CLINICAL PATHOPHYSIOLOGY OF THE BLOOD SYSTEM
ANEMIA
Formation of blood cells
The hematopoietic tissue, i.e., red bone marrow in adults, the spleen and liver in the fetus, contain pluripotent stem cells that, under the effect of hematopoietic growth factors, differentiate into myeloid, erythroid, and lymphoid precursor cells. These stem cells reproduce in such a way that their stock is maintained throughout life. While the lymphocytes that originate from the lymphoid precursors still require further maturation (partly in the thymus, partly in the bone marrow) and are later on formed in the spleen and the lymph nodes (lymphopoiesis), all other precursor cells proliferate and mature up to their final stage in the bone marrow (myelopoiesis), until they finally pass from there into the blood. Among other factors, two renal hormones are involved in this, namely erythropoietin for the maturation and proliferation of erythrocytes, and thrombopoietin for megakaryocytes and thrombocytes, respectively. There are additional paracrine factors that regulate blood cell formation in the bone marrow. Because of their action in cellculture, they are sometimes also called colony-stimulating factors (CSFs). Other stem cell growth factors are stem cell factor (SCF = steel factor = c-kit ligand) and fit3 ligand (FL). They trigger the release of synergistically active factors, such as CSF and interleukins (IL-3, IL-6, IL-11, IL-12) and are inhibited, among others, by transforming growth factor β (TGF-β) and tumor necrosis factor α (TNF-α).
Hematopoiesis is the process by which the formed elements of the blood are produced. All blood cells are made in the marrow. When the cells are formed and functional, they leave the marrow and enter the blood. The red cells and the platelets carry out their respective functions of delivering oxygen and plugging up injured blood vessels throughout the body. The white cells (neutrophils, eosinophils, basophils, monocytes and lymphocytes) enter the tissues (for example, the lungs) to combat infections, such as pneumonia, and perform other immune functions.
Anemia is the term given to the reduction in the number of erythrocytes, in the concentration of hemoglobin and/or in the hematocrit as long as the total blood volume is normal. Shortly after acute major blood loss, in dehydration, or in hyperhydration the blood volume must first be normalized before anemia can be diagnosed. Using the erythrocyte parameters mean corpuscular volume (MCV) and mean corpuscular hemoglobin (MCH), anemias can be classified according to cell volume (MCV: microcytic, normocytic, or macrocytic) and according to the ratio of Hb concentration/erythrocyte count (MCH: hypochromic, normochromic, or hyperchromic). Pathogenetic division of the anemias reflects the individual steps of erythropoiesis as well as the life-span of the erythrocytes circulating in blood (haemolytic anaemia. Finally, acute or chronic blood loss can also lead to anemia.
Hematological attributes of anemias are subdivided on quantitative and qualitative.
The quantitative displays include:
1) reduction of the maintenance of erythrocytes in unit of blood volume – in men is lower than 4×1012, in women is lower than 3,5×1012 in 1L of blood;
2) reduction of hemoglobin concentration – in men is lower than 130 g/l, in women is lower than 120 g/l;
3) reduction of hematocrit – in men is lower than 0,43 l/l, in women is lower than 0,40 l/l;
4) change of a color index – is not lower than0,85 and not higher than 1,15.
Qualitative attributes of anemias are presence in blood of:
1) regenerative, but not mature forms of erythrocytes;
2) degenerative changes of erythrocytes;
3) cells of pathological regeneration.
The peripheral blood smear provides important information about defects in red cell production. As a complement to the red cell indices, the blood smear also reveals variations in cell size (anisocytosis) and shape (poikilocytosis). The degree of anisocytosis usually correlates with increases in the RDW or the range of cell sizes. Poikilocytosis suggests a defect in the maturation of red cell precursors in the bone marrow or fragmentation of circulating red cells. The blood smear may also reveal polychromasiaѕred cells that are slightly larger thaormal and grayish blue in color on the Wright-Giemsa stain. These cells are reticulocytes that have been prematurely released from the bone marrow, and their color represents residual amounts of ribosomal RNA. These cells appear in circulation in response to EPO stimulation or to architectural damage of the bone marrow (fibrosis, infiltration of the marrow by malignant cells, etc.) that results in their disordered release from the marrow. The appearance of nucleated red cells, Howell-Jolly bodies, target cells, sickle cells, and others may provide clues to specific disorders.
Variations in cell size (anisocytosis)
Variations in cell shape (poikilocytosis)
Anulocytes
Howell-Jolly bodies
Classifications of anemias.
І According to the ratio of Hb concentration/erythrocyte count (color index):
а) normochromic (the color index is within the limits of 0,85-1; for example, acute posthemorrhagic anemia during first days after hemorrhage);
b) hypochromic (the color index is lower than 0,85; for example, irondeficiency anemia);
c) hyperchromic (the color index is higher than 1,0; for example, B12-deficiency anemia).
