HEMOPOIESIS

From Big Medical Encyclopedia

HEMOPOIESIS (synonym hemogenesis) — the process consisting in a series of cellular differentiations which leads to formation of mature cells of peripheral blood. In large part this process was studied at germs, in an organism of the adult it can be tracked at recovery To. after heavy cytostatic influences.

In studying To. the big role was played by A. A. Maximov, A. N. Kryukov, A. D. Timofeevsky, N. G. Hlopin, A. A. Zavarzin, A. Pappenheim's works. In a research of processes of cellular differentiations use of special methods of coloring of cells in the smears developed by P. Ehrlich and D. L. Romanovsky in the 70th 19 century was essential.

The scheme of a hemopoiesis of I. A. Kassirsky and G. A. Alekseev (1967) was the most widespread in the USSR, edges summed up the result morfol, a stage of studying of this process. It reflected A. A. Maximov's hypothesis of a unitary origin of all blood cells — from one type of cells (hemocytoblusts). At the same time it was assumed that the close neighbourhood of stromal elements (fibroblasts) forming cells of marrow, and hemopoietic cells serves as reflection of their gistogenetichesky relationship. This assumption was wrong. Along with unitary representation about To. also the dualistic hypothesis allowing a separate origin of lymphocytes and all other elements of blood took place. The Polifiletichesky theory To., representing an origin of many ranks of the hemopoietic cells independently from each other, has only historical interest.

Long coexistence of various hypotheses of an origin of blood cells is explained by the fact that visually to track the most initial stages To. it was impossible because of a morph, similarities of parent cells of all sprouts To., and funkts, methods did not exist.

In 1961 Mr. Till and Mac-Kallok (J. E. Till, E. A. McCulloch) offered the method based that after introduction to fatally irradiated mice of donor marrow in their spleens macroscopically visible centers (colonies) of the hemopoietic cells develop. By means of a method of the chromosomal markers (which are steadily changed after radiation of chromosomes) Becker (And. j. Becker, 1963) was shown that each such colony represents a clone — posterity of one cell called colony-forming unit in a spleen (KOEs). At formation of colony one KOEs produces several million differentiated cells descendants, at the same time supporting own line of colony-forming cells which at a retransplantation of the following irradiated mouse give hemopoietic colonies in her spleen again. Thus, existence in an adult organism of the special cells having ability to long self-maintenance and a differentiation in mature cells of blood was shown. New clonal methods of a research allowed to study posterity of a separate colony-forming cell and to directly reveal the hemopoietic cells — predecessors of different classes, to estimate their differentsirovochny and proliferative opportunities (see. Cultures of cells and fabrics ).

Scheme of a hemopoiesis. Cells of the first, second and third upper ranks are taken in a framework and given in two morphologically different options in which they are capable to be: limfotsitopodobny (smaller size) and blast (bigger size). Shooters point to a possibility of transition of cells of one option to cells of other option here.

Lymphocytic colonies in spleens of the irradiated mice after introduction of marrow are not formed therefore the question of an origin of lymphocytes from the general polipotentny cell — predecessors of both hemopoietic, and lymphoid cells — long time was a subject of discussions. Using a method of splenic colonies in combination with method of radiation markers, it was succeeded to show that lymphocytes bear the same markers, as the hemopoietic cells of splenic colonies. Thus, existence of a polipotentny cell was experimentally confirmed, to the general for all sprouts To., including and for lymphocytes. These cells called trunk were capable both to self-maintenance, and to differentiations on all ranks K. (tsvetn. tab.).

Concentration of stem cells in hemopoietic bodies (see) it is rather small — in marrow of their mice apprx. 0,5%. Morphologically they are indistinguishable from lymphocytes. The differentiation of a stem polipotentny stem cell in the first morphologically recognizable cells of this or that row represents the multistage process leading to considerable expansion of number of each of ranks. On this way there is a gradual restriction of ability of cells predecessors (this term designate all set of morphologically similar cells of upper three rows of the scheme K.) to various differentiations and gradual decrease in their ability to self-maintenance. Stem polipotentny cells have very high ability to self-maintenance — the number of the mitoses made by each cell can reach 100; their most part stays at rest, at the same time is in a cycle apprx. 20% of cells.

