Polycythemia ([polycythaemia rubra vera,)

POLYCYTHEMIA [polycythaemia rubra vera, syn. erythraemia], a disease of the blood system, accompanied by a prolonged and progressive increase in the number of red blood cells in the body. The first case of this disease was described in 1892 by Vaquez, and the first detailed work on it was published in 1903 by Osler; hence the names for this disease: Vaquez disease, Osler disease, Vaquez-Osler disease. From symptomatic polycythemia or erythrocytosis, P. differs in the absence of concomitant diseases of other systems or organs that could lead to an increase in the number of red blood cells (diseases of the lungs, cardiovascular system). P. is a disease mainly of old age (from 40 to 60 years); however, individual cases of P. in childhood have been described. Men and women are affected by P. approximately equally.

The symptomatology of P. The main symptom of P., which gives it its name, is an increase in the number of red blood cells per unit volume of blood, which in most cases fluctuates between 7 and 9 million per 1 mm³. However, cases of polycythemia with higher figures are not uncommon: cases with 11.6 million (Osier), 12 million (Miller, Engelbach), 13.5 million (Koster), 13.8 million (Stern), 14 million (Forschbach), and 14.2 million (Tapsjö) have been described. On the other hand, especially at the beginning of the disease, figures bordering on normal (6 million) and even completely normal can be observed; Vaquez and Lutembacher described cases where the number of red blood cells increased from 4.8 million to 8 million over 4 months, Naegeli from 4.8 million to 11 million (over 4 years), Watson from 4.9 million to 13.2 million.

That this polycythemia is quite real and not merely a consequence of redistribution of red blood cells is proven by finding similar figures in capillaries, veins, and arteries. Thus, Vaquez in his first case found in blood from the pulp of the finger 8,200,000 and in venous blood 8,450,000 red blood cells; Gaisbock found in blood from the finger 10,675,000, from the vein 10,775,000, and from the artery 10,530,000. Along with this, many authors describe significant fluctuations in red blood cell counts observed in erythremics, reaching 2-3 million not only throughout the day but even within hours, and attributed to changes in capillaries.

In terms of the morphology and biology of red blood cells, the following are noted, but not always and to varying degrees: polychromasia, reticulocytosis, nuclear remnants, normoblasts (quite often); megaloblasts are not observed in P. Morawitz found increased respiration of red blood cells. The resistance of red blood cells can be normal, increased, and decreased, and often extended in both directions. Pronounced poikilocytosis, anisocytosis, and megalocytosis are never observed.

The content of Hb in the blood usually lags significantly behind the number of red blood cells: although cases have been described where hemoglobin reached 200 (Rosenhart) and 240 units (Koster), in the vast majority of cases it remains at the level of 120, rarely 150 units, accordingly the color index is always below 1, and often falls to 0.5-0.6. This is clearly visible on blood smears in P., where red blood cells usually appear pale, often resembling chlorosis.

The number of white blood cells is usually normal, but mostly fluctuates between 12,000 and 20,000, reaching in individual cases 50,000 (Osier), 54,000 (Weintraud), and even 86,000 (E. Meyer). Extremely important in this is the absolute and relative increase in the number of neutrophils (up to 90%), relative and often absolute decrease in lymphocytes (down to 7-5-4%), increase in the number of eosinophils (up to 10 or more percent), and finally the extremely rare occurrence in other diseases of an increase in basophilic leukocytes reaching 3-4-5%. In addition to these features of the leukocyte formula, indicating increased activity of the myeloid system, in very many cases myelocytes up to 3-4-5% (12% in one case by Hirschfeld) and transitional forms to them, myeloblasts (Naegeli) and megakaryocytes were also found.

In natural connection with the sharp increase in the content of formed elements in the blood is a significant increase in its viscosity, reaching 11.4 (Parkes-Weber), 20.9 (Wepse), and even 23 (Mimzer) instead of the normal 5.2; the specific gravity of whole blood reaches 1.083 (Glaesner), the dry residue up to 29%. The possible assumption based on many of these data that there is thickening of the blood in P. is refuted by the fact that the blood serum is not only not thickened, but on the contrary is rich in water, contains little protein, of low specific gravity (Bene, Weintraud, Senator, Naegeli, Lutembacher).

