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MINISTRY OF PUBLIC HEALTH OF UKRAINE BUKOVINIAN STATE MEDICAL UNIVERSITY Approval on methodological meeting of the department of pathophisiology Protocol № Chief of department of the pathophysiology, professor Yu.Ye.Rohovyy “___” ___________ 2008 year. Methodological Instruction to Practical Lesson Мodule 2 : PATHOPHYSIOLOGY OF THE ORGANS AND SYSTEMS. Contenting module 4. Pathophysiology of blood system. Theme 3: Leucocytosis and leucopenia Chernivtsi – 2008 1.Actuality of the theme. Leucocytosis are considered as a reaction hematopoietic system due to action of physiological and pathological irritations. Leucocytosis is a pathological symptom of many diseases. In a basis of leucocytosis lay pathophysiological mechanisms connected with proliferation, maturation going out of leucocytes and their flow into vessels and redestribution. Different kinds of leucocytosis may be the additional criteri for establish the diagnosis. Eosinophilia, for example, is characterized for allergy reactions, neutrophile leucocytosis - for acute inflamation processes. Leucopenia may depend upon oppressive influence of some toxines on the maturation and outflow of leucocytes from the bone-marrow. Often these phenomenas are observed during the infectious diseases. They have significanse for the differential diagnostic. If for the disease is characterised leucocytosis, the availability of leucopenia testifies on depression of hemopoietic system. It is regarded as a criteri weakenes of reactivity of the body on action of pathological factors.Directness and character of changes of white blood cells due to various diseases - significant for the diagnosis and control of the treatment. 2.Length of the employment – 2 hours. 3.Aim: To khow: types of the left nuclear deviation. To be able: to analyse of the quantitative and qualitative changes of leucocytes in blood. To perform practical work: to analyse of the pathogenesis of the quantitative and qualitative changes of leucocytes in blood. The increase of leucocyte quantity is called leucocytosis, and the decrease-leucopenia. The norm is 4-9G/l or 4-9*109/l. The quantitative changes are increased quantity of immature forms in blood and degeneration of leucocytes. 4. Basic level. The name of the previous disciplines 1. histology 2. biochemistry 3. physiology The receiving of the skills Scheme of leucopoesis. Leucocytes formula of blood. Function of leucocytes. Methods of counting of leucocytes maintenance in blood. 5. The advices for students. 1. Leucocytosis. Leucocytosis –is the increase of total leucocyte quantity in blood – over 9G/l (9/109/l). 2.Classification of leucocytosis. Absolute leucocytosis is the increase of leucocyte number in blood, caused by the increased production of leucocytes of reactive of reactive or tumor character in the organs or their increased coming from the bone marrow depot into the blood vessels. Relative leucocytosis –is the increase of leucocyte number in blood caused by their redistribution from the parietal pool into circulating one or their accumulation in the focus of inflammation. Leucocytosis is divided into neutrophilosis, eosinophilosis, basophilosis, lymphocytosis and monocytosis, depending on the type of leucocytes being increased. 3. Etiology of the leukocytosis. The causes of neutrophilosis are various. They are infectious factors (strepto- and staphylococci, fungi), the products of tissue malignant tumours in myocardial infarction, hemolysis, disintegration toxic metabolites in uremia, hepatic coma, physical factors (cold, heat), chronic myeloleucosis and psychical factors (fear, fury). Eosinophilia is observed in allergic and parasitical diseases, chronic myeloleucosis. Basophilia is caused by ulcerative colitis, chronic myeloleucosis after splenectomy and myxedema. Some viruses (infectious mononucleosis, hepatitis, measles) microorganisms (causative agents of whooping cough, tuberculosis and syphilis), chronic lympholeucosis provoke lymphocytosis. Monocytosis develops under the influence of viruses, microorganisms, protozoa, specific endocarditis. 4.The mechanisms of leucocytosis. There are the following mechanisms of leucocytosis: 1. The increase of leucocyte production in the bone marrow. 2. The acceleration of leucocyte entrance from the bone marrow into blood, as a result of increased permeability of the bone marrow. 