ANEMIAS. LEUKEMIAS
Definition of concept, hematological indexes
The anemia is decrease of erythrocytes amount and hemoglobin maintenances in unit of blood volume which is accompanied by qualitative changes of erythrocytes.
Hematological attributes of anemias are subdivided on quantitative and qualitative.
The quantitative displays include:
1) reduction of the maintenance of erythrocytes in unit of blood volume – in men is lower than 4×1012, in women is lower than 3,5×1012 in 1L of blood;
2) reduction of hemoglobin concentration – in men is lower than 130 g/l, in women is lower than 120 g/l;
3) reduction of hematocrit – in men is lower than 0,43 l/l, in women is lower than 0,40 l/l;
4) change of a color index – is not lower than0, 85 and not higher than 1,15.
Qualitative attributes of anemias are presence in blood of:
1) regenerative, but not mature forms of erythrocytes;
2) degenerative changes of erythrocytes;
3) cells of pathological regeneration.
Regenerative forms of erythrocytes (cells of physiological regeneration) are young immature cells of red blood sprout appearance of which in peripheral blood testifies to amplification of regeneration of cells erythroid lines in red bone marrow or increase of medullar barrier permeability.
Regenerative forms include:
а) reticulocytes. They are found in smear of blood after supravital staining. Represent denuclearized cells dirty – staining colouring with black inclusions as granules (substantia granulofilamentosa). Iorm their contents in blood is 0,2-2 %. At the strengthened regeneration of cells red sproud blood their quantity may increase to 50 %.
b) polychromatophils. They are found in blood smear colored as in the method bu Romanovsky-Gimza. They are denuclearized cells cytoplasm of which shows property to perceive both acid, and the basic dye-stuffs. Therefore polychromatophils different from mature erythrocytes by cyanotic shade of the colouring. In essence reticulocytes and polychromatophils are cells of an identical degree of maturity – direct predecessors of erythrocytes. Different names are connected with their different properties which come to light at different ways of staining.
c) normocytes (basophilic, acidophilic, polychromatophilic). They are nuclear predecessors of erythrocytes. Iorm its absent in peripheral blood, and contain only in a red bone marrow. At the intensification of regeneration of cells erythroid lines they may occur in blood as acidophilic and polychromatophilic rarely as basophilic normocytes. Sometimes, erythroblasts can be found in blood (predecessors of normocytes) during hyperregenerative anemias.
Changes of erythrocytes, which testify about inferiority of these cells, named degenerative. Such changes are characterized by the following phenomena:
а) anisocytosis – change in the size of the erythrocytes. Occurrence of macrocytes and microcytes;
b) poikilocytosis – change in the form of the erythrocytes. In conditions of a pathology may occur pear-shaped, extended, sickle-cell, oval erythrocytes, and also erythrocytes with the spherical form (spherocytes);
c) change in the staining of the erythrocytes, that depends on the contents of hemoglobin in them. Erythrocytes, intensively colored, are named hyperchromatic, with pale staining – hypochromatic.
d) presence of pathological inclusions. They include Jolly’s bodies – are the rests of nuclear substance; Cabot’s rings – the rests of nuclear environment having the form of ring or eight; basophilic granularity – the rests basophilic substances of cytoplasm significative of toxic defeat of red bone marrow.
Cells of pathological regeneration occur when there is changed of erythropoesis from erythroblastic to megaloblastic:
а) megaloblasts are big cells with basophilic, polychromatophilic or acidophilic cytoplasm, containing large, located usually eccentrically nucleus with soft chromatin grid;
b) megalocytes – denuclearized cells which are formed during maturing of megaloblasts. They usually intensively stained, some the oval form, non an brighten up in the central part.
Occurrence of the specified cells in red bone marrow and blood is typical for megaloblastic anemias, in particular of the B12-deficiency anemia.
Classifications of anemias
І. According to color index:
а) normochromic (the color index is within the limits of 0,85-1; for example, acute posthemorrhagic anemia during first days after hemorrhage);
b) hypochromic (the color index is lower than 0,85; for example, irondeficiency anemia);
c) hyperchromic (the color index is higher than 1,0; for example, B12-deficiency anemia).
ІІ. Pathogenetic classification:
А. posthemorrhagic anemias: a)acute posthemorrhagic anemia; b) chronic posthemorrhagic anemia.
B. hemolytic anemias.
1. acquired: а) toxic-hemolytic; b) immune; c) mechanical; d) acquired membrane pathy.
2. hereditary: а) hereditary membrane pathy; b) enzymopathy; c) hemoglobinopathy.
C. Anemias as a result of erythropoiesis disorders.
1. deficient: а) irondeficient; b) B12-deficient; c) proteindeficient.
