Anemias and leukocytoses

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					 The changes in the blood occurring in disease in some measure reflect the
 dysfunctions of various organs and tissues. The changes originally
 arising in the blood itself and especially, in the organs of hematopoiesis are
 of particular interest. These diseases have long been classified in a special
 group designated a«, diseases of the blood and hematopoiesis.
        Changes in the total volume or mass of the blood, its formed
 elements, and its biochemical and physicochemical composition are
 distinguished according to the character of the phenomena observed.
            CHANGES IN THE TOTAL VOLUME OF THE BLOOD
        Various forms of increased and decreased total volume of the blood
are observed in pathology.
        An excess of the total volume of blood in the budy is called
 polyemia, hypervolemia or plethora.
        Depending on the ratio of plasma to erythrocytes, three? forms of
hypervolemia are distinguished: 1) hypervolemia plasma-erythrocyte ratio:
2) hypervolemia with an excess of erythrocytes; 3) hypervolemia with an
excess of plasma.
        The first form - simple hypervolemia with a normal plasma –erythrocyte ratio -
occurs very rarely. It may arise for short time following transfusion of large
amounts of blood from the blood depots in the beginning of strenuous work,
or under high external temperature.
       Repeated experiments have been made to produce hypervolemic, in
animals by transfusion of homogenous blood. However, thest* attempts
were for the most part accompanied only by a brief increase in the blood
volume and a slight, and also brief, rise in blood pressure.. Processes of
compensation follow immediately. The blood plasma very soon passes
into the tissues., while the transfused erythrocytes are gradually
destroyed, which             is attested by       excessive formation of bile
pigments from the hemoglobin.
       Plethora with a 150 per cent or higher increase in the mass of blood
artificially produced in animals imperils their life. Г: disturbs the
regulation of the volume of circulating blood, reduces vascular tone,
excessively dilates the vessels and-causes
circulatory disorders; these disturbances are soon followed by
hemoconcentration (as a result of increased transudation o^: plasma into the
tissues and serous cavities), considerable disintegration of erythrocytes and
cardiac failure.
       The second form is polycуtheroic hypervolemia, i.e., with an increased
       number of erythrg_cytes, the increase in the amount of hemoglobin lagging
       behind the increase in the number 'of erythrocytes. The erythrocytes may
       number from 10 million to 13 million per 1 mm3 of blood. This disease ig
       also kn'own^'aVb-utp plethora or true polyemia and is characterised bv
       increased
   hematopoiesis vMhose signs are usually easily observed in the marrow, spleen ~ad ot h
     er h emaifbp оТеТГс~ог gahs Г~ I t "is supposed that the increased hematopoietic function
     of the bone marrow !•;•> stimulated by some substance formed in the process of
     disturbed metabolism.
            In addition to the increased number of ery throcytes, true plethora is, as a
     result of the increase in the volume of blood, often characterised by t^egLementary
     ^hypereinia, elevated blood ressure, hypertrophy of the left ventricle which
     with -each systole drives more blood into the aorta.
             The third form is oligocythemic hypervolemia or hydremic pletora with an
execess of plasma. It may be due to retention of
     water in the blood stream as a result of certain diseases of the kidneys or the
     hematopoietic system, or disturbances in water metabolism.
             Attempts have been made to produce oligocythemic hypervolemia
     experimentylly by intravenous injections of physiologic saline solution in
     the dog or rabbit. As a rule, these attempts have failed because the excess of
     fluid rapidly passed from the blood into the tissues and was gradually
     eliminated mainly through the kidneys.
             The changes occurring in connection with intravenous administration of
     physiologic saline solution are observed in the following experiment: a 0.7 per
     cent sodium chloride solution is slowly introduced through a cannula into the
     frog^s abdominal. vein. While this is done the circulatory changes are observed
     in the stretched web. The circulation of the blood in the vessels is
       «4
     noticeably accelerated, the blood is diluted, the volume of the fluid part increases
     and the mass of corpuscles relat i'/*iy diminishes. Vascular permeability
     appreciably increase. These phenomena are soon followed by increased excretion
     of fluid into the lymph sac, urxnary bladder and abdominal cavity. All i:h.^»e
     phenomena must be considered compensatory sin'ce the-y -эег'-у» t.o restore the normal
     volume of blood.
             Rapid administration of large amounts of fluid leads to the animal’s death
             due to extensive disturbances in blood circulation, congestion in
             pulmonary circulation, hemorrhages and affection* of the myocardium.
           Hydremic plethora should be distinguished from hydremia whose
  characteristic feature is a decrease in the dense residue without a general
  increase in the total volume of blood
*rrv
  (oliigocythemic normovolemia). Such phenomena often occur in cachexias,
  anemias and avitaminoses.
           A decrease in the total volume of blood - oligemia or hypavoleraia -
  may be very brief in its pure form. Hypovolemia is most frequently
  accompanied by a decrease in the number and changes in the quality of
  erythrocytes.
         Analogously with hypenyplemia three forms of hypovolemia may also be