3. The redistribution of leucocytes to the circulating blood or to the focus of inflammation. Usually, leucocytosis is accompanied by the disturbance of maturation in the bone marrow and the production of pathologic forms. Reactive hyperplasia of the leucocytic tissue leads to the increase of the organism resistance. Neutrophilic leucocytosis and monocytosis have parallel increase of the phagocytic activity of leucocytes. Eosinophiles play a compensatory role in allergic reactions due to antihistamine function of eosinophilic granulocytes. But, leucocytosis during leukemia may life be accompanied by immunological hyporesistance. The organism gets auto- and secondary infection. 5.Blood picture under the leukocytosis. The increase of total number of leucocytes is accompanied by the change of leucocyte formula (of separate forms of leucocytes in per cent, by counting 200 cells in the stained blood smear). Absolute or relative character of these changes is established with counting absolute amount of different forms of granulo- and agranulocytes in one litre. The count is made on the basis of total amount of leucocytes in one litre of blood and leucocytic formula. So, absolute neutrophile leucocytosis in purulent inflammatory diseases is accompanied by decrease of the amount of leucocytes in percent in the leucocytic formula (relative lymphopenia). However the count of absolute quantity of lymphocytes on the back-ground of general leucocytosis allows establishing absence of inhibition of lymphocytic stem. In leucocytosis, especially neutrophilic one, immature cells not infrequently appear in blood. A great number of generatively altered leucocytes in leucocytosis is noted in blood in sepsis, purulent processes, infectious diseases, disintegration of malignant tumor. 6. Leucopenia. Leucopenia –is the decrease of total leucocyte number in blood –below 4G/l (4*109). 7.Classification of the leukopenia. There are absolute and relative leucopenias. Depending on the type of leucocytes, there are neutropenia, eosinopenia, lymphopenia and monocytopenia. 8.Etiology of the leukopenia. Neutropenia is caused by infectious gripe viruses, measles, enteric fever toxin, rickettsia of typhus, physical factors (ionizing radiation), medicines (sulfanilamides, barbiturates, cytostaties), benzol, the deficiency of vitamin B12, folic acid, anaphylactic shock, hypersplenism, genetic defects of neutrophile production and differentiation. Eosinophilia is observed in the increase production of stress, Itsenco-Cushing disease, corticosteroids, infectious diseases, introduction of corticotrophin and cortisone. Lymphopenia develops under the influence of hereditary and acquired immunodeficiency, stress, radiation disease, military tuberculosis, myxedema. Monocytopenia is found in all syndromes and diseases, connected with the depressed myeloid stem shot of the bone marrow hemopoiesis (for example, in radiation disease, severe septic conditions, and agranulocytosis). 9.Pathogenesis of the leukopenia. The following mechanisms are in the basis of leucopenia: 1. The decrease of leucocyte production in the hemopoietic tissue. 2. The disturbance of leucocytes entrance into blood. 3. Their destruction in blood and hemopoietic tissue. 4. Redistribution of leucocytes in the vessels. 5. The increase discharge of leucocytes from the organism. The defect of the tissue membrane, leads to the decrease of leucocyte bile ability. It is called the syndrome of “lasy leucocytes”. As a result, the granulocytes come into blood from the bone marrow very slowly. The increased destruction of leucocytes may be caused by the change of their physico-chemical features and permeability of leucocyte membranes due to ineffective leucopoiesis. It leads to increased lysis of leucocytes, including spleen macrophages, and by the action of the same pathogenic factors provoking cell destruction in the hemopoietic organs. The redistribution of leucocytes is observed in hemotransfusional shock, inflammatory diseases, in altered ratio between the circulating and parietal pools of leucocytes. Sometimes, leucopenia may be conditioned by the increased discharge of leucocytes from the organism (in purulent endometritis, cholecystoangiocholitis). The main consequence of leucopenia is the decrease of the organism resistance caused by reduction of phagocytic activity of neutrophile granulocytes and lymphocyte function of antibody formation not only due to reduction of their total quantity but also due to possible combination of leucopenia with production of functionally inferior leucocytes. Such patients often suffer from different infectious and tumor diseases, especially in hereditary neutropenias deficiency of T- and B-lymphocytes. The examples of severe areactivity are AIDS of viral and radiation origin as well as agranulocytosis and alimentary-toxic aleukia. It is caused by different medicines, radiation and some infections. 