2. hypo–, aplastic.
3. metaplastic.
4. dysregulative.
The characteristic of posthemorrhagic anemias
Posthemorrhagic anemia is an anemia which develops as a result of hemorrhage. There are two types of anemias of this group according to the character of hemorrhage: 1) acute posthemorrhagic and 2) chronic posthemorrhagic anemia.
Acute posthemorrhagic anemia arises after fast massive hemorrhage as a result wounding of vessels or their damage by pathological process.
Chronic posthemorrhagic anemia develops after repeated hemorrhages, caused by injury of blood vessels during number diseases (dysmenorrhea, ulcer of stomach, hemorrhoids etc.)
The picture of blood of acute posthemorrhagic anemias depends on time which has passed after hemorrhage. Depending on it it is possible pick out three periods, each of them is characterized by the certain picture of peripheral blood.
1. The first several hours after acute hemorrhage. At this period of time the total amount of blood, and also total number of erythrocytes in an organism decreases. However in unit of blood volume the contents of erythrocytes and concentration of hemoglobin do not vary.
2. The period of time from several hours untill several days after acute hemorrhage. Dillution of blood takes place as a result of transition of liquid from interstitial spaces into blood vessels. As a result of it the quantity of erythrocytes and hemoglobin in unit of volume of blood decreases, as well as hematocrit. A color index stays without changes (normochromic anemia). Qualitative changes of erythrocytes in blood smear are not found yet.
3. The period of time from several days untill 1-2 weeks after acute hemorrhage. The most typical feature of picture of blood in this period is occurrence of plenty regenerative forms of erythrocytes, due to amplification of erythropoiesis in red bone marrow. Because young unripe erythrocytes contain less hemoglobin in comparison with mature cells, the color index decreases also and anemia becomes hypochromic.
During chronic posthemorrhagic anemia after the loss of iron hematologic attributes of irondeficiency anemia develop: concentration of hemoglobin and color index decrease, in blood smear there are degenerate forms of erythrocytes (micro– and poikilocytosis, hypochromy). Quantity of erythrocytes and hematocrit may remain without changes.
The characteristic of hemolytic anemias
Anemias which arise after destruction (hemolysis) of erythrocytes are called hemolytic. According to the mechanism of development hemolysis anemias may be: 1) anemias with intravascular hemolysis; 2) anemias with endocellular hemolysis.
Intravascular hemolysis arises in blood vessels under the action of factors that damage erythrocytes. These factors are called hemolytic. They include:
а) Factors of physical nature (mechanical trauma, ionizing radiation, ultrasound, temperature);
b) Chemical agents (hemolytic poisons);
c) Biological factors (causative agents of infectious diseases, toxins, enzymes);
d) Immune factors (antibodies).
Intravascular hemolysis it is accompanied by an output of hemoglobin from cells to blood plasma where it partially connects with protein haptoglobin.
Endocellular hemolysis develops after absorption and digestion of erythrocytes by macrophages. In its basis the following reasons may lay: а) occurrence of defective erythrocytes. b) occurrence on surface of erythrocytes the chemical groups capable to cooperate specifically with receptors of macrophages. In this case antibodydependent phagocytosis of erythrocytes is activated; c ) hypersplenism – increase of phagocytic activity of spleen macrophages.
Acquired hemolytic anemias
Depending on the reasons of development is allocated the following kinds of acquired hemolytic anemias.
1. Toxic hemolytic anemias.
2. Immune hemolytic anemias.
3. The anemias caused by mechanical damage of erythrocytes.
4. Acquired membranopathy.
Mechanical hemolysis of erythrocytes arises at prosthetics vessels or valves of heart traumas of erythrocytes in capillaries of foot during a long march (marching hemoglobinuria), at their collision with strings of fibrin (microangiopathic hemolytic anemia of DIC-syndrome).
Immune hemolytic anemias arise due to participation of specific immune mechanisms. They are caused by interaction of humoral antibodies with the antigenes fixed on a surface of erythrocytes. Their reason may be:
а) receipt from the outside antibodies against own of erythrocytes (hemolytic desease of newborn);
b) receipt into organism of erythrocytes which in plasma there are antibodies (the blood transfusion, not compatible on groups AB0 or Rh);
c) fixing on a surface of erythrocytes foreing antigenes (haptens), in particular, medical products (antibiotics, sulfanilamides), viruses; d) formation of antibodies against own erythrocytes.
