Inquiry

Semiotics of main syndromes (anaemic, hemorrhagic, haemolytic) and blood system diseases (anaemia, acute and chronic leukaemia’s, hemorrhagic vacuities, thrombocytopenic purpura haemophilia).Clinic-immunological characteristic of HIV infection

Inquiry

Complaints. Some general complaints, such as weakness, fatigue, vertigo, exertion dyspnoea, palpitation, and loss of work capacity can be symptoms of anaemia. But the same symptoms are characteristic of leukaemia and myeloid hypoplasia (aplasia). In acute and profuse haemorrhage (e.g. gastro-intestinal), the patient develops acute weakness, vertigo, and syncope.

Many diseases of the blood system are attended fever. Temperature elevates to subfebrile in haemolytic and vitamin B12 deficiency anaemia, which is explained by the pyrogenic effect of the erythrocyte decomposition products. Subfebrile temperature can be observed in other types of anaemia due to compensatory intensification of basal metabolism. Moderate and high temperatures often occur in acute and chronic leucosis, especially in leukaemic forms due to intense decomposition of leucocytes, during which great quantity of pyrogenic purine bases are released. This also explains increased sweating of leukaemia patients. And finally, elevated temperature may be the result of necrotic-ulcerous processes and concurrent secondary infections, especially in acute leucosis, in the terminal stage of chronic leucoses, and also in myeloplastic syndrome (pan-myelophthisis, agranulocytosis). Fever in lymphogranulomatosis is undulant, with gradual (in the course of 8-15 days) elevation and lowering of temperature.

The patient often complains of skin itching. Intense itching in lym-phogranulomatosis can be the first symptom of the disease, which develops long before the other symptoms of the disease appear. Skin itching is also characteristic of erythraemia and chronic lympholeukaemia.

Patients with many diseases of the blood system complain of poor appetite and loss of weight. Wasting is especially pronounced (cachexia) in chronic leucoses and malignant lymphoma,e.g.in,lymphogranulomatosis,lymphosarcomatosis, etc. Vitamin B12 deficiency anaemia is characterized by burning sensation in the tip and edges of the tongue. Iron deficiency anaemia, especially the so-called early and late chlorosis, is characterized by perverted taste: the patient readily eats chalk, clay, earth, coal (pica chlorotica). The olfaction changes as well: the patient finds pleasure in smelling ether, petrol, and other substances with unpleasant odour.

Haemorrhagic diathesis, myeloaplastic syndrome and leucosis are attended by increased bleeding. Haemorrhagic eruptions on the skin and mucosa develop spontaneously or due to insignificant causes (pressure, mild contusion). Bleeding from the nose, gums, gastro-intestinal tract, lungs, kidneys, and the uterus also develop. Slightest injuries to the skin and mucosa stimulate prolonged bleeding in haemophilia and in over-dosage of anticoagulants.

Diseases with intense proliferation of cells of the bone marrow and its hyperplasia (e.g. acute leucosis, chronic myeloleucosis, erythraemia) are often attended by pain in the bones, especially in flat bones. The pain can be spontaneous, but it becomes especially pronounced, when pressure is exerted on the bone or it is slightly tapped over. Acute leucosis is often attended by pain in the throat during swallowing because of developing necrotic and ulcerous tonsillitis.

Many diseases are manifested by severe pain in the left hypochondrium due to involvement of the spleen. The spleen is quickly enlarged and its capsule is overdistended to cause dull pain in cardiac decompensation and thrombosis of the splenic vein. Pronounced enlargement of the spleen, e.g. in chronic myeloleucosis (and in some forms of liver cirrhosis), is attended by the feeling of heaviness and distension in the left hypochondrium. Sharp pain develops in perisplenitis. It is intensified during deep breathing and coughing. But the most severe pain develops in massive infarction of the spleen, torsion of the vascular-ligamentous bundle (if the spleen is mobile) and spleen rupture. If enlargement of the spleen is significant, it may be ruptured by a slight injury.

Considerable enlargement of the liver, e.g. due to myeloid or lymphoid metaplasia in chronic leucosis, can be the cause of a subjective feeling of heaviness and pain in the right hypochondrium. Right hypochondriac pain of the colic type is characteristic of haemolytic anaemia. It can also be caused by pigmented stones in the gall bladder and bile ducts that are formed due to pronounced hyperbilirubinaemia and hypersecretion of the bile pigment.

History of the present disease. When inquiring the patient it is necessary to obtain information concerning his general condition in the period preceding the onset of the present disease and also the conjectured causes of the disease. It is necessary to establish the time of the appearance of the symptoms, to study thoroughly the dynamics of the disease, to establish if the patient had his blood examined in the past, and the results of these studies. It is also necessary to find out if the patient was treated for the present disease and the results of this treatment.

Anamnesis. When collecting the anamnesis, it is necessary to remember that improper way of life, insufficient time spent in the open air, inadequate nutrition and vitamin deficit can be the cause of anaemia. Acute and chronic industrial poisoning with mercury salts, lead, phosphorus and other noxious substances, and also exposure to radiation due to neglect of safety regulations, often become the cause of affection of the haemopoietic system.

Past medical history can be quite valuable to establish the aetiology of the present disease. Diseases of many organs that can be complicated by obvious or latent haemorrhages (e.g. tumours or ulcers of the gastro-intestinal tract, bronchiectasis, pulmonary tuberculosis, etc.) can be the cause of anaemia. Atrophy of the gastric mucosa and removal of the stomach or even its partial resection can impair assimilation of iron and vitamin B12, which are prerequisites for normal erythropoiesis. The haemorrhagic syndrome due to upset production of some coagulating factors, e.g. prothrombin and fibrinogen, often accompanies chronic diseases of the liver. Severe anaemia may develop against the background of chronic diseases of the kidneys attended by renal insufficiency. Prolonged uncontrolled intake of medicinal preparations without doctor’s prescription (amidopyrin, butadiene, chloramphenicol, sulpha drugs, cytostatics, etc.) can inhibit the function of the bone marrow and provoke haemolytic or aplastic anaemia and the haemorrhagic syndrome.

Some diseases of the blood system can be hereditary. These are haemolytic anaemias and haemophilia. It is therefore necessary to inquire the patient about his relatives, paying special attention to the presence in them of signs of anaemization or increased tendency to haemorrhages.Physical Examination.

INSPECTION

Inspection reveals the general condition of the patient and his consciousness. A very grave condition and loss of consciousness characterize many diseases of the blood system at their terminal stages. These are progressive anaemia, myeloid aplasia, and leucoses.

The skin and mucosa should be inspected at diffused daylight. Their colour is important: anaemia is characterized by pallor of the skin and visible mucosa, the hue differing in various types of anaemia. For example, the skin of patients with juvenile chlorosis is “alabaster” pallid, sometimes with a greenish hue. The skin of patients with vitamin B12 deficiency is slightly yellowish and waxy. The yellow hue of the skin and visible mucosa is more pronounced in haemolytic anaemia. It should be remembered that a mild yellow hue can be easier revealed on the sclera. Pallid skin does not always indicate anaemia and can also be due to special anatomic properties of the skin (deep vascularization), spasm of the peripheral vessels (collapse, nephritis), and some other factors. Moreover, pallor of the skin can also be masked by its hyperpigmentation (tan due to exposure to the sun). A more informative sign is therefore pallor of the mucosa. Inspecting the conjunctiva of the upper and lower eyelids can easier reveal anaemization. In chronic leucoses the skin becomes greyish. Erythraemic patients have “plethoric” cherry-red skin, the colour being especially marked on the face, the neck, and the hands.

Haemorrhagic spots of various size and shape (from petechia and ecchymoses) develop on the skin and mucosa of patients with haemorrhagic diathesis; large haemorrhagic spots are called bruises. Haemorrhagic lesions are first red but as haemoglobin converts into biliverdin, bilirubin or its other coloured products of oxidation, the colour changes to cherry-blue, green, and yellow (before the ecchymosis resolves). In contrast to inflammatory rash and telangiectasia, haemorrhagic spots do not disappear when they are pressed upon.

Trophies of the skin are also important. The skin is dry and sometimes scaling in patients with iron deficiency anaemia. Hairs become brittle and their ends break.

Changes characteristic of some diseases of the haemopoietic system can be revealed during inspection of the mouth. Pronounced atrophy of the tongue papillae is characteristic of vitamin B12 deficiency anaemia: the tongue surface becomes smooth, as if varnished (Hunter’s glossitis). Intense caries of the teeth and inflammation of the mucosa round dental necks (alveolar pyorrhoea) often occur in patients with iron deficiency anaemia. Nectoric ulcerous tonsillitis and stomatitis are frequent symptoms of acute leucosis.

Regional swelling on the neck, above the clavicles, in the armpits and the groin, less frequently swelling of other location can be revealed by inspection of patients with certain forms of leucosis. A considerable enlargement of the corresponding lymph nodes that become palpable (see below) explains this. The left part of the abdomen is distended in considerable enlargement of the spleen (e.g. in chronic myeloleucosis), which can also be confirmed by palpation.

PALPATION

Patients suspected for leucosis or some forms of anaemia should be palpated to examine the bones: palpation of flat bones or epiphyses of tubular bones (and also tapping over them) is painful in the presence of marked hyperplasia of the bone marrow.

Palpation of the lymph nodes and the spleen is however more informative. Enlargement of lymph nodes is most pronounced in lympholeucosis, lymphogranulomatosis, and lymphosarcoma. Regular and multiple affection of the lymph- nodes characterize these diseases. The lymph nodes of only one group are first affected, but later other groups become involved too (both surface and deep nodes of the mediastinum and the abdominal cavity). It should be remembered that lymph nodes can be enlarged not only in diseases of the blood system but also in some other diseases, such as tularaemia, tuberculosis, cancer metastases, etc.

Enlarged lymph nodes in leucoses and malignant lymphomas are painless, they never fuse with the skin, do not suppurate or form fistulae, as distinct from affections of other aetiology (e.g. in tuberculosis). The nodes are pasty and elastic in lymphoid leucosis; in lymphogranulomatosis, and especially in lymphosarcoma, they are firm and fuse into conglomerates, sometimes as large as 15-20 cm in diameter.

The spleen should be palpated with the patient in the recumbent position or on his right side. In the former case the patient should lie on a low pillow, the arms and the legs being stretched. If the patient lies on his right side, his head should be slightly down, the left elbow bent and resting freely on the chest; the right leg should be stretched and the left knee bent and drawn up to the chest. The prelum is relaxed to a maximum. In this position, the spleen is displaced anteriorly to facilitate its palpation even if it is slightly enlarged. The physician sits on the right side of the patient and faces him. The left hand of the physician is placed on the left part of the patient’s chest, between the 7th and 10th ribs in the axillary lines and slightly presses on the chest to limit its respiratory movements. The physician’s right hand is placed on the anterolateral surface of the patient’s abdominal wall at the edge of the costal arch, at the point of junction of the costal arch and the 10th rib, or (if preliminary inspection and percussion suggest enlarged spleen) at the antero-inferior edge of the spleen. During expiration the physician moves his hand gradually into the abdomen to form a pouch and the patient is asked to make a deep inspiration. If the spleen is palpable (and provided the palpation is performed correctly), it is displaced during inspiration by the descending diaphragm to come in contact with the palpating fingers of the right hand and to slip over them. This manipulation should be repeated several times in order to examine the entire palpable edge of the spleen. The size, shape, sensitivity, density, mobility, and configuration of the anterior edge of the spleen should be determined by palpation.

One or several notches on the anterior edge of the spleen can be palpated if its enlargement is considerable. The notches are used to identify the spleen (to differentiate it from other organs, e.g. from the left kidney). The anterior surface of the enlarged spleen emerges from under the costal arch and also becomes palpable.

A normal spleen is impalpable. It can only be palpated in rare cases of extreme ptosis, and more frequently in enlargement of the organ. The spleen is enlarged in some acute and chronic infectious diseases (enteric and recurrent fever, Botkins’s disease, sepsis, malaria, etc.), in liver cirrhosis, thrombosis or compression of the splenic vein, and also in many diseases of the haemopoietic system (haemolytic anaemia, thrombocytopenic purpura, acute and chronic leucosis). A considerable enlargement of the spleen is called splenomegaly. The greatest enlargement of the spleen is observed at the terminal stage of chronic myeloleucosis: it often occupies the entire left part of the abdomen, while its lower pole is found in the small pelvis. After the size of the spleen is determined by palpation and its contours marked on the skin of the abdomen by a dermograph, a skin test is sometimes performed with subcutaneous injection of 1 ml of a 0.1 per cent adrenaline solution (Frey test) by which the contractile function of the spleen is determined. In most cases the smooth muscles of the spleen contract in response to adrenaline to diminish 2-3 times. The spleen does not diminish appreciably in this test in the presence of its fibrosis, in perisplenitis, or in the presence of its tumours or cysts.

The spleen is not firm in acute infectious diseases; it is especially soft (the consistency of dough) in sepsis. In chronic infectious diseases, liver cirrhosis, and leucosis the spleen is firm, especially in amyloidosis.

In most diseases the spleen is insensitive to palpation. It becomes tender in infarction, perisplenitis, and in distension of the capsule, due to the rapid enlargement, e.g. in venous blood congestion due to thrombosis of the splenic vein. The spleen surface is usually smooth; the edges and the surface are irregular in perisplenitis and old infarctions (depressions in the surface). In syphilitic gummas, echinococcosis, cysts and very rare tumours of the spleen its surface is tuberous.

The spleen is normally quite mobile, but the mobility becomes limited in perisplenitis. A markedly enlarged spleen remains motionless during respiration but the palpating fingers can however displace it.

Not only the spleen but also the liver sometimes becomes enlarged due to metaplasia (as determined by palpation).

PERCUSSION

Percussion is not important for the study of the haemopoietic organs; it is only used to outline tentatively the spleen. Since the spleen is surrounded by hollow organs (the stomach, the intestine), which give loud tympany during percussion, it is impossible to determine accurately its borders by percussion.

During percussion, the patient stands upright or lies on his right side. Light percussion should be used with transition from clear resonance to dullness. Obraztsov’s percussion is recommended. In order to determine the transverse dimensions of the spleen dullness, percussion is carried out in the line passing 4 cm laterally of the left costoarticular line (the line connecting the stemoclavicular articulation with the free end of the 11th rib). Normally spleen dullness is determined between the 9th and 11th ribs. It is 4-6 cm wide. The long axis of the spleen is percussed by the 10th rib; normally the anterior edge of the spleen does not extend beyond the costo-articular line; its dullness zone is 6-8 cm long.

AUSCULTATION

Auscultation is used to study the spleen: peritoneal friction sound can be heard in perisplenitis in the region overlying the spleen.Instrumental and Laboratory Methods

MORPHOLOGICAL STUDY OF THE BLOOD

Total blood counts are widely employed. Blood studies include quan­titative and qualitative determination of the composition of the formed blood elements: counting erythrocytes and determining their haemoglobin contents, total leucocytes and their separate forms, and platelets. Additional counts are sometimes necessary depending on the character of the disease (counting reticulocytes, deriving the thrombocyte formula, etc.).

The concept of a reticular cell as a source of all cell elements of the blood has undergone a substantial revision in recent years in connection with advances in haematology. The hacmopoictic scheme is now described as follows.

Xhe first class of polypotent precursor cells is represented by the stem cell. The stem cells are self-sustaining, characterized by rapid proliferation and differentiation.

The second class of partly determined polypotent precursor cells is represented by precursors of lymphopoiesis and haemopoiesis; their self-sustaining power is limited; the cells are found in the bone marrow.

The third class of unipotent precursor-cells includes colony-forming cells (precursors of granulocytes and monocytes), erythropoietin-sensitive cells, precursors of B-lymphocytes and T-lymphocytes precursors.

The fourth class includes morphologically identifiable proliferating cells;The fifth class includes maturating cells and the class sixth mature cells with a limited life cycle. The cells of the sixth ctau are mainly delivered to the peripheral blood.

The cell composition of the blood of a healthy individual is constant and any changes are therefore diagnostically important. But minor changes in the blood can be observed during the 24-hour period: after meals, exercise, etc. In order to remove these interfering factors, blood specimens should be taken under the same conditions.

Taking blood specimens. The study of blood begins with obtaining its specimen. Blood is taken from the 4th finger of the left hand. A mixture of alcohol and ether first disinfects the finger. The skin on the side of the first phalanx is then punctured by a blood lancet to a depth of 2.5-3 mm. Blood should issue freely because any pressure on the finger will express other tissue fluids to impair the accuracy of studies. The first emerging drop of blood should be wiped off with dry cotton wool.

Determining haemoglobin. There are the following three major groups of methods for determining haemoglobin: colorimetric (widely used in practical medicine), gasometric, and determination by the iron contained in the haemoglobin molecule. Sahli’s method of estimating haemoglobin (1895) was widely used until recent times.

The cyanmethaemoglobin method has now been universally accepted as the most accurate and objective technique, which was approved by the Interrnational Standardization Committee (in haematology). The method is based on oxidation of haemoglobin (Hb) to methaemoglobin (MetHb or Hi) by potassium ferricyanide. Methaemoglobin reacts with CN-ion to form a stable red complex, cyanmethaemoglobin (CNMetHb) or haemoglobin cyanide (HiCN). Its concentration can be measured on a spectrophotometer,photoelectrocolorimeter,orhaemoglobino-

meter.

According to this method, 0.02 ml of blood taken from the finger is transferred into 5 ml (dilution 1:251) of a transforming solution consisting of acetone cyanhydrine, potassium ferrocyanide, and sodium hydrocar-bonate; the mixture is stirred thoroughly, allowed to stand for ten minutes, and the optical density of the solution is measured at 500-560 nm (a green optical filter) against a blank solution (the transforming solution or pure water). Concentration of haemoglobin is determined from a calibration curve. Concentration of haemoglobin in healthy people varies from 120-140 g/1 in women and from 130-160 g/1 in men.

Erythrocyte counting. In order to count erythrocytes in the chamber, blood is diluted to 1:200 in 3.5 per cent sodium chloride solution. To that end 0.02 ml of blood is added to 4 ml of the diluting solution. The mixture is stirred thoroughly and transferred into the counting chamber.

