Bone Marrow

BONE MARROW (medulla ossium), a soft mass that fills all spaces within bones not occupied by bone tissue itself. Two main types of bone marrow are distinguished: red and yellow. 1. Red (medulla ossium rubra, also called active, cellular, lymphoid, embryonic), the color of which depends on its richness in blood vessels and the presence of red blood cells. These two factors can vary quantitatively, resulting in variations in shade (for example, pink, pinkish-red). Red bone marrow is tissue that actively participates in hematopoiesis: within it, the continuous maturation and formation of red blood cells, white blood cells, and platelets occurs. 2. Yellow (medulla ossium flava, fatty) bone marrow, which in consistency resembles ordinary fatty tissue, consists almost exclusively of fat cells (see separate table, fig. 7). The color, consistency, and cellular composition of both types of bone marrow change depending on age, nutritional status, and pathological conditions of the body. In newborns and during the first 2-3 years of life, red bone marrow is present in all bones, which is gradually replaced by yellow marrow (fatty involution, or so-called lipomatosis of bone marrow); the process begins with the small bones of the extremities-metatarsals, phalanges-and proceeds in a centripetal direction, involving the bones of the trunk and long tubular bones of the extremities. By the age of 15, involution is almost complete, and red bone marrow persists throughout life only in the flat and short bones of the trunk (sternum, vertebrae, skull). Varying-sized areas of it may be found in the adult normal organism and in long tubular bones, located most often in the metaphyseal region and in the form of a narrow rim in the subcortical layer [see separate table 1 (t. XIII, p. 743-744), fig. 1]. These areas are the starting points for hyperplasia of bone marrow in diseases when the reverse replacement of yellow marrow by red begins, proceeding already in a centrifugal direction [see separate table, fig. 8 and separate table (t. XIII, p. 743-744), fig. 2]. Under normal conditions, the amount of red and yellow bone marrow is approximately equal. In old age and during prolonged debilitating conditions, mucoid, gelatinous bone marrow is encountered, resulting from atrophy of fatty tissue and edema of the interstitial substance with its transformation into mucoid-like tissue. Increasing with age, the total mass of red and yellow bone marrow in an adult averages 2,600 g, constituting 3.4-5.9% of the total body weight, which exceeds the weight of any organ or system, excluding blood, muscles, and skeleton. In men, bone marrow is greater than in women. In the right lower extremity, bone marrow is less than in the left. Conversely, the right hand contains a greater or equal amount of bone marrow compared to the left. For every 1 g of liquid blood in an adult, there are ⁵/₉ g of bone marrow. Embryology and Comparative Morphology of Bone Marrow In the human embryo, bone marrow is laid down relatively late-at the 3rd month of intrauterine life and at this moment does not yet participate actively in hematopoiesis; primary hematopoiesis precedes it. The formation of bone marrow occurs in such a way that from the side of the perichondrium, richly vascularized embryonic connective tissue (mesenchyme) penetrates into the deep parts of the calcified cartilage, the cells of which (especially the endothelium) begin to resorb the cartilaginous substance, forming small, irregularly shaped cavities, which represent the primary marrow spaces. The embryonic bone marrow filling these spaces consists only of capillaries and branching mesenchymal cells and plays no hematopoietic role. Moreover, the mesenchymal cells composing it can differentiate into osteoblasts, fat cells, myeloplaxes (osteoclasts). Only somewhat later in this tissue, primary, lymphoid-type cells with basophilic protoplasm appear, gradually increasing in volume and resembling myeloblasts in general appearance. In the initial period of cartilage resorption, they are very few, but their number gradually increases, and finally they begin to predominate; because of this, bone marrow in general appearance resembles lymphoid tissue. Red blood cells and granulocytes are still absent; they appear in the middle of embryonic life. In most mammals, yellow bone marrow is present in the diaphyses of long tubular bones, while in the spongy substance of the trunk bones-red. In some rodents (rabbit, guinea pig, rat), red bone marrow fills the diaphyses of long bones throughout most of life. The histological structure of red bone marrow is almost identical in all mammals. Only wide variability is observed in the content of fat cells and differences in the nature of