distinguished according to the ratio of the plasma to the ereythrocytes: 1)
hypovolemia with a normal plasma-erythrocyte .ratio; 2) ' hypovolemia with a
decreased amount of plasma, or hemoconcentration; 3) hypovolemia with a -
decreased number of erythrocytes.
        The first form – hypovolemia with a normal plasma-erythrocyte ratio - is
 observed directly after acute hemorrhages which may be due to injuries of
 large vessels, ulcers, active forms of pulmonary tuberculosis or rupture of the
 fallopian tubes.
       The results of acute hemorrhages vary greatly. They depend on the rate
of the blood flow, the mass of blood, lost and the general condition of the
organism. For a healthy organism a single loss of 50-60 per cent of the total
amount of blood is fatal. After such a hemorrhage restoration of the mass of
blood by natural means becomes impossible and insufficiency of oxygen^ in
the blood (hypoxemia), oxygen deficiency (hypoxia), disorders ^of
hemodynamics and respiration, shock and phenomena of asphyxia result. The
condition is also accompanied by a drop in arterial pressure; acute cerebral
anemia, extreme pallor, increasing depression of the functions of the
respiratory and vasomotor centres, and cardiac failure; the pulse becomes
thready. The diminution in the mass of the circulating blood and the oxygen
deficiency give rise to excitation of the motor zone of the cerebral cortex and
convulsions. These phenomena are the more strongly pronounced the more
rapid the hemorrhage. The organism may die exhibiting a considerable drop in
blood pressure, a fall of the body temperature and paralysis of the respiratory
centre. Repeated minor hemorrhages cause a slow development of
hypovolemia.
        Simultaneously with the disorders of a number of vitally in^tartant
 functions hemorrhages lead to mobilisation of the adaptive physiological
 defence mechanisms by means of which it is possible to restore the blood pressure,
 as well as the volume" and function of the blood.
       The lowered blood pressure is compensated by the following processes: 1)
reflex stimulation of the vasomotor centre with a resultant increase in vascular tone
and spasm of the peripheral vessels;-2) increase in the mass of the circulating blood
through an inflow of blood from the blood depots and tissue fluid; 3) increased
blood clotting which lead to arrest of the hemorrhage, and 4) subsequent
hyperfunction of the hematopoietic apparatus stimulated by the hemorrhage and
insufficiency of available oxygen (hypoxia) .
       Restoration of the blood pressure after a hamorrhage is noticeably
accelerated by protective inhibition in the cerebral cortex. It is therefore facilitated by
means of "artificial sTeep", which closely resembles natural sleep, but is retarded by
deep narcotic sleep. This denotes participation of the higher parts of the nervous
system in the restoration of the blood.
       The resultf of hemorrhage consist not only in the , changed volume of the
blood, . but also in its altered composition. The first result is an increase in the
number of blood platelets (sometimes to 1 mrllion per 1 mm ) and in intensified
blood clotting. Within a few days the number of leukocytes increases a^ a result of
their discharge from the intensely functioning bone m'arrow. The number of
erythrocytes at first decreases owing to dilution of the blood by tissue lymph and
then gradually increases as a result of increased hematopoiesis in the bone
marrow. Young forms of red blood cells - normoblasts, reticulccytes and
polychromatophilic erythrocytes appear in the blood. The extent of restoration of the
blood elements varies and/ depends on the amount of blood lost, the rate of
bleeding, and regenerative capacity of the organism and its hematopoietic system.
       Since the principal cause of death after a massive *c:ute hemorrhage is a drop
in blood pressure, transfusion of blood or blood substitutes, which is usually
resorted to in operations or in cases: of injuries to vessels, is the most effective
measure.
       The pathogenic role of the diminution in the mass of blood and of the drop
in blood pressure during hemorrhage is evidenced by the favourable effect
produced by blood- and plasma-substituting solutions which diffuse in the
tissues slowly and are longer retained in the blood stream. In addition to blood,
especially treated foreign proteins have been proposed and are successfully used
<N.A.Fyodorov). Plasma or serum containing hypnotics and anodynes are used
for the same purposes. , In hemorrhages» anemia, shock, etc., blood
transfusion produces a very favourable effect. Firstly, the blood is for some
time restored quantitatively. Secondly, by stimulating the interoceptors of the
vessels the transfused blood and the physiologically active products of partial
disintegration of erythrocytes reflexly stimulate the function of the
hemotopoietic: apparatus/ improve the process of blood clotting and raise the
general immunobiological stability of the? organism,
       The second form of hypovolemia, i.e., with * decreased amount of
 plasma - polycythemic hypovolemia or anhydremia - j.s characterised by
 appreciable concentration and increased viscosity of the blood.
       Anhydremia is observed in connection with considerable losa" of water
by the organism, as in cholera, dysentery, infantile Diarrhea, intractable
vomiting, and extensive burns involving loss of a great deal of fluid with the
exudate and evaporation from burned surfaces.
      The third form of oligemia is oligocythemic hypovolemia – a diminished
      volume of blood mainly because of a decreased number of erythrcfcytes.
      It is observed after hemorrhages in cases of increased passage of fluid from
      tissues into the vascular syflftem and in certain forms of anemia, for
      example, pernicious anemia.
                    IN ADDITION TO THE LECTURE «ANEMIAS»