The counting chamber is a glass plate with one or two counting grids. Burker haemacytometers are usually used for the purpose. Three elevated strips, separated from each other by grooves pass across the main plate. The middle strip is divided into halves by another groove. Each half has a graduated counting grid. The lateral strips are 0.1 mm higher than the middle one. The cover glass rests on the elevated lateral strips to ensure a 0.1 mm spacing be­tween the grids and the cover glass (the depth of the counting chamber). In order to ensure the accurate spacing, the cover glass should be pressed tightly against the strips. A well-washed and wiped glass is ground-in by reciprocating sliding movements until the iridescent (Newto­nian) rings and lines appear over the lateral strips. A drop of diluted blood is placed by a pipette under the ground-in cover glass. The fluid is sucked in by capillary force to fill the space over the grid.

If the blood was diluted in a test tube, the mixture should be first jolted, then a glass rod dipped into the fluid and a hanging drop transferred onto the slit between the counting chamber and the cover glass. Counting should be done one minute later (when the erythrocytes precipitate to the chamber bottom).

There exist many counting grids but they all employ one principle. They consist of larger and smaller squares with the area of 1/25 and 1/400 mm², respectively. Goryaev’s grid is commonly used in the Soviet Union. It consists of 225 greater squares, 25 of which are divided into smaller ones, 16 squares in each greater square. Erythrocytes are counted in 5 greater squares (divided into smaller ones). A certain rule is followed in counting: cells are counted in each square in one direction, and then this direction is reversed in the next row of squares. Counted are not only the cells inside the square but also those lying by two lines (e.g. the left and the upper line) without counting blood cells lying on the right, and lower line. The quantity of erythrocytes counted in 5 greater squares is recalculated with reference to one litre.

Normal erythrocyte counts in women are 3.9—4.7 x 10¹² and in men 4-5 x 10¹² per 1 l  of blood.

There are instruments by which the counting procedure is either simplified or automated. These are erythrohatresemome and absorp-tiometres where concentration of erythrocytes is assessed by the amount of absorbed or scattered light passed through a suspension of erythrocytes, or directly reading automatic instruments. In the latter case blood cells pass a narrow capillary to change resistance of an electric circuit. Each cell gives a pulse on the screen of an oscilloscope and is recorded on the instrument scale.

Once the quantity of erythrocytes and haemoglobin in a given blood specimen is known, it is possible to calculate the haemoglobin content of each erythrocyte. There are many methods by which haemoglobin saturation can be determined. One of them is the calculation of the colour index. This is a conventional value derived from the ratio of haemoglobin to the number of erythrocytes. This value is found by dividing a tripled quantity of haemoglobin in grams by the first three figures expressing the quantity of erythrocytes. Normally this value approaches 1. If it is less than 1, the erythrocyte saturation of haemoglobin is insufficient; if the value exceeds 1, the volume of erythrocytes is higher thaormal. Oversaturation with haemoglobin is impossible. A normal erythrocyte is saturated with haemoglobin to the utmost limit.

At the present time, in accordance with the general tendency to express blood constants in absolute values, the weight percentage of haemoglobin in erythrocytes is calculated, instead of determining the colour index of the blood. To that end haemoglobin content in one litre is determined and the found quantity divided by the number of erythrocytes in the same volume. Normally one erythrocyte contains 33 ng of haemoglobin.

Leucocyte counting. Blood for counting leucocytes is diluted either in a special mixer or a test tube. A 3-5 per cent solution of acetic acid destroying erythrocytes is mixed with a small amount of a suitable aniline dye to stain leucocyte nuclei. The counting chamber is filled as for counting erythrocytes. It is convenient to count leucocytes in 100 greater (undivided) squares. A constant factor is found from the dilution of blood and the volume of fluid in each square. With 1:20 dilution it is 50. When test tubes are used for dilution, 0.02 ml of blood is added to 0.38 ml of the diluting liquid in the test tube. Saponin is used for haemolysis of erythrocytes in automatic counting instruments. The normal leucocyte counts are 4000-9000 in 1 l or 4.0-9.0 x 10⁹ per 1 1 of blood.

The leucocyte formula is counted in stained smears. An adequate smear meets the following requirements: it is thin and the formed elements are arranged in one layer; the smear is yellow and semitranslucent. The width of the smear is 2-3 mm narrower than the glass, while the length, 2/3-3/4 the length of the glass. A good smear is uniform and the cells are intact (not damaged during their application to the glass). In order to ensure an even layer, the glass is first defatted over a gas burner or in a mixture of alcohol and ether. A small drop of fresh blood is touched by the glass edge and spread immediately over the entire glass surface. A polished cover glass of the counting chamber or another object glass with polished edges and made slightly narrower than the main object glass can be used fouhyurpose. This glass is positioned behind the blood drop at an angle of 45° to the plane of the first glass and moved back to bring it in contact with the blood. As soon as the blood spreads over the entire width of the polished edge, the glass is moved forward along the surface of the object glass. Blood is thus spread in an even layer over the object glass. Before staining, the smear is fixed in methanol for 3 minutes, or in ethanol or a mixture of ethanol and ether for 30 minutes. Other fixing agents can also be used. When the smear is dry it is covered with a layer of stain.

Differential staining is used for blood cells. Romanovsky-Giemsa staining method is commonly used. The stain is a mixture of weakly acid (cosin) and weakly alkaline (azure II) stains. Depending on the reaction of the medium, the cells and their parts dyferently accept the stain: acid (basophilic) substances are coloured blue by azure, while alkaline (oxyphilic) substances are coloured red by eosin. Neutral substances accept both dyes and turn violet. Azure  II, which is generally blue, contains a small quantity of azure I. In some cells the cytoplasm contains grains which selectively accept red azure I. The grains are called azurophilic.

Romanovsky-Giemsa stain is diluted before use with distilled water, 1-2 drops per 1 ml of water. Smears are placed on glass rods fixed in the sides of the cell and the stain is added in the maximum quantity that can remain on the glass. The staining time (15-30 min) depends on concentration of the stain, quality of water (neutral) and temperature; it is determined em­pirically. The stain is then removed by a jet of water and the smears are placed in the vertical position to dry.

Differential blood count is the percentage of separate forms of blood leucocytes. In order to ensure accuracy, it is necessary to observe not less than 200 leucocytes using the immersion system. Since the cells are not evenly distributed over the surface  (larger cells tend to move toward the edges) it is necessary to follow a certain rule in counting, so that both the centre and the peripheral parts of the smear might be inspected. The smear can be moved from its upper edge to the lower one, then in the lateral direction, through 2 or 3 fields of vision, then back, from the lower to the upper edge, and so on. According to another method, the smear is moved from the edge, through 5 or 6 vision fields toward the centre, then the smear is moved in the lateral direction through the same distance, then again to the periphery, and so on, until 50 cells are counted. Four sites by the four angles of the smear should be thus inspected. Each cell should be identified and recorded. A special 11-key counter is convenient for cell counting. When 200 cells are thus counted, the number of each leucocyte is divided by two.

Leucocytes quickly respond to various environmental factors and changes inside the body. Shifts in their counts are very important diagnostically. But individual variations in leucocyte composition are quite significant and it is therefore necessary to compare individual findings not with the average values, but with a certain range within which these variations are normal.

When assessing the composition of leucocytes, it is necessary to bear in mind that changes in percentage ratios can give an incorrect picture of the shifts occurring in the blood. For example, an increase in the absolute amount of a given type of cells in the blood decreases the percentage of all other cell elements. The picture is reverse with decreasing absolute amount of this given type of blood cells. A correct conclusion can be derived not from relative (percentage) but absolute values, i.e. the quantity of a given type of cells contained in 1 m1 (in 1 1 of blood, according to the SI).

The total quantity of leucocytes alone is of great diagnostic significance, because it characterizes the condition of the haemopoietic system and its response to harmful effects. The increased number of leucocytes (leucocytosis) is the result of activation of leucopoiesis. The decreased number of leucocytes (leucopenia) depends on the inhibition of the haemopoietic organs, their exhaustion, increased decomposition of leucocytes under the effect of antileucocytic antibodies, etc.

Neutrophils are the most changeable group of leucocytes. Their number increases in many infections, intoxication, and tissue decomposition. Neutropoiesis is characterized not only by the increased total number of neutrophils but also by the appearance in the blood of immature forms: the quantity of stab neutrophils increases; juvenile neutrophils and even myelocytes appear. This rejuvenation of the neutrophil composition is called the blood shift to the left, because the figures grow on the left side of the laboratory blank where leucocyte counts are normally recorded. Regenerative and degenerative shifts are distinguished. In the regenerative shift to the left the mentioned changes are observed, while in the degenerative shift to the left, the number of stab neutrophils only increases along with the degenerative changes ieutrophils in the absence of leucocytosis (vacuolization of cytoplasm, nuclear pyknosis, etc.). The regenerative shift indicates active protective response of the body, while the degenerative one indicates the absence of this response. The protective role of neutrophils consists in phagocytosis, bactericidal action, and production of proteolytic enzymes promoting resolution of necrotized tissue and healing of wounds.

The regenerative shift to the left occurs most frequently in the presence of an inflammatory or necrotic focus. An especially marked shift to the left (to promyelocytes and even myeloblasts in the presence of significant leucocytosis) is called leucaemoid reaction. The number of neutrophils decreases (absolute neutropenia) in the presence of the inhibiting action of toxins of some microbes (e.g. causative agents of typhoud fever or brucellosis) and viruses, ionizing radiation, and some medicinal preparations.

The absolute number of lymphocytes increases less frequently. Lymphocytosis occurs during recovery in acute infectious diseases, infectious mononucleosis, infectious lymphocytosis, lymphoid leucosis, rubella, brucellosis, and thyrotoxicosis. More frequently lymphocytosis is only relative, associated with a decreased number of neutrophils (like relative lymphopenia in the presence of increased number of neutrophils). Absolute lymphopenia occurs in radiation sickness and systemic affections of the lymphatic system: lymphogranulomatosis and lymphosarcoma.

Eosinophils are present in the blood in relatively small quantity but their number increases, and sometimes significantly, in allergic processes (serum sickness or bronchial asthma), in helminthiasis, and itching dermatosis. Eosinophilia in allergic processes is associated with the role played by eosinophils in removal of toxic substances produced in these reactions. Decreased number of eosinophils (eosinopenia), to their complete absence, occurs in sepsis, severe forms of tuberculosis, typhus, and poisoning.

Basophils are carriers of important mediators of tissue metabolism. Their number increases in sensitization of patients and decreases markedly during decomposition caused by the repeated administration of the allergen.

Increased number of monocytes (monocytosis) indicates development of the immune processes. Monocytosis occurs in some chronic diseases (e.g. chroniosepsis, tuberculosis, malaria, visceral leishmaniasis, syphilis) and in infectious mononucleosis. Monocytopenia sometimes occurs in severe septic (hypertoxic) forms of typhoid fever and other infections.

Leucocyte counting procedure requires special skill. The laboratory technician should be able to differentiate between various blood cells. Granulocytes have specific segmented nuclei (violet like in all leucocytes) and oxyphilic (pink) cytoplasm containing grains. Grains of a neutrophilic leucocyte (10-15 /*m) are small, their size varies; they are stained brown-violet. The nucleus has a rough structure, with alternation of intense- and light-coloured sites; it consists of 2 to 5 (mostly 3 or 4) segments of various size and shape connected by thready bridges. The nucleus of a stab neutrophil is about the same size and colour, but it is a uniform curved band, which never thins to a thread. The eosinophil nuclei consist mostly of two symmetrically arranged segments of about the same size (three segments can also be present); their structure and colour are similar to those of neutrophil segments. Eosinophils are highly granular. Grains are large, round, bright-orange and of equal size; they stuff the entire cytoplasm. The diameter of the cell is about 15 nm. A basophil is slightly smaller than the other granulocytes (9-14 /nn). The nucleus can be segmented. Often it has an irregular oval shape and is stained intensely. The grains are large and dark-violet; their size varies. Due to metachromasia, their dark-blue colour makes them look violet.

Agranulocytes are characterized by a non-segmented nucleus and basophilic (blue) cytoplasm. The lymphocyte is the smallest of all leucocytes; its diameter usually varies between 7 and 12 lira, but some lymphocytes are as large as 12-15  nm. The nucleus is round, oval, or bean-shaped; it occupies almost the entire cell and is intensely coloured. The cytoplasm of most lymphocytes surrounds the nucleus by a narrow circle; it is pale-blue and becomes lighter toward the nucleus. In addition to these “small” lymphocytes, there are “medium size” ones having a large sky-blue zone of a cytoplasm. Some lymphocytes have several large cherry-red (azurophilic) grains in their cytoplasm. A monocyte is the largest blood cell. Its diameter is 20 nm. Its large nucleus is of irregular shape and relatively light-coloured. The cytoplasm is greyish-blue and smoky; the colour intensity does not diminish toward the nucleus. If stained well, dust-like azurophilic granularity is revealed in some cells.

In rare cases, apart from the mentioned cells, normal blood contains plasma cells. Their number increases in pathology. The cells have an eccen-tricaUy arranged dense nucleus (often a wheel-like structure) and a markedly basophilic vacuolized cytoplasm. Their number increases in certain infectious diseases, wound sepsis, hypemephroma, myeloma, etc. These cells are probably responsible for the production of gamma globulins.

When counting leucocytes, it is necessary to pay attention to both quantitative and qualitative shifts in the formed elements. The degenerative shifts were discussed above. In grave toxicosis, granularity of neutrophils becomes even more pronounced, the granules become larger and coloured; this granulation is called toxicogenic. Indistinct spots are sometimes revealed in blood smears; they are stained like the nuclear substance of leucocytes. These arc Botkin-Gumprecht shadows, the remains of nuclear chromatin characterizing brittleness of leucocytes due to which they decompose (leucocytolysis).

Erythrocytes arc studied in the same smears . The size, shape, colour and cell inclusions should be assessed. Normal erythrocytes in the smear are rounded, their diameter varying from 6 to 8 nm (the average diameter, 7.2 nm). The size of erythrocytes often changes in anaemia of various natures. Various erythrocytes change differently. Excessive variation in the size of erythrocytes is called anisocytosis. Prevalence of smaller erythrocytes (microcytosis) occurs in iron deficiency anaemia. Macrocytosis develops in haemopoietic dysfunction of the liver. Megalocytes (large, over 12 nm, oval hyperchromic erythrocytes formed during maturation of megaloblasts) appear in the blood of patients with vitamin B12 deficiency (vitamin B12 deficiency anaemia). In pathological conditions of erythrocyte maturation, along with anisocytosis, the change in the shape of erythrocytes (poikilocytosis) is also observed; in addition to round erythrocytes, blood contains also erythrocytes of oval, pear-shaped and other configurations. If erythrocytes are undersaturated with haemoglobin (colour index less than 0.85) they are poorly stained to become hypochromic; in vitamin B12 deficiency they are coloured intensely, i.e. hyperchromic (colour index higher than 1). A mature erythrocyte is oxyphilic, i.e. coloured pink.  An immature erythrocyte is polychromatophilic. In supravital staining these erythrocytes appear as reticulocytes (see below). Normal blood contains polychromatophilic erythrocytes in meagre quantity: single cells per 1000 erythrocytes. Since they are less noticeable than reticulocytes, the latter are counted to assess the number of juvenile polychromatophilic cells. The importance of this count is that the number of reticulocytes in the blood is a measure of the activity of the bone marrow. Normally this number is 2-10 per 1000 erythrocytes. Erythropoiesis is activated in blood loss and haemolysis, and the number of reticulocytes iormal bone marrow and peripheral blood increases. The absence of this increase indicates decreased function of the bone marrow and conversely reticulocytosis in the absence of anaemia indicates latent but well compensated loss of blood. High reticulocytosis is observed in effective treatment of vitamin B12 deficiency anaemia.

In erythropoietic hypofunction of the bone marrow, more immature nuclear (but still containing nuclei) elements of the red blood, i.e normoblasts and erythroblasts, are delivered into the blood from the bone marrow. During maturation of erythrocytes in pathological conditions, nuclear remnants, known as Jolly bodies, may be preserved. These are round chromatin formations 1-2 nm in size stained cherry-red. Red Cabot rings (thread-like rings or convolutions) may also remain. They are believed to be the remnants of the nuclear envelopes, and occur mostly in vitamin B12 deficiency anaemia.

Basophilic granulation of erythrocytes is also the result of their abnormal maturation. Blue granules are seen against the pink background during ordinary staining of a fixed smear. It should not be mistaken for reticulocyte granulation, which is revealed only in supravital staining. Basophil-granular erythrocytes occur in pernicious anaemia and some intoxications, especially in lead poisoning.

Reticulocytes are stained in unfixed smears of fresh blood in which erythrocytes are still alive. Various alkaline dyes are used to stain smears by various techniques. Best results are attained with brilliant cresyi blue. A drop of a saturated alcoholic solution of the stain is applied to a defatted object glass and a smear is made by the usual way. As soon as the stain dries up, a thin blood film is smeared over it and the glass is transferred to a moist chamber (a Petri dish containing a piece of wet blotting paper). The smear is kept there for 5 minutes and then removed and allowed to dry. The smear is inspected with an immersion system. Mature erythrocytes are stained green. Against this background, reticulocytes (depending on their maturity) have blue granules, filaments, or other formations that may resemble a crown, a ball, or a network. Filaments and grains are more mature forms and they usually predominate in reticulocytes.

When counting reticulocytes, their number per 1000 erythrocytes is determined. For convenience of counting, placing a special window in the eyepiece diminishes the vision field of the microscope. The total number of erythrocytes and reticulocytes is counted in the field of vision. Counting is continued till the number of erythrocytes is 1000.

Thrombocytes (platelets) have a diameter of 1.5-2.5 nm. Their normal number is 180.0-320.0 x 10⁹ per 11 (180 000-320 000 per I *l) of blood. Using the Romanovsky-Giemsa staining technique, the central part, the granulomere with intense azurophilic granulation, and non-granular hyalomere around it are distinguished. If the number of thrombocytes decreases significantly (thrombocytopenia), a tendency to haemorrhages develops. The critical figure at which haemorrhage occurs is believed to be 30 x 10⁹ per 11 (30 000 per 1 *l). Thrombocytopenia occurs in affection of the bone marrow by infectious causative agents, some medicinal preparations, ionizing radiation, and in auto-immune processes. Thrombocytosis occurs after haemorrhage, in polycythaemia, and malignant tumours.