leukocyte granulations. In birds, very active bone marrow is found in the long tubular bones, resembling that of rodents; it is rich in granulocytes with acidophilic granulation, young forms, and nucleated red blood cells, but lacks megakaryocytes. The formation of leukocytes, as in humans, occurs outside the vessels, while the formation of red blood cells is exclusively intravascular [in the so-called sinuses (Sabin, Doan)]. In reptiles, the bone marrow of the diaphyses resembles that of birds, but is generally much poorer in cellular elements and also lacks megakaryocytes. In tailless amphibians, the diaphyses of long bones and the cavities of short bones are filled with both red and yellow bone marrow, with red being located mainly parietally, forming a cortical layer, and yellow predominantly in the central part of the diaphyseal canal. During the active period-May, June, July-the bone marrow contains many granular and non-granular, dividing myelocytes mixed with red blood cells, erythroblasts, and spindle-shaped cells. In fish, the medullary cavities do not contain true bone marrow resembling that of mammals and birds, but are filled with poorly differentiated connective tissue consisting of star-shaped cells, few fibrils, and fat cells. In young individuals, the bone marrow of the skull bones resembles mucoid, in older individuals it has a fibro-fatty character. Its hematopoietic function is very limited. Conversely, in ganoid fish, the bone marrow of the skull bones is active, rich in fat, and approaches that of mammals. Histology. In bone marrow, supporting tissue-reticulum, fatty tissue, vascular apparatus, nerves, parenchyma, and lymphatic tissue are distinguished. 1. The supporting reticular tissue in the form of a delicate, fine-meshed network is the true stroma of the marrow substance and consists of small, spindle-shaped or angular cells with processes connected by fibers running in various directions, which belong to the collagenous fibers in terms of staining. Cells and fibers are poorly visible during hyperplasia of hematopoietic tissue and appear more clearly during its atrophy, during the deposition of any pigment, or during inflammation at the time of proliferation. 2. Fatty tissue of bone marrow of ordinary structure in the form of individual cells or groups appears already in the embryonic period and by 3-4 years reaches significant sizes. Often in the form of nodules, it is found in bones with red bone marrow in adults (sternum, etc.). The presence of fatty tissue in active bone marrow should be considered a normal phenomenon, and its absence may indicate a hyperplastic process on the part of the bone marrow parenchyma. 3. The vascular apparatus in bone marrow is represented by the blood and little-studied lymphatic systems. Blood enters through the artery entering the middle of the bone, which divides in a forked manner and then breaks up into numerous obliquely inward, mostly microscopic branches, embedded in a delicate connective tissue membrane with an admixture of elastic fibers and very thin adventitia.

The epiphyses of long bones are supplied by special arteries anastomosing with the central and perichondral networks of small arteries. From the axial small arteries, numerous arterial capillaries branch off in a radial direction, emptying into funnel-shaped wide venous capillaries-sinuses. From the venous capillaries, the blood richer in cells enters the veins, which do not abound in anastomoses and are enclosed in bony trabeculae, consequently they cannot contract. The veins empty into a large central vein, which, accompanying the artery, leaves the bone at the point where the latter enters. The unique system of venous capillaries and the weak contractility of the veins explain the very slow venous circulation in the bone marrow. Between the venous sinuses, lined with delicate flat endothelium and playing an important role in hematopoiesis, there is a network of very thin capillaries that are impermeable in the normal state. The question of whether the just described circulatory system represents a strictly closed system of tubes or whether in the area of the venous sinuses there are spaces devoid of walls where the blood flow comes into direct contact with the parenchymal cells has not yet been resolved. As confirmation of the latter position, the easy transition of parenchymal cells into the general blood flow and the presence of erythrocytes between its elements are indicated. But such pictures may be artifacts, and at present, there is a growing tendency to the opinion of the closedness of the vascular system of the bone marrow. In view of this, the bone marrow can be considered as an organ important in functional relation, built in the form of a network of blood vessels resembling the vascular systems of the liver and spleen. Lymphatic vessels of the bone marrow accompany the small venous trunks and capillaries in the form of perivascular spaces, the walls of which consist of a layer of endothelium. 