Along with the described changes in blood composition, an essential sign of P. is an increase in blood mass. Both researchers who determined blood mass by the inhalation method (Parkes-Weber, Haldane, Hutchinson) and those who worked with dyes (see Blood, its mass) found it consistently elevated, with the increase reaching two- and even threefold compared to normal. Characteristically, with improvements achieved by one or another method of treatment, the blood mass, although it decreases, remains above normal, even if the number of red blood cells falls to normal. As for the ratio between the mass of formed elements and plasma, in most cases the mass of red blood cells is particularly sharply increased, while the mass of plasma is relatively and absolutely decreased (80-90% red blood cells, 20-10% plasma), i.e., there is hypervolemia polycythaemica; in some cases, a simultaneous increase in both the mass of red blood cells and the mass of plasma is observed while maintaining a more or less normal ratio between them - hypervolemia normocythaemica. Comparing the corresponding literary data with their observations, Seyderhelm and Lampe came to the conclusion that the second type of hypervolemia becomes possible because in these cases the volume of individual red blood cells is significantly reduced (to 60 μ³), while in cases of the first type it usually exceeds normal and decreases slightly only when the number of red blood cells per 1 mm³ exceeds 8-9 million. According to these authors, the first type is characteristic of Vaquez's P., the second of Gaisbock's P. (see below).

Corresponding to the composition and mass of the blood in P. are changes in the circulatory system. Particularly striking is the bright red with a brick tint coloration of the skin of the face, hands and feet, and the cherry-red coloration of the mucous membranes of the lips, mouth, pharynx, conjunctiva of the eyes, female genital organs. This erythrosis, resembling acne rosacea in alcoholics, is a consequence of dilation and filling of superficial capillaries with blood. Brown and Giffin on a large material of 57 cases subjected to capillaroscopy were able to confirm that this dilation mainly affects the venous part of the capillaries, separated from the arterial part by a sharp transition, while in cardiac polycythemia both parts dilate more or less uniformly. In addition to dilation, there is also lengthening of capillary loops (up to 0.6 mm instead of 0.36) and slowing of blood flow in them. Since the visible coloration of the skin is largely determined by the thickness of the epidermis, erythrosis is not observed on the skin of the trunk, forearms, thighs; it may also be absent on the skin of the face and hands, but the coloration of the mucous membranes, especially the pharynx and conjunctiva of the eyes, remains unchanged, which often led researchers to discover P. On the other hand, the coloration of the coverings is influenced by all circumstances that cause dilation or constriction of blood vessels: emotions, being in cold or warm environments, etc. Finally, in later stages of the disease, when stagnation occurs, erythrosis may give way to a cyanotic coloration.

The filling and stretching of the capillary network in severe cases reach such a degree that they lead to numerous ruptures and hemorrhages into the mucous membranes, into the conjunctiva, loosening and bleeding of the gums, even skin hemorrhages resembling scurvy or Werlhof disease.