In order to determine the number of thrombocytes, it is necessary to prevent their agglutination. To that end, a drop of a 14 per cent magnesium sulphate solution is placed over the puncture point on the finger. The blood issuing from the wound mixes with the solution and smears are made from this mixture, which are then fixed and stained after Romanovsky-Giemsa. The fixing and staining time should be doubled (compared with the blood smear staining time). Using a window to restrict the field of vision (like in counting reticulocytes), 1000 erythrocytes and all thrombocytes that occur among them are counted in vision fields. Once the  number of erythrocytes in 1 *l is known, the number of thrombocytes can be calculated in  1 *1 and  in 1 l of blood.

Apart from the described indirect counting of thrombocytes, they can also be determined directly in a counting chamber. The blood is diluted by a suitable solvent, e.g. by a 1 per cent ammonium oxalate solution. A phase contrast microscope is used for counting. This method is more accurate than indirect counting. In certain diseases of the haemopoietic organs, thrombocyte counts are also necessary. Juvenile, mature, and old thrombocytes are distinguished. They also differ in size, shape, colour and struc-ture; their degenerative forms appear, sometimes.

Changes in the morphological composition of the blood should be used to establish diagnosis of a disease together with the other findings of examination of the patient.

Erythrocyte sedimentation rate (ESR). Erythrocytes do not clog together in the stream of blood because they are all negatively charged. If a blood specimen is placed in a vertical vessel and an anticoagulating agent is added to it, erythrocytes gradually settle by gravity. Then they agglomerate into heavier groups, which precipitate at a faster rate. Agglomeration is promoted by some protein components of the plasma (globulins, fibrinogen) and by mucopolysaccharides. Therefore, the processes which increase their accumulation in the blood are attended by acceleration of erythrocyte sedimentation. This condition occurs in most inflammatory processes, infections, malignant tumours, collagenoses, nephroses, and tissue decomposition; to a certain measure, this acceleration is proportional to the gravity of the affection. In certain diseases erythrocyte sedimentation is not accelerated in their initial stage (epidemic hepatitis, typhoid fever); in other pathological conditions erythrocyte sedimentation rate is slowed (heart failure).

Erythrocyte sedimentation rate is not an independent diagnostic symptom; it only indicates the activity of the process. It is important in this aspect in the diagnosis of tuberculosis, rheumatism, and collagenosis. Changes in the erythrocyte sedimentation rate do not always agree with other signs of activity. For example, ESR lags behind the rate of temperature elevation and leucocytosis in appendicitis or myocardial infarction; its normalization is also slower than normalization of the mentioned symptoms. The normal ESR does not rule out the presence of disease, which would be usually attended by an increased erythrocyte sedimentation rate. But it should be remembered that ESR does not increase in healthy people.

The Panchenkov method of ESR determination is widely used in the Soviet Union. A Panchenkov capillary graduated in 1 mm (100 divisions) is used for the purpose. It is filled with a 5 per cent sodium citrate solution to a half of full capacity (50 divisions). The solution is blown out onto a watch glass or into a test tube. Using the same capillary, 100 mm of blood is taken from the punctured finger (2 times). To that end, the capillary is held horizontally and brought in contact with the issuing drop of blood: the blood is drawn in by the capillary force. The blood is then mixed with the reagent in the 4:1 ratio. The mixture is taken into the capillary, to the mark 0 (100 divisions), and placed in a Panchenkov stand, in a strictly vertical position. The number of millimetres of a settled plasma column is noted in 60 minutes. The normal rate for men is 2—10 mm/h and for women 2—15 mm/h.

PUNCTURE OF HAEMOPOIETIC ORGANS

The morphological composition of the blood does not always show the changes occurring in the haemopoietic organs. For example, the cell composition of blood remains almost unaltered in aleukaemic form of leucosis despite significant changes in the bone marrow. M. Arinkin (1928) proposed a stemal puncture for intravital study of the bone marrow. Owing to the simplicity and safety of the procedure, it is used for the study of almost all patients with diseases of the haemopoietic system. The Kassirsky needle is used for the purpose in the Soviet Union. This is a short thick-walled needle with a mandrin and a stopping device that prevents deep penetration of the needle. After the skin, subcutaneous fat and the periosteum are anaesthetized, the soft tissues are punctured over the sternum, at the level of the second or third intercostal space (or above the manubrium). Then the stopping device is fixed at a distance of 5 mm from the skin surface and the anterior plate of the sternum is punctured: the operator’s hand has a feeling of entering a cavity. The mandrin is now removed and a dry 10-20 ml syringe is attached to the needle. About 0.5 or 1 ml of bone marrow is now aspired into the syringe and transferred onto a watch glass. If the bone marrow is mixed with an unknown quantity of blood, its composition cannot be definitely determined. Using a blotting paper (or by inclining slightly the watch glass), the blood is separated, and the small grains of bone marrow are carefully pressed against the glass to prepare a smear of the crushed marrow. After fixation and staining (Romanovsky-Giemsa), not less than 500 elements containing nuclei are counted in the smear. A myelogram is then derived

The marrow specimen can show upset maturation of the cells: increased number of juvenile forms or prevalence of primary undifferentiated elements, upset proportion between the red and white cells, changes in the total number of cells, presence of the pathological forms, etc. Apart from the sternum, other bones (e.g. iliac bone) can also be used for taking the bone marrow.

More accurate information on the composition of the bone marrow is given by trepanobiopsy. A special needle (troacar) is passed into the iliac crest to cut out a column consisting of the bone-marrow tissue, which is then used for making histological preparations. The structure of the bone. marrow remains unchanged in the preparations while the absence of blood makes it possible to evaluate its cells composition and to reveal focal and diffuse changes in it.

Enlarged lymph nodes are often punctured. It makes it possible to establish the character of changes in the cell composition and to verify the diagnosis of some systemic diseases of the lymph apparatus (lymphoid leucosis, lymphogranulomatosis, lymphosarcomatosis), to reveal me-tastases of tumours, etc. More accurate data can be obtained with biopsy of the lymph node. The puncture is made without anaesthesia, by a simple injectioeedle attached to a 10-ml syringe. The obtained material is used to prepare smears. The spleen is punctured by the same method. The patient is asked to keep breath at the inspiration height to prevent possible injury of the spleen during respiratory movements. Combined study of cell composition of the bone marrow, spleen and lymph nodes reveals the relations between these organs of the haemopoietic system and the presence of extramedullar haemopoiesis which develops in some affections of the bone marrow.

 

 

 

Clinical Considerations

 

As stated previously, the mass of hemoglobin or red cells in the circulation is almost always expressed in terms of concentration per volume of blood. Consequently the concentration of plasma (predominantly water) in the blood influences the measurement of these constituents. Therefore, a patient who has bled acutely, losing both plasma and red cells, may not appear anemic for 12 to 24 hours even though his red cell mass is considerably depleted. Obviously, dehydration also influences the assessment of red cell or hemoglobin concentration. Furthermore, since the range of normal values is wide, a patient with a seemingly normal hemoglobin concentration may in fact be anemic in comparison to values obtained when he was healthy.

Anemia might also be defined as a reduction in the amount of hemoglobin in the blood below that necessary to maintain, without physiological adaptation, the normal requirements of the tissues for oxygen. By this definition a patient with reduced oxygen requirements (such as a patient with hypothyroidism) might have hemoglobin and red cell concentrations below the normal range and not be considered anemic.

It should be emphasized that there is not necessarily a correlation between the degree of anemia and the severity of the underlying disease. Bleeding hemorrhoids or benign epistaxis may produce profound anemia whereas one of the early signs of carcinoma of the colon may be a relatively slight anemia.

It should also be emphasized that a thorough history and physical examination may not detect anemia. Therefore, every complete examination should include a reliable measurement of the concentration of hemoglobin, red cells, or packed red cells (hematocrit) in the blood.

APPROACH TO THE DIAGNOSIS IN THE ANEMIC PATIENT. Anemia is not a disease. It is a manifestation of some underlying disorder, and the search for its cause should take into account what is understood of red cell production and destruction. The clues that help identify the underlying disorder come from the history, physical examination, and examination of the blood.

Signs and Symptoms. The signs and symptoms of anemia may be separated into those that are common to all anemias and those that suggest a specific disorder . The reduction in hemoglobin concentration decreases the capacity of the blood to transport and deliver oxygen to the tissues. Certain signs and symptoms are the result of this hypoxia, others are the consequence of the body’s attempt to compensate for the low concentration of hemoglobin. The most important physiologic alterations take place in the cardiovascular system. The heart rate and cardiac output increase. Circulation time, blood viscosity, peripheral resistance, and blood flow into the skin decrease. In time, the rate of ventilation may increase and the heart may enlarge. The effects of anemia on the cardiovascular system are exaggerated if there is coexisting heart disease.

Fatigue, listlessness, and irritability are common. Vertigo, headache, “spots before the eyes” (tychopsia), and tinnitus may be noted. Palpitations and dyspnea may occur. Although skin pallor has long been considered a hallmark of anemia, the marked variation in skin color and the fact that certain disorders, such as hypopituitarism and uremia, may produce pallor out of proportion to any degree of anemia make this an unreliable sign. Pallor of the mucous membranes is more reliable, but mild, moderate, and occasionally even profound anemia may be present with little recognizable alteration in the skin or mucous membranes. The blood pressure is slightly reduced or not altered. An important exception is vitamin B₁₂ deficiency (pernicious anemia), in which an impressive reduction in arterial pressure may be noted.

Tachypnea and tachycardia may be present. A variety of heart murmurs may be heard. These are most often blowing, systolic murmurs located primarily at the apex and along the left sternal border, but they may be rough and harsh and occur at other times

in the cardiac cycle to mimic the murmurs of valvular disease. This is particularly true in sickle cell disease.

The occurrence of symptoms attributable to anemia per se depends on the severity of anemia, the length of time anemia has been present, the rate at which anemia has developed, and the status of the cardiovascular system.

A remarkable degree of adaptation is possible, even to profound anemia. Just as mountaineers may function quite well at altitudes above 20,000 feet, individuals who are severely anemic with hemoglobin concentrations below 7 g per 100 ml may have very few symptoms and lead reasonably normal lives if the anemia has developed slowly. The sudden development of the same degree of anemia or a rapid ascent to an altitude of 20,000 feet would produce symptoms and might threaten the life of the individual.

Although one may suspect the diagnosis from a consideration of the constellation of historical and physical findings, examination of the blood is necessary in order to detect anemia or to acquire further information concerning the mechanism of its production.

Initial Laboratory Studies.  Every patient should have the following laboratory studies as part of an initial evaluation: hematocrit, white blood cell count, and examination of the stained blood film.

If anemia is detected, its cause may be suspected by characterizing the morphology of the red cells . One of the best ways to assess morphology is to examine carefully a stained smear of freshly shed blood (blood not mixed with an anticoagulant). Since almost any abnormality can be produced artifactually in the preparation of the smear, care must be taken to use clean coverslips or slides, to use just the right amount of blood, so that the smear is neither too thick nor too thin, and to draw the blood smoothly and evenly across the glass surfaces.

An estimate of the average size and hemoglobin concentration of the red cells may be made by calculation of the red cell indices . The mean corpuscular hemoglobin concentration (MCHC) is determined by dividing the hemoglobin concentration in g/100 ml by the hematocrit and multiplying by 100. A rapid estimate of the MCHC may be made by realizing that the hemoglobin concentration is normally one-third of the hematocrit and calculating appropriately. The red cells are either normochromic or liypochromic; hyperchromia does not occur.

The mean corpuscular volume in cubic microns (MCV) is determined by dividing the hematocrit by the red cell count in millions per mm³. Basically the red cell count is only reliable if measured by an electronic counter.

It is also helpful to determine whether there is variation in shape of the red cells since poikilocytosis indicates an abnormality in erythropoiesis or a fragmentation of the cells in the circulation. In addition certain abnormal cells such as spherocytes, sickle cells, and nucleated red cells may suggest specific diagnostic categories. Similarly evaluation of the number of platelets on the blood smear and the morphology of the white cells may contribute to an understanding of the cause of the anemia.

The initial evaluation of anemia should include a reticulocyte count, appropriately corrected, as a measure of effective erythropoiesis. A low, normal, or slightly elevated corrected reticulocyte count is indicative of an inability to increase erythropoiesis appropriately in response to anemia.

A bone marrow aspirate from the patient should be examined if there is reason to suspect a disorder in production of red cells or a disorder involving the presence of abnormal cells in the marrow (such as leukemic cells, myeloma cells, etc.). A biopsy of the marrow is more likely than an aspirate to identify tumor whose primary source is external to the marrow and provides a better estimate of cellularity.

Other studies which may be helpful in delineating the cause of anemia will be discussed in relation to specific disorders in subsequent diseases.

 

                                 Anemia

Anemia is a pathological condition characterized by decreased number of erythrocytes and/or haemoglobin content in a blood unit volume due to their general deficiency (Gk aot, haemia blood, i.e. deficient of blood).

Anemia should be differentiated from hydraemia (abnormally watery blood) in which the erythrocyte and haemoglobin are deficient as well, but not at the expense of their absolute reduction but due to dilution of blood in renal, cardiac and other oedema. Anemia should also be differentiated from oligohaemia, which is the reduction of the total volume of blood, e.g. immediately after a profuse haemorrhage. The total mass of circulating blood can be normal in Anemia (normovolaemia), increased (hypervolaemia) or decreased (oligohaemia or hypovolaemia). Thickening of blood in persistent vomiting and profuse diarrhea can mask Anemia because the total amount of plasma decreases and the number of erythrocytes and haemoglobin in a unit volume of the circulating blood can be normal or even increased.

Anemia is often characterized not only by quantitative changes in the red blood composition, but also qualitative changes in the structure of erythrocytes and haemoglobin molecules. These changes are important for the transport function of blood and tissue respiration, and can be the cause of additional pathological changes in the body. For example, a congenital defect of erythrocytes in some hereditary haemolytic Anemia may (due to their intense haemolysis) cause haemosiderosis of the internal organs, formation of pigment stones in the gall bladder, etc.

Anemia has a pronounced effect on the vital activity of the body. Anaemization causes oxygen hunger of organs and tissues (hypoxia) and their dystrophy. For example, if the blood haemoglobin content is halved (70—80 g/1), initial symptoms of myocardial dystrophy develop. If the haemoglobin content decreases to 50 g/1, the dystrophic changes become pronounced. Unoxidized products of metabolism (lactic acid, in the first instance) accumulate in the body due to hypoxia. The alkaline reserve of blood decreases. In grave cases, a tendency to acidosis develops which causes further dystrophy of tissues. Severe Anemias attended by marked disorders in tissue metabolism are incompatible with life.

Anemia of any origin is accompanied by some compensatory processes, which partly remove or lessen its consequences: (1) blood circulation is intensified, i.e. stroke and minute volumes increase, tachycardia develops, and the rate of blood flow increases; (2) blood distribution is altered, blood depots in the liver, spleen, and muscles are activated, and the blood supply to the peripheral tissues becomes limited at the expense of the increased blood supply to the vital organs; (3) oxygen utilization in tissues is intensified and the role of anaerobic processes in tissue respiration increases (anaerobic respiration with glutathione); (4) the erythropoietic function of bone marrow is stimulated. More than 50 types of Anemia are now differentiated.

According to their origin, the following types of Anemia are distinguished.

1.      Anemia due to loss of blood (acute and chronic).

2.      Anemia due to disordered haemopoiesis in deficiency of iron (necessary for the production of haemoglobin), in vitamin B₁₂ deficiency (necessary for normal erythropoiesis), in inhibition of the bone marrow by endogenous or exogenous toxicosis, radiation, or by some unknown factors, and also in cases where red bone marrow is replaced by other tissue, e.g. myeloma or multiple metastases.

3.      Anemia due to excessive haemolysis. This type of Anemia is subdivided into: (a) Anemia with prevalent extravascular (intracorpuscular) haemolysis of erythrocytes in macrophages of the spleen, and, to a lesser extent, in the bone marrow and liver. These are Anemia caused by hereditary morphological and functional erythrocyte deficiency (spherocytic and ovalocytic Anemia), and auto-immune haemolytic Anemia. They are all characterized by hyperbilirubinaemia and splenomegaly; (b) Anemia with intravascular, usually acute haemolysis (in various poisoning, transfusion of incompatible blood, cold and effort Anemia) attended by release into the plasma of unbound haemoglobin and by haemoglobinuria; haemosiderosis of the internal organs is observed also in chronic haemolysis (e.g. in Marchiafava-Micheli disease). This classification is only conventional because both intracorpuscular and vascular haemolysis can occur in one and the same form of haemolytic Anemia.

Haemolytic Anemia is also often subdivided as follows: (a) hereditary (congenital) Anemia, which includes membranopathy of erythrocytes (associated with abnormality of protein or lipid complexes of erythrocyte envelope, causing changes in their shape and premature decomposition; microspherocytic Anemia, ovalocytic Anemia, etc.); enzymopenic Anemia (due to deficiency of various enzyme systems of erythrocytes, which promotes their accelerated decomposition) and haemoglobinopathy in which the structure of haemoglobin or its synthesis are disturbed (sickle-cell Anemia, thalassaemia); (b) acquired Anemia (auto-immune haemolytic and iso-immune Anemia, and also Anemia caused by mechanical injury to erythrocytes, acquired membranopathies, toxic Anemia, etc.).

Apart from the pathogenetic classification, there are classifications based on other principles. Three groups of Anemia, for example, are distinguished in accordance with haemoglobin saturation of erythrocytes (by the colour index): normochromic (0.8-1.0), hypochromic (less than 0.8) and hyperchromic Anemia (more than 1.0). The group of hypochromic Anemia includes iron-deficiency Anemia: chronic (less acute) posthaemorrhagic Anemia, gastrogenic iron-deficiency Anemia, and juvenile chlorosis. Hyperchromic Anemia is caused by the deficiency of vitamin B_12. This is Addison-Biermer Anemia, bothriocephalus Anemia, and also achrestic Anemia (due to defective utilization of vitamin B₁₂). Other Anemias proceed without considerable changes in the colour index of blood and are therefore normochromic.