        Anemias of diminished erythropoiesis        (diserythropoietic anemias)' impairec
Ted cell production.
       Classification (according to Robins' textbook).
       A. Disturbance of proliferation and differentiation of stem cells:
       aplastic anemias, pure red cell aplasia,
       anemia of renal failure, anemia of
       endocrine disorders.
       B. Disturbance of proliferation and maturation of erythroblasts:
       1. Defective DNA synthesis: deficiency or impaired utilization of vit В12 and
           filic acid (megaloblastic anemias).
       2. Defective hemoglobin synthesis.
              a. Deficient heme synthesis: iron deficiency
              b. Deficient globin synthesis: Thalassemias
       3. Unknown or multiple mechanisms:
              sideroblastic anemia,
              anemia of chronic infections,
              myelophthisic anemias due to marrow infiltrations.


                               MEGALOBLASTIC ANEMIAS.
       Megaloblastic anemias develop as the result of vit В and folic acid deficiency.
The daily requirement is of the order of 2 to 3 g, and the normal balanced diet
contains significantly larger amounts.
      The main steps of vit В absorption.
      I. In the stomach:
             (Vit В12 + salivary binding protein) - complex forms.
      II. In the duodenum:
             (vit В12 + salivary binding protein) - complex is broken by pancreatic
proteases action.
               (vit В12 + Intrinsic factor) - complex forms.
        Intrinsic factor (iFO is secreted by the parietal cells of the fundic mucosa along
 with HCL.
       III. In the ileum:
                   (vit В12 + Intrinsic factor) - complex adheres to Intrinsic factor -
        receptors on the ileal cells.
        Vit В12 then transverse the plasma membrane to enter the mucosal cell. It is
 picked up from the cell by a plasma protein, transcobalamin, which is capable to
 deliver it to the liver and other cells, particularly in the bone marrow.
       IV. In the blood:
              (vit В12 + transcobalamin II) - complex is transported.