10. Aleukia – is an aplastic damage of the bone marrow, accompanied by the sharp inhibition of total stopping of leucocyte production. Alimentary-toxic form develops in eating grains, infected by mould. Usually, we can observe pancytopenia in such cases –a sharp decrease of leucocytes (aleukia) and thrombocytes (thrombocytopenia). However, we can observe some compensatory reactions, manifested as the reactions of some stems of leucocytes, when the other ones are inhibited. For example, neutropenia may be accompanied by compensatory increase if production of monocytes, macrophages, eosinophiles, plasmatic cells. It decreased as a little the severity of clinical manifestations. The disturbance of correlation between mature and immature of leucocytes in blood. The appearance of immature forms of leucocytes in blood is conditioned by the disturbance of their maturation in the hemopoietic tissue and the increase of the bone marrow permeability. These changes are usually on the background of increased leucopoiesis due to reactive and tumor hyperplasia of the leucopoietic tissue. If there is predominance of mature, segmentocellular cells, cells of the granulocyte kind (first of all neutrophile granulocytes) and there are no stab neutrophiles and metamyelocytes, such hematological picture is connected with inhibition of the bone marrow hemopoiesis. If there are a lot of mature leucocytes and no young forms, the bone marrow hemopoiesis is depressed. 11. Blood picture under aleukia. We must find out if there is a right or left nuclear deviation of the neutrophile granulocytes. Immature of Shillings forms of leucocytes (myelocytes, metamyelocytes, stab neutrophile granulocytes) are placed in the left part of the leucocyte formula, the mature ones (segmentonuclear neutrophile granulocytes) in the right part. The increase of the young neutrophiles in blood is evidence of the left nuclear deviation. The prevalence of the mature forms (5-6 segments) on the background of absence of young cells is evidence of the right nuclear deviation. There are the following types of the left nuclear deviation: 1. Regenerative one indicative of reactive activation of leucopoiesis. 2. Hyperregenerative deviation-reflects an excessive hyperplasia of the hemopoietic tissue. Them maturation is broken. There are may immature forms in blood. The number of stab neutrophile granulocytes and metamyelocytes increases sharply. Myelocytes and promyelocytes appears the total number of leucocytes may be increased, unchanging and even decrease due to exhaustion of the myeloid stem after preceding activation. 3. Degenerative of deep disturbances and inhibition of leucocyte production. On the background of general leucopenia here are many stab neutrophile granulocytes with degenerative range and no metamyelocytes and nucleus with decreased number of the segmentonuclear forms in blood. 4. Regenerative-degenerative deviation. It is observed in hyperproduction of the pathologically changed leucocytes in the bone marrow and their immaturation. In this case there is leucocytes and the number of stub neutrophile granulocytes, metamyelocytes and myelocytes with signs of degeneration increases in the blood smear. A sharp increase of the immature forms is typical for the leukaemoid reaction. Blood picture is close to leukemia but is differs by (the cause is often known-infection, malignant tumors, acute hemolysis etc.) etiology and pathogenesis (reactive hyperplasia of the leucopoietic tissue). This reaction is temporary, reversible and doesn’t change into leukemia. There are some types of leukaemoid reaction, they are: myeloid neutrophiles, eosinophiles, monocytes and lymphoid ones (in sepsis cancer metastases into the bone marrow myeloid reactions in infectious lymphocytosis and mononucleosis-lymphoid type leukaemoid reactions). The right nuclear deviations is evident of the depression of leucocyte production in leucopenia (radiation disease, B12 and folic acid deficiency anemia). The right nuclear deviation is observed in 20% of healthy people. 