It is very important to assess the regenerative capacity of the bone marrow upon which (to a certain degree) depend treatment and prognosis of the diseases. Distinguished are regenerative Anemia, i.e. Anemia in which the bone marrow preserves its capacity to produce new erythrocytes; hyporegenerative Anemia, in which this capacity is impaired; and aregenerative or aplastic Anemia, in which bone marrow function is completely or almost completely lost. The regenerative function of the bone marrow is assessed by the rate at which the quantity of reticulocytes increases in the peripheral blood and by the proportion of the erythro- and leucoblastic elements in the sternal punctate. Their normal ratio is 1:3 or 1:4, while in regenerative Anemia, in which erythropoiesis dominates in the compensatory function of the bone marrow, this ratio becomes 1:1,2:1 and even higher. This shift is absent in hypo- or aregenerative Anemia, while the reticulocyte content of the peripheral blood is low.

ACUTE POSTHAEMORRHAGIC ANEMIA

Anemia caused by an acute blood loss (acute posthaemorrhagic Anemia) occurs mostly in various injuries associated with traumatized large vessels (extrauterine pregnancy, delayed placental detachment during labour, etc.). Acute posthaemorrhagic Anemia occurs in diseases that can be attended by profuse bleeding, e.g. in gastric and duodenal ulcer, degrading tumour of the stomach, kidneys, or the lung, in tuberculosis and abscess of the lung, bronchiectasis, varicose dilation of the oesophageal veins in liver cirrhosis, haemorrhagic diathesis, and especially in haemophilia.

Clinical picture. In cases with external haemorrhage, the physician can often locate the source of bleeding at first sight (e.g. in injury). The patient’s grave condition can in these cases is directly attributed to profuse blood loss. Haemorrhage from the internal organs can be manifested by blood vomiting (unaltered blood originates from the oesophagus; brown blood from the stomach), by expectoration of blood (scarlet foaming liquid), by the presence of blood in faeces (melaena in haemorrhage from the stomach or the small intestine; dark or scarlet blood originates from the large intestine, especially from its terminal part) and by blood presence in the urine (haematuria). It should be remembered that in gastro-intestinal haemorrhage, the blood could only be discharged into the environment in a certain lapse of time (with the vomit or excretions). Moreover, haemorrhage caused by the rupture of the spleen, liver, or by the internal injury to the chest can be difficult to establish because blood will accumulate in the abdominal or pleural cavity.

The first sign of a sudden haemorrhage is the feeling of weakness, dizziness, noise in the ears, palpitation of the heart, nausea, and in rare cases vomiturition. In severe cases with profuse blood loss, the patient is in the state of shock (if the bleeding is caused by an injury) or collapse (if haemorrhage is due to affection of the internal organs). The patient’s condition depends not only on the amount of blood loss, but also on the rate at which blood is lost. Inspection reveals pronounced and in some cases deadly pallidness; the skin is covered with sticky cold sweat, the skin temperature is subnormal. Respiration is superficial and accelerated. The pulse is fast, small, and (in severe cases) thready. Arterial pressure (both systolic and diastolic) is low. Auscultation of the heart reveals marked tachycardia.

The pathological and compensatory changes in acute blood loss with benign outcome can be divided into three stages (or phases). First oligohaemia develops. It causes a reflex spasm of the vessels to decrease the volume of the vascular system and to recover blood from its reserves (depots). For this reason, the blood haemoglobin and erythrocyte content may remaiormal within the first hours (or even within 1 or 1.5 days) following the blood loss. Tissue fluids are drawn into the vessels to cause hydraemia in 2 or 3 days: the erythrocyte and haemoglobin content in unit volume decreases. Signs of marked activation of erythropoiesis appear on the third to seventh day. Anemia becomes hypochromic in the loss of considerable amount of blood due to exhaustion of the iron store.

Treatment. Bleeding should be arrested as soon as possible by placing a tourniquet or by a tamponade of the external haemorrhages in wounds. Surgical intervention is indicated in continuing haemorrhage from the internal organs. Measures to prevent shock or collapse should also be taken. Blood loss should be compensated for by infusion of whole blood or its substitutes; cardiac and vascular medicinal preparations should be administered. Iron preparations should be given to patients with profuse blood loss in several days after the haemorrhage has been arrested.

IRON DEFICIENCY ANEMIA                             

Iron deficiency Anemia (Anemia sideropriva gastroenterogenica) arises in the deficit of iron, which is necessary for the production of haemoglobin in erythrocytes. This type of Anemia develops in patients with decreased iron absorption due to resection of the stomach (“agastric-Anemia”), removal of a considerable part of the small intestine, especially of its proximal part, in intestinal diseases attended by abnormal absorption, and in the iron deficit in food. The latter occurs mostly in children with prolonged milk diet and copper deficit. Increased iron demands occur during intense growth of the body. During establishment of the menstrual cycle in young girls (menstrual loss of blood and iron ions) juvenile iron deficiency Anemia (juvenile chlorosis) may develop. Chronic haemorrhage also causes iron deficiency Anemia.

Repeated (not profuse) loss of blood cause anaemization due to exhaustion of the iron store, which is necessary for the production of haemoglobin in erythrocytes. Daily intake of iron with food is small, about 11—28 mg, and one fourth of this quantity is only absorbed. This is equivalent to the iron content of 15 ml of blood. Daily loss of 15 ml (or even smaller amount) of blood therefore inevitably exhausts the iron store to cause iron deficiency Anemia.

Chronic blood loss and chronic posthaemorrhagic Anemia attends many diseases of the internal organs, and in the first instance, of the gastro-intestinal tract. In most cases these are gastric or duodenal ulcer, cancer, polyposis of the stomach and intestine, haemorrhoids, and certain types of helminthiasis. Chronic posthaemorrhagic Anemia often occurs in tumours of the kidneys, cavernous tuberculosis of the lungs, and in uterine haemorrhage.

Some other factors promote Anemia. These are mainly those factors which can decrease the iron stores of the body. For example, patients with secondary gastric hyposecretion and enteritis develop Anemia sooner and it runs a more severe course in the presence of even insignificant chronic haemorrhage. Gravity of chronic posthaemorrhagic Anemia arising in patients with degrading tumours of the gastro-intestinal tract, kidney, or the uterus, is intensified by the toxic effect of the tumour on the haemopoiesis and by multiple metastases into the bone marrow, etc. Hydrochloric acid of the gastric juice promotes reduction of trivalent iron to its divalent form, which is easier assimilated. But recent studies show that hydrochloric acid does not play a decisive role in activation of iron absorption.

In the absence of adequate iron supply to the body or its utilization from the store, the synthesis of haemoglobin, myoglobin, and iron-containing enzymes of various cells involved in the oxidation processes is upset. This impairs nutrition of tissues and accounts for the development of many symptoms of the disease. The clinical picture of iron deficiency Anemia is explained by insufficient oxygen transport to tissues due to Anemia on the one hand, and by disordered cell respiration on the other.

Clinical picture. Slow development (within months and years) of iron deficiency Anemia accounts for actuation of the compensatory mechanisms. Most patients therefore are well adapted to the disease and can satisfactorily stand even significant Anemia.

We shall not discuss patient’s complaints associated with the main disease, to which Anemia is secondary (e.g. the cause of chronic haemorrhage). The specific complaints of anaemic patients will only be emphasized: weakness, dizziness, dyspnoea (especially exertional), increased fatigue, noise in the ears, and fainting. Many patients develop various dyspeptic symptoms: decreased appetite, perverted taste, slight nausea, heaviness in the epigastrium after meals, and regurgitation. Diarrhoea is also frequent. Slight paraesthesia (tingling and pricking) is possible. Excruciating dysphagia sometimes develops during swallowing dry or solid food in especially severe cases. This sideropenic dysphagia was first described by Rossolimo and Bekhterev in 1900-1901. Later this syndrome was described by Plummer and Vinson. The dysphagia is explained by extension of the atrophic process from the stomach onto the oesophageal mucosa, and sometimes by its development in the proximal part of the soft connective tissue membranes and bridges.

Inspection of the patient reveals pallor. Certain trophic changes in the skin, its appendages, and mucosa can be due to the general iron deficit. The skin is dry and sometimes slightly scaling. The hair is brittle, early gray, and showing the tendency to falling. The nails become flat, sometimes spoon-like, opaque, marked by transverse folds, and brittle (koilonychia). The mouth angles often have fissures (angular stomatitis), the papillae of the tongue are levelled (atrophic glossitis). The teeth lose their luster and quickly decompose despite a thorough care. If iron preparations are taken for a long time, the teeth may blacken due to formation of black iron sulphite (by the reaction of iron with hydrogen sulphide which is liberated by the carious teeth). Purulent inflammation of the gum mucosa around the tooth necks develops (alveolar pyorrhoea).

Physical examination can reveal a slight indistinct enlargement of the left ventricle, systolic murmur at the heart apex, and nun’s murmur over the jugular vein (mostly on the right). Lymph nodes, liver and spleen are not enlarged.

Study of the blood reveals decreased erythrocyte and even more decreased haemoglobin content of the blood. The colour index is less than 0.85; in grave cases it is 0.6—0.5, and even lower. Microscopy of blood reveals pallid erythrocytes (hypochromia), anisocytosis, and poikilocytosis. The average diameter of erythrocytes is less thaormal (microcytosis). The number of reticulocytes is small. Anemia is usually attended by thrombocytoleukopenia, sometimes relative monocytosis, lymphocytosis, and eosinopenia. The iron content of the serum is decreased (1.5-2.5 times and more). The percentage of transferrin saturation also decreases (below 15).

Decreased activity of the iron-containing enzymes of tissue respiration provokes (or intensifies) atrophy of the gastro-intestinal mucosa. The study of gastric juice reveals in most cases achlorhydria or even achylia; the total amount of the excreted juice is much decreased. X-rays reveal levelled folds of the oesophageal and gastric mucosa. Oesophagoscopy and gastroscopy confirm atrophy of the oesophageal and gastric mucosa.

Course. The course of the disease is chronic and gradually progressive if

iron deficit in the body increases.

Treatment. Iron preparations (haemostimulin, etc.) are given. If the patient has gastritis or peptic ulcer, the iron preparations should better be given intramuscularly or intravenously (ferbitol, fercoven, etc.). The therapy gives a comparatively rapid and permanent effect: work capacity is rapidly restored, erythrocyte and haemoglobin of blood normalize in 3-5 weeks. The patient should however be regularly (several times a year) given prophylactic courses of therapy with iron preparations in order to prevent possible relapses of the disease. The diet of patients with iron deficiency Anemia should be rich in iron salts, e.g. liver, meat, eggs, apples, dried fruits. Efficacy of treatment of Anemia caused by chronic loss of blood depends on removal of the source of blood loss.

VITAMIN B₁₂ (FOLIC ACID) DEFICIENCY ANEMIA

Aetiology and pathogenesis. Vitamin B₁₂  (folic acid) deficiency Anemia was first described by Addison in 1855. One of its forms was later given the name of Addison-Biermer Anemia. In 1868, Biermer published a more detailed description of the disease, which he called pernicious or malignant Anemia, because its prognosis was then grave and patients usually died in a few months or years after the appearance of the first symptoms.

The disease was effectively treated for the first time by Minot and Murphy (1926). The patients were given raw calf liver in large amounts every day. Minot and Murphy noted that distinct remissions followed in patients who were given this diet and conjectured that raw liver contained a certain substance which is necessary for normal haemopoiesis, and whose absence or deficit causes pernicious Anemia. The next stage in the study of this disease is connected with experiments carried out by Castle (1929). He noted that meat treated with gastric juice (containing various amounts of hydrochloric acid) produces an anti-anaemic effect when administered into the stomach of patients with the Addison-Biermer Anemia. Gastric juice alone, untreated meat, or meat treated with gastric juice of patients with the Addison-Biermer Anemia have no anti-anaemic effect. Castle suggested that a special substance, haemopoietin, was necessary for normal maturation of erythrocytes. Haemopoietin is produced by combination of a certain extrinsic factor supplied with food and the intrinsic factor contained iormal gastric juice.

At the present time, Castle’s conjecture concerning the pathogenesis of Addison-Biermer Anemia has been proved experimentally and clinically. The extrinsic and intrinsic factors and their biological role have been studied sufficiently well. The factor is vitamin B₁₂ (cyanocobalamin) discovered by Smith in 1948 which is contained in calf liver, kidneys, meat, eggs, and gastromucoprotein produced by the accessory cells of the glands found in the fundus of the stomach. In healthy subjects, vitamin B₁₂ combines with gastromucoprotein in the stomach to give a sufficiently stable complex which protects vitamin B₁₂ from intestinal microflora to ensure adequate absorption of vitamin B₁₂ (mainly in the ileum). Gastromucoprotein is absent from the gastric juice of patients with the Addison-Biermer Anemia due to pronounced atrophic gastritis. In the absence of gastromucoprotein, vitamin B₁₂ delivered with food is decomposed by intestinal flora and is not assimilated by the body to cause vitamin B₁₂ deficit. In other cases, vitamin B₁₂ (folic acid) deficiency Anemia is the result of vast resection of the stomach, severe enteritis, increased demands for vitamin B₁₂ in pregnancy, its consumption by helminths (bothriocephaliasis), and in disordered assimilation of this vitamin by the bone marrow (achrestic Anemia).

An important biological effect of vitamin B₁₂ is activation of folic acid. Like vitamin B₁₂, folic acid belongs to substances included in the group of vitamin B. It is contained in leaves of various plants, fresh vegetables, beans, liver, and kidneys of animals. Folic acid is deposited in the human body mainly in the liver, where it is present in inactive state. Vitamin B₁₂ promotes formation of folic acid derivatives, folates, which are probably the factor necessary for haemopoiesis in the bone marrow. In conditions associated with vitamin B₁₂ and folate deficiency, the synthesis of DNA is disordered; this in turn causes disorders in cell division; the cells become large and qualitatively inadequate. Erythroblasts are affected most severely: large cells of embryonal haemopoiesis, megaloblasts, are found in the bone marrow instead of erythroblasts. They are not only larger than erythroblasts; they also differ in the structure of their nuclei and protoplasm, earlier and more intense saturation with haemoglobin during their differentiation (at the stage of reticular structure of the nucleus), retarded mitotic division, and mainly in their inability to grow to normal erythrocytes. Most megaloblasts are decomposed in the bone marrow before they reach the stage of a nucleated cell. Only a small quantity of megaloblasts is differentiated to anuclear cells (megalocytes) and enter the blood vessels. Megalocytes are larger and more saturated with haemoglobin than erythrocytes and differ from them by morphological and functional inadequacy. Megalocytes have no such high oxygen-transport capacity as the erythrocytes and are quickly decomposed by reticuloendothelial cells: the average life of megalocytes is about three times shorter than of erythrocytes.

The absence of gastromucoprotein in gastric juice (like achlorhydria which usually attends this disease) is due to atrophy of the gastric mucosa. Some investigators believe that atrophy of gastric mucosa is not inflammatory in its origin as it was believed earlier (atrophic gastritis) but is a result of congenital insufficiency of its glandular apparatus, which is manifested with time. In the opinion of other authors, the atrophy of gastric mucosa is caused by antibodies produced by the patient’s body to the gastric glandular cells, which can however be slightly altered by toxic effects or inflammation (auto-immune mechanism).

If the second coenzyme of vitamin B₁₂ desoxyadenosylcobalamin, is deficient, fat metabolism becomes upset with accumulation of methylmalonic acid, which is toxic for the nervous system (provokes funicular myelosis).

The Addison-Biermer Anemia attacks commonly the aged; the incidence among women is higher than in men.

Clinical picture. The onset of the disease is insidious. The patient grows weaker, he complains of heart palpitation, dizziness, and dyspnoea, especially during exercise or brisk movements; the work capacity is impaired, the appetite becomes poor; slight nausea is possible. The first complaint is often the burning sensation in the tongue. This is explained by the

development of atrophic glossitis (see below) which usually attends this disease. The patient often develops achylic diarrhoea or, on the contrary persistent constipations. Dystrophic changes in the nervous system cause skin anaesthesia and paraesthesia; the gait is often affected in grave cases: spastic paresis develops (incomplete spastic paralysis of the lower extremities); the knee reflex disappears, the function of the urinary bladder and the rectum can also be affected. All these symptoms are known as the funicular myelosis, which develops due to the predominant affection of the lateral spinal columns. Symptoms of the disordered activity of the central nervous system (deranged sleep, emotional lability, etc.) become apparent.

Inspection of the patient reveals pallor of the skin and mucosa, usually with a yellowish tint due to increased decomposition of megalocytes and formation of bilirubin from the released haemoglobin, and a slight swelling of the face. The patient is not thin. Quite the reverse: most patients are well fed. The bright-red smooth and glossy tongue (because of the pronounced atrophy of the papillae) is quite characteristic of the Addison-Biermer Anemia. This symptom is known as Hunter’s glossitis (W. Hunter was the first to describe this symptom). The mouth mucosa and the posterior wall of the throat are also atrophied. The tip and edges of the tongue, and also the mouth mucosa can be ulcerated. The tendency to caries is often seen in the teeth.

Pressing or tapping on the flat and some tubular bones (especially the tibia) is often painful. This is the sign of bone marrow hyperplasia. Palpation can reveal a slight enlargement of the liver and the spleen.

The cardiovascular system is usually involved as well. The left border of the heart is displaced to the left, tachycardia develops, “anaemic” systolic murmur is heard at the heart apex in 75 per cent of cases; the nun’s murmur is often heard over the jugular veins. The pulse is soft and accelerated. Most patients develop hypotension. ECG shows a certain decrease in the general voltage, the decreased T wave and the S-T interval.