                                   The causes of vit В12 deficiency:
I. Impaired utilization:
       1. Achlorhydria and loss of pepsin secretion
       (vit В is not readily released from its protein - bound form);
       2. Gastrectomy and atrophic gastritis: the deficiency of intrinsic factor
formation and disturbance in vit В transport of the ileum;
       3. Loss of exocrine pancreatic function: vit В cannot be released from vit В12
+ salivary binding protein complexes.
       4. Ileal diseases can disturb vit В + intrinsic factor complex absorption.
II. Increased requirements: relative deficiency under some circumstances (pregnancy,
hyperthyroidism, etc).
III. Food deficiency, or decreased intake.


                               Biochemical functions of vitamin В


      Vitamin В (methylcobalamin), the synthetic form of it is a stable
cyanocobalamin.       It     has        two    pathways      of        biochemical   effects.
           1.         Methylcobalamin is an essential cofactor for the enzyme
       ensuring transmethylatipn reaction. It is involved in the DNA synthesis. The
       tetrahydrofolic acid (FH) is required for the formation of immediate precursor
       of DNA. The fundamental cause of impaired DNA synthesis in vitamin В
       deficiency is the reduced availability of tetrahydrofolic acid. The internal
       folate deficiency results from the lack of vitamin В12.
           2.         Another derivative of cobalamin - desoxyadenosyl cobalamin is
       a prosthetic group on the enzyme that is necessary for the metabolism of
       methylmalonic acid. This disorder is followed by increased levels of
       methylmalonate and its precursor propionate. It leads to the formation of
       abnormal fatty acids incorporated into neuronal lipids that results in myelin
       breakdown and development of neurologic complications.
       Thus, lack of either vit В or folic acid causes diminished DNA and
consequently failure of nuclear maturation and division.
       Furthermore, the erythorblastic cells of the bone marrow, in normal,
developing into so - called megaloblasts, and the adult erythrocytes have a flimsy
membrane and is often irregular, large, and oval instead of the usual beconcave disc.
This altered type of erythoropoieses resembles embryonal type and is called
megaloblastic.
       The cause of the abnormal cells seems to be as follows:
       The inability of the cells to synthesize adequate quantities of DNA leads to slow
reproduction of the cells but does not prevent formation of RNA by the DNA that is
already available in each presently existing cell. Therefore the quantity of RNA in
each cell becomes much greater than normal, leading to excess production of cytoplasmic
hemoglobin and other constituents which causes the cells to enlargement because of
abnormalities of some of the genes (the DNA), the structural components of the L
:11 membrane and cytoskeleton are malformed wuich leads to abnormal cell shapes and
especially greatly increased cell membrane fragility.
       Pernicious anemia (Addison's or Biermer's anemia) is a megaloblastic anemia in
 which there is atrophy of the gastric mucosa with consequent failure of intrinsic factor
 production and vit В melabsorption.
       Pernicious anemia is believed to result from immunologically mediated,
 possibly autoimmune, destruction of gastric mucosa. The resultant chronic gastritis is
 marked by a loss of parietal cells.
       Three types of antibodies are present in many, but not all, patients with
 pernicious anemia:
       1.          Blocking В12 - IF binding (Ig G);
       2.          Binding antibodies reacts with both IF and (vit В +IF) - complex;
       3.          Parietal antibodies.
       Autoantibodies cause gastric mucosal injury.
       The major specific changes in pernicious anemia are found in the bone
marrow, alimentary tract and CNS. The principal alterations involve the spinal cord,
where there is myelin degeneration of the dorsal and lateral tracts (sensory ataxia,
severe parethesias).
       Blood picture.
       Certain morphologic features are common to all forms of megaloblastic
anemia. The peripheral blood reveals.
      1.          Marked variation in the size and shape of red cells - anisocytosis.
      2.          They are nonetheless normochromic.
      3.          Many erythrocytes are macrocytic and oval shaped (macro-
            ovalocytes).
      4.          They are thicker than normal and well filled with hemoglobin; most
            macrocytes lack the central pallor of normal cells and may even appear
            "hyperchromic".
      5.          The reticulocyte ',ount is lower than normal and occasionally with
            severe anemia, nucleated red cells appear in the circulating blood.
      6.          Neutrophils are larger than normal (macropolymorphonuclear) and are
hypersegmented. They may have five to six or more nuclear lobules.
        The bone marrow.
                                                                  •                   r-m
            The megaloblastic change is detected in all stages of red cell development (the
   - embryonal type of hemopoiesis). Because DNA synthesis is impaired in all
    proliferating cells nuclear - cytoplasmic asynchrony becomes apparent in all cells.
    The cells are large, the nuclei are large. Ineffective erymropoiesis occurs: premature
  destructfon of all cells in marrow.
       Folate deficiency.
       A deficiency of folic acid, more properly pteroylmonoglutamic acid, results in a
megaloblastic anemia having the same characteristics as those encountered in vitamin
В deficiency. However, the neurologic changes seen in vit В deficiency do not occur.
FH derivatives acts as an acceptor of one - carbon fragments for the synthesis of
biologically active molecules. Supressed synthesis of DNA, the common
denominator of folic acid and vit В12 deficiency, is the immediate cause of
megaloblastosis.
       There are three major causes of folic acid deficiency:
       (1) decreased intake;
       (2) increased requirements (pregnancy, infancy)
       (3) impaired utilization (manifestations: cheilosis, glossitis, dermatitis).
       In addition to Addison's or Biermer's pernicious anemia, there are also
secondary pernicious anemias, as in cases of infestation with tapewarms
(Diphyllobothrium latum), and certain severe affections of the stomach (syphilis,
cancer, pellagra). In all these cases a pathogenetic role is also played by the
antianemia factor deficiency due to its diminished absorption or utilization in the
organism.