Toxic hemolytic anemia may be caused by:
а) exogenous chemical agents: phenylhydrasin, lead, copper salts, arsenous hydrogen etc.;
b) endogenous chemical factors: bile acids, products formed at burn desease, uraemia;
c) poisons of biological origin: snake, beer, poison of some kinds of spiders, aumber of infectious agents, in particular, hemolytic streptococcus, malarial plasmodium, toxoplasma, leishmania.
Acquired membranopathy arise due to the acquired defects of erythrocytes membranes. As an example may be paroxysmal noctural hemoglobinuria. This disease as a results of a somatic mutation erythropoietic cells with defects of membrane. It is considered that disorders of membranes are connected with changes of ratio of fat acids which are part of their phospholipids. Erythrocytes of abnormal population get ability to fix complement and hemolyse.
The picture of blood of acquired hemolytic anemias is characterized by reduction of erythrocytes quantity and hemoglobin. The color index in norm, however may be higher than 1 unit that is connected with extraerythrocytic hemoglobin. In blood smear the significant amount regenerative forms of erythrocytes is found out: reticulocytes, polychromatophils, normocytes.
Hereditary hemolytic anemias
All hereditary caused hemolytic anemias are subdivided into three groups.
1. Membranopathies. Defects of erythrocytes membranes are in basis of this anemias group.
2. Enzymopathies. Anemias of this group are caused by disorder of erythrocytes enzymes .
3. Hemoglobinopathies. Arise after qualitative changes of hemoglobin.
Hereditary membranopathies may be caused by two groups of defects erythrocytic membranes:
1) membranopathies, caused by disorders of membrane proteins:
а) microspherocytic anemia Minkovsky-Shoffar’s;
b) ovalocytic hemolytic anemia;
Anemia Minkovsky-Shoffar’s is hereditary, endoerythrocytic (membranopathy) hemolytic anemia with endocellular hemolysis. Type of inheritance – autosomal dominant. Hereditary defect mentions membrane proteins of erythrocytes, in particular spectrin. Therefore permeability of erythrocytic membranes for ions sodium is considerably increased. Sodium and water pass from plasma inside of erythrocytes. In spleen they lose part of erythrocytes membrane and turn into microspherocytes. Life expectancy of erythrocytes decreases untill 8-12 days instead of 120.
Hereditary enzymopathies arise due to defect of erythrocytes fermental systems:
1) deficiency of enzymes pentose cycle. The most widespread enzymopathy is glucose-6-phosphatedehydrogenase deficiency anemia, caused by absence or significant decrease (reduction) of glucose-6-phosphatedehydrogenase activity;
2) deficiency of enzymes of glycolysis. The most widespread is deficiency of pyruvatekinase which results to disorders of energy provision Na-K-pumps of plasmatic membranes. Erythrocytes thus turn into spherocytes which are exposed to phagocytosis by macrophages;
3) deficiency of enzymes of glutathion cycle (glutathionsynthetase, glutathionreductase, glutathionperoxidaza) results in oppression antioxidant systems of erythrocytes, barrier properties of erythrocytic membranes to ions and osmotic hemolysis;
4) deficiency of utilization АТP enzymes. An example is deficiency of albuminous components Na-K-pump of erythrocytic membranes. Thus concentration of sodium that results them to hemolysis is increased in a cell.
Hereditary hemolytic anemia. Reticulocytoses
Qualitative and quantitative changes of hemoglobin lay in basis of development of hereditary hemoglobinopathies. The most widespread clinical form is sickle-cell anemia at which in β-chain of a molecule of hemoglobin glutamine acid is replaced on valine (HbS).
HbS is crystallized easily, erythrocyte loses its shape and cells of red blood get the sickle-like form. Macrophages phagocytose and hemolyse them, especially when hypoxia is present.
Quantitative hemoglobinopathies are characterized by disorder of hemoglobin chains synthesis. An example of this group are α- and β-thalassemia.
Thalassemias are hereditary caused hemolytic anemias with endocellular hemolysis. Pathological forms of hemoglobin which can easily drop out in deposit are appeared in the erythrocytes during α-thalassemia and erythrocytes look like targets (target cell anemia). Macrophages phagocytose and hemolyse the erythrocytes.
Synthesis of β-chains of hemoglobin molecule is broken during β- thalassemia (disease of Cooley).
Anemias as a result of erythropoiesis disorder
The reasons of anemias with disorders of erythropoiesis may be:
1) disorder of formation of erythrocytes: deficiency of hemopoietic cells due to their damage or replacement, disorder of cells maturation of hemopoiesis (disorders of DNA resynthesis), defects of erythrocytes maturing and their output(exit) into blood flow (deficiency erythropoiesis);
2) disorders of hemoglobin synthesis: deficiency of iron, disorder of synthesis porphyrines (hereditary disorders of enzymes, poisonings by lead, deficiency of vitamin B6, frustration of albuminous chains synthesis of hemoglobin molecules).