Changes in the gastro-intestinal tract are pronounced. Especially characteristic is atrophy of gastric mucosa which can be revealed by X-ray examination, and more distinctly by gastroscopy. The atrophy is often focal, and the affected sites (mostly in the fundus of the stomach) can be seen as iridescent spots. Atrophy can combine with polyps in the folds of gastric mucosa and its polypous thickening. It should be remembered that Anemia, including pernicious Anemia, can be a symptom of a malignant tumour in the stomach. Cancer of the stomach occurs in patients with the Addison-Biermer Anemia 8 times more frequently than in healthy persons. Patients with this disease should therefore be systematically inspected by X-rays (by gastroscopy whenever possible). Almost all patients develop achlorhydria. In 98 per cent of cases it has the histamine-resistant character. The total amount of juice produced during the study is usually significantly diminished; the pepsin content of the juice is very low or it cannot be determined at all (achylia). Usually achlorhydria develops many years before the first symptoms of Anemia develop,

Elevated temperature is a common symptom of vitamin B₁₂ (folic acid) deficiency Anemia; the temperature is usually subfebrile.

Blood plasma contains slightly increased amounts of free bilirubin due to increased haemolysis of the red cells, especially megalocytes; the plasma iron content increased to 30-45 mmol/1 (170-200 mg/ml).

The blood picture is characterized by a sharp decrease in the quantity of erythrocytes (to 0.80 x 10¹² per 1 l) at a comparatively high haemoglobin saturation. Despite the decreased total haemoglobin content of the blood, the colour index remains high (1.2-1.5). Red blood cells differ in size (anisocytosis), with prevalence of large erythrocytes (macrocytes). Especially large slightly oval and intensely red megalocytes appear (in many cases megaloblasts are also seen). The volume of each cell increases. Many erythrocytes are oval, or they have the shape of a sickle and other shapes (poikilocytosis). Megalocytes often have remnants of the nucleus or its envelope in the form of Jolly bodies or Cabot rings. The content of reticulocytes is not high. The number of reticulocytes sharply increases (reticulocytic crisis) during vitamin B₁₂ therapy to indicate the beginning remission. Blood leucocytes decrease mostly at the expense of neutrophils. Eosinopenia, relative lymphocytosis, and thrombocytopenia are observed. Large neutrophils with poly segmented nuclei also occur.

The quality of erythroid precursors in a specimen of bone marrow sharply increases, by 3-4 times compared with the number of leucopoietic cells (the proportion being reverse in physiological conditions). Megaloblasts are observed in varying amounts among the erythroid precursors; in grave cases they are found in prevailing quantity. Both erythropoiesis and leucopoiesis are disordered. Megakaryocytes are also large, with a multi-lobed nucleus: thrombocyte separation is disordered.

Course. If untreated, the disease progresses. Before Minot and Murphy proposed their effective treatment of the disease, patients rarely survived more than 3 years. At the terminal period, many patients developed coma (coma perniciosum) with loss of consciousness, arephlexia, decreased arterial pressure and temperature, vomiting and involuntary urination.

At the present time the patient recovers from the Addison-Biermer Anemia if treated properly and if adequate prophylactic measures against relapses of the disease are taken.

Treatment. Vitamin B₁₂ is given. In most cases treatment begins with moderate doses of the vitamin (100-300 mg) which is given once a day intramuscularly or subcutaneously. Considerable shifts in the bone marrow punctate toward normalization of erythropoiesis are observed already in 24 hours after the first dose of the vitamin is given. Cells produced by division and differentiation of juvenile forms are very much like the cells produced at the corresponding stages of normal erythropoiesis. Erythropoiesis normalizes completely in 2 or 3 days. In 5 to 6 days of the therapy, the newly formed erythrocytes enter the blood vessels in considerable amounts: the reticulocytic crisis occurs. The number of reticulocytes in the peripheral blood increases to 20-30 per cent and then gradually decreases. General weakness lessens, work capacity is regained, and gastric secretioormalizes in certain cases.

Signs of funicular myelosis are eliminated much slower and do not always disappear completely. After the blood picture normalizes and the symptoms of the disease markedly subside, the patient is given maintenance therapy with small doses of vitamin B₁₂ (100 mg weekly, or 2-3 times a month). This therapy should be maintained for the rest of the patient’s life. Clinical blood counts should be done periodically. The treatment ensures adequate subjective condition of the patient, his work capacity is regained, and relapses of the disease are prevented.

AUTO-IMMUNE HAEMOLYTIC ANEMIA

Aetiology and pathogenesis. The pathogenesis of acquired auto-immune haemolytic Anemia (Anemia haemolytica chronica) is underlain mainly by the immunopathological shifts, which are manifested by the production of antibodies to own erythrocytes (autoagglutinins). This condition may be caused by acute infections, poisoning, medicamentous intoxications, especially severe forms of malignant lymphomas and collagenosis, and by some other factors. These antibodies belong to the immunoglobulin fraction and are incomplete or “weak” antibodies. Erythrocyte-bound antibodies do not cause agglutination in the blood vessels but block erythrocytes to promote their deposition in the reticulohistiocytic system (mostly in the venous sinuses of the spleen) and their capture and destruction by macrophages.

Sometimes auto-immune haemolytic Anemia is associated with the appearance of cold an-tibodies which are bound (together with the complement) to erythrocytes. Their action is manifested in the peripheral parts of the body (finger tips, ears) in overcooling. In addition to auto-agglutinins, autohaemolysins are also found in some patients. The disease may proceed in them with signs of both extra- and intravascular haemolysis.

Clinical picture. The disease develops either gradually and incidiously or acutely with a haemolytic crisis. The main complaints of the patient are weakness, dizziness, fatigue, and slightly elevated temperature. All these symptoms intensify during the haemolytic crises. Skin itching is absent. The skin is pallid with a slightly icteric hue. Applying pressure to the sternum and its percussion are painful. Palpation reveals enlarged and consolidated spleen; the liver is enlarged only slightly.

The blood erythrocyte and haemoglobin content is low, while the colour index remains normal. Erythrocytes vary in size, shape, and colour (poikilocytosis, anisocytosis, anisochromia). The average size of the erythrocytes is slightly smaller thaormal (microcytosis). As distinct from congenital haemolytic Anemia, the erythrocytes of healthy individuals, as well as of patients with acquired Anemia, are less intensely coloured in the centre than by the periphery, which depends on their form (planocytes). The number of reticulocytes is high; reticulocytosis is especially marked in considerable anaemization and after the haemolytic crisis. The osmotic resistance of erythrocytes is not substantially changed. The blood serum of patients is yellowish. Study of the blood confirms increased content of unbound bilirubin on which the colour depends. Hypergammaglobulinaemia is also determined. The iron content of the serum is increased. Iron is liberated in large amounts during haemolysis of erythrocytes. Owing to increased liberation of bilirubin, bile obtained by duodenal probing is very dark. The urine and faeces of the patient are darker thaormal; daily excretion of stercobilin with faeces and of urobilin with urine is increased. Study of specimens of bone marrow indicates more or less significant intensification of erythropoiesis.

Both cell-bound (blocking) antibodies and those found in the free state in the plasma (con-glutinins) are revealed in the blood of patients with auto-immune haemolytic Anemia. Coombs’ test is used to reveal them. A direct Coombs’ test is used to reveal cell-bound (blocking) antibodies. A suspension of the patient’s erythrocytes washed in isotonic sodium chloride solution is added to the serum of a rabbit immunized by human blood globulins. Erythrocytes agglutinate if anti-erythrocytic antibodies are present on their surface. Erythrocytes of individuals without acquired haemolytic Anemia are not agglutinated. Conglutinins in the serum of patients are revealed by adding erythrocytes of a healthy individual (donor) in order to absorb the antibodies on them. The cells are washed and carried through the test as described above. This is the indirect Coombs’s test.

Course. The course of the disease is usually undulant. The disease is exacerbated by infections, big doses of some medicines, e.g. salicylates, and by some other transient factors. In grave and long-standing cases, the patient’s bone marrow may be exhausted and Anemia becomes hyporegenerative. In some cases the activity of the bone marrow may also be inhibited by the production of auto-antibodies to erythroblastic precursors. Formation of the pigment stones in the gall bladder is a complication of the disease. Thrombophlebitis, and thrombosis of the splenic vein are other possible complications.

Treatment. Corticosteroids inhibit the production of antierythrocytic auto-antibodies. Blood transfusion should be carried out in rare cases because it can markedly enhance haemolysis.

Haemoblastosis

Haemoblastosis is proliferation of the haemopoietic tissue; it can be diffuse and focal.

Haemoblastosis is a disease of the whole blood system characterized by (1) progressive cell hyperplasia in the haemopoietic organs with  pronounced prevalence of proliferation of certain cells (which determine the morphological essence of the disease in each particular case) over their differentiation (maturation), and the loss of their typical morphological and functional properties; (2) substitution (metaplasia) of these pathological cells for normal cells of the haemopoietic organs; (3) development of pathological foci of haemopoiesis in various organs.

Haemoblastosis is a comparatively rare disease. Its mortality rate is 1.7—8.1 per 100 000 population. The share of leucosis among therapeutic cases is 1.5—2.6 per cent. However the incidence of haemoblastosis especially of acute forms, has recently increased in all countries.

Aetiology and pathogenesis. Most authors regard haemoblastosis as tumours whose morphological basis are haemopoietic cells of various organs. This has been proved by numerous observations and experiments. For example, some factors can provoke the growth of tumours and haemoblastosis. These factors are cancerogenic substances (3,4-benzpyrene, methylcholanthrene, etc.) and radiation. There are common features in the character of tissue proliferation in haemoblastosis and tumours. Metabolic disorders in haemoblastosis-affected cells and tumour cells have been proved to be of the same type (anaerobic glycogenolysis prevails in them). Concurrence of haemoblastosis and tumour is not infrequent. Administration of an extract of tumour tissue to experimental animals causes haemoblastosis in some of them; and vice versa, administration of the bone marrow or lymph node punctates of haemoblastosis patients may provoke the growth of tumours.

There are two main theories explaining the aetiology of haemoblastosis and tumours. These are the virus and the genetic theory. At the present time more than 20 viruses have been isolated that can cause haemoblastosis  in animals. Attempts at isolating the virus of the main forms of haemoblastosis in man end in failure. According to the genetic theory, haemoblastosis develops due to the congenital or acquired damage to the chromosome structures of low differentiated cells of the haemopoietic organs. A clone theory has been launched recently, according to which haemoblastosis arises due to primary chromosome mutation in one of the haemopoietic cells with its subsequent multiplication and formation of a clone of blast cells.

Nomenclature and classification of haemoblastosis. All types of haemoblastosis are designated in accordance with the name of cells which determine the cytomorphological essence of the disease. For example, acute myeloblastic leucosis, chronic erythromyelosis, lymphoid leucosis, etc. The traditional names of certain types of haemoblastosis describe the major syndrome of the disease, e.g. osteomyelosclerosis, macroglobulinaemic haemoblastosis, etc. Certain types of haemoblastosis have a second name (the name of the author who was the first to study or describe the disease), e.g. Waldenstrom disease, Cesaris disease, etc. Like other tumours, haemoblastoses can be benign and malignant.

More than 30 forms of haemoblastosis have been well studied. Recent advances in haematology have made it possible to improve the classification of the diseases.

The following two groups of haemoblastosis are distinguished: leucosis and haematosarcoma (malignant lymphoma).

Leucosis is the disease of the haemopoietic cells with the primary locus of the tumour in the bone marrow. The release of tumour (leucosis) cells into the blood cause leukaemia as a symptom of the disease. The following forms of leucosis are distinguished.

1. Acute leucosis in which haemopoiesis is transformed at the expense of low differentiated blast cells or precursor cells of the 3rd and even 2nd series. Haemocytoblastosis is now absent from the modern classification because it has been proved that the “youngest” cell of haemopoiesis is not the haemocytoblast but three consecutive series of precursor cells. Various forms of acute leucosis are differentiated mainly by the cytochemical characteristics of leukaemic cells. In adult patients, acute myeloblastic leucosis occurs in 60 per cent and lymphoblastic leucosis in 25-30 per cent of cases. Other forms occur less frequently.

2. Chronic leucosis, in which haemopoiesis is transformed at the expense of more mature cells of differentiated haemopoiesis. Separate forms are differentiated quite easily by cytomorphological signs of leukaemic cells: chronic myeloid leucosis, chronic lymphoid leucosis, chronic erythromyelosis, erythraemia, etc.

It should be remembered that differentiation between acute and chronic leucosis first of all depends on the cytomorphological sign (the degree of cell maturity) rather than on the clinical course of the disease, although both these signs coincide in most cases. Acute leucosis may continue for a year or even longer, while a patient with chronic leucosis may die within a few months. Therefore, the diagnosis, in addition to the definition of the type of leucosis (acute, chronic), should also determine its course. It is also important to remember that acute leucosis almost never transforms into the chronic form because it is characterized by anaplasia (the cells lose ability to further maturation) of the initial elements of haemopoiesis. Quite the reverse, chronic leucosis can be exacerbated with formation of nondifferentiated elements (blasts) in the foci of haemopoiesis and in the peripheral blood. Exacerbations may be spontaneous or provoked by some causes of progressive anaplasia of leukaemic cells. Chronic leucosis in the stage of blast crisis is similar to acute leucosis.

Leucosis can have the following three variants: with considerable increase in the quantity of pathological cells in the peripheral blood {leukaemic form), with moderate increase in their number (subleukaemic form), and without appreciable leukaemic shift in the presence of normal or decreased quantity of white blood elements ((aleukaemic form).

Leukaemic forms of leucosis are sometimes difficult to differentiate from leukaemoid reactions (extreme leucocytosis to 0.1 x 10¹² per 1 L of blood) which are observed in some infectious diseases. In leukaemoid reactions, the leucocyte counts can be shifted to the left, to myeloblasts. But this leucocytosis in leukaemoid reactions is characterized by its potential reversibility (provided the causes are removed) and by preservation of the functional and morphological properties of leucocytes. Although leukaemic cells are called normal haemopoietic cells, in fact they cannot perform their usual function, and patients with leucosis have decreased immunity. The cells cannot differentiate into more mature cells; they decompose at a quicker rate. It has been established that leukaemic cells have an inhibiting effect oormal haemopoiesis.

Leucosis is characterized by lability, pronounced ability to transformation with exacerbation of the process (with the progress of anaplasia to less differentiated cells) and with involvement of other haemopoietic cells. Moreover, both morphological and clinical changeability of the process are characteristic. In some cases more or less long remissions can occur spontaneously or under certain effects (infectious disease, treatment). Remissions are then followed by exacerbations (to blast crisis).

Each type of leucosis is a static expression of the specific features of clinico-cytomorphological picture of the diseases and at the same time can also include certain elements of the dynamic process. This should be taken into consideration during establishing a diagnosis and in prescribing the appropriate therapy.

Haematosarcoma (malignant lymphoma, or regional tumours with their possible generalization) is also a tumour of haemopoietic cells but its localization is mostly extra-marrow and focal. Lymphogranulomatosis is the most common haemoblastosis. Paraproteinaemic haemoblastosis (mutliple myeloma, Waldenstrom’s disease) is a special form arising from precursors of B-lymphocytes and characterized by production of pathological globulins. Reticulosarcoma and some other diseases are also special forms of paraproteinaemic haemoblastosis.

Leucosis can also transform into some types of malignant lymphomas, except lymphogranulomatosis. The reverse process is also possible: ample leukaemic cells appear in the blood and bone marrow in malignant lymphomas, i.e. the blood picture and the course of the disease are similar to those observed in leucosis.

                        ACUTE LEUCOSIS

Acute leucosis is characterized by profuse proliferation of the youngest (blast) elements of blood with their subsequent disturbed differentiation and also with development of foci of pathological haemopoiesis in various organs. Lympho- and myeloblastic forms of the disease are common.

Acute leucosis occurs at any age, but men and women from 20 to 30 are mostly affected.

Clinical picture. The onset of the disease is in most cases acute or subacute: high temperature (remittent or hectic), profuse sweating, chills, pronounced weakness, pain in the bones, and other general symptoms resembling those of acute septic affections. Pain in the throat is often one of the first complaints: swallowing becomes painful because of necrotic ulceration of the throat and fauces. For this reason the disease is often mistaken for necrotic tonsillitis and only further observation of the patient and the study of the bone marrow and blood help the physician establish a correct diagnosis. Fever, chills and sweating, which are so characteristic of acute leucosis, are explained by the pyrogenic effect of purines released in great quantity during the decomposition of immature leucocytes. Fever can also be caused by secondary infections; despite the markedly increased production of white blood cells, their function is inadequate, and resistance of leucosis patients to various infections decreases.

In some cases the onset of the disease is gradual, with non-pronounced general symptoms: slight weakness, disposition, rapid fatigue, and subfebrility. The condition then worsens and a complete clinical picture of the disease develops. Anaemia and various haemorrhagic complications and secondary infection develop.

Inspection of the patient usually reveals grave condition from the very onset of the disease. In the terminal period the condition is particularly grave: the patient is passive, answers the doctor’s questions with difficulty, or is unconscious. The skin is pallid, sometimes with yellowish or greyish hue, and moist; its turgor is decreased. Traces of subcutaneous and intracutaneous haemorrhages can be seen. The tourniquet and the pinch tests are positive; hemorrhage is considerable at points of injections. Necrosis and bed-sores are possible. Necrosis of the mucosa, especially of the mouth and throat, is especially pronounced. Ulcerous and necrotic tonsillitis, gingivitis, and stomatitis are quite characteristic of the disease. Necrotized surfaces are covered with a poorly removable grey or yellowish coat. When removed, it reveals bleeding ulcers. The breath of the patient is putrefactive. Palpation reveals enlargement of separate groups of the lymph nodes, spleen, and the liver. The heart borders are broadened; tachycardia, systolic murmur at the heart apex (due to dystrophic processes in the heart muscle), and anaemia are revealed. Pericarditis and pleuritis are possible. Each haematological form of leucosis is characterized (though not necessarily) by some special clinical features.