4. Nerves, very numerous, enter the bone marrow together with the artery, penetrate with it into the diaphyseal canal and accompany it to the smallest branches. They represent vaso-motor fibers. 5. The parenchyma of the bone marrow represents its most essential part, giving it this or that imprint. In the parenchyma, three kinds of cellular elements are distinguished, arising as a result of erythro-, leuko- (granulo-) and thrombocytopoiesis; in their aggregate they form the myeloid group of hematopoiesis. In a healthy organism there is a relatively regular and orderly distribution of all bone marrow elements (see below). 6. A very frequent but inconstant finding in the bone marrow are lymphocytes, observed mostly in small amounts but sometimes in the form of lymphatic nodules resembling true follicles. In pathological conditions, the relationships between cells can substantially change, and in the entire picture of the bone marrow a predominance of one or another form is revealed, whereby a histological subdivision of the bone marrow into several types can be established. According to the old classification of Naegeli, an erythroblastic bone marrow, a myelocytic, a myeloblastic and a true lymphatic bone marrow (e.g. in lymphatic leukemia) are distinguished. According to Schilling-Yamamoto: 1. Mature neutrophilic bone marrow (many transitional forms to young and segmented) - in chronic inflammatory processes without complications. 2. Immature neutrophilic bone marrow with predominance of myelocytes and almost complete absence of segmented - in acute severe infections. 3. A more mature promyelocytic bone marrow (with predominance of promyelocytes and cells of the Pappenheim leukoblast type) represents the type of children's bone marrow; in adults it is encountered extremely rarely. 4. Immature promyelocytic bone marrow (with predominance of basophilic promyelocytes) - in severe chronic diseases causing neutrophilia, in atonal complications. 5. Myeloblastic bone marrow (predominance of myeloblasts) - only in acute myeloblastic leukemia often with a clearly greenish tint of the color of the marrow. In certain diseases a picture characteristic only of them is found in the bone marrow: megaloblastic bone marrow in pernicious anemia; aplastic (see Anemia) - in aplastic anemia, Frank's aleukia, agranulocytosis; leukemic [see separate table (Vol. XIII, pp. 743-744), Figs. 4 and 5] (see Leukemia). The question of the regulation of the functions of the bone marrow is complex and unclear. In addition to the purely mechanical moments of influence on the bone marrow in the form of pressure from bone tissue, the most important regulating moment is the changes in the constituent elements of the blood. A quantitative decrease in the latter, e.g. in hemorrhages, causes increased activity of the bone marrow. An even more stimulating effect on the function of the bone marrow is exerted by the increased breakdown of erythrocytes and leukocytes. But changes in the bone marrow depend not only on these factors of the blood itself. They can arise under the influence of various substances (e.g. toxins, products of breakdown in inflamed tissue) arising in organs remote from the bone marrow, when the blood is only a transmitter of these influences. In addition, the influence on the bone marrow may not come directly from the blood flow, but through the autonomic nervous system and endocrine glands. The latter is given particularly great importance in the occurrence of a whole series of pathological changes in the blood, e.g. the appearance of anemias in lesions of the thyroid gland, adrenal glands. Non-inflammatory pathological conditions of the bone marrow Anemia of the bone marrow is encountered in acute anemia of the whole organism, e.g. after severe arterial hemorrhages; the marrow is pale-red, pink in this case. It must be remembered that the red color of the bone marrow depends not only on the filling of the vessels with blood, but also on the amount of erythropoietic tissue, and its true state can be judged only by microscopic examination. In view of the abundance of anastomoses between the vessels of the bone marrow, true anemic infarcts are hardly observed in it. Hyperemia of the bone marrow can be of active and passive nature; the first arises under the direct influence of pathological causes, in vaso-motor influences (tetanus), in status thymico-lymphaticus and others. Congestive hyperemia occurs with local or general difficulty in blood flow, but it does not