Deficiency anemias
Irondeficiency anemia arises as a result of:
1) Insufficient receipt of iron with organism:
а) an alimentary anemia in the infants (feeding with cow or goat milk);
b) disorder of iron absorbtion (resection of stomach, intestines, gastritises, enteritis);
2) Hemorrhage. It is the most widespread reason of iron deficiency in organism;
3) Strengthened use of iron – pregnancy, lactation.
Insufficiency of iron in organism results in disorder of ferriferous proteins synthesis and consequently to the following disorders:
1) disorder of heme synthesis,
2) disorder of cytochromes formation and tissue hypoxia,
3) decrease of catalase activity hemolysis of erythrocytes and development of dystrophic changes in cells,
4) reduction of synthesis myoglobin and decrease(reduction) of resistance to hypoxia.
Decrease of hemoglobin concentration in peripheral blood and reduction of color index are typical for iron deficiency anemia. The quantity of erythrocytes decreases a little.
In blood smear the quantity regenerative forms of erythrocytes (reticulocytes, polychromatophils) decreases and their degenerative forms (anulocytes, microcytosis, poikilocytosis).
Irondeficiency anemia
Iron refractory anemia results from disorder of iron inclusion in heme at decrease of enzymes activity, which catalase synthesis of porphyrines and heme. The reasons may be:
1) genetic down turn of decarboxylase activity of coproporphyrinogen – the enzyme providing one of final stages of heme synthesis (it is inherited recessively, is linked to the X-chromosome);
2) reduction of the maintenance pyridoxalphosphate – the active form of vitamin B6 and as a result of this iron is not taken from mitochondria of erythroblasts and is not included in heme;
3) lead blockade of sulfhydryl groups of the enzymes participating in synthesis of heme.
B12-(folate)deficiency anemia. The reasons of vitamin B12 insufficiency in an organism:
1. Exogenous (alimentary) insufficiency – insufficient receipt in an organism with food stuffs. May develop in small children as a result feeding goat milk or dry dairy mixes.
2. Disorders of vitamin B12 absorbtion:
а) disorder of formation and secretion of gastromucoprotein (internal Castle’s factor). It happens at hereditary caused disorders, an atrophy of a mucous membrane of stomach, autoimmune damages of parietal cells of stomach mucous, due to gastrectomy or removal of more than two thirds of stomach;
b) disorder of small intestine function: chronic diarrheas (celiac disease, sprue), resection of the big parts of intestine;
c) competitive use of vitamin B12 by helmints and microflora of intestines (diphyllobothriasis).
3. Disorder of transcobalamines formation in liver.
4. Disorder of vitamin B12 deposition in liver.
5. Increased use of vitamin B12 (at pregnancy).
Deficiency of vitamin B12 results in development of the frustration connected with formation disorder of its two coenzyme forms: methylcobalamine and 5-desoxyadenosilcobalamine. In a red bone marrow erythroblastic type of hemopoiesis is replaced on megaloblastic, inefficient erythropoesis increases, life expectancy of erythrocytes is shortened. The anemia with the expressed degenerate shifts not only in a bone marrow, but also in blood develops. Changes in cells of myeloid and megacariocytic lines are shown by reduction of leukocytes quantity and thrombocytes, expressed by atypia of cells (huge neutrophils, megacaryocytes with degenerative changes in a nucleus). Occurrence of atypic mitosis and huge cells of epithelium digestive tract results in development of inflammatory-atrophic processes in mucous membrane of its parts (glossitis, stomatitis, esophagitis, achylic gastritis, enteritis). As a result of the second coenzyme forms insufficiency of vitamin B12 – 5-desoxyadenosilcobalamine in organism propionic and methylmalonic acids, which are toxic for nervous cells. Besides fatty acids with the changed structure are synthesised iervous fibres results in disorder formation of myeline and to damage of axones. The degeneration of back and lateral columns of a spinal cord develops (funicular myelosis), cranial and peripheral nerves are damaged.
Occurrence in blood and red bone marrow of pathological regeneration cells – megaloblasts, megalocytes is the most typical feature of this anemia.
the color index is increased, that is explained by the big saturation of cells by hemoglobin. The phenomenon of degeneration erythrocytes is typical: anisocytosis (macrocytosis), poikilocytosis (occurrence of the oval form cells), pathological inclusions (Jolly’s bodies, Cabot’s rings).
The maintenance granulocytes (especially neutrophils) and thrombocytes in blood is reduced. Huge neutrophils with the hypersegmented nucleus are found out.