The blood of patients contains increased number of white blood cells:

to 1 x 10¹¹ and even 2 x 10¹¹ per 1 L (in rare cases even this figure may be exceeded). Subleukaemic forms of the disease can occur. Leucopenia can develop in some cases at the early stage of acute leucosis. Leucopenia is then succeeded by leucocytosis. The most specific haematological sign of the disease is the presence of blast cells in the peripheral blood. All blast cells are similar morphologically but special cytochemical reactions can be used to differentiate between them. Prevalence of their certain forms is determined by the haematological variant of leucosis (acute lymphoblastic, acute myeloblastic, acute monoblastic leucosis, etc.). The immature forms may amount to as high as 95 and even 99 per cent. Leukaemic cells often have some specific defects in their nuclear and cytoplasmic structure. Only the youngest and the most mature cells can be revealed in the blood of most patients with acute leucosis, while intermediate forms are absent (hiatus leucaemicus). Eosinophils and basophils are absent; other cell forms are decreased significantly not only relatively but also absolutely. Thrombocytopenia and anaemia are observed which can be explained by the displacement of megakariocytes and erythroblasts from the bone marrow by vigorously proliferating blast cells and also by the prevalent development in the direction of leucopoiesis. Anaemia may intensify due to haemorrhage (characteristic of this disease) and also due to the intensified haemolysis of erythrocytes. Coagulability of blood and the bleeding time are abnormal in most cases; ESR sharply increases.

The bone marrow punctate contains 80-90 per cent of leukaemic blast cells, which displace all other cell elements.

Course. The course of the disease is progressive. Prognosis is unfavourable. The average life expectancy of patients with acute leucosis is about 2 months; in separate cases from 2 days to 18 months. But modern therapy can prolong the patients’ life to 2-3 years; in rare cases to 5 years and more.

Treatment. Combined therapy, including 3-5 preparations, depends on the clinico-haematological variant of the disease. Corticosteroids (e.g. prednisolone) in large doses are prescribed together with cytostatic (6-mercaptopurin, vincristin, methotrexate, etc.). Anaemia is removed by blood transfusion and by preparations preventing haemorrhagic complications (vicasol, calcium chloride, aminocaproic acid). If secondary infection arises, antibiotics are indicated. Intense vitamin therapy is also useful.

CHRONIC MYELOLEUCOSIS

Chronic myeloleucosis is the most common variety of leucosis. It develops from precursors of myelopoiesis. It is characterized by myeloid hyperplasia of the bone marrow attended by delayed maturation of the myeloid elements at a certain stage of their development and by myeloid  metaplasia of the spleen, liver, lymph nodes and other organs. Karyological studies reveal, in the overwhelming majority of cases, the so-called Philadelphia (Ph¹) chromosome in the myeloid precursors. Chronic myeloleucosis occurs at any age but its incidence at the age of 20-45 is higher.

Clinical picture. The initial symptoms of the disease are not specific:

weakness, fatigue, excess sweating, and subfebrile temperature. The symptoms become more pronounced with time and the patient consults a doctor. The work capacity decreases appreciably, weakness increases, sweating becomes profuse, and the body temperature rises periodically to 37.5-39 °C; cachexia develops. A common symptom is the feeling of heaviness in the left part of the abdomen, which depends on the pronounced enlargement of the spleen. Pain may be due to a considerable distension of the spleen capsule. Splenic infarction is manifested by piercing pain, which intensifies during breathing. Pain in the bones is not infrequent. It is due to hyperplasia of the myeloid tissue.

 Myeloid infiltration in various internal organs can be the cause of some additional symptoms, such as dyspeptic signs in affections of the gastro-intestinal tract, coughing in the presence of infiltrations in the lungs and the pleura, neurological changes due to affection of the brain, the spinal cord, nerve radices, etc. In the terminal period of the disease, the heart is overloaded due to pronounced anaemization; dyspnoea and oedema develop (their origin being dependent also on hypoproteinaemia). Thrombocytopema and shifts in the blood coagulation system cause haemorrhagic complications. Inspection of the patient helps physician assess his general condition and determine (approximately) the stage of the disease (stage I-the initial symptoms, stage II-pronounced symptoms, and stage III-dystrophy; this is the terminal stage). The terminal stage is characterized by pronounced cachexia and considerable enlargement of the abdomen due to markedly enlarged liver and spleen. The skin is pallid, with a yellowish or greyish hue; it is flaccid and moist. The legs are affected by oedema. Gingivitis and necrosis of the mouth mucosa are possible. Palpation reveals moderate enlargement of the lymph nodes of various groups. The liver and especially the spleen are markedly enlarged It is believed that no other disease is attended by enlargement of the spleen to the extent to which it is enlarged in the terminal stage of chronic myeloleucosis. The liver and the spleen are firm. In the presence of infarctions of the spleen it is tender to palpation. Peritoneal friction sound can be heard over the spleen by auscultation. Applying pressure to the bones and tapping over them are painful.

The leucocyte count is markedly high . It can be 3 x 10¹¹ and even 6 x 10¹¹ per 1 L. Leucocyte count can first only slightly exceed the normal level but later it increases, gradually or suddenly. Temporary remissions are possible, especially in the appropriate therapy. In addition to the main form of myeloleucosis characterized by a considerable increase in the white blood cells count (leukaemic), there may be cases with their moderately increased (subleukaemic) and normal counts (aleukaemic). Study of the blood smears reveals mainly cells of granulocytic series, which make 95—97 per cent of all white blood elements. There are many immature forms among them (myelocytes, promyelocytes, and even myeloblasts). During exacerbation, the number of young forms markedly Increases. Only the youngest cells, myeloblasts, and a relatively small number of mature granulocytes (stab and segmented ones) can be revealed in the blood, while the intermediate forms are absent (hiatus leucaemicus). Basophils and eosinophils are usually present in the smear; their percentage can even be increased. Basophilia in 4-5 per cent of cases is regarded as a sign of myeloleucosis. The number of lymphocytes and monocytes decreases to 3—0.5 per cent in grave cases with significant leucocytosis, but their absolute amount in the blood does not change substantially. Red blood changes are only observed at stages II and III of the disease, when anaemia joins the process and progresses. Erythrocyte and haemoglobin content of the blood decreases synchronously. The colour index therefore remains within the normal range (0.8— 1.0). Thrombocytopenia develops as the terminal period approaches. ESR usually increases to 30-70 mm/h.

The content of the erythroid precursors markedly decreases in the bone marrow (especially when the disease approaches its terminal stage). Cells of the myeloid series prevail (especially juvenile forms: promyelocytes, myelocytes, and myeloblasts). Megakaryocyte count slightly increases in the first half of the disease. Characteristic also is the increase in the number of basophilic and eosinophilic promyelocytes and myelocytes.

Course. The course of the disease is progressive, sometimes with transient spontaneous remissions. Before modern methods of treatment of the disease were introduced into clinical practice, the average life expectancy of patients was 2.5—3 years (sometimes to 10 years). Today the life of patients is prolonged more significantly. Patients die of cachexia, anaemization incompatible with life, haemorrhagic complications, or from a joining infection.

Treatment. Myelosan and other cytostatics are prescribed, usually in combination with 6-mercaptopurine, prednisolone, etc. Patients with a marked splenomegaly are given radiotherapy or dopan. Repeated transfusions of blood or packed red cells are indicated in cases with pronounced anaemization.

CHRONIC LYMPHOID LEUCOSIS

Chronic lymphoid leucosis is now regarded as a benign tumour of the immunocompetent  tissue.  Its  haematological  basis  is  mainly B-lymphocytes (morphologically mature but functionally inadequate). Chronic lymphoid leucosis is characterized by systemic hyperplasia of the lymphoid apparatus, lymphoid metaplasia of the spleen, bone marrow, and other organs. Chronic lymphoid leucosis is a common form of leucosis. It usually occurs in the middle-aged and aged individuals (from 35 to 70), mostly in men.

Clinical picture. The initial symptoms are general weakness, indisposition, and rapid fatigue. The first symptom which troubles the patient and makes him feel like consulting a doctor is usually enlargement of the subcutaneous lymph nodes. General weakness gradually increases, excess sweating develops along with subfebrile temperature. Depending on a particular enlarged lymph node group and the organ affected by lymphoid infiltration, additional symptoms develop: dyspepsia, diarrhoea (in affection of the gastro-intestinal tract), dyspnoea and attacks of asphyxia (in compression of the trachea and bronchi by the bifurcation lymph nodes), erythema, dryness and itching of the skin (in leukaemic lymphodermia), etc. Lymphoid metaplasia of the bone marrow may cause haemorrhagic symptoms (due to thrombocytopenia) and anaemia. Leukaemic infiltration can cause radicular pain and exophthalmos. Diffuse lymphatic proliferation in the nasopharynx can develop.

Enlarged lymph nodes can often be revealed during inspection of the patient. Lymph nodes of one or several groups are often enlarged; later all other lymph nodes become also involved. The tonsils can be enlarged too.

Skin infiltration is attended by its consolidation, reddening, dryness and scaling. At the terminal stage, the patients are extremely thin (cachexia).

Palpation is used to assess accurately the enlargement of the lymph nodes and their properties. The lymph nodes are elastic-pasty; they do not fuse with the skin or with one another, and are painless in most cases. They can grow to the size of a hen egg. Even markedly enlarged, the lymph nodes never ulcerate or suppurate (as distinct from tuberculosis affection of the nodes). The liver and the spleen are enlarged and consolidated. Infarctions of the spleen can occur; its palpation then becomes tender.

Leucocyte counts in the leukaemic form of the disease are as high as 3 x 10¹¹ per 11, and more. Lymphocytes make 80-95 per cent of the white blood , they are mostly mature. The structure of their nucleus and cytoplasm is sometimes quite peculiar: the cells are very soft and are easily destroyed when preparing a smear; specific Botkin-Gumprecht shadows are formed. Small amounts of juvenile cells, prolymphocytes and lymphoblasts, occur. During exacerbation their number increases. The relative quantity of neutrophils is much decreased (to 20-4 per cent). The blood picture is less specific in subleukaemic and aleukaemic forms of the disease, where lymphocytosis is usually less pronounced. Anaemia and thrombocytopenia (mainly of the auto-immune genesis) join at the terminal period.

Study of the punctate of the bone marrow reveals its lymphoid metaplasia: great quantity of lymphoid cells are found (to 50 and even 90 per cent in especially grave cases). The number of cell elements of the granulocytic and erythroid precursors is decreased. The results of studying the lymph node punctate are less convincing because lymphoid cells are common elements of its parenchyma while the hyperplastic character of the lymphoid tissue is sometimes difficult to determine.

Course. The disease progresses in cycles or gradually. The average life expectancy of patients is 4-5 years. Some survive for 10-12 years and over. The patients die of secondary infections, usually pneumonia (which is promoted by inhibition of humoral immunity), of haemorrhagic complications, and cachexia.

Treatment. Active treatment is not given during the initial period of the disease (like in chronic myeloleucosis). Special attention is given to nor-malization of conditions of work and rest of the patients, who must be fed an adequate diet rich in vitamins and proteins. The patient should walk in the open air. X-ray therapy is given in the presence of toxicosis or if the disease is rapidly progressing. The enlarged lymph nodes and the spleen are irradiated. Leukeran, prednisolone, cyclophosphane and other chemical cytostatics are given. Blood transfusion is indicated in anaemia and thrombocytopenia

                       ERYTHRAEMIA

Erythraemia (chronic erythromyelosis, Vaquez’ disease) is a benign myeloproliferative disease characterized by total hyperplasia of the bone marrow cell elements, which is more pronounced in the erythroid precursor. Erythraemia was first described by the French clinicist Luis Vaquez in 1892. Aged males are mostly affected.

Erythraemia should be differentiated from erythrocytosis which may be a symptom of some other diseases (chronic diseases of the lungs and the heart, essential hypertension, some kidney diseases, etc.) and erythrocytosis developing in the presence of hypoxia (at high altitudes, e.g. in highland; less frequently in pilots). The symptoms of the main disease prevail in the clinical picture of symptomatic erythrocytosis. During remission, or in cases of recovery, the erythrocyte count in the peripheral blood normalizes. Symptomatic erythrocytosis is not attended by neutrophilic leucocytosis or thrombocytosis, or else splenomegaly, which are common in erythraemia.

Clinical picture. The onset of the disease is slow and indistinct. When the symptoms are activated, the patient complains of headache, heaviness in the head and noise in the ears, exertional dyspnoea, impaired memory, and skin itching. Vision and hearing function are also impaired in some cases. Pain in the abdomen can develop, probably due to excess blood delivery to the internal organs. Unbearable and burning pain can transiently develop in the finger tips (erythromelalgia), which can be explained by transient vascular spasms.

Inspection of the patient reveals peculiar plethoric redness of the exposed skin (face, neck, hands). The tongue and the lips are bluish-red, the eye conjunctiva is hyperaemic. This peculiar colour of the skin and mucosa is due to overfilling of the surface vessels with blood and its slow movement in the vessels. The greater part of haemoglobin is thus converted into its reduced form. Palpation reveals moderately enlarged spleen and liver. Tapping over flat bones and exerting pressure on them are painful, which is characteristic of bone marrow hyperplasia.

Arterial pressure (both systolic and diastolic) is often increased. It is believed that arterial hypertension is a compensatory reaction of the vessels to the increased viscosity of blood. In these cases palpation of the apex beat and electrocardiography reveal left ventricular hypertrophy.

The erythrocyte count increases and is usually from 6 x 10¹² to 8 x 10¹² per 1 L, and more; haemoglobin increases to 180-220 g/L; the colour index is less than 1. The total blood circulatory volume increases significantly (1.5—2.5 times) mainly at the expense of increased erythrocyte count. The blood reticulocyte content increases to 15—20%_o which indicates intensified regeneration of erythrocytes. Polychromasia of erythrocytes is observed; separate erythroblasts can be found in the smear. The number of white blood cells also increases (1.5-2 times) at the expense of neutrophils, whose content is 70-85 per cent. The nuclear shift to the left is observed. The number of eosinophils, less frequently of basophils, increases. The number of thrombocytes increases sharply to 1.5 x 10¹² -2 x 10¹² per 1L of blood. ESR is slow, blood viscosity increases significantly, while coagulability of blood and the bleeding time remaiormal.

Histological study of the bone marrow (obtained by trepanobiopsy) shows significantly increased number of cells of the erythroid series. The number of juvenile cells of the granulocytic series and of megakaryocytes is also increased.

Course. The disease progresses slowly. The average life expectancy of patients is 10-14 years. The outcome of the disease is myelofibrosis with progressive hypoplastic anaemia or transformation into myeloleucosis. Most frequent complications are thrombosis of the cerebral vessels, spleen, lower extremities, and less frequently of other parts of the body. Tendency to bleeding also develops which is due to both functional inadequacy of thrombocytes and the low relative content of fibrinogen in the blood. Erythraemia patients often develop gastroduodenal ulcer.

Treatment. Radioactive phosphorus (³²P) is the best therapeutic means for erythraemia. It produces a cytostatic effect on haemopoiesis in the bone marrow. Clinical remission, lasting from 1 to 3 years is attained in most cases. New cytostatics (myelosan and marcofan) are also used. Symptomatic therapy includes phlebotomy (500 ml) at 5-7 day intervals.

Haemorrhagic Diathesis

Haemorrhagic diathesis is the disease characterized by the tendency to bleeding and repeated haemorrhages; they may occur spontaneously and may be caused by injuries; injury can be quite insignificant, which other­wise would never provoke bleeding in a normal individual.

Aetiology and pathogenesis. These are quite varied. Some types of haemorrhagic diathesis are hereditary but many of them can be caused by some external factors.

Avitaminosis (deficit of vitamins C and P) is an especially predisposing factor. Some infections (long-standing sepsis, louse-born typhus, virus haemorrhagic fevers, icterohaemorrhagic leptospirosis), allergic condi­tions, some diseases of the liver, kidneys, and of the blood system can also provoke the onset of haemorrhagic diathesis.

Haemorrhagic diathesis can be classified by the pathogenesis into two major groups: (1) haemorrhagic diathesis due to disordered capillary permeability (haemorrhagic vasculitis, vitamin C deficiency, some infectious diseases, trophic disorders, etc.); (2) haemorrhagic diathesis due to disorders in the blood coagulation and anticoagulation system. The latter group is further subdivided into the following conditions:

A. Haemorrhagic diathesis caused by disordered blood coagulation system:

(1) first phase: congenital deficit of plasma components of thromboplatelet formation (factors VIII, IX, XI), haemophilias A, B, C, etc.;

deficit of thrombocytic components (thrombocytopathy, e.g. thrombocytopenic purpura; see below);

(2) second phase: deficit of plasma component of thrombin formation—factors II, V, X, the presence of antagonists to them and of their in-hibitors;

(3) third phase: deficit of plasma components of fibrin formation factors I (fibrinogen) and XII.

B. Haemorrhagic diathesis caused by accelerated fibrinolysis (due to increased synthesis of plasmin and insufficient synthesis of antiplasmin).

C. Haemorrhagic diathesis caused by disseminated intravascular coagulation (thrombohaemorrhagic syndrome or coagulopathy of consumption) in which all procoagulants are utilized during massive in­travascular coagulation and the fibrinolysis system is activated.

This concise classification of haemorrhagic diathesis is only conventional because several pathogenic factors are often involved. This classification covers a very large group of diseases, both hereditary and acquired, and also secondary syndromes arising against the background of the main disease (metastasizing malignant tumour, burn disease, etc.)

Clinical picture. The general clinico-morphological symptoms of haemorrhagic diathesis are haemorrhages into various organs and tissues, external and internal haemorrhages (from the gastro-intestinal tract, lungs, uterus, kidneys, etc.) and secondary anaemization. The disease is complicated by dysfunction of the haemorrhage-affected organs, by hemiparesis in disordered cerebral circulation, regional paralysis and paresis in compression of large nervous trunks by haematomas, haemarthrosis in repeated haemorrhages into the joints, etc.

Despite the great variety of haemorrhagic diatheses and certain diagnostic difficulties, accurate diagnosis is quite important for efficacious therapy in each particular case. The aetiological and pathogenetic factors of the disease should be properly considered for an accurate diagnosis. Haemorrhagic diathesis is the subject of special study of senior medical students. Here we shall only acquaint the reader in general with thrombocytopenic purpura (Werlhof’s disease).

The prophylaxis of hereditary (familial) haemorrhagic diathesis includes medico-genetic studies that may give the wife and husband the necessary information and advice concerning possible complications in their offspring; if haemorrhagic diathesis is not hereditary but acquired, measures should be taken to preclude development of diseases that may promote the onset of haemorrhagic diathesis.

Thrombocytopenic purpura (Werlhof’s disease). Thrombocytopenic purpura is a haemorrhagic diathesis due to the deficit of blood platelets. The disease was first described by Paul Werlhof in 1735. Thrombocytopenic purpura occurs mostly in young females.