After existence of stem cells by means of a method of culture of marrow for a granulotsitarno-monocytic sprout, and then and for erythrocyte and megakariotsitarny was proved, poetinochuvstvitelny cells predecessors were found. Development of methods of cultivation of these sprouts allowed to estimate and morfol., and funkts, features of the corresponding poetinochuvstvitelny cells. The absolute majority them is in a stage of active proliferation. Morphologically poetinochuvstvitelny cells as well as trunk, are indistinguishable from lymphocytes. Basic feature of a poetinochuvstvitelny number of cells is their ability to answer the humoral regulating influences. At the level of these cells mechanisms of quantitative regulation are implemented To., a cut meets specific needs of an organism for cells of this or that row. In agar culture of marrow there is a consecutive development of the granulocytes replaced then the monocytes turning in macrophages. Monocytes appear to replace granulocytes, needing, as well as the last, in a so-called colony stimulating factor — the estimated specific hormonal regulator.

Colonies of fibroblasts never give growth of the hemopoietic cells, and there is never a transformation of the hemopoietic cells in fibroblasts.

Essential addition to idea of a lymphocytopoiesis was opening of two types of lymphocytes — In - and T-cells, first of which are responsible for humoral immunity, i.e. development of antibodies, and the second carry out cellular immunity, participate in reaction of rejection of alien fabric (see. Immunocompetent cells ). It turned out that V-lymphocytes as a result of an antigen challenge can turn from morphologically mature cell into a blast form and be differentiated further in cells of a plasmatic row. Under the influence of an antigen challenge are transformed to a blast form and T lymphocytes. Thus, earlier seeming uniform limf, a row is presented by three rows of cells: In - T lymphocytes and plasmocytes which are closely connected with V-lymphocytes. Besides, usual idea of a blast cell (a blast the cell having usually rather narrow cytoplasm, a nezhnostrukturny kernel is called, a cut differs in uniformity of caliber and coloring of chromatinic threads, often contains nukleola) as about the ancestor of a row was not absolutely exact for lymphocytes: end-stage lymphocytes at impact on them of specific antigens are again capable to be transformed to blast cells. This phenomenon received the name of reaction blastotransformation of lymphocytes (see). The lymphocytes transformed under the influence of antigens are called immunoblasts. In the scheme K. it was necessary to enter the arrows pointing to a possibility of transition of morphologically end-stage lymphocytes to the corresponding blast forms.

Between stem and poetinochuvstvitelny cells there are cells predecessors of a myelopoiesis and a lymphocytopoiesis. Existence of these cells strictly is not proved, however a number of leukoses, first of all hron, a myeloleukemia, and also a subleukemic myelosis, an erythremic myelosis at which the cells which younger were (less differentiated), than poetinochuvstvitelny, but more mature, than trunk can be the only source of tumoral proliferation is found. Also existence limf, the leukoses presented and In - and T lymphocytes at the same time, i.e. arisen from their common precursor is shown.

In the scheme K. the stem cell and cells of the 2nd and 3rd ranks are taken in a framework and given in two morphologically different options in which they are capable to be: limfotsitopodobny and blast.

At the level of poetinochuvstvitelny cells there is a further restriction of differentsirovochny opportunities of cells. On this and the following morphologically recognizable stages of a differentiation the vast majority of cells is in a condition of proliferation.

The last cells capable to division, among granulocytes are myelocytes, and among eritrokariotsit — polychromatophilous normocytes. In the course of a differentiation morphologically recognizable erythroid cells make 5 — 6 mitoses; granulotsitarny cells — 4 mitoses; at a monocytopoiesis from a monoblast to a macrophage there pass 7 — 8 mitoses. In a megakariotsitopoeza allocate several morphologically distinguishable predecessors who since a megakaryoblast undergo 4 — 5 endomitoses (nuclear fissions without division of cytoplasm).

By means of a method of cloning and the analysis of chromosomal markers it was shown that the englobing cells, in particular kupferovsky cells of a liver and all other fabric macrophages united in system of the englobing mononuklear, treat derivatives of the hemopoietic cells and are posterity of monocytes, but not reticular macrophages and not an endothelium. Cells of this system have no gistogenetichesky community neither with reticular macrophages, nor with endothelial. The main funkts, the characteristics inherent in the cells entering this system — ability to phagocytosis, a pinocytic, strong sticking to glass. In process of a differentiation in cells of this row receptors for immunoglobulins and a complement appear thanks to what cells gain ability to active to phagocytosis (see).