Such syndromes are observed for B12-(folate)deficiency anemia:
1. hematologic syndrome: а) anemia; b) leukopenia; c) thrombocytopenia.
2. Damages of the digestive tract which are shown by development inflammatory –atrophic changes in mucous membrane.
3. Damages of the central and peripheral nervous system: funicular myelosis, degeneration of peripheral nerves.
Hypoplastic anemias
Hypoplastic (аplastic) anemia is characterized by oppression hemopoietic functions of red bone marrow and shown by insufficient formation of erythrocytes, granulocytes and throrombocytes or only erythrocytes.
There are acquired and is hereditary caused forms of hypoplastic anemia. The type of hereditary is autosomal-recessive type of inheritance concerns.
The acquired forms may be caused by the following reasons:
1) physical factors (ionizing radiation);
2) chemical agents (benzene, lead, steams of mercury, medical products: cytostatic agents, chloramphenicol, sulfanilamids);
3) biological factors (virus of hepatites).
Essential forms of anemia, which reason is not established belongs to acquired anemias.
Reduction of erythrocytes maintenance and concentration of hemoglobin when color index is within the limits of norm is characterised for the peacture of peripheral blood. Regenerative of erythrocytes (reticulocytes, polychromatophils ) as a role are not found in a blood smear. The maintenance of granulocytes (especially neutrophils) and thrombocytes decreases. The quantity of lymphocytes may remain without changes.
In a red bone marrow the quantity of hemopoietic cells decreases with increase of maintenance of fatty tissue (picture of devastation red bone marrow). Because of iron is not used for the purposes hemopoiesis, its maintenance in erythroblasts and extracelulary is increased.
Appearence of hypoplastic anemias are connected with reduction of three kinds formation of form blood elements: erythrocytes, granulocytes and thrombocytes. It results in development of the following clinical syndromes:
1. the anemia and connected to it hypoxic syndrome.
2. hemorrhagic syndrome.
3. the inflammatory processes caused by infectious agents (pneumonia, otitis, pyelitis etc.).
Metaplastic anemias
The metaplastic anemia is the result of hemopoietic tissue replacement on tissues: leucosis cells, connective tissue (fibrosis ), metastasises of tumor.
Dysregulative anemias
Dysregulative anemias arise as a result of erythropoiesis regulation disorders (infringement of ratio between erythropoietins and inhibitors of erythropoiesis due to insufficiency of kidneys, damage of strome elements – microenvironments of erythropoietins cells, hypofunction of hypophysis, thyroid gland).
LEUКЕМІА
Leukemia (leucosis) is a tumour, which arises from bloodforming cells and is primary damages bone marrow.
The most characteristic signs of leucosis is the filling bone marrow by malignant cells of the local origin. It can be leucocytes and their predecessors, erhytroblasts, megacaryoblasts. They are made multiple copies in quantities, overcome a natural barrier between bone marrow and blood and get in vessels channel. There is leucocytosis – very often, though also unessential symptom of leucosis.
Classification of leucosis
On clinical picture leucosis divide on two groups – acute and chronic. This classification is entered into clinical practice and in a scientific turn-over at the end of ХІХ centuries Roux (1890) and Cabot (1894). The classification was based to duration of illness.
In
At the end of 70-th – beginning of the 80-th years of the last century the French, American and British experts created a modern, so-called FAB-classification of acute leucosis. It is constructed on stable morphological and cytochemical characteristics of leucosis cells. These characteristics reflect features them metabolism.
According to modern conception, all bloodforming at level of the ІІ class is divided into two shoot – myeloid and lymphoid. Therefore all acute leucosis divide on two groups – myeloblast and lymphoblast. They are represented by many nosologic forms.
Acute myeloblastic leucosis differentiate on five cytochemical signs – presence or absence in leucosis cells of the following substances: peroxidase, acid phosphatase, unspecific esterase, lipids and glycogen.
Acute myeloblastic leucosis
To them belong undifferentiated leucosis, myeloblastic leucosis without signs of maturing (worse 3 % of promyelocytes), myeloblastic leucosis with signs of maturing (over 3 % of promyelocytes), promyelocytic leucosis (over 30 % of promyelocytes), myelomonoblastic leucosis – over 20 % of promyelocytes, monoblastic leucosis, erythroblastic leucosis, megacaryoblastic leucosis.
Acute lymphoblastic leucosis is distinguished both cytochemical, and morphological signs. Pick out acute leucosis general type – from cells – predecessors of B– lymphocytes, T-lymphoblastic leucosis, B-lymphoblastic leucosis.