The aetiology and pathogenesis of the disease are unknown. It has only been established that the immune-allergic mechanism is positively involved in about 50 per cent cases: anti-thrombocytic antibodies are produced and fixed on the surface of thrombocytes to damage them and to prevent their normal separation from megakaryocytes. The triggering factors (the im­petus to production of auto-antibodies) may be infection, toxicosis, individual hypersensitivity to certain foods and medicines. In some cases the disease is caused by hereditary insufficiency of certain enzyme thrombocyte systems which is probably activated by some additional factors.

Pathological anatomy. Multiple haemorrhages in the skin and the internal organs are characteristic. The spleen may be considerably enlarged. Separation of thrombocytes from megakaryocytes in the bone marrow is disordered (according to histological findings).

Clinical picture. The main symptom of the disease is the appearance on the skin and mucosa of multiple haemorrhages in the form of small dots (petechiae) or large spots (ecchymoses). Haemorrhage may be spontaneous and due to insignificant injuries, mild contusion, pressure on the skin, etc. Haemorrhagic lesions are first purple, then they darken to cherry-red and brown, and then lighten to yellow and disappear in several days. But new lesions develop to succeed the disappearing ones. Bleeding from the nose, gastro-intestinal tract, kidneys or uterus are not infrequent; haemorrhages into the internal organs (brain, fundus oculi, myocardium, etc.) are also possible. Grave and prolonged bleedings arise in extraction of teeth or in other minor operations. The tourniquet test (and especially the pinch test) is positive. The spleen and the lymph nodes are usually not enlarged; tapping on the bones is painless.

Thrombocyte counts are usually less than 50 x 10⁹ per 1 L; in some cases only single blood platelets can be found in preparations. The degree of bleeding can be assessed by the degree of thrombocytopenia. Hypochromic anaemia can develop after profuse bleeding. The clotting time is normal in most cases, but it can be slightly longer (due to the deficit of thromboplastic factor III of blood platelets). The bleeding time increases to 15-20 min and more; clot retraction is disordered. Thromboelastography reveals greatly increased reaction and clotting time.

Course. Both acute and chronic recurrent forms of the disease are observed. The patient dies of profuse bleeding and haemorrhages into the vital organs.

Treatment. Removal of the spleen is indicated in grave cases: the number of thrombocytes increases in the blood of patient and haemorrhage stops in a few days following the operation. The effect of splenectomy is probably explained by decreased decomposition of blood platelets in the spleen and by the removal of the inhibiting effect that the spleen has on thrombocytopoiesis. Blood transfusion is useful for haemostasis and blood substitution. Repeated transfusion of thrombocytic mass gives positive haemostatic effect. Vitamin P, vitamin C, calcium chloride and  vicasol are given to strengthen the vascular walls. Since the allergic factor is  involved in the pathogenesis of the disease, corticosteroid hormones are quite effective in certain cases.                                         .

                                                                                                                        

 

 Semiotics of main syndromes (anaemic, hemorrhagic, haemolytic) and blood system diseases (anaemia, acute and chronic leukaemia’s, hemorrhagic vacuities, thrombocytopenic purpura haemophilia).

 Associated  Proff. Nykytyuk S

 

The knowledge ot peculiars ies of the blood system in children of differenl age groups, methods of clinical-laboratory examination of children with their blood system affection and semiotics of the main haematological syndromes (anaemic, haemolytic, haemorrhage and others)

 

Contents

Peculiarities of the blood system in children of different ages. Methods of clinical and laboratory examination of children with affection of the blood system. Clinical-haematological semiotics of the main syndromes (anaemic, haemolytic, haemorrhage and others) and diseases of the blood system in children,

Blood is a liquid tissue of the organism which surrounds all its cells. Blood consists of the formed elements (erythrocytes, leukocytes, thrombocytes) and the plasma The latter contains of water, proteins, vitamins and a large number of active substances {hormones, enzymes, antibodies, etc.).

The functions of blood are as follows: transport and protection The transport function includes delivering of oxygen, nutrient substances, hormones, enzymes, other physiologically active substances to tissues and discharging of waste products ol metabolism from tissues. The protection function is provided with leukocytes, which realize phagocytosis, and with immune agents, which resist microorganisms with their toxins and destroy foreign proteins. A quota of the formed elements of blood is 40-45 %t thai of the plasms being 55-60 %

Haemopoiesis is the proccss of origin an J maturing of formed elements of blood in (he haemopoietic organs. Formation of blood, or haemopoiesis, is parallel to cardiovascular development. The hemopoietic system originates in the mesoderm. There are 3 periods in the development of this system: out-of-embryo period, liver period and bone-marrow period. At about 13 to 15 days of gestation, angioblasts organize as “blood islands” in the mesoderm of the yolk sac. Spaces develop within these islands and become lined with angioblasts, forming the primitive blood vessels and endothelium. Cells of the endothelium give rise to primitive blood cells, megaloblasts This all occurs outside the embryo, in the yolk sac. Blood is not formed within the embryo until the fifth week of gestation. This short period is called the out-of-embryo period, or megaloblastic haemopoiesis. The primary site for haemopoiesis in the embryo is the liver, which grows larger as the process continues. The liver increases in size until, by the ninth week of gestation, it is responsible for about 10% of the total foetal weight. This id the period of liver haemopoiesis. Later in gestation the reticuloendothelial system, comprised of the liver, spleen, bone marrow and lymph nodes, becomes the primary site of haemopoiesis as the yolk sac regresses. Mega lob lasts are gradually replaced by erythroblasts. Erythro-, granulo-, and megakaryocytopoiesis take place in the spleen. Active lymphopoiesis starts to appear in the spleen late, in the end of the 7th month of gestation. At 4-5 months of gestation, the bone marrow period of haemopoiesis starts. By term, the bone marrow is the main site for production of all red cells and most other cellular components of blood. However, the liver, spleen, and lymph nodes can be stimulated to produce blood cells during periods of extreme and continued demand.

The stem cell, the germinal cell Tor all blood cell production, is found within the reticuloendothelial system. The stem cell is a polypotent cell-precursor, it can keep up its population and can differentiate itself in more mature cells. In lymph nodes, reticulum cells will develop into lymphocytes and monocytes. Elsewhere in the

reticuloendothelial system, reticulum cells will differentiate into cither haemoblasts or myeloblasts Haemoblasts undergo several other stages of transformation before emerging as erythrocytes, while myeloblasts may differentiate into granulocytic leukocytes or megakaryocytes {platelet precursors).

Table 1

Scheme of haemopoiesis

 

 

During postnatal life the bone marrow produces erythrocytes, granulocytes, blood platelets and monocytes; lymphocytes arc produced in the spleen, lymph nodes, intestinal follicles, Payer’s patches (aggregate nodules) and other lymphoid formations.

Cells, circulating in the peripheral blood, continue to be functionally changed; the contents or enzymes and energy output in cells gradually decrease Cells are aging and destroyed by phagocytes. The term of life oo erythrocytes is 120 days, thrombocytes 9-11 days, leukocytes from 100 to 300 days, but some of them live only 3-4 days, while others more than 1.5 years. There is balance between formal ion and destruction of blood ceils.

The central nervous system, endocrine glands and kidney have influence on haemopoiesis, this influence is realized through erythro, leuko- and thrombopoietines.

Blood must be liquid. This condition of blood is guaranteed by the haemocoagul&t ion system, which supports blood in liquid condition, prevents thrombosis and haemorrhage and ensures stop of bleeding. Disorder of this system causes thrombosis and bleeding, The main components of this system arc: vascular wall, blood cells

and plasma factors.

The vascular chain of haemostasia consists of the intact vascular wall; the thrombocytic chain ensures adherence and aggregation of thrombocytes; besides, thrombocytes contain 9 factors, which take part in blood coagulation The plasmatic chain contains 13 factors of blood coagulation. If a vascular wall is injured, local angiospasm begins, thrombocytes adhere to damaged endothelial cells and basal membrane, and thrombocyte aggregation takes place, All this process is realized for 2 minutes. During this period plasma factors, which were not in active condition, activate consecutively and are converted into active enzymes; a complex multiple cascade enzyme process takes place. The formation of thrombi and cessation of bleeding occur.

 

Retraction of blood clot occurs due to ability of thrombocytes to gather fibrin fibres in a dot. As result of this process, the volume of a clot decreases. Lysis of a clot, re const ruction of vascular permeability and blood flow occur under the influence of fibrinolysin.

The ability of the foetus to synthesize clotting factors is genetically determined. In genetically normal foetuses and newborns.

the production of adequate amounts of clotting factors depends on maturation of the liver and presence of vitamin K. The latter is produced in the gastrointestinal tract through the interaction of bacieria, food and time. Synthesis of pratrombin and factor Yll

cannot occur without it.

Blood type. This is determined at conception. The group indication appears in children quite early. Agglutinogens A and 3 can be discovered in 3-4-month-old foetuses. Erythrocytes contain agglutinogens cc and j9, serum agglutinins A and B. Blood of every person contains different agglutinogens and agglutinins. There are 4 groups of blood: 1(0) – O; 11(A) – A; 111(D) – B; IV(AB), Rh factor is one of blood antigens; this can be positive (S5 %) and negative (15 %). Blood of a newborn has aji essential quality of Rh factor and it remains to be constant during the whole life The HTA system (Human Leukocyte Antigen) is the system of human leukocyte antigens- It is a complcx of genes situated on the 6L1 chromosome; the complex has its genetic snoctures, i.e. loeuses A, U, C and D. Every human being has a set Of 4 paired antigens. A quantity of combinations of gene alleles only in A and B loeuses exceeds 250 million, what confirms the individuality of every person and explains difficulties in selecting donors for organs transplantation. Mature erythrocytes do not have tiLA on their cell membrane; this fact explains the possibility of blood transfusion without taking into consideration HLA phenotype.

Haemoglobin. Foetal haemoglobin, or HbF, is a specialized form of liaemoglobin, found only during gestation and in early infancy, HbF accounts from 70% to 90% of the total haemoglobin in the perinatal period.

During the foetal life, oxygen supplement is lower than in the extrauterine life (p02 is 30 mm Hg in the umbilical venous blood, but 60 to 90 mm Hg in the arterial blood after birth). Foetus adaptation to hypoxia includes:

I) an increase in total haemoglobin concentration (150 to 200 g/1 vs 110-130 in the adult);

red cell mass is increased in the foetus to 5-6 million/ mmJ;

foetal haemoglobin has high haemoglobin-oxygen affinity. Amount of blood. The total amount of blood of an adult is

approximately 5-5.5 % of his body weight. The amount of blood in children is higher, In a newborn, the amount of blood makes 10.5* 19.5 % of the body weight, in later infancy it is 9-12.5 %, in the school-age period it is approximately 7 % of the body weight.

There are many differences in morphofunctional character!sties

of blood between children and adults. Blood of the newborn infant.

Its red blood count is 5.0-7,0 10 J/1 following birth, but by the 14* day, it usually drops down to 4.0 lO11/!. Haemoglobin level during the first two days may be as high as 170-220 g/i, falling to ! 65 g/1 by the end of the 14th day, Anisocytosis (erythrocytes of unequal size) is typical for newborn infants., Anisocytosis is expressed by the presence of macrocytes (abnormally large erythrocytes with high

haemoglobin content).

The number of reticulocytes (immature or young erythrocytes) is from 50 to 100 per 1,000 mature erythrocytes during the first days; their number also drops rapidly down by 10-15 days of life aud makes 5 to 10 per 1.000 mature erythrocytes.

Osmotic fragility. Blood of the newborn contains erythrocytes with elevated and reduced osmotic fragility.

Erythrocyte sedimentation rale (ESR) of the newborn is slower than in adult and is 2-3 mm/h; beginning with the age of 2 months ESR rises and reaches the level of S-!0 mm/h (the same as in adults). The number of thrombocytes varies during the first days of life

within 100^2 00-x 109/1,

The picture of their white blood in newborns is quite specific. During the first 8-12 hours of life the number of leukocytes is as high as 25^30xl09,’l; neutrophilic leukocytosis is marked, a regenerative deviation to the left is present, ii means the presence of many immature neutrophils in peripheral blood.

By the I01h-I5111 day white blood count gradually drops to an average of 10-12 x 10*/]; immature cells, as a rule, disappear from the peripheral blood almost completely; primary neutrophils is replaced by lymphocytosis,

A gradual increase in the number of lymphocytes begins in the first days of life, attaining 50-60 % by the fifth day; this level is sustained throughout infancy; at the same time the number of neutrophils is gradually reduced to 30 %.

There are two intersections iumbers of neutrophils and lymphocytes: between the 4* and 6th days and between the 4 and 5L year.

The coagulation (clotting) and bleeding times in the newborn are the same as normal for adults: coagulation time is 5-5-5 minutes; bleeding time is 1-3 minutes. Clot retraction is normal.

According to the opinion or some authors, high haemoglobin and red and white cell levels in the newborn are caused by the maternal hormones; the hormones circulating in the body of the pregnant woman and stimulating tier haematopoietic system penetrate into the body of the foetus and thus stimulate its haematopoietic organs. The delivery of these hormones into the infant’s blood ceases after birth, and therefore a rapid drop of haemoglobin, erythrocytes and

leukocytes occurs.

Blood in infancy has some characteristic features. Red blood count rates 4^4.5*10,J/1. haemoglobin level is 95-140 g/L and it easily drops to 70.0-80.0 gfl, so that the colour index stays below norm. Anisocytosis is rather marked. Reticulocytes do not number more than 5-6 per 1,000 normal erythrocytes.

The maximum and minimum osmotic fragility of erythrocytes is slightly elevated in comparison with the newborn period.

Thrombocyte count varies between 200^ 300×1071.

Coagulation, hi ceding time, and clot retraction almost do not dilTer from what is no mi a I in adults.

While count is usually 10-12 * I0y/1 in infants, lymphocytosis is marked (the level of lymphocytes is 50 %), neutrophil eount during this period vanes within the range of 35-40%.

It is possible lo note the development of physio logical anaemia at the age of 3-4 months as a result of iron deficit, because breast and

cow’s milk is low in iron.

HT^ri of children fmm 2 U> fi years. Between the ages of 2 and

6 years the level of haemoglobin is 105-140 g/1 (averaging 120 g/1),

red blood count is 4.5xl0lM> with 2-3 % of reticulocytes, the colour

index is lower thaorm and is 0,85-0,95. Anisocytosis is marked,

White count gradually diminishes, becoming 8-8,5×10 /I by the

age of 6 years.

The number of lymphocytes gradually decreases, going down to 40-35 % by the age of 5-7 years. The number of neutrophils grows

(the second intersection).

Rinnd of Children between ft and 14 years. The composition ot

blood at this period is approximately the same as in the preceding period. Anisocytosis gradually disappe^s. Leukocyte count continues to fall and by 14 years is 7-7,5x 10 t\.

Differential white count is characterized by a farther nsc in the number of neutrophils and a drop of lymphocyics. By 14 years the count indicates 60-05 % of neutrophils and 25-30 % of lymphocytes

Rlnod of adolescents. Red blood count is 4.5-5×10 IL Haemoglobin is at a high level, averaging 140 g/1. White count is 6-7.5×10^1.

Methods of the clinical and par aclinic a 1 investigation Clinical examination of the haematological system of children includes questioning, general examination, physical Examination of the skin, lymph nodes, liver, spleen and bones

The most typical complaints are; bleeding, haemorrhage, enlargement of lymphatic nodes, paleness of the skin and mucous

membranes, ossalgia.

Complaints of the common character are: hyperthermia,

headache, dizziness, weakness, exhaustion, memory disorders, poor

appetite, exertional dyspnoea.

Case history taking:

– LO establish the first day of appearance of symptoms, under which circumstances they appeared, especially bleeding and

haemorrhage (spontaneously, under influence of some strong or

superficial damaging);

to ask about the dynamics of symptoms (when fresh elements appeared, simultaneously or subsequently);

-to ask about treatment, including the dose and duration of using the medicines, their effectiveness;

to get acquainted with results of laboratory and other methods of examination before the patient1 & admission to the hospital

Life history is very important m cases of inheritable diseases (haemophilia) and possible tendency to pathology of the hhemopoietic system and blood. The obstetric anamnesis is very important for infants.

The following signs must be assessed during examination:

position of a patient (active, passive, forced);

bleeding (its location, intensity, duration);

colour of the skin: a) pallor, b) jaundicc;

rash (macula, petechia, purpura, bruise), papule, exanthema, haemorrhage, haematoma, haemarthrosis; enlargement of lymph nodes;

di si ended abdomen;

oedema;

enlargement of the liver and spleen.

Paraclinical investigation includes: blood count; coaguiogram; puncture of the liver, spleen and bone marrow; study of myelogram: puncture of a lymph node; radioography, CT. The main methods of examination of the system of haemostasia are as follows: capillary resistance tests, thrombocyte count, tests of thrombotic adhesion [aggregate functions), time of capillary bleeding according to Duke, retraction of blood clots.

Myelogram gives information about the quality and quantity of bone marrow ceils. In order to get some bone marrow, the breastbone is lo be punctured. It is necessary to count not less then 500 cells and calculate percentage for every type of ceils.

The main peculiarity in the bone marrow of children of the first

3 years of life consists in a large quantity of lymphocytes: infancy –

tne main peculiarity in me tKmfc rnaribw ui lmuuicu ul ujv, i±w»

3 years of life consists in a large quantity of lymphocytes: infancy – 10-18%, at 3 years – 7-14 %, after 3 years – 2-8%,

There are no significant differences in other parameters of the bone marrow of healthy children arid adults.

The main clinical symptoms of the blood system diseases are: pallor, jaundice, fatigue, irritability, seizures, enlargement oi the liver spleen, lymph nodes, petechia, ecchymosis, gastrointestinal haemorrhage, mucosal bleeding, bscteriaemm, cellulitis, pha^gitis, oral ulceration.

Combination of these symptoms may be various and depends on the nosological form of haemopathy.

Symptomatology of blood chances.

I Quantitative changes in red blood.

L. The increase in the number of erythrocytes {polyglobulia}:

true polyglobulia is associated with intensification of bone marrow activity (iewborns, congenital heart disease, in

polycylhaemia, etc );

false transient polyglobulia results from condensation of blood due to fluid losses (acute dyspepsia, dysentery, excessive perspiration).