arise so regularly and does not have such severe consequences as in other organs. Hemorrhages into the bone marrow can be caused by purely local processes of traumatic (fractures, etc.), inflammatory nature, local foci of infections, tumors and general diseases in the form of hemorrhagic diatheses, intoxications, sepsis. Pigmentation of the bone marrow with hemosiderin is observed as a result of hemorrhages and in general hemosiderosis. In the first case it is noticeable to the naked eye only in large foci. The deposition of pigment occurs mainly in reticular and endothelial cells, while giant cells and the vessel wall do not show it. Of practical importance is the clearly visible to the naked eye hemomelanosis of the bone marrow in malaria, because with simultaneous pigmentation of other organs it is the most certain means for establishing the diagnosis of the disease in a corpse. Of other endogenous pigments, the brown-red pigmentation without iron and insoluble in water hematoporphyrin in hematoporphyrin (see) should be mentioned. Of exogenous pigments, the deposition of coal particles is noted; around the latter a shell of hemosiderin may form. Of deposits of organic substances in the vessel walls or reticular cells of the bone marrow, the deposition of lipoids in diabetes, Niemann-Pick disease and others, glycogen in children who died from acute diseases should be mentioned. Amyloidosis of the bone marrow, as of other organs, occurs either in the form of an exclusively local process or as a partial manifestation of general amyloidosis. In the first case, it is a matter of rarely encountered nodular foci; in the second, also rare lesion, the vessel walls are exclusively involved in the process, which is discovered only microscopically (see Gaucher disease). Primary tumors of the bone marrow - myelomas, myelosarcomas (see Myeloma). Among tumors having a special tendency to metastasize in the bone marrow, cancer of the breast, prostate, bronchi, malignant strumas, hypernephromas and more rarely - others should be mentioned. As a result of metastases [see separate table (Vol. XIII, pp. 743-744), Fig. 3] certain changes occur in the peripheral blood (anemia, appearance of normoblasts). Heteroplastic development of bone marrow is observed with simultaneous heterotopia of bone and is encountered in the brain, meninges, lungs and other places where only scar tissue is present.

p. Dvizhkov» Bone marrow can be affected by certain parasites, mainly protozoa. Malarial parasites can be found in bone marrow both in erythrocytes and in erythroblasts. Affected erythrocytes can enter the bone marrow from the bloodstream or be among those developed in the bone marrow itself and there acquiring Plasmodium vivax. In the capillaries of the bone marrow, multiplication of tropical malaria parasites (schizogony) occurs; young forms of Plasmodium immaculatum are also found here. The causative agent of kala-azar (Leishmania Donovani) is also found in the bone marrow, and leishmanias can be seen in myelocytes, large mononuclear cells and polymorphonuclear leukocytes, macrophages, and endothelial cells. It is remarkable that after death, leishmanias retain their morphological features in the bone marrow longer than in cells of other organs. For the diagnosis of kala-azar and canine leishmaniasis, trepanation of the bone marrow is sometimes used both for preparing microscopic specimens and for seeding. Stages of division of Trypanosoma Cruzi are also common in the cells of the bone marrow. Among parasitic worms, ECHINOCOCCUS can begin its development in the bone marrow.

E. Pavlovsky. Functional diagnosis of bone marrow. Clinical medicine tries to determine the function of bone marrow in all its diversity using its research methods. A. General research methods. I. External appearance. a) Coloration of the skin and mucous membranes (pallor, jaundice, cyanosis) can allow some conclusions about the state of hematopoiesis. b) Presence of hemorrhagic rashes, presence of positive Rumpel-Leede phenomenon can indicate a deficiency of blood platelets and allow the conclusion of insufficient function of the bone marrow in this regard. c) The same can be indicated by necrotic anginas and stomatitis. -II. Percussion. Tenderness on percussion of bones (sternum) indicates increased blood filling of the bone marrow and in particular enhanced pathological hematopoiesis. The sternum is often tender in malignant anemia, in hemolytic jaundice, in leukemias, in bone carcinoma. Tenderness is usually absent in weak regeneration, in aplastic anemia, in aleukia. B. Blood examination. I. Erythrocytes and amount of Hb.