In the FBA-classification, as against
Chronic leucosis differ from acute, that the cells bone marrow mature normally (up to VІ class), but proliferate in very plenty. Chronic leucosis passes in the development three stages:
1. Chronic stage, during which the illness represents a benign tumour and can be treatment.
2. The stage of accelerated development of illness, during which illness progresses in the party malignisation. Dynamics of illness it is ever more and leaves from under control. The treatment becomes all less effective.
3. The stage crisis of blastic cells, during which illness is exposed to radical transformation: chronic leucosis passes in acute (in 70 % – in acute myeloblastic, in 30 % – in acute lymphoblastic). Crisis of blastic cells approaches suddenly and becomes the reason of majority patients death.
Chronic leucosis also are divided on myeloid and lymphoid. To myeloid leucosis belong myelocytic leucosis, monocytic leucosis, erythrocytic leucosis, megacaryocytic leucosis, eosinophilic leucosis.
To lymphoid leucosis belong B-lymphocytic leucosis, Т-lymphocytic leucosis, haircell leucosis.
Etiology and pathogenesis of the leucosis
On modern conception, leucosis arise on genetic, mutational basis. The speech does about specific of bloodforming cells mutations, which result to superexpression of cells oncogenes, or protooncogenes. These genes are an integral part of cells genome and answer for proliferation of cells. Cells oncogenes vitally are necessary. Without them would become impossible fill of the cells, worn out and lost during vitality. At the same time cells oncogenes, as has appeared, have latent blastomogenic potentions. Excessive expression them the regeneratioormal of bone marrow cells in leucosis stipulates.
To major etiological factors, which are capable to transform protooncogenes in active oncogenes, the chemical agents, ionising rays and retroviruses concern. It is know a few mechanisms of the cell oncogenes activation.
Point mutations. Consider, that in most cases protooncogenes are activated as a result of structural changes them under influence of the chemical and physical agents.
From chemical substances in this plan the most better is investigated benzol. There is an increased risk to be ill leucosis on productions, where is used benzol: chemical clearing of materials with use of the solvents benzolcontaining, production of film materials on the basis of rubber, paper and woodworking an industry. The mechanism of chemical leucosogenesis consists that chemical leucosogenes cause chromosomal and genes mutations. Some from these mutations seize cells oncogenes or them regulatory genes environment and initiate leucosis transformation of bone marrow cells.
From the physical agents strongest leucosogenic by action has ionising rays. Is exactly proved, that increase of frequency leucosis take place after nuclear bombardment of Hiroshima and Nagasaki in 1945. The appearance leucosis is fixed also in case of use ionising radiation with the medical purpose – in the patients with ancilosing spondilitis (Bechterev’s illness), myelomic illness, lymphogranulomatosis, autoimmune diseases, some dermatoses. The approximately 25-35 % of cells, mainly lymphocytes, after therapeutical of an irradiation contain chromosomal aberrations as ring chromosomes, dicentric chromosomes and acentric of fragments.
It is known leucosogenic action of radioactive isotopes. The radioactive phosphorum, which is used for treatment erythremia, caused acute leucosis at 15-18 % of the patients.
It was detected also chromosomal aberrations in the specialists as a result of professional irradiation. Here, first of all, the staff belongs which serves nuclear reactors. The anomalies of chromosomes are found too in the people which have got in to breakedawn with throw away of radiation.
Chromosomal aberrations. The precise correlation between lay out oncogenes and specific translocations of chromosomes is marked. It is established, that cell oncogenes frequently place just in those sites chromosomes, where it is easy and naturally there are their breaks with consequent translocations of deleted fragments. From here also there was an assumption, that translocations can be by original activators protooncogenes.
To the present time in chromosomes of malignant cells more than 80 points are registered, where the breaks are observed. The analysis of distribution has shown these malignant spesific points and localization protooncogenes in genome of the person, that the majority protooncogenes places just in zones of specific breaks chromosomes.
Significant practical interest in the plan of the analysis of chromosomal role aberrations in activation of protooncogenes represent chromosomal and genes of illness, which are characterized by increased instability of chromosomes. To them belong Dawn’s illness, Fankony’s anemia, Blum’s syndrome, Louis-Bar’s syndrome and etc.
It is established, that among patients with Dawn’s illness the frequency leucosis in 20 times is higher, than among persones without Dawn’s illness. Fankony’s anemia the diverse deviations karyotype from norm are found: chromatide breaks, acentric fragmentation, dicentric chromosomes, chromatide exchanges. In children with the Blum’s syndrome large percent of breaks chromosomes, as for want of Fankony’s anemia is observed. The frequency of exchanges between sister chromatides in 9 times is higher, than in the healthy people. The chromosomal instability consists in breaks and translocations of a long shoulder of 14-th chromosome in Louis-Bar’s syndrome.