12. Leucocyte degeneration in blood. They are: unisocytosis vacuoles in cytoplasm, toxigenic granules, the appearance of inclusions in cytoplasm such as Cnyazcov-Dele’s bodies basophilically stained small bundle of cytoplasm and others, the presence of large asurophilic granulation and absence of the normal one, the swelling of the nucleus, its hypo- and hypersegmentation, different degree of mutation of the nucleus and cytoplasm, cytolysis. Degenerative changes are most frequently observed in neutrophile granulocytes and monocytes. The causes are the disturbance in leucocyte metabolism, which to structural anomalies (in leucosis and hereditary enzymopathy), and the damage of leucocytes in the hemopoietic organs and blood under the influence of different pathologic factors (bacteria, viruses and antibodies). 5.1. Content of the theme. What is leukocytosis? Classification of the leukocytosis. Etiology of the leukocytosis. The mechanisms of leucocytosis. Blood picture under the leukocytosis. What is leukopenia? Classification of the leukopenia. Etiology of the leukopenia. The mechanisms of leucopenia. What is aleukia ? Blood picture under the leukopenia. Leucocyte degeneration in blood. 5.2. Control questions of the theme: 1.What is leukocytosis? 2.Classification of the leukocytosis. 3.Etiology of the leukocytosis. 4.The mechanisms of leucocytosis. 5.Blood picture under the leukocytosis. 6.What is leukopenia? 7.Classification of the leukopenia. 8.Etiology of the leukopenia. 9.The mechanisms of leucopenia. 10.What is aleukia ? 11.Blood picture under the leukopenia. 12.Leucocyte degeneration in blood. 5.3. Practice Examination. Task 1. During the medical examination of a boy 5 years old were founded the significant increase of eosinophiles in the blood. What from mentioned below can be the cause of eosinophilia? A. Helminthiasis B. Obesity C. Hypodynamia D. Hypotermia E. Physical strain Task 2. In the liquidator of consequences of failure in Chornobil atomic power station, which has received dose of ionising radiation 5 Gr, after one week during the blood examination leucopenia is revealed. Which pathogenetic mechanism is main in occurrence it? A . Emigration of leucocytes from vessels in tissues B. Excessive destruction of leucocytes in blood C. Depression of leucopoiesis in bonemarrow D. Delay of go out the leucocytes from bone-marrow E. Appearance autoantibodies against leucocytes Task 3. In different diseases due to activation of leucopoiesis occurs not only increase of number of leucocytes, but also appearance in blood of the young forms. Hyperregenerative nuclear shift to the left is expressed for. A. Pneumonic fever B. Acute appendicitis C. Leukemoid reaction D. Disintegration of tumor C. Abscess of lung Task 4. The patient suffering for a long time of bronchial asthma. What changes of cellular structure of blood are characterized for this illness? A. Neutrophilousis B. Lymphocytosis C. Monocytosis D. Basophilia E. Eosinophilia Task 5. The patient with systemic red lupus was treated for a long time with glucocorticoids. From his blood is expect: A. Lymphocytosis B. Neutrophilousis C. Eosinophilia D. Monocytopenia E. Eosinopenia Real-life situations to be solved: Amount of Baso- Eosinoleucocytes philes philes Task1 12,0∙109/l Task 2 18,3∙109/l Task 3 1,35∙109/l Task 4 11,4∙109/l Myelocytes Neutrophiles LymMetaStab- Segmen- phocytes myelo- nucleo- tonuccytes nic leonic Monocytes 1% 2% - 1% 15 % 57 % 20 % 4% 1% 3% Single 3% 38 % 48 % 4% 3% 0,5 % 1,5 % - - 4% 17 % 65 % 12 % 2% 16 % - - 1% 55 % 24 % 2% Control questions 1. Analyze above mentioned leucocytes formulas and indicate, what changes of total leukocytes and separate forms are present in each of them. 2. What pathological processes and diseases ites are characteristed for? Give examples. Literature: 1. Gozhenko A.I., Makulkin R.F., Gurcalova I.P. at al. General and clinical pathophysiology/ Workbook for medical students and practitioners.-Odessa, 2001. 2. Gozhenko A.I., Gurcalova I.P. General and clinical pathophysiology/ Study guide for medical students and practitioners.-Odessa, 2003. 3. Robbins Pathologic basis of disease.-6th ed./Ramzi S.Cotnar, Vinay Kumar, Tucker Collins.-Philadelphia, London, Toronto, Montreal, Sydney, Tokyo.-1999.