In an erythrocytopoiesis (erythrogenesis) the youngest cell is the erythroblast (it is called also a proerythroblast), which has blast structure and usually round kernel. Cytoplasm during the coloring dark blue, is located with a narrow rim, often gives peculiar outgrowths. Concerning cells of an eritrokariotsitarny row there is no uniform nomenclature. One call them normoblasts, others erythroblasts. As for other ranks the term «blast» is applied only to cells — ancestors of this or that sprout (from here and the name «blast» — a sprout), all cells which are posterity of an erythroblast shall have in the name the termination «tsit». Therefore the term «normoblasts» was replaced with «normocytes».

Behind an erythroblast there is a pro-normocyte which differs from an erythroblast in more rough structure of a kernel though it also keeps the correct structure of chromatinic threads. Diameter of a kernel is less, than at an erythroblast, the rim of cytoplasm is wider, and the perinuclear zone of an enlightenment becomes visible. During the studying miyelogramma (see) it is easy to confuse a pro-normocyte with an erythroblast. Due to the difficulty of division of these cells some authors offer them in practical hematology not to differentiate at all.

Further the basphilic normocyte is located, at to-rogo a gruboglybchaty kernel has kolesovidny structure, cytoplasm is painted in dark blue color.

Following — polychromatophilous — the normocyte has even more dense structure of a kernel; cytoplasm occupies the most part of a cell and has basphilic coloring at the expense of the structures containing RNA, and oxyphilic due to emergence already of enough hemoglobin.

Ortokhromny, or oxyphilic, the normocyte has a small dense kernel (as a cherry stone), oxyphilic or with a basphilic shade cytoplasm. It is normal of oxyphilic normocytes a little since, pushing out a kernel at this stage, the cell turns into an erythrocyte, but in a «newborn» erythrocyte the remains of a basophilia at the expense of a small amount of RNA always remain, to - paradise disappears within the first days. Such erythrocyte from the remains of a basophilia is called a polychromatophilous erythrocyte. At use of special vital staining basphilic substance comes to light in the form of a reticulum; then this cell is called a reticulocyte.

The mature erythrocyte has the form of a biconcave disk therefore in a blood smear it has the central enlightenment. In process of aging the form of an erythrocyte gradually comes nearer to spherical (see. Erythrocytes ).

The youngest cell of a thrombocytopoiesis (thrombopoiesis) is the megakaryoblast — a one-nuclear small cell with a large blast kernel, hromatinny threads to-rogo more thickly and more roughly, than at an erythroblast; in a kernel 1 — 2 dark blue nukleola can be visible. Cytoplasm bezzernisty, dark blue color, otrostchaty, surrounds with a narrow rim a kernel. The pro-megacaryocyte results from several endomitoses. A kernel polymorphic with a rough structure of chromatin; cytoplasm dark blue, bezzernisty.

The mature megacaryocyte differs from a pro-megacaryocyte in a big kernel. Cytoplasm has blue-pink coloring, contains azurophilic reddish granularity. In a megacaryocyte form thrombocytes (see). In a smear it is possible to see also the breaking-up Megacaryocytes surrounded with small groups of thrombocytes. At trombotsitolitichesky states the otshnurovka of thrombocytes can occur also at a stage of a pro-megacaryocyte, thrombocytes at the same time are deprived of azurophilic substance, but they actively participate in a hemostasis.

Leykotsitopoez (leukopoiesis) includes a granulocytopoiesis (granulopoiesis), a lymphocytopoiesis (lymphopoiesis) and a monocytopoiesis (monopoez).

In a granulotsitarny row the myeloblast is the first morphologically distinguishable cell. It has a nezhnostrukturny kernel, single nukleola. The form of a kernel round, the sizes is slightly less, than at an erythroblast. The myeloblast differs from nondifferentiable blasts from a class of cells predecessors in existence of granularity in cytoplasm; the form of a cell is more often round, equal.

The following stage of maturing of granulocytes is the promyelocyte — neutrophylic, eosinophilic and basphilic. The round or fabiform kernel of a promyelocyte is more than kernel of a myeloblast almost twice though this cell is also not polyploid; it often is located excentricly, and in it it is possible to see the remains nukleol. The structure of chromatin already loses a gentle filamentous structure of blast cells, though has no gruboglybchaty structure. The area of cytoplasm is approximately equal to the area of a kernel; cytoplasm is plentifully sated with the granularity having features, characteristic of each row. For a neutrophylic row the promyelocyte is the most granular cell. Its granularity polymorphic — large and small, is painted by both acid and main dyes. In a promyelocyte granularity often is located also on a kernel. Granularity of an eosinophilic promyelocyte, having uniformity of grains, characteristic of eosinophils (like «whale caviar»), at the same time it is painted by both acid, and main dyes. The basphilic promyelocyte has large polymorphic basophilic stippling.