The persones burdened with any of these illnesses, are exposed to strong risk of development in them malignant tumor, including leucosis. The approximately half of patients with Fankony’s anemia suffers acute myeloid leucosis. About 80 % of the patients with Louis–Bar’s syndrome are sick lymphoid leucosis or various lymphomas.
With the help of precision methods of differential colouring chromosomes it was possible to clarify, that for each type leucosis are characteristic specific chromosomal aberrations.
The most better is investigated translocation 9/22, characteristic for chronic myelocytic leucosis. This anomaly for the first time was described in
Expression of Abelson’s oncogene in bone marrow to a cell stipulate appearance in it special oncoprotein with molecular weight 210 kD and by thyrosine activity. This oncoproteine is coded simultaneously Abelson’s oncogene from 9-th chromosome and site 22-nd chromosome, which adjoins to the point of break.
The data about a role of chromosome aberrations in leucosis ethiology can be generalized as follows. The anomalies karyotype only when can cause leucosis, if they seize chromosome locuses, where are located protooncogenes. The activation stipulates these protooncogenes pathological proliferation and leucosis. Each chromosome has so-called fragile sites, which can be identified with the help of differential colouring. Just here there are deletion, inversions and translocation, which become by the initiators of activation protooncogenes more often. Therefore, all hereditary syndromes, with which is peculiar high chromosomal instability, should be considered as causes factors of leucosogenesis.
Virus transduction. On leucosogenic properties retroviruses divide on two groups – fast-transformed (viruses acute leucosis) and slow- transformed (viruses of chronic leucosis).
Retroviruses of the acute leucosis differ by that their gene has an additional gene. It represents cells oncogene, which was snatched out from genome of cell and is built in virus RNA. Only now of it to name uncellular, and virus oncogene. Just this additional gene consider as the specific factor, which causes malignant transformation of a cell, and the process of massage cells oncogene through a virus is named virus transduction.
After repeated introduce in a cell virus (form cells) oncogene shows high propensity to expression. The reason, first of all, that it is seized by virus without surrounding regulatoring repressors genes. The second reason that a DNA-copy retrovirus is not absolutely exactly reading out return transcriptase. When the again created virus particles are introduced into the following cell, their DNA-copies with an additional gene (virus oncogene) are built in cell by the gene and easily expression – or because mutational virus oncogene becomes inaccessible repressoring gene to environment, or because this environment in general is absent.
Highoncogenic retroviruses is the most effective leucosogenes. It is explained by that presence in them oncogenes have cell origin and iorm answer for proliferation of cells. Therefore in conditions of loss genome and epigenome control they are exposed stronger expression, than for want of chemical and physical mutation.
Insertion of provirus. Most of viruses leucosis belongs not to fasttransformational, and to slowtransformational retroviruses. They do not contain oncogenes and induce experimental leucosis in an animal less effectively, than fasttransformational. Slowtransformational retroviruses cause transformation of cells because their DNA-copies are inserted in cells by a gene near to cells oncogene. The presence of another’s DNA somehow activates cells oncogene up to very high level expression.
Genes amplification. This increase of copies of separate genes in reply to change of the external environment. In leucosis cells are detected amplificated of copy some protooncogenes. In itself amplification of oncogene does not concern to initiating events in leucogenesis. It is connected to a progression already of initiated cells. But in any case amplification of gene results in increase of level expressed RNA and precisely is proportional to level amplificated DNA.
Leucosis clone
The pathogenetical analysis of leucosis is compound. The first question, which arises for want of consideration pathogenesis leucosis: which cells bone marrow are targets for action various leucosogenis of factors – ionising rays, chemical leucosogenes retroviruses? The modern researches testify that cells – targets are stem cell of bone marrow, though it is possible, that cells ІІ and ІІІ classes also can be involved in process leucosogenesis. However stem of cell much earlier and more often are included in leucosis process, therefore submission about leucosis as about “illnesses of stem cells” now dominates.
The second major question of pathogenesis arises on base of transformation by one stem cell or many simultaneously?
Normal hemopoiesis is polyclonic. It provides valuablis and uniform development all shoots of bloodforming lymphoid myeloid erythroid megacaryoblastic. For want of leucosis the picture varies. For want of leucosisе the special pathological autonomous clone of the transformed cells will be derivated. Cells of this clone have selective advantage before other cells – they are capable to very intensive proliteration. The cells of leucosic clone can be differentiated in the party anyone called above shoot. Already there will be no uniform development of all shoots. On the contrary, any one of them, originating from transformed stem cell, will prevail above others and to supplant their from bone marrow.