2. Reduced red blood counts and lower haemoglobin levels, i.e. condi ti ons corresponding to the cl i nical concept of anaemi a:

reduction of bone marrow function (starvation, infection, intoxication, tumours), congenital inferiority of the haematopoietic system (prematurity, tumours in the bone marrow):;

the number of erythrocytes may l>e reduced due to increased expenditure (chronic bleeding, erythrocytes disintegration during chrome infections, worms, malaria), haemolysis of erythrocytes (fami \ ial hacmolyti c j aun dice).

IT. Qualitative changes in red blood.

Changes in the quality of blood elements are connected with changes in the process of blood formation. These are characterized by the appearance of embryonal precursors:

meg&loblasts, megalocytes: these indicate return to (lie embryonal type of blood formation;

erythroblasts, normablasts: these demonstrate intensified bone marrow activity;

increased reticulocytes counts: these display intensified bone marrow function;

the appearand of macrocytcs: this is a sign of healthy blood regeneration,

hyperchromia indicates regeneration; this i& a sign of functional deficiency of bone marrow;

anysocytosis is inequality in the size of erythrocytes; this is a signofnorma! regeneration; poikilocytosis means different shape of erythrocytes and signals about degeneration of erythrocytes.

White b too d:

I. Quantitative change in while blood,

Leukocytosis is an increase in the quantity of leukocytes more than tO x 10y/l ( over 20×105/! is hyperlcukocytosis). An increase in the number of while blood cclls, leukocytosis, results from heightened activity of the bone marrow under the influence of some pathological and also physiological stimuli.

The following forms oflcukocytosis are distinguished:

1. Physio logical leukocytosis:

in the newborn (20,000-25.000),

in infancy <10,000-12,000).

2- Pathological leukocytosis, associated with local and generalised infection processes and intoyications:

pseudo leukocytosis results from condensation of blood, digestive leukocytosis is possible;

neutrophilic leukocytosis is associated with infections; sepsis diseases, pneumonia, scarlet fever, dysentery, rheumatic fever, meningitis.

Leukaemia is characterized by a particularly high leukocytosis (100,000 and higher) and the appearance of numerous immature forms. There are many different forms of leukaemia, but myeloid f grann locytic) and lymphatic leukaemia are moreoflen.

Besides determination of the total number of leukocytes, estimation of the nuclear shift of neutrophils is highly important. A deviation to the left (an increased number of young fontis of leukocytes) is a sign of accelerated production of white blood eells. Presence of a deviation to the left and neutrophilosis is a favourable

prognostic symptom. Prognosis is !ess favourable when a deviation to the left is not combined with an increase in the total white count.

Lymphocytosis is an absolute and relative increase of the number of lymphocytes in peripheral blood. It is a stable physiological condition throughout infancy and early childhood-

The number of lymphocytes increases in certain acute and chronic infections (pertussis, rubeolla, typhoid fever), during convalcscencc, certain forms of glandular fever, tonsillitis. Especially high lymphocyte counts are observed in lymphatic leukemia and in cases of so-called lymphatic reactions in children, more often in

whooping cough.

Monocytosis is a transient increase in the number of monocytes,

it is typical for certain acute infections (malaria, measles, tuberculosis

and infwfious mononucleosis).

Eosinophilia is observed iumerous pal ho logical conditions. Normally blood contains 2-4 % of eosinophils, in some pathologic*! conditions the amount goes up to 20-30 %, or even higher. Eosinophil occurs in bronchia! asthma, serum sickness anaphylactic status, scarlet fever, leukaemia, _ certain cases ot lymphogranulomatosis, and in all types of worm diseases

Basophilia Normally basophil count does not exceed 0.5-1 /o- A rise is observed in association with acute and chronic leukaemia,

1 ytn pb ogranu lomatosis,

Leukopenia is diminution in tho number of leukocytes, it is a characteristic sign of certain infections (typhoid fever, measles rubella), in sepsis, pneumonia leukopenia is an indication of depression of the haematopoietic organs and an unfavourable

prognostic sign.          ,

Reduction of white blood count may result from the bone

marrow hypofanction due to infections, chemical poisons (arsenic,

benzene), ionizing radiation or lesion of the myeloid tissue

(agranulocytosis).

Neutropenia is a sign of a severe form of infection or sepsis. Absolute neutropenia is characteristic of agranulocytosis.

Lvmphopenia develops in certain infectious diseases in association wjtb neutrophilic leukocytosis. Absolute lymphopenia is

observed in lymphogranulomatosis, Jymphosareomatosis, and certain forms of myelosis.

Monocytopenia is seen in severe septic and infectious processes

Eosinopenia is typical for typhoid fever, measles, pneumonia, septicaemia, aggravation of tuberculosis and rheumatic fever.

H. Qualitative changes in white blood,

High leukocytosis is rather often accompanied by a marked deviation to the left and appearance of primary and immature elements of white blood in the circulating flow such as myeloblasts (the youngest of the precursor cells of granulocytic series) or nest intermediate forms of granulocytes (promyelocytes, myelocytes and juvenile neutrophils) It is typical for a number of infcclions.

Thc deviation degree demons!rates activity with appearancc of myelocytes; juvenile neutrophils are more typical for pyoseptic and infectious diseases, haemolysis, chronic leukosis, allergic reactions, bleeding.

An increased quantity of juvenile and band forms is a sign, which demonstrates an increase in hemopoiesis,

Hiatus lcukcmicus is such a type of content of ail neutrophils when an increase in the quantity of immature forms (myelocytes, juvenile forms) and a small number of mature forms (segmental neutrophils) are present, hut transitional forms (juvenile, band neutrophils) are absent. Hiatus leukemic us is a sign of acute leukosis.

A deviation of the differential count to the right means an increased amount of mature leukocytes (segmental neutrophils), practically without any immature (hand) neutrophils. 1< can be very rare and displays a disorder in the bone marrow haemopoiesis.

Neutropenia is such a condition of the differential blood count when the quantity of neutrophils decreases more than by 1/3 versus the age norm. Pathogenesis of neutropenia (which may be leukopenia) can be caused by:

disorder in the haemopoictic function of the bone marrow and incomplete going out of mature neutrophils into peripheral blood,

acceleration of the destruction of fanned elements;

increase in Lhc removal of neutrophils from haemocirculalion^ Neutropenia is a rather rare condition and appears in:

-some infectious diseases (malaria, measles, typhoid fever, influenza, severe forms of bacterial infections with an increased duration);

tuberculosis;

prolonged treatment by cytostatic medicmcs, sulfonamides, antibiotics;

some type of anaemia (B,rfoiled ficit, hypoplastic anaemia);

increased irradiation,

aplasia of the bone marrow.

Lymphocytosis is an increase in the quantity of lymphocytes which can cause leukocytosis, Its pathogenesis is based on an increased formation of a large number of lymphocytes from the lymphopoietic organs and their arrival in the circulating blood. The

main causes are as follows:

acute infectious diseases (whoopingcough, viral hepatitis);

chronic infectious diseases (tuberculosis, syphilis, brucellosis);

chronic lympholeukosis.

Lymphopenia is a decrease in the quantity of lymphocytes, caused by some hypo function of the lymphopoietic organs; lymphopenia can produce leukopenia. Lymphopenia can occur in: congenital immunodeficiency, -acquired immunodeficiency syndrome;

lymphogranulomatosis.

True leukaemia is differentiated from leukaemoid reaction on the basis of bone marrow studies.

Toxic granulation of leukocytes is a sign of infection. Thrombocytes. The number of blood platelets is normally

200,000-300,000.

Throtrtbocytosis is typical for many infection diseases (pneumonia, rheumatic fever).

Thrombopenia is found in severe forms of anaemia, leukaemia,

idiopathic thrombocytopenic purpura.

Erythrocyte sedimentation rate (ESR). The normal erythrocyte sedimentation rate is: iewborns – 0-2 mm/h, in infants – 2-4 mm/h, later -4-10 mm/h.

An increase of ESR is a sign of different pathology: an inflammatory process of any sysiem (the higher ESR, the more acute pathological condition), infectious diseases, allergic reactions,

malignant pathology.

Decreased ESR is rare; it may be found out in dehydration, anaphylactic shock, dystrophy, peptic ulcer, heart failure, acute viral hepatitis.

Below are listed the main pathological syndromes of haematological disease,

Anaemic syndrome.

Leukocytic and leukopenic .syndromes.

Haemorrhagic syndrome:

haemalomatic type,

petechial type;

vaseulitic type;

angiomatotic type.

Syndrome of lymph node enlargement:

a} regional enlargement of lymph nodes;

b) generalised enlargement of lymph nodes.

The main diseases of blood are as follows:

1, Anaemiae (deficiency, haemolytic or aplastic origin, haemoglobin structural abnormalities, secondary anaemiae).

2 Disorder of Icukocytes (quantitative disorders of neutrophils, qualitative abnormalities of neutrophils; leukaemiac).

3. Hacmorrhagic and thrombotic diseases (congenital and inherited coagulation disorders; acquired disorder: idiopathic thrombocytopenic purpura).

Anaemia is condition which is characterised by decrease of quantity of erythrocytes and content of haemoglobin {separately or in combination) in the Unite of blood volume.

There are 3 main group of etiological factors of anaemia:

Anaemia as a result of bleeding (posthaemorThagic). Decrease of quantity of erythrocytes and haemoglobin is marked in blood analysis, normochromic reticulocytosis after some time.

Anaemi a as result of di sorder o f hacmopoi esis,

Deficiency anaemia (more often iron deficiency anaemia), iron deficit due to disorder of its supply, absorption or intensive loses Causes: exogenic insufficiency, if a child docs not get necessary amount of iron with food (nutritional, or alimentary anaemia) exogenic insufficiency of iron in time of ns intensive need (infectious diseases), endogenic insufficiency of iron due to disorders of its assimilation (diseases of the gastrointestinal system).

It is acceplcd, as a rule, to single out 3 degrees of anaemia, depending upon the quantity of haemoglobin:

 

 

Laboratory criteria of anaemia in the neonatal period:

 

Iron deficiency anaemia ts (he most often type of anaemia in children of the first 3 years of life. Frequent anaemia in children IS caused by lability of their hemopoietic system. Many unfavourable factors (disoiders of nutrition, hygienic regimen, intercurrent diseases) can cause anaemia in children. However after eradication of the cause the bone mano* function rapidly improve? and blood

count data become normal.

In older children, posthaemoirhagic anaemia occurs as a result o! gastrointestinal, Tenal or uterine bleeding.

“Truc’* anaemia may be erroneously diagnosed in cases of haemodilution or liaemocondensation caused by oedema or dehydration of various origin.

Haemolybc sffldjrome. Haemolysis is the process of destruction of erythrocytes, accompanied by haemoglobin going out from erythrocytes into plasma,

Pathological haemolysis can be caused by e*oerythiocylic and endoerytluocytic factors.

Ejtoerythrocytic factors:

-haemoiytic poisons and toxins (snake, helminthcs, bee, scorpions, arsenic, benzol, bacteria, chronic lead intoxication);

transfusions of incompatible (by group and Rh factor) blood,

-doctors1 mistakes in intravenous transfusions of hypotonic

solutions;

severe infections (malaria, sepsis);

severe burns;

presence of antibodies to erythrocytes.

Haemoiytic disease of newborn due to Rh or group conflicts is an example of haemolysis.

Endoerythrocyiic haemoiytic factors; congenital diseases (icterohaemolytic anaemia, acquired disorders).

Haemolytic syndrome is a sign of group of diseases, whose common sign is haemolysis of erythrocytes with development of anaemia and ail increased destruction of erythrocytes, and in the same time with some increase of erythropoicsis as compensation for anaemia.

Haemoiytic syndrome has such signs as:

clinical:

severe general condition (fever, headache, pain in muscles, joints, consciousncss disorders, such as collapse and coma);

pallor;

incterus;

dyspnoea;

enlargement of the liver and spleen;

in laboratory analyses:

normochromic anaemia,

degenerative changes of erythrocytes (poikilo-, anisocytosis);

hypergemogjobinacmia;

neutrophilic leukocytosis with a deviation to the left;

heperbilinibinaemia with indirect bilirubin;

large quantity of scrum iron;

reticutocytosis;

in urinalysis:

haemoglobinuna;

stercobilinogen, urobilinogen;

in coprogramme:

increase of stercobilinogen.

Disseminated intravascular coagulation (DlC) syndrome This, or thrambohflemorrhfigic, syndrome is a complex of nonspecific pathological symptoms, based on the arrival of exo- and endogenic factors to vessels; these factors activate the coagulative system of blood and aggregation of thrombocytes in the vital organs, causing their dysfunction. DIGS is. not an independent disease. There are many causes of DICS development:

generalized infections of bacterial and viral origins (sepsis by

50 %);

-embolism of amnionic fluid;

shock;

bums;

Rehydration (bleeding, dyspeptic disorder);

injury:

■ dystrophic changes oi organs; acute intravascular haemolysis;

mal ignant diseases;

diseases of blood (gemorrhagic vasculitis, leukosis);

snake and insect bites;

mas&ive bleeding,

allergic reactions to medicines and of other origins;

blood contact with a foreign surface (hacmodyalysis and artificial haemocirculation apparatuses, etc.).

Pathogenesis and clinical signs.

The arrival of tissue thromboplastin is a start in the process of D1CS (III factor), then through VIT factor and other factors the external mechanism of coagulation is activated. Other factors, through activation of XI( factor, cause activation of the internal mechanism of haemostasia. Sometimes the process can start from haemolysis- Vascular epithelium is affected by this whole proccss. Finally, a lot of microscopic clots of fibrin are organized, thereby thrombosing vessels.

There are 4 stages of the above syndrome.

1: the phase of hypercoagul&tion and aggregation of thrombocytes. The symptoms of this stage include hyperthermia, pallor and “marble” pattern of skin, convulsion syndrome and petechias Clotting time (Lee-White and Barker’s tests) is accelerated (Lee White lest is less than 4 minutes)

II: the transition phase with increased coagulopathy and thrombocytopenia, different directions of change in coagulation tests:

clotting time and prothrombinc index arc typical for hypercoagulation;

thrombine time is prolonged due to deficit of fibrinogen.

Ill: the phase of expressed hvpocoagu latum up to complete (absolute) absence of blood clotting **

Indices of clotting time will be increased or blood clotting cannot be realized.

IV; the phase of restitution (in unfavourable eases – the phase of complication or lethal outcome occur).

Hemorrhagic diathesis. Hemorrhagic syndrome is a clinical manifestation Of the organism’s tendency to recurrent bleeding and haemorrhage spontaneously or under influence of a minor injury. l laemOTThagic syndrome is typical for a group of diseases which are callcd haemorrhage diatheses.

Diatheses are divided into 3 groups according to the main pathological syndrome, which is based on 3 factors of haemostasis:

coagulation system of blood; quality and quantity of thrombocytes;

vascular wall (normally, formed elements of blood do not come through the vascular wall).

Haemorrhagic diatheses are classified as:

-coagulopathies (disorders of coagulation are the base of

path ogenesis), haemophi 1 ia and others;

thrombocytopathy (disorder of formation and quantity of thrombocytes) – Werlhofs disease and others;

-vasopathy (affection of the vascular wall) – SchOniein s

disease and others

Leukosis is a maligna! tumour originating in haemopoehc cells

and accompanied by affection of the bore marrow with ousting of the

normal haematopoelic sprout. The term “leukaemia” is the synonym

for the term “leukosis”.

The origin of leukosis is unknown This disease is known to occur more often in cases of: X-ray radiation, ionizing irradiation, prolonged taking of eytosialic immunologic depressants, influence of radioactive and some chemical substances (benzol)

Inherited predisposition to leukosis is noticed- All leukoses are divided into acute and chronic (not according to the duration of the disease, but by the character of Jibordcr of haemopoiesis and blood

cell composition).

In compliance with the type of cell precursor of malignant hemopoietic cell (Ivmp hob last, eiyth rob last, megakaryoblasl), tt is possible to determine such types of acute leukosis as lymphoblastic, myeloblast* and megakaryoblastic. The form of leukosis, which originates in undifferentiated cells, is called undifferentiated leukosis.

In children, acute leukosis is more common than chronic, i he latter is charactered by increased proliferation of immature cells and their ability to differentiate to matured cells. Almost all

malignant cells are represented by the morphologically matured cells (lymphocytes in case of lympholeukosis, monocytes in monocytic leukosis, erythrocytes in erythremia, and so on).

Malignant proliferation of blood cells from the bone marrow is the main pathogenic sign of acute leukosis These changes arc accompanied by haemorthagic syndrome, necrotic-ulcerated and dysthrophic processes, infectious complications.

At the onset of the disease its symptoms have common features: general weakness, tiredness, dyspnoea, tachycardia, divines s.

The most typical symptoms appear in the aeutc stage of the disease:

-ostealgia, arthralgia, pain in the sternum during a slight beating, then symptoms of leukosis rapidly develop;

fever, haemorrhagic syndrome (petechias, haemorrhages on the skin, in I he subcutaneous tissue and brain) Haemorrhagic syndrome is caused by disorders of 3 haemostatic factors: thrombocytopenia, affection of the vascular wall (leukemic infiltration} and disorders of the coagulation system, ulcerous-necratic process in the oral cavity and intestines, anaemia.

Il is possible to reveal during examinalion:

enlargement of lymph nodes,

Miculicz’s syndrome, i.e. leukaemic infiltration of the lacrimal ^land tissue and saliva;

myocardiodys trophy; tachycardia;

low BP;

-pneumonia with leukaemic meningoencephalitis.

Laboratory data

Bone marrow puncture:

-enlargement in the quantity of blast cells to 70-100 % of cells;

-decrease in the quantity of erylhronorma blasts, cells of granulocytic type and mcgakaryoblasts,

Blood count:

erythropema (up to 1.0-1.5×10 /I);

decrease of haemoglobin (down to 20-30 g/l);

thrombocytopenia (below its critical level);

-leukocyte count can be different (from leukopenia to hyperleukocytosis);

leukaemic blast cells (the main count of leukograms), whose quantity can reach 100 %;

hiatus leukenncus is an Important sign;

increase of tiSR