                                Anemias due to marrow aplasia.
      1. Inciting or causative agents may be radiation, drug (especially benzene
derivatives), certain antibiotics, viruses. Not only the marrow but also other sites of
 hematopoiesis reflect injury to the stem cells. The marrow spaces are occupied only
 by fat.
      2. Some cases of aplasia involve only one hematopoietic line, as in Diamond -
 Blackfan syndrome, a congenital defect involving erymroid hypoplasia, Certain
 tumors, such as thymomas, are associated with pure red cell aplasia.


                                    Myelophthisic anemias.
       In this conditions, the marrow is replaced by foreign "invaders" (e.g.
carcinomas, leukemias, granulomas). Extramedullary hematopoiesis, particularly in
the spleen (as in the fetal period), is found. Primary bone marrow myofibrosis also
induces this types of anemia by replacing marrow in fibrosis of unknown causes.


                              Anemias due to systemic disorders.
       Endocrine diseases, such as hypothyroidism, hypopituitarism are associated
with low blood counts. Poor marrow function and anemia can be seen in uremia and
malignancy.


                                   Iron deficiency anemias. Iron
       distribution in healthy young adults:
       1. Functional compartments: hemoglobin (80%), myoglobin, iron - containing
enzymes (catalase, cytochromes);
      2. Storage compartments: ferritin, hemosiderin (15-20% of total body iron).
      Ferritin is essentially a protein - iron complex that can be found in all tissues
but particularly in liver, spleen, bone marrow and skeletal muscles. In the liver, most
of the ferritin is stored within the parenchymal cells, whereas in other tissues, such as
spleen, a bone marrow, it is mainly in the mononuclear phagocytic cells.
      Ths iron within the hepatocytes is derived from plasma transferrin, in the
mononuclear phagocytic cells is obtained from the breakdown of red blood cells).
      Iron    from ferritin   is   aggregated      into   hemosiderin     granules   (in
        Very small amounts of ferritin normally circulate in the plasma (a good
 indicator of the adequacy of body iron stores).
          Iron is transported in the plasma by an iron - binding glycoprotein called
  ^ transferrin, which is synthesized in the liver. The major function of plasma
   transferrin is to deliver iron to the cells including erythroid precursors. Immature
   red cells posses high - affinity receptors for transferrin, and iron is transported into
 erythroblasts by receptor - mediated endocytosis.
       The fix daily losses of iron rangers between 1 and 1,5 mg.
       Because only 10 to 15 % of the ingested iron is absorbed, the daily iron
requirement for adult males is 5 to 10 mg and for adults females 7 to 20 mg.
Ascorbic acid, citric acid, aminoacids, and sugars in the diet enhance absorption of
inorganic iron, but tannates (as in tea), carbonates, oxalates, and phosphates inhibit its
absorption.
       An iron deficiency may result from
       (1) dietary lack (diets a predominantly vegetarian);
       (2) impaired absorption;
       (3) increased requirement, or growing infants and children, adolescent}',
pregnancy;
      (4) chronic blood loss.
      Whatever the basis, iron deficiency induces a hypochromic microcytic anemia.
      Simultaneously, depletion of essential iron - containing enzymes in cells
throughout the body may cause other changes including brittle nails, coilonychia,
alopecia, atrophic changes in the tonque and gastric mucosa, and intestinal
malabsorption, hypotension, fatiqubility.