The dilation of vessels is not limited to capillaries, but is also observed in the subcutaneous veins, especially of the face and extremities, as well as the chest cavity, often reaching quite significant degrees and causing the appearance of ampullary protrusions and varicose nodes. Nevertheless, these changes appear relatively late and are subject to large fluctuations; much earlier and with greater constancy, dilation of veins is observed upon examination of the fundus of the eye, where they sharply differ from arteries in their volume and dark color, sometimes present varicose dilations and are accompanied by small hemorrhages. Despite the congestion and stagnation in the capillary and venous network and the enormous increase in blood viscosity, the heart in P. suffers very little: in P. neither dilation nor hypertrophy of the heart is found as a rule. Blood pressure in classic cases remains normal or stays at low figures. In 1904, Gaisbeck considered it possible to isolate a special form of P., accompanied by an increase in blood pressure (polycythemia hypertonica Gaisbock) and differing from the disease of Vaquez by the absence of splenomegaly (see below), hypertrophy of the heart (see also the data provided by Seiderhelm and Lampe above regarding the mass of blood). However, to this day "among authors there is no unanimity regarding the recognition of this form as an independent nosological entity, all the more so that between both forms there exist many transitions. In particular regarding splenomegaly, which was for some time considered a necessary component of the Vaquez syndrome (hence the name polycythemia megalosplenica), it is now known that it not only can be absent in individual cases, but can also disappear where it was previously present (Weintraud).- The liver is involved in the suffering mainly due to its engorgement with blood, leading to more or less significant increase in its size, subject however to large fluctuations. A number of changes in the other organs present nothing specific.- Changes on the part of the digestive organs sometimes appear first: loss of appetite, thirst, sensation of fullness in the stomach, abdominal bloating, vomiting regardless of food intake, prolonged constipation. In the respiratory organs, phenomena of bronchitis, similar to that in congestion due to cardiac insufficiency, are often observed; in far advanced cases, patients complain of dyspnea on exertion. In the urine, slight albuminuria, hyaline and granular casts, occasionally erythrocytes are found, but kidney function usually remains normal. From the nervous system in P., sensations of blood rushing to the head, migraines, dizziness of the Meniere syndrome type, sometimes irresistible drowsiness, sensations of constant fatigue are observed. Finally, in some cases, mental confusion, amnesia, increased excitability, depressive states are observed. Excessive engorgement of blood in veins and capillaries leads to the appearance of various hemorrhages into internal organs, playing an essential role in the picture and course of P. Hemorrhages gastric, intestinal, metrorrhagias, hematurias, hemorrhagic pleuritis are observed. Of particular importance are cerebral hemorrhages, which are one of the most frequent causes of death in P. Along with hemorrhages, thromboses are often observed, especially of the veins of the lower extremity; infarcts of the spleen accompanied by severe pains have been frequently noted; thromboses of cerebral vessels lead to multiple softening of the latter. Finally, fairly frequent attacks of pain in the extremities of the erythromelalgia type, sometimes ending in gangrene, as well as pains in the joints simulating acute articular rheumatism should be noted.- In connection with the pathogenesis of P., data on the gaseous and pigment exchange in P. are of interest. Regarding the first, Senator found in most cases increased oxygen consumption, Mosse in a summary of 19 cases found increased gas exchange only in 8, Schill-in three cases only in one. As for urobilin, its amount in the urine and feces is usually increased, reaching, according to Adler and Sachs (Adler, Sachs), 2 g per day (with a norm of 200-400 mg). In addition, Senator found an increased iron content in the urine. The course of P.