-a) Number of erythrocytes, their size, range of size variation (diversity of size - anisocytosis), shape, colorability, inclusions (Jolly bodies, Cabot rings), granularity allow one to speak about the function of the bone marrow. -b) Presence of nucleated erythrocytes (erythroblasts) indicates enhancement or perversion of erythropoiesis. Presence of eryroblasts with loose young nucleus (megaloblasts) in malignant anemia indicates a megaloblastic character of hematopoiesis in the bone marrow. Normoblasts with pyknotic nucleus are found in all anemias. -c) Supravital granularity (subst. reticulo-filamentosa, granulo-filamentosa) gives a more correct idea of the energy of erythropoiesis than erythroblasts. II. Leukocytes. Number of leukocytes, percentage ratio of various forms speaks about the energy of granulopoiesis. III. Platelets, megakaryocytes. Number of platelets in peripheral blood can speak about the state of thrombocytopoiesis of the bone marrow (e.g. sharp rise of their curve around the 12-14th day of typhus coincides with increase in number of megakaryocytes in these days of illness). Presence of excessively large blood platelets ('tails' of 30-40 μ), platelets with excessively wide basophilic periphery, with coarse granularity speaks about disturbance of work of bone marrow. The same is indicated by findings of megakaryocytes in peripheral blood (in myeloid leukemia). Sharp fall in number of platelets goes parallel with disappearance of megakaryocytes in bone marrow in thrombopenias. Nevertheless we have no right to conclude definitely about the state of bone marrow from peripheral blood. B. Examination of bone marrow in vivo. Ghedini (1910) proposed for obtaining bone marrow to trepanate the tibia. Seyfarth (1922) modified Ghedini's proposal. He trepanates the sternum at the level of III-IV ribs with a small trepan with crown height of 5 mm after preliminary incision of soft parts. After removal of the bone plate, bone marrow is obtained with a sharp curette. It is examined bacteriologically (seeding), histologically (placing in formalin, Zenker's fluid) and in smears. This operation, although small, has not received wide distribution. Arinkin in 1927 proposed to puncture the manubrium of sternum with a Bier needle. The puncture site is anesthetized with 1% novocaine in amount of 3-5 cm³. Anesthesia is done layer by layer, starting with intradermal injection of novocaine. The periosteum is well infiltrated. After 5 min. the puncture is performed. The passage of the needle into the cancellous part of the bone is perceived as a characteristic crack. 0.3-0.5 cm³ of bone marrow mass is aspirated. Puncture can also be performed into the body of sternum at the level of III-IV ribs, giving the needle an inclination of 45°. The needle can be shortened by half and must be well sharpened. From the puncture, smears are usually made on slides. Excellent preparations are made by the agar-osmium method of Deetjen-Weidenreich. 1% solution of agar in 0.8% NaCl is prepared. Sterilization, pouring into tubes of 3-4 cm³. Before work, agar is dissolved and poured onto slides. Plates of agar are cut slightly smaller than the cover glass. Bone marrow is taken on the cover glass. The glass is placed with drop down onto the agar plate. After 3 min. 1% solution of osmic acid is poured under the cover glass. After 3-5 min. fixation is finished. The glass is taken from agar with tweezers, washed. Staining with May-Giemsa. According to Lossen (1910), in bone marrow (children) in 1mm³ there are from 270 to 1,500 thousand white corpuscles. According to Timofeevsky (ribs of dogs)-from 1 to 1.4 million. According to data of Tushinsky-Kotlyarenko (typhus) in punctate-25-230,000. Such fluctuations are partly explained by greater or lesser admixture of blood to the punctate. According to Schilling and Benzler (1915), percentage relations of nuclear elements of bone marrow are remarkably constant in healthy person. According to Arinkin (1929) (punctate), in normal myeloblasts - 1.0 - 2.4%, promyelocytes - 1.0 - 2.8%, neutrophilic myelocytes - 4.5 - 8.6%, eosinophilic myelocytes - 0.3-1.0%, neutrophilic metamyelocytes - 1.4-3.4%, eosinophilic metamyelocytes - 0.3-1.0%, mature neutrophils - 41-55%, eosinophils - 0.6-4.0%, basophils - 0-0.7%, monocytes - 2.1-4%, reticulo-endothelial cells - 2.1-9.3%, lymphocytes - 7.3-16.5%, plasma cells - 0.3-0.9%, megakaryocytes - 0.6-6.1%, proerythroblasts - 0.8-2.9%, erythroblasts - 5.7-16.2%. In malignant anemia the amount of giant erythroblasts reaches 10%, proerythroblasts - 15%, normoblasts - 29.1%. According to puncture data in remissions of malignant anemia (liver diet) bone marrow remains megaloblastic. Puncture of bone marrow makes it possible to establish diagnosis in various diseases caused by blood parasites-leishmaniasis, relapsing fever in apyrexia, malaria.

m. Tushinsky» bone suture