              HEMOLYTIC ANEMIAS (INCREASED RATE OF RED CELL
                                    DESTRUCTION).
      Classification (according to Robins' textbook).
      A. Intrinsic (intracorpuscular) abnormalities of red cells:
  Hereditary: 1. Disorders of red cell membrane cytoskeleton (spherocytosis,
                 elliptocytosis).
             2. Red cell enzyme deficiencies
             a) Glycolytic enzymes: pyruvate kinase hexokinase
             b) Glutathione synthetase
             3. Disorders of hemoglobin synthesis:
                             a)Thalassemia syndromes - deficient globin synthesis,
                             b) Structurally       abnormal         globin         synthesis
                             (hemoglobinopathies): Sickle cell anemia.
Acquired: 1. Membrane defect: paroxysmal nocturnal hemoglobinuria.
B. Extrinsic (extracorpuscular) abnormalities.
       1. Antibody mediated.
              a) Isohemagglutinins: transfusion reations
              b) Autoantibodies: idiopathic (primary) drug - associated
       2. Mechanical trauma to red cells.
              a) Microangiopathic hemolytic anemias
              b) Cardiac traumatic hemolytic anemia

       3. Infections: Malaria
       4. Chemical injury: lead poisoning
       5. Sequestration in mononuclear phagocyte system: hypersplenism
The hemolytic anemias all are characterized by

       (1) shortening of the normal red cell life span, that is, premature destruction of
red cells;
       (2) accumulation of the products of hemoglobin catabolism, and
       (3) a marked increase in erythropoiesis within the bone marrow, in an attempt
to compensate for the loss of red cells.
       Intravascular hemolysis is manifested by:
       (1) hemoglobinemia,
       (2) hemoglobinuria,
~     (3) methemalbuminemia,
        (4) jaundice, and
        (5) hemosiderinuria.
        When hemoglobin escapes into the plasma, it is promptly bound by an alpha
 globin (haptoglobin) to produce a complex that prevents excretion into the urine,
 since the complexes are rapidly cleared by the reticuloendothelial system.
       A decrease in serum haptoglobin level is characteristically seen in all cases
 intravascular hemolysis. When the haptoglobin is depleted, the unbound or free
 hemoglobin is in part rapidly oxidized to methemoglobin, and both hemoglobin and
 methemoglobin        are   excreted   through     the   kidneys    (hemoglobinuria,
 methemoglobinuria).
       Extravascular hemolysis takes place whenever red cells are injured, are
rendered "foreign", or become less deformable. For example, in hereditary
spherocytosis an abnormal membrane cytoskeleton decreases the deformability of the
red cell.
       Analoquously, in sickle cell anemia, the abnormal hemoglobin «gels» or
«crystallizes» within the erythrocyte, deforming it and reducing its platicity.
       With extravascular hemolysis it is obvious that hemoglinemia,
hemoglobinuria, and the relatide intravascular changes do not appear.
      However, the catabolism of erythrocytes in the phagocytic cells induces
anemia and jaundice.
      Erythrophagocytosis may lead to hypertrophy of the mononuclear phagocyte
system and splenomegaly. Blood picture.
      The accelerate compensatory erythropoiesis leads to a prominent reticulcytosis
in the peripheral blood. The elevated level of billirubin promote the formation of
pigment gallstones.


