the pigment-granules. The kidneys--particularly the Malpighian tufts--the mucous surfaces, and the skin may also be the seat of pigmentary deposition. These coarse changes in the organs in chronic malaria were known to the older writers, and in Bright's _Medical Observations_ a beautiful representation is given of the condition of the brain. To American physicians, with their extensive experience of malarial fevers, these changes were well known, and Stewardson of the Pennsylvania Hospital gave an admirable description of them in 1841;[53] and from the same institution in 1868 came another important contribution to the subject by Meigs, Pepper, and Rhoads.[54] Meckel[55] and Virchow[56] gave the first satisfactory explanation of the discoloration, showing that it was due to pigment, which might also be free in the blood. Frerichs in his well-known work on the liver gave an exhaustive account of the coarse and microscopical appearances.

[Footnote 52: _Virchow's Archiv_, lxi.]

[Footnote 53: _Am. Journal Medical Sciences_.]

[Footnote 54: "On the Morphological Changes of the Blood in Malarial Fever," _Penn. Hospital Reports_, 1868.]

[Footnote 55: _Deutsche Klinik_, 1850.]

[Footnote 56: _Virchow's Archiv_, Bd. i.]

There is still some difference of opinion as to the mode of origin of the pigment. Most writers hold that it results from the destruction of the red corpuscles in the spleen and liver, and from these situations the pigment gets into the blood; but more recently Arnstein[57] and Kelsch[58] have urged the view that the melanæmia is the primary process, the destruction of corpuscles going on in the blood itself, and the particles and coloring material taken up by the leucocytes are transformed into melanin, and then the cells collect in the spleen, liver, and bone-marrow, producing the condition of melanosis. It is probable that the older view is the true one, and we may regard the process as an exaggeration or intensification, under the stimulus of the malarial poison, of the normal process of blood-destruction which goes on in the spleen and bone-marrow, and under some circumstances in the liver and lymph-glands. We can often trace in the cells of these organs the stages of transformation from red corpuscles to melanin-granules, just as can be done in the tissues in the neighborhood of an extravasation, where also the process is chiefly intracellular (Langhans). On the other hand, in those very states in which the red corpuscles are destroyed in the blood and the hæmoglobin set free, we do {898} not find melanæmia. It happens occasionally in fevers that we meet with colorless cells in the blood containing red blood-corpuscles, which in time would be transformed into pigment, but, so far as we know, such a condition has not been observed in the blood in malaria. The connection between the fever paroxysm and the appearance of the pigment in the blood depends, most likely, on changes in the volume of the organs under the influence of the fever, whereby cells containing the pigment are dislodged and get into the circulation. This explains, too, their rapid appearance in some cases with the onset of a paroxysm. No doubt, as Virchow originally taught and as well shown in Gussenbauer's[59] observations, the pigment may result from the diffusion of the coloring matter and gradual precipitation of it in the granular form within the protoplasm of colorless cells; but of the occurrence of such a process in the circulating blood in malaria we have no satisfactory evidence, and we incline to the belief that the melanosis of the organs is the primary condition, while the melanæmia is secondary and inconstant.

[Footnote 57: _Loc. cit._, and _ibid._, lxxi.]

[Footnote 58: _Archiv de Physiologie_, 1875.]

[Footnote 59: _Virchow's Archiv_, lxiii.]

Occasionally, in cases of extensive melano-sarcoma, pigment-granules may be found in the blood in large numbers, and even appear in the urine and be deposited in the organs and skin. In a few instances also free pigment has been observed in the blood in Addison's disease.

PROGRESSIVE PERNICIOUS ANÆMIA.

DEFINITION.--Extreme and progressive anæmia developing without evident or apparently adequate cause.

SYNONYMS.--Idiopathic anæmia (Addison); Essential anæmia (Lebert); Anæmatosis (Pepper).

HISTORY.--During the first two or three decades of this century cases of severe and fatal anæmia were noted by Andral and others, but the credit of having given the first accurate series of cases belongs to Walter Channing of Harvard, who in the _New England Quarterly Journal of Medicine_ for 1842 published a paper entitled "Notes on Anhæmia, particularly in connection with the Puerperal State and with Functional Disease of the Uterus, with Cases."[60] Any one who reads this communication will be convinced that Channing's description, particularly of the seven cases occurring in the puerperal state, is that of the disease to which Gusserow and Biermer have more recently directed attention.

[Footnote 60: My attention was accidentally called to Channing's observations in the Periscope of Hall's _British-American Journal_ for 1845. Since then Musser, in the _Med. News_, Oct. 7, 1882, has given a valuable abstract of the paper.]