ANEMIA
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 membranopathy.
2. hereditary:
а) hereditary membranopathy;
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
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 iorm, 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.
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.
The group also includes hereditary membranopathias: hereditary eliptocytosis, hereditary piropoykilocytosis, hereditary stomatocytosis, hereditary akantocytosis, and hereditary ehinocytosis.
Hereditary enzymopathias arise due to defect of erythrocytes enzymes 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.
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 is 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).
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 (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.).
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).