                                    POLYCYTHEMIA
      Polycythemia is defined as an increase in red cell count in blood volume unit
and also increase in hemoglobin content and hematocrit. It can't be divided into
        (1) an absolute erythrocytosis where there is a true increase in red cell volume
  or
        (2) relative erythrocytosis where red blood cell volume is normal but there is a
. decrease in the plasma volume (dehydration, burns, etc.).
        Absolute erythrocytosis may be due to (1) primary polycythemia or (2)
 secondary polycythemia.
        Primary polycythemia (polycvthemia vera) ervthremia is a clonal stem cell
 disorder in which there is an alteration in the pluripotent progenitor cell leading to
 excessive proliferation of erythroid, myeloid and megakaryocytic elements. The main
 clinical problems are due to the increased volume and viscosity of the blood and to the
 bone marrow overactivity.
       Red blood cell count may be as high as 7 to 8 million/mm and hematocrit as
 high as 60 to 70 %. The total blood volume also increases, rarely to almost twice
 normal. The entire vascular system becomes intensely engoged. Many of the
 capillaries become plugged by the viscous blood.
       The bone marrow shows erythroid hyperplasia and increased number of
 megakaryocytes. It is a myeloproliferative disorder, however, in polycythemia very the
 erythroid precursors dominate.
       Secondary polvcvthemia may be physiologic condition in response to hypoxia and
due to an appropriate increase in erythropoietin production. Physiologic polycythemia
occurs in natives who live at altitude of 14, 000 to 17, 000 feet. Secondary
polycythemia may be caused by a variety of hypoxic conditions, such as impaired
pulmonary ventilation and heart diseases. In such disorders, erythropoietin is elevatide
and stimulated marrow cells to produce erythrocytes. Other marrow element are
normal in number, function and morphology.
                 In addition to lecture "Leukocytosis Leukopenia"