As transition from a promyelocyte to the following stage of maturing of cells — to a myelocyte — is not sharp, there was an intermediate form called «a maternal myelocyte», edges on all signs corresponds to the described promyelocyte, but differs from it in more rough kernel. In practice this form is not considered, it did not enter a miyelogramma.

The myelocyte represents a cell with round or oval, often eccentric the located kernel which lost any signs of a blast. Cytoplasm is painted in grayish-bluish tone, its granularity at a neutrophylic myelocyte more small, than at a promyelocyte. Otnositelnaya Square of cytoplasm accrues. The eosinophilic myelocyte has characteristic same orange-red granularity, a basphilic myelocyte — polymorphic large basophilic stippling.

The metamyelocyte is characterized by the fabiform krupnoglybchaty kernel located usually excentricly. The area of its cytoplasm is more than the area of a kernel and cytoplasm contains the same granularity, as a myelocyte, but in neutrophylic metamyelocytes it scantier, than in myelocytes.

A monocytic row is presented by quite simple stages of transition. Normal it is difficult to distinguish a monoblast from a myeloblast or a nondifferentiable blast, but at monoblast acute or monocytic hron, a leukosis it is easy to reveal these cells with the help gistokhy, colourings. The promonocyte has a kernel of a promyelocyte, but is deprived of granularity (see. Leukocytes ).

In a lymphocytic row the lymphoblast (a big lymphocyte) has all lines of a nondifferentiable blast, but is characterized sometimes by single large nukleola. Detection in a smear from limf, a node or a spleen of a blast without granularity allows to carry it to lymphoblasts. The attempt to differentiate a lymphoblast, a monoblast and a nondifferentiable blast in size and a form of a kernel, on width of a rim of cytoplasm does not make success since the lymphoblast under the influence of antigenic stimulation can undergo the most various changes.

The prolymphocyte has rather homogeneous structure of a kernel, quite often the remains nukleol, but in it is not present characteristic of an end-stage lymphocyte of a large glybchatost of chromatin (see. Lymphocytes ).

The plasmablast has a blast kernel, bezzernisty violet-blue cytoplasm. The pro-plasmocyte in comparison with a plasmocyte possesses more dense kernel located usually excentricly, rather bigger cytoplasm of blue-violet color. The plasmocyte is characterized by the kolesovidny dense kernel lying excentricly; cytoplasm — blue-violet, sometimes with several azurophilic reddish granules. Also is normal and in pathology it can be multinuclear (see. Plasmocytes ).

Being gistogenetichesk uniform, the hemopoietic system in the functioning is characterized by a certain independence of behavior of separate sprouts.

A hemopoiesis in the antenatal period

the Hemopoiesis in the antenatal period for the first time is found in a 19-day embryo in blood islands of a vitellicle, in a stalk and chorion. By 22nd day the first blood cells get into mesodermal fabric of an embryo, into heart, an aorta, arteries. On the 6th week activity decreases To. in a vitellicle. Completely the first (mesoblastic) period of a hemogenesis, preferential an erythrocytopoiesis, comes to an end by the beginning of the 4th month of life of an embryo. Primitive hemopoietic cells of a vitellicle accumulate hemoglobin and turn into the primitive erythroblasts called by P. Ehrlich megaloblasts.

The second (hepatic) period To. would begin after week and reaches a maximum by 5th month. To. this period preferential erythroidal though on the 9th week in a liver the first neutrophils already ripen. The hepatic period of an erythrocytopoiesis is characterized by disappearance of megaloblasts; at the same time eritrokariotsita have the normal sizes. For 3 months of embryonal life the erythrocytopoiesis joins a spleen, but the person has its role in prenatal To. it is limited.

On 4 — the third (marrowy) period begins 5th month To. The myeloid erythrocytopoiesis of a fruit — erythroblastic and, as well as leykotsitopoez, differs from an erythrocytopoiesis of the adult a little.

The general pattern of an embryonal erythrocytopoiesis is gradual reduction of the sizes of erythrocytes and increase in their number. According to various periods To. (mesoblastic, hepatic and marrowy) there are three different types of hemoglobin: embryonal, fetalis and hemoglobin of the adult. Generally transition from fetalis hemoglobin to hemoglobin of the adult begins on the 3rd week of life of a fruit and comes to an end in 6 months after the birth.