It is proved, that all cells leucosis of clone occur from one transformed cell. The system character of leucosis testifies like against this rule. It’s leucosis very fast inclusions all bloodforming tissue. However, all this only external symptom, which does not reflect true events. Actually all weight leucosis cells, where they were not, (in other words, all leucosis the clone) is descendants by one transformed stem cell. The difference from usual tumours consists only that metastasing for want of leucosis begins at very early stages of illness.
Leucosis clone – is not homogeneous. It consists of cells of two populations – proliferational (G1) and non- proliferational (G0). Proliferational population makes only 10 % leucosis cells. Others 90 % of cells are not proliferational. On proliferational of ability the population G1 differs from normal cells. It proliferative the activity much below also makes approximately 40 % of activity of normal cells. For example, the time of reproduction of normal cells bone marrow is equal to 12-20 hours. The time of reproduction leucosis cells in 4-5 times more also makes 40-80 hours. How then to explain, what proliferational cell of leucosis a clone for short time give huge cells weight? It’s they make only 10 % of total leucosis cells and are made multiple copies in 4-5 times slower, thaormal cells. It’s founded, that affair here not in speed of division, and in an amount of divisions. Iormal bone marrow sten cell has enough 5-10 divisions, that it has reached up to myelocyte. For want of leucosis the amount of divisions is sharply increased. Leucosis the cell becomes not submit to a limit Heiflick’s. For want of acute leucosis cell in addition to completely lose ability to differentiation. Their maturing, as a rule, does not go further blast forms (ІV classes).
Count show, that one leucose transformed stem cell for 40 divisions gives cells weight equal to
The G0-population of leucosis cells executes role of reserve. These cells can long time stay in sleeping state both in bone marrow and in blood. From time to time they leave from vessels in serround tissue, subside there and give extramedullar centers of bloodforming. The correlation between two populations leucosis cells – G1 and G0 – determines state of leucosis process – progression, remission, recurrence.
Major chain of pathogenesis leucosis is oppression by leucosis cells normal of hemopoiesis. Select some mechanisms of this phenomenon. Firstly, leucosis cell are capable produced in redundant amount colonialstimulation factor – stimulator of myelopoiesis. Secondly, this factor acts on leucosis cell, than on the normal predecessors hemopoiesis stronger. Thirdly, leucosis of a cell have property selectively to oppress proliferation and differentiation of normal cells – predecessors with the help humoral inhibitors. Forthly, leucosis cell is more active, than normal, answer to action of the growth factors.
Gradually pool of normal cells – predecessors is exhausted. Bone marrow is filled in leucosis with weight. This modification stipulates main clinical signs leucosis – metaplastic anemia, thrombocytopenia, hemorrhagic syndrome, secondary immunodeficiency, decrease of resistantion to infectious agents. The patients die or from bleeding in brain, or from an infection. In conditions immunedeficiency even saprofit flora can become pathogenic.
As was already told, the disorders of hemopoiesis for want of acute and chronic leucosis are not identical. These distinctions define an originality hematological picture for want of each them. For want of acute leucosis in peripheral blood will be a lot of young cells forms ІІ, ІІІ and ІV classes and there are not enough of mature cells VІ class for want of complete absence of the transition forms V classes. Absence of the transition forms in peripheral blood – very characteristic morphological difference acute leucosis from chronic. This hematological symptom is called leucemic failure (hiatus leucemicus). The reason that the absolute majority of cells leucosis of a clone is not differentiated further of the blast forms. At the first they are stored in bone marrow, and then break in blood. Only single cells manage to pass usual path of differentiation and to get in blood in mature state. Let’s give for example acute myeloblastic leucosis. For want of it leucosis in peripheral blood will be much myeloblasts (ІV classes), of cells – predecessors ІІ-ІІІ classes and there are not enough of mature forms (sticknucleus and segmentnucleus neutrophils). Characteristics will be absence of the transition forms V classes – promyelocytes, myelocytes, metamyelocytes (leucemic failure).
Completely other hematological picture for want of chronic leucosis. As the maturing of cells goes up to the end, in blood there will be an abundance of cells of all classes – young, transition and mature. Leucomic failure is absent. For want of chronic myelocytic leucosis blood there will be cells – predecessor ІІ and ІІІ classes, myeloblasts (ІV classes), cell V classes – promyelocytes myelocytes metamyelocytes sticknucleus neutrophils and mature cells of the VІ class (neutrophils). For want of chronic lymphocytic leucosis the picture of peripheral blood is characterized by the following features: it is a lot of mature lymphocytes, is prolymphocytes and lymphoblasts, and also desroyed cells lymphoid number (Gumprecht’s bodies).