--is very chronic, lasting for years, and the onset of the disease can only be guessed at, since patients often have a 'florid appearance', and only complete examination allows one to conclude that the patient has had erythrocytosis for many years. The reasons prompting the patient to consult a physician are the most diverse: symptoms of dyspepsia, bleeding gums, hemorrhages into the skin, bleeding, pains in the region of the spleen, flushes, dizziness, drowsiness etc. Usually at this time all the main signs of P. can already be detected, but it often happens that, for example, in the presence of enlargement and tenderness of the spleen, erythrocytosis is absent or even clearly expressed changes in blood composition; similarly, after significant bleeding, these most important symptoms may be absent. This is facilitated by the second most important feature of the course of P.--the alternation of exacerbations and remissions, especially in not far advanced cases. However, in later stages remissions become less and less pronounced, erythrocytosis, venectasia, polycythemia, splenomegaly become more and more persistent. In the end, phenomena of congestion develop, erythrocytosis is replaced by cyanosis, signs of heart insufficiency appear and patients die either from the latter, or from cerebral or gastro-intestinal hemorrhage, or finally from cachexia. Among complications and concomitant diseases of P., arteriosclerosis, nephritis, cirrhosis of the liver, heart defects should be particularly noted, which can often substantially obscure the picture of the disease. Pathological anatomy. Upon autopsy of those who died from P., what first strikes the eye is the enormous engorgement of all vessels, down to the smallest branches, 'which as if injected in the preparation of the anatomical specimen' (Lutenbacher). This is particularly sharply expressed in relation to the mesenteric, splenic and portal vein vessels. Thus, the first stage of autopsy shows the undoubted presence of true plethora and confirms the above data regarding the mass of blood. The most important are the changes in the bone marrow: in a longitudinal section of the long bones, the bone marrow is found to be red with a bluish tinge throughout, of gelatinous consistency. Under the microscope: very few fat cells or even they are completely absent; blood vessels are extremely dilated and engorged with red corpuscles; in the intervals-abundance of cells of all kinds, among which normoblasts with sharply stained, often budding nuclei, and anuclear erythrocytes predominate, many polynuclears with all transitions to myelocytes, many promyelocytes. Thus, the bone marrow presents a state of increased erythroblastic activity, with simultaneously increased activity of leukopoiesis, which in individual cases even predominates. The spleen in most cases is enlarged and just as engorged with blood as other internal organs. Under the microscope: the structure of the spleen is not essentially changed, Malpighian corpuscles of normal size and structure, but are pushed apart by hypertrophied and engorged with erythrocytes splenic pulp. According to Lutenbacher, hyperemia of the spleen in P. is active and extends mainly to the Billroth strands, in contrast to congestive hyperemia, localized in the sinuses. In addition to this hyperemia, increased macrophagocytosis is observed, but siderosis is rarely encountered and only to a very slight degree (the siderosis found by Tsyupkin and some others may be caused by therapeutic measures). Depending on the thromboses and hemorrhages that have occurred, corresponding changes are encountered. In isolated cases, foci of myeloid metaplasia were found in the spleen. The liver may retain normal size, but more often it is enlarged due to hyperemia and dilation of vessels. Under the microscope-general dilation of all capillaries and vessels (in contrast to the congestive liver, where mainly the hepatic vessel system is affected); dilation of capillaries sometimes reaches such a degree that the liver cords disappear, capillaries merge and give the corresponding areas an angioma-like appearance'. In the other organs, only phenomena of sharp hyperemia, traces of infarcts, hemorrhages are noted. The etiology of P. remains to this day unexplained. All attempts to find its cause in various infections or intoxications ~ diseases of the cardiovascular system, kidneys, endocrine glands etc. have remained fruitless. In this connection, the cases of familial P. described by a number of authors are of particular interest. One can assume that many more such cases would be discovered if attention were paid to this aspect of the question and if the numerous not sharply expressed forms (formes frustes, formes de debut) of this disease were better recognized.- The pathogenesis of P. also continues to remain controversial. Of the multitude of theories, the following should be mentioned: 1. The theory which as the basis of P. places the lowering of the function of the erythrolytic apparatus of the spleen and liver.