In the first days at newborns the polyglobulia and a neutrophylic leukocytosis is observed. Then activity of an erythrocytopoiesis decreases. It is normalized at the age of 2 — 3 months. The neutrocytosis of the first days of life is replaced by a lymphocytosis; only by 5 years in a leukocytic formula neutrophils begin to prevail.

Regulation of a hemopoiesis

Regulation of a hemopoiesis is carried out by hl. obr. in the humoral way. And for each of ranks K., probably, this way is independent. Concerning an erythrocytopoiesis it is known that the differentiation of poetinochuvstvitelny cells in erythroblasts (with the subsequent their differentiations to mature erythrocytes) is impossible without erythropoetin (see). A stimulator for production of erythropoetin is power failure of oxygen in fabrics. The differentiation of granulocytes in culture requires presence of a colony stimulating factor which, as well as erythropoetin, belongs to alfa2-globulins.

Except specific hormones like erythropoetin, on To. also other hormones, napr, androgens work. They stimulate an erythrocytopoiesis, mobilizing endogenous erythropoetin. Mediators (adrenaline, acetylcholine) influence the hemopoietic system, not only causing redistribution of uniform elements in blood, but also by direct influence of a pas stem cells (also holinoretseptor are found in them adreno-).

The question of nervous control is a little developed To., though the plentiful innervation of the hemopoietic fabrics cannot but have biol, values. The nervous tension, emotional overloads lead to development of a short-term neutrophylic leukocytosis without essential rejuvenation of structure of leukocytes. Increases the level of leukocytes in blood meal a little. The similar effect is caused by administration of adrenaline. Mobilization of a vascular granulotsitarny reserve is the cornerstone of this reaction preferential. At the same time the leukocytosis develops during several tens minutes. The leukocytosis with band shift is caused by administration of pyrogenal and glucocorticoid steroid hormones, reaching a maximum through 2 — hour, and is caused by an exit of granulocytes from a marrowy reserve. The maintenance of granulocytes in a marrowy reserve exceeds their quantity in a blood channel by 30 — 50 times.

Humoral regulation of a hemopoiesis is carried out preferential at the level of poetinochuvstvitelny cells. In experiences with uneven radiation it was shown that recovery of the hemopoietic cells in the irradiated extremity happens irrespective of composition of blood and a condition of unirradiated sites of marrow. Bone marrow transplantation under the capsule of a mouse kidney showed that the volume of the marrow developing from a transplant is defined by quantity of the replaced stromal cells. Therefore, they also define limits of reproduction of stem cells from which then marrow in a kidney of a mouse recipient develops. A. Ya. Fridenstein's works, etc. (1968, 1970) showed specificity of stromal cells of various hemopoietic bodies: stromal cells of a spleen define a differentiation of stem cells in the direction of a lymphocytopoiesis, marrowy stromal cells — in the direction of a myelopoiesis. At the same time, apparently, there are powerful stimulators which inclusion happens at unusual states (e.g., sharp anemia) that leads to development in a spleen of the centers unusual for it To. with preferential reproduction of eritrokariotsit. More often it is observed at children's age. Such centers To., called by extramedullary, contain along with eritrokariotsita small percent of other elements of marrow — myelocytes, promyelocytes, megacaryocytes. At acute massive or at the long increased loss of cells To. can go on additional ways in each of ranks. Apparently, there are opportunities to emergence of special cells predecessors of the 3rd number of the scheme K., which give rise to such shunt pathways To., providing bystry products of a large number of cells. It is well tracked at an erythrocytopoiesis, but probably exists also in other ranks.

Inclusion of stem cells in a differentiation is most likely accidental process, probability to-rogo at stable To. makes about 50%. Regulation of number of stem cells carries not the general, and local character also is provided with the mechanisms functioning in each specific site of hemopoietic microenvironment. Much less it is clear, whether the direction of a differentiation of stem hemopoietic cells is regulated. On the basis of a number of experimental data are suggested that the probability of a differentiation of stem cells in the direction of an erythrocytopoiesis, a granulocytopoiesis etc. is always constant and does not depend on external conditions.

The facts testimonial of existence of the specialized system regulating To., no. Maintenance of a certain quantity of mature cells in blood is carried out by multistage transfer of neurohumoral signals. The signal arrives to a cellular reserve or cellular depot, from to-rogo erythrocytes will be mobilized very quickly at acute blood loss. Then products of the corresponding cells at the level of poetinochuvstvitelny elements by increase in their number at first without differentiation («horizontal mitoses»), and then with a differentiation are stimulated. The category of mature cells is as a result created.