                   Neural mechanisms of leukocytosis development.
It is known that tissue injury and also their antigenic and biochemical changes cause
the reflex activation of CNS. If the sympathetic-adrenal system activation is
predominant two following mechanisms of neutrophilia development are involved:
(1) the stimulation of the bone marrow activity and acceleration of leukocyte ejection
into the peripheral blood
(2) adrenergic vasoconstriction and the mobilisation of leukocytes from the marginal
pool;
(3) the accumulation of lymphocytes in the bone marrow.
If the parasympathetic nervous activity is predominant the elevated counts of
lymphocytes and eosinophils in the peripheral blood are arised, i.e. lymphocytosis
develops.
                The character and expression of leukocytosis depend on
(1) the strength and character of pathogenic action;
(2) organises reactivity
(3) the localization of pathologic processes
It is known that pathology of respiratory system and the thorax is followed by the
sympathetic activation and development of neutrophilia and lyrnphocytopenia. On the
contrary the pathology of the gastrointestiral tract often is followed by the
parasympathetic activation and the development of lymphocytesis and eosinophilia.
The distinct mechanisms of leukocytosis development may be activated in the certain
sequence. There is the evidence of the certain sequential induction induction of the
different mechanism controlling leukocytosis development in particular in aciite
different infectious diseases In these cases three following phases of leukocytosis
development were found:
 (1) neutrophilia;
 (2)monocytosis;
 (3)lymphocytosis.
Neutrophilia corresponds to the beggining of an acute infectious disease. The main
mechanisms of its development are as follows
(1) adrenergic activation causing neutrophilia cells mobi1ization from the bone
marrow and marginal reserves (2) hypothalamo-pituitary system and target-gland
activation promoting to netrophillia and lymphopenia;
(3) the humoral activation of the bone marro via colony stimulating factors. The
emigration of T-cells from blood to the damaged tissue and lymphatic node also
ensures lymphonia development. Monocytosis phase corresponds to the marked period
of the disease and to the onset of recovery/ This period is characterized by the enhance
of macrophage system activity. The principal mechanism of this system activation is
formation of antigen antibody complex. Limphocytosis phase corresponds to the
recovery. It is observed as result of antigen elimination stopping of the antigen
activation of T-cells come back in the blood from tissue. The recurrence of T-cells in
the blood from the tissue is thought the important mechanism of limphocytosis
development.
                                     Leukemoid reactions
Leukomoid reactions are the pathologic reactions of the blood system resembling
leukemia because of the appearance of immature white blood cells and very high
leukocyte count. The principal difference leukemoid reaction in comparison with
leukemias it completely disappears after stopping of it arises in severe infectious
diseases and completely dissappears after infection elimination. Two forms of
leukemoid reactions are known
(1) myeloid and
(2) monocytic-lymphocytic.
Lymphatic myeloid reaction may be observed in infectious mononucleousi
A leukemoid reaction is an overproduction of white cells with many immature cells. It
may occur in severe infections, tuberculosis, and occasionally after hemorrage or
hemolysis.
                          The principal differences from leukemia
(1) in etiology leukemoid reaction arises as the result of certain causative action;
(2) it has in its basis the reactive hyperplasia of the bone marrow but not neoplasin
(3) it is a temporary disorder and stops after the cessation of primary disease.
                                         Leukopenia
Leukopenia is a decrease in the leukocyte count in the volume unit of the circulatory
blood below 4.0* 10 cell
In the most cases extent the total leukocyte blood count is ensured by decrease in
absolute neutrophil count.
Three main mechanisms are (underlied) based the basis of the 1enkopenia
pathoqenesis. They are
(1) decrease in leukocyte production in the bone marrow;
(2) disturbances in leukocyte ejection from the bone marrow;
(3) inorease in leukbcyte distruction.
(4) the redistribution of leukocytes within blood vascular system;
                         THE disturbances in leukocyte production
(1) the internal deficiency of stem cells to proliferate and differentiate
(2) the autoimmune injury of bone marrow progenitor cells -the consequence of it: the
distinct forms of aplastic and hypoplastic anemias, panleukopenia, acute
agranulocytasis;
(3) the damage of the precursors of granulopoiesis (leukopoisis) by T-cells;
(4) the direct action of myelotoxic agents (some drugs, benzene radiation);
(5) the viral damage of hemopoiesis;
(6) the deficiency of hemopoietic agents v.B12 folic acid)
(7) the toxic action of neoplastic cell in leukemia;
(8) the ousting of leucopoiesis cells by neoplastic metastasis tissue
(9) the deficiency of leukopoietic factor format ion (for example the deficiency of the
monocyte secretion of the g-CSF (granulocyte colony stimulating factor)). These
deficiencies may occur in immune deficiency diseases.
                 Disturbances in leukocyte ejection from the bone marrow
(1) the disorders of leukocyte motile activity as the result of memranopathy -. the
syndrome of "leasy" leukocytes. These disorders are divided into hereditary and
acquired ones (as the result of some drug action).
             Decrease in the duration of leukocyte circulation in the blood.
(1) the autoimmune damage of circulating (neutrophils) leukocytes via agglutinins;
(2) the autoimmune damage of circulating (neutrophils) leukocytes via opsonins with
the following phagocytosis;
(3) the autoimmune damage of circulating (neutrophils) leukocytes via T-cells
(4) the destruction of leukocytes by toxins;
(5) the elevated destruction of leukocytes in liver and spleen,
(6) the elevated destruction of leukocytes as the result of memfaranopattiy (for
example, in magaloblastic anemia) .
    The redistribution of leukocytes within blood vascular system (shock, chills,
                                 strenuous muscle work).
Aqranulocytosis is the disorder characterised by complete or about complete
disappearance blood neutrophils the neutrophil count is less 750 eel Is/ limn Two main
forms of agranulocytosis are distinguished according to the etiology into
   (1) acquired and
   (2) idiopathic
Acquired agranulocytosis is often caused by some drug application, namely
cytostatic drugs, sulfonilamides, antibiotics, antithyroid drugs and some others.
According to the mechanisms of development the drug caused agranulocytoses are
divided into myelotoxic and immune ones.
Myelotoxic agranloucytosis arises as a result of toxic inhibition action of drugs on the
proliferative activity of granulopoiesis. It is usually combined with anemia and
thrombocytopetvia involvement has the following explanations drug substance serves
as hapten, produces formation of complete antigen, causes the antibody production.
Formed antibodies act on the leukocytes and destroy them.

				
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posted:3/18/2011
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