First put forward by Weintraud, it was later supported by Eppinger, who in a number of cases did not find an increase in the amount of pigments in the urine, feces, and duodenal juice, and in two cases with autopsy did not find signs of intensified hemolysis either in the spleen or in the liver, and Westenhoffer, who did not find hemosiderosis in the liver; as for the function of the bone marrow, while being forced to admit its hyperplasia, Eppinger considers that the increased production of red corpuscles remains unproven. Against this theory one can object: a) that according to the author's own data, the question may not be about absolute insufficiency of hemolysis, but only about relative insufficiency compared to the number of erythrocytes in the blood; however (thus concludes his own chapter on P. Eppinger) it cannot be otherwise, because if the breakdown were 'sufficient', there would be no hyperglobulinemia; b) that the absence of hemosiderosis does not prove the absence of increased breakdown: there are known diseases with undoubtedly increased breakdown without hemosiderosis, and siderosis itself can be considered not so much as a sign of intensified breakdown, but as a sign that the latter takes place under abnormal conditions; c) that the increased production of erythrocytes is proven not only by the hyperplasia of the bone marrow, but also by the abundance of its formed elements and by signs of regeneration in the circulating blood (Morawitz and others); d) that in many cases the total excretion of urobilin is sharply increased, but one cannot judge only by the urine in these cases, since a healthy liver may not allow urobilin to pass into the urine even with intensified breakdown.-2. Supported by Pribram, Loevy, Ransom, the theory of decreased breakdown of red corpuscles due to hypercholesterolemia, protecting them from hemolysis; however, in this theory the very fact of the protective action of cholesterol remains unproven, and moreover hypercholesterolemia is observed in P. by no means always (Gutzeit and others). The viewpoint prevailing at the present time is that of increased erythroblastic (and myeloblastic) activity of the bone marrow in P. However, there remain disagreements as to whether this increase in activity is primary or secondary. Thus, Bene and Koranyi expressed the opinion that in P. hemoglobin has a decreased ability to bind oxygen, and the hyperfunction of the bone marrow is a reaction to oxygen deficiency. However, the research of Leschke and Neu-feld, Morawitz and others showed that this assumption is not justified. A number of authors (Lommel, Bene and others) consider that the hyperfunction of the bone marrow is a reaction to stagnant processes hindering hematosis; however, hyperglobulinemias caused by stagnation phenomena in various diseases do not give the symptom complex of P. Hirszfeld, Brieger and Forschbach, Arinin and others, supporters of the theory of the inhibitory hormonal action of the spleen on the bone marrow, see the main cause of P. in the loss of this function of the spleen, and Brieger and Forschbach cite a case of typical P. that developed after splenectomy and lasted more than thirteen years. However, among the numerous splenectomies performed, this case remains the only one, and as a rule removal of the spleen does not lead to P. Finally, quite a number of supporters (including Shustrov) view P. as a reaction of the bone marrow to increased hemolysis and as having affinity with pernicious anemia, from which it differs only in the lesser intensity of the hemolytic factor. However, it is impossible to agree with this theory, since 1) the hypothetical hemolytic poison has never been found in P. by anyone; 2) experiments with the introduction of small doses of hemolytic poisons often lead to polyglobulinemia, but have never yet given the phenomena of P.; 3) in P. signs of intensified hemolysis are by no means always present; 4) the character of hematopoiesis in pernicious anemia essentially differs from that observed in P.; 5) with respect to pernicious anemia it by no means can be considered proven its hemolytic primary source. As for the individual cases of 'transition' of P. to pernicious anemia, here it is quite possible a coincidental occurrence of two diseases. If one is not satisfied, like Naegeli, with the unsubstantiated assertion about the loss of vegetative regulation of erythropoiesis, one will have to admit in the end that to this day the existence of any extramedullary factor capable of reproducing all the peculiar features of P. remains unproven. On the other hand, however, from the example of pernicious anemia one can see with what caution one should speak about 'primary' diseases of the bone marrow. The question should therefore be considered open.-The question of the relationship between P. and myeloid leukemia is of considerable interest. The very fact of extremely significant hyperglobulinemia and hyperplasia of the bone marrow, observed cases of P. being replaced by leukemia and vice versa, combination of both diseases and the presence of transitional forms between them (disease of Bluementhal), peculiarities of the leukocyte formula in P., reflecting the hyperfunction of the myeloblastic apparatus, similar observations at autopsies,-all this prompts authors, starting with Turk, to consider both these diseases as fundamentally homogeneous hemoblastoses, taking one or another character depending on constitutional or etiological factors not yet subject to accounting (Oberten, Brieger and Forschbach, Minot and Buckman and many others); Tsypkin even considers polycythemia one of the varieties of pseudoleukemia. Treatment of P. The uncertainty of questions about the etiology and pathogenesis of P. and the diversity of existing hypotheses have led to the diversity of methods of treatment used. Thus, Koranyi, Bene, Lommel used inhalations of oxygen, which gave good results in their hands, but were rejected by other authors. Rentzky, Schneider and some others removed the spleen in P., but the abundance of fatal cases forced them to recognize this method unacceptable. Turk saw good results from the use of large doses of arsenic (30 drops of Liq. arsen. Fowleri), but this was not confirmed in other cases. In addition, treatment with lacto-vegetarian diet, thyroidin, irradiation of the spleen with X-rays, rays, thorium X etc. was used. At present the following are used: 1) repeated bloodlettings, which in any case give temporary relief; at the same time it is recommended to simultaneously inject physiol. solution to avoid further decrease in plasma mass; 2) treatment with benzene; starting from 3 times a day with 15 drops gradually increasing to 100 drops a day (Hirszfeld) or up to 3.0-4.0 a day in gelatin capsules; however, despite the observed improvements, this method of treatment should be considered dangerous in view of the frequent development of severe anemic conditions; 3) the same should be said about treatment with hydrochloric acid phenylhydrazine (Phenylhydraz. hydrochl.-2-3 times a day in capsules or under the skin from 2 to 7 cm³ of 1% solution-Eppinger); 4) treatment with spleen in fried, stewed, ground and other forms; good results are reported by Nipperdey, Pashkis and Diamant, but Keller in 4 cases obtained no results. The best and at the same time long-lasting effect was obtained by a number of authors with X-ray irradiation of the bones (Ludin, Bottner, Guggenheimer, Naegeli, Aubertin and many others). However, here too it is necessary to carefully monitor the dosage and often check the condition of patients, since transitions of polycythemia to anemia and to leukemia are noted.