Pathology of a hemopoiesis

Pathology of a hemopoiesis can be shown by disturbance of maturing of cells, an exit in blood of unripe cellular elements, emergence in peripheral blood of cellular elements unusual for this age category. The bacterial infection, extensive fabric disintegrations (the breaking-up tumors, phlegmons, etc.), an endotoksinemiya are followed by the expressed neutrophylic leukocytosis with increase in percent of band neutrophils, frequent emergence in blood of metamyelocytes, myelocytes, promyelocytes. There is no accurate dependence of degree of a leukocytosis on weight of damage of an organism. The leukocytosis depends, on the one hand, on the volume of a marrowy and vascular granulotsitarny reserve and on activity of marrowy products, with another — on intensity of consumption of granulocytes in the center of an inflammation. Opposite to a leukocytosis (see) a state — leukopenia (see), caused first of all by a granulocytopenia, it can be connected with suppression of products of granulocytes as a result of influence of protivogranulotsitarny antibodies, an aplasia of marrow of the immune nature, napr, characterized by simultaneous oppression of granulotsitarny, erythrocyte and megakariotsitarny sprouts, or an aplasia of an unknown origin (actually aplastic anemia); in other cases the granulocytopenia and a leukopenia can be caused by the increased disintegration of granulocytes in the increased spleen (e.g., at hron, hepatitis, cirrhosis). Due to the existence of a marrowy reserve falling of quantity of granulocytes in blood due to their increased use meets seldom (e.g., at extensive drain pneumonia). The leukopenia is a frequent sign of tumoral substitution of marrow at miliary metastasises, at acute leukoses and is occasionally observed at the beginning hron, a lymphoid leukosis. At leukoses (see) quantity of leukocytes in blood can increase; constantly it happens at hron, leukoses. At acute leukoses the maintenance of leukocytes in blood can be various: at the beginning of process the leukopenia is more often noted, then in process of an exit of blast tumor cells in blood there can be a leukocytosis.

The viral infection, antigenic influences conduct to the strengthened products of specific lymphocytic clones, increase in level of lymphocytes in blood. Reduction of quantity of thrombocytes (see. Thrombocytopenia ) it is observed at emergence of autoantibodies to thrombocytes (more rare to megacaryocytes), at the increased destruction by their increased spleen. Decrease in maintenance of thrombocytes is possible as a result of blood losses, during the developing of extensive hematomas, the intravascular disseminated coagulation (thrombocytopenia of consumption). Increase in maintenance of thrombocytes (see. Trombotsitemiya ) it is observed at some hron, leukoses (hron, a myeloleukemia, a subleukemic myelosis, an erythremia), it is frequent at cancer. Sometimes at cancer of a kidney cancer cells produce erythropoetin and, perhaps, trombotsitopoetin (see) that is followed by sharp increase in quantity of erythrocytes and thrombocytes.

The maintenance of erythrocytes in blood is defined by a ratio of their disintegration and products, blood losses, security of an organism with iron. Deficit of iron leads to decrease in level of hemoglobin in erythrocytes at normal number them in blood — a low color indicator. On the contrary, deficit of polyneuramin 12 is followed by disturbance of cellular division as a result of disturbances of synthesis of DNA; at the same time erythrocytes are ugly, they are not enough, but in them it is more hemoglobin, than normal — the raised color indicator (see. Hyperchromasia, hypochromatism ).

Also reactions of several sprouts to the nonspecific stimulating influences are in some cases possible. E.g., development in an organism of a cancer tumor can lead to increase in blood of contents both granulocytes, and thrombocytes. The similar picture is occasionally observed at sepsis.

To. undergoes profound changes at acute beam influence. These changes in the main manifestations correspond to the changes developing quite often at chemotherapy of tumors. Under the influence of ionizing radiation the sharing cells of marrow, limf, nodes perish. Mature granulocytes, erythrocytes keep viability even at obviously lethal doses of radiation. On the other hand, end-stage lymphocytes belong to radio sensory cells. Bystry reduction of their quantity in peripheral blood in the first hours after radiation is explained by it. As erythrocytes live in blood apprx. 120 days, anemia develops in 1 — 1,5 month after radiation. By this time in hard cases begins active To., increase in maintenance of reticulocytes is observed, and anemia does not reach high degree.

In mild cases the recovery reticulocytosis develops in 1,5 months after radiation, but anemia at the same time also does not happen deep.

One of effects of radiation is death of cells of marrow and the reduction of cells developing further in peripheral blood. For manifestations of acute radiation injury the formula «dose — effect» characterizing strict dependence of primary changes on an absorbed dose of ionizing radiation is specific. Injuries of marrow belong to primary changes, and the infections arising owing to oppression of marrow, hemorrhages — to secondary; their expressiveness and emergence of damage strictly are not caused by a dose. Conditionally consider that total radiation in a dose more than 100 I am glad leads to development of acute radial illness (see). Smaller doses, though lead to essential death of marrowy cells, do not constitute direct danger (beam damage without wedge, manifestations). At radiation in a dose more than 200 I am glad the lymphopenia, an agranulocytosis, deep thrombocytopenia develops; anemia, as a rule, does not arise. At smaller doses the same disturbances, but to a lesser extent are noted. Body irradiation, total or close to it, in doses more than 200 I am glad leads to the maximum falling of quantity of leukocytes, thrombocytes and reticulocytes. Time of approach of a leukopenia also is in strict dependence on an exposure dose. Here not only pattern «a dose — effect», but also pattern «a dose — time of effect» is shown, i.e. the term of clinically found damages at an acute radial illness is defined by an exposure dose.

Changes of quantity of leukocytes of peripheral blood of the person depending on a dose of total radiation: on abscissa axis — time after radiation (in days), on ordinate axis — quantity of leukocytes (in thousands in 1 mkl).

Pattern of change of quantity of leukocytes in peripheral blood depends on an exposure dose. These changes consist of the period of initial rise within the first days, the period of initial decrease (5 — the 14th days), the period of temporary rise which is observed at doses less than 500 — 600 is glad and is absent at higher exposure doses; the periods of the main falling and final recovery which are observed at doses less than 600 I am glad (fig.). The same pattern is observed at thrombocytes and reticulocytes.

The mechanism of fluctuations of quantity of leukocytes can be presented as follows. Initial rise has, apparently, redistribution character and continues usually no more days, its height is not connected with an exposure dose; in blood only the level of granulocytes increases and rejuvenation of their structure is not observed that is caused by mobilization of a vascular granulotsitarny reserve.

After the period of initial rise gradual falling of the quantity of leukocytes reaching the minimum value in different terms depending on a dose begins. The dose is higher, the earlier there will come the moment of the maximum decrease. At exposure doses over 600 — 1000 I am glad further reduction of this period does not come though at reduction of a dose it is extended and at a dose apprx. 80 — 100 I am glad it is necessary approximately for the 14th days. Level of falling of quantity of leukocytes during initial decrease is depending on a dose. The period of initial decrease in leukocytes should be explained with an expenditure of a marrowy gra-nulotsitarny reserve (to 5 — the 6th days) and only partly ripening and a differentiation of the cells which remained after radiation (from the moment of radiation until the end of initial decrease). Such conclusion is possible in connection with preservation of granulocytes in blood to 5 — the 6th days even at such high doses (more than 600 — 1000 I am glad) when in marrow there is no cell left capable to any differentiation, and only the high-radio sensitive not sharing mature granulocytes remain. At exposure doses of marrow higher than 600 I am glad practically all cells have rough damages of the chromosomal device and perish right after the first mitosis in the next few days after radiation. At smaller doses of nek-paradise a part of marrowy cells keeps ability to division and a differentiation. The their is more, the later there comes the end of the period of initial decrease in quantity of leukocytes.

The fact that to 5 — 6th days the reserve is exhausted is confirmed also by the fact that these days in blood huge neutrophils — products of the cells of a proliferating pool, apparently, irradiated in a mitosis begin to appear. Huge neutrophils find from the 5th on 9-e days after radiative effects in blood of persons, is total irradiated in any dose (these cells find in blood and after action of tsitostatik). At radiation in a dose more than 600 an exit of huge neutrophils directly is glad precedes approach of an agranulocytosis.

The following stage — temporary, so-called abortal, rise in quantity of leukocytes — is noted at exposure doses less than 500 — 600 is glad, and at higher doses the period of initial falling directly is replaced by the period of the main decrease in quantity of leukocytes. The origin of abortal rise is completely not found out. Its duration is defined by an exposure dose: the dose is higher, the it is shorter; at the same time the level of leukocytes is clearly not connected with a dose. The same abortal rise is characteristic of thrombocytes and reticulocytes. At rather small doses — apprx. 100 — 200 I am glad — abortal rise continues to 20 — the 30th days and is replaced by the period of the main falling, and at doses more than 200 is glad — an agranulocytosis, very low level of thrombocytes and almost total disappearance of reticulocytes. Final recovery of a hemopoiesis (after the period of the main falling) occurs the later, than less dose. Duration of the period of the main falling at doses from 200 to 600 I am glad it is approximately identical. Abortal rise is caused by activation temporary To., perhaps coming from myelopoiesis of a cell predecessor, a cut before it is exhausted, blocks a differentiation of the stem cells responsible for final recovery To. in marrow. After the period of the main falling in blood there occurs normalization of cellular level. In some cases this recovery happens not absolutely full and the level of leukocytes and thrombocytes is slightly reduced.

Detection of the period of temporary raising of granulocytes, thrombocytes and reticulocytes (but not lymphocytes) with a paradoxical phenomenon of earlier final recovery of composition of blood at high doses of radiation (in limits to 500 I am glad) allowed to assume existence of the braking influence of cells predecessors of a myelopoiesis on proliferation of stem cells.

Changes in structure of marrow at an acute radial illness are studied worse, than changes in peripheral blood. Marrow is surprised radiation even in the small doses which are not causing an acute radial illness though right after radiation it is not always possible to reveal reduction of quantity of cells. Important information on weight of damage of marrow is given it tsitol, by the characteristic. In the first days after radiation cells of a red row, percent of myeloblasts and promyelocytes considerably decrease. Than the exposure dose is higher, especially these changes are deep. In the next weeks devastation of marrow gradually accrues. Preferential the maintenance of granulocytes decreases. Devastation of marrow in the first days advances emergence of an agranulocytosis in peripheral blood. According to marrowy punctate it is possible to judge disappearance of the centers of a hemogenesis; the hemopoietic cells (at moderately severe defeats) are almost absent. Important changes of cellular structure of marrow and peripheral blood are revealed as a result of use of the chromosomal analysis. By the end of the first days emergence of mitoses with structural disturbances of chromosomes — aberation chromosomes is noted (see. Mutation ), which number is strict in proportion to an exposure dose: at a dose 100 I am glad quantity of aberrant mitoses makes 20%, at a dose 500 I am glad — apprx. 100%. The method of determination of quantity of leukocytes during primary falling (on 7 — the 8th day), time of the beginning of the period of the main falling of leukocytes formed the basis of system biol, dosimetry at acute beam influence.

Essential changes happen also in a lymphocytopoiesis. Since first day the quantity of lymphocytes in blood decreases and clearly depends on an exposure dose. In 2 months after radiation their content in blood reaches datum level. The research in vitro of chromosomes of peripheral blood lymphocytes, stimulated to a mitosis phytohemagglutinin (see), finds dose dependence. Lymphocytes in peripheral blood are in the intermitotic period many years; therefore even several years later after radiation it is possible by quantity of aberrant mitoses in them to determine the fact of the increased radiation in the past and to define approximately an exposure dose. In marrow of a cell with aberation chromosomes disappear in 5 — 6 days since as a result of loss of fragments of chromosomes during a mitosis they become impractical. At stimulation of marrowy cells phytohemagglutinin (FGA) chromosomal damages to them find in many years after radiation. These cells after radiation were all years in rest, and the answer to FGA confirms their lymphocytic nature. The usual analysis of aberation chromosomes of cells of marrow is made without stimulation of FGA.

Overseeing by recovery of composition of blood after acute exposition showed that the recovery rate is connected not only with an exposure dose, but also with secondary displays of a disease (e.g., with inflammatory processes in skin, in intestines, etc.). Therefore at the same exposure dose time of approach of an agranulocytosis at different patients is identical, and elimination of an agranulocytosis depends on extent of defeat of other bodies.

At hron, a radial illness, edge results from repeated reirradiations of an organism for months or years in a total dose more than 200 — 300 I am glad, recovery To. has no so natural dynamics; death of cells is dragged out on a long term, during to-rogo there are also processes of recovery To., and processes of its further damage. At the same time the cytopenia can not develop. Separate signs of an asthenic syndrome inherent hron, a radial illness, can appear at some patients and at radiation in a total dose apprx. 100 is glad. In marrow at hron, a radial illness find separate small accumulations of undifferentiated cells, reduction of quantity of cells. In blood or there are no changes, or the moderate not progressing cytopenia — a granulocytopenia, thrombocytopenia is noted,



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A. I. Vorobyov, I. L. Chertkov.

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