ІІ. Pathogenetic classification:
А. posthemorrhagic anemias: a)acute posthemorrhagic anemia; b) chronic posthemorrhagic anemia.
B. hemolytic anemias.
1. acquired: а) toxic-hemolytic; b) immune; c) mechanical; d) acquired membrane pathy.
2. hereditary: а) hereditary membrane pathy; b) enzymopathy; c) hemoglobinopathy.
C. Anemias as a result of erythropoiesis disorders.
1. deficient: а) irondeficient; b) B12-deficient; c) proteindeficient.
2. hypo-, aplastic.
3. metaplastic.
4. dysregulative.
Blood Loss Anemia
With anemia caused by bleeding, iron and other components of the erythrocyte are lost from the body. Blood loss may be acute or chronic.
Acute blood loss is accompanied by a loss of vascular volume and carries with it a risk of hypovolemia and shock. The red cells are normal in size and color. Hemodilution caused by movement of fluid into the vascular compartment produces a fall in red blood cell count, hemoglobin, and hematocrit. The hypoxia that results from blood loss stimulates red cell production by the bone marrow. If the bleeding is controlled and sufficient iron stores are available, the red cell concentration returns to normal within 3 to 4 weeks.
Chronic blood loss does not affect blood volume but instead leads to iron-deficiency anemia when iron stores are depleted. Because of compensatory mechanisms, patients commonly have no symptoms until the hemoglobin level is less than 8 g/dL. The red cells that are produced have too little hemoglobin, giving rise to microcytic hypochromic anemia.
Iron deficiency anemia
Iron deficiency is a common worldwide cause of anemia affecting persons of all ages.
The causes of Iron deficiency anemia:
– Blood loss (gastrointestinal tract, increased menstrualbleeding) in adults is the most common cause of iron deficiency (0.5 mg Fe lost with each mL of blood)
– Fe recycling is decreased; this form of anemia (the second most common worldwide) occurs with chronic infections. In this situation the Fe regained by the macrophages is no longer adequately released and thus cannot be reused
– Fe uptake is too low (malnutrition, especially in the developing countries)
– Fe absorption is reduced due to: 1) achlorhydria (atrophic gastritis, after gastrectomy; 2) malabsorption in diseases of the upper small intestine or in the presence of Fe-binding food components (phytate in cereals and vegetables; tannic acid in tea, oxalates, etc.)
– There is increased Fe requirement (growth, pregnancy, breast-feeding)
– An apotransferrin defect (rare).
Iron deficiency anemia is the condition in which there is anemia and clear evidence of iron deficiency. However, it is worthwhile to consider the steps by which iron deficiency occurs.
These can be divided into three stages. The first stage is negative iron balance, in which the demands for (or losses of) iron exceed the body’s ability to absorb iron from the diet. This stage can result from a number of physiologic mechanisms including blood loss, pregnancy (in which the demands for red cell production by the fetus outstrip the mother’s ability to provide iron), rapid growth spurts in the adolescent, or inadequate dietary iron intake. Most commonly, the growth needs of the fetus or rapidly growing child exceed the individual’s ability to absorb the iroecessary for hemoglobin synthesis from the diet. Blood loss in excess of 10 to 20 mL of red cells per day is greater than the amount of iron that the gut can absorb from a normal diet. Under these circumstances the iron deficit must be made up by mobilization of iron from RE storage sites. During this period measurements of iron storesѕsuch as the serum ferritin level or the appearance of stainable iron on bone marrow aspirationsѕwill decrease. As long as iron stores are present and can be mobilized, the serum iron, total iron-binding capacity (TIBC), and red cell protoporphyrin levels remain withiormal limits. At this stage, red cell morphology and indices are normal.
When iron stores become depleted, the serum iron begins to fall. Gradually, the TIBC increases, as do red cell protoporphyrin levels. By definition, marrow iron stores are absent when the serum ferritin level <15 ug/L. As long as the serum iron remains within the normal range, hemoglobin synthesis is unaffected despite the dwindling iron stores. Once the transferrin saturation falls to 15 to 20%, hemoglobin synthesis becomes impaired. This is a period of iron-deficient erythropoiesis. Careful evaluation of the peripheral blood smear reveals the first appearance of microcytic cells, and if the laboratory technology is available, one finds hypochromic reticulocytes in circulation. Gradually, the hemoglobin and hematocrit begin to fall, reflecting iron deficiency anemia. The transferrin saturation at this point is 10 to 15%.
When moderate anemia is present (hemoglobin 10-13 g/dL), the bone marrow remains hypoproliferative. With more severe anemia (hemoglobin 7-8 g/dL), hypochromia and microcytosis become more prominent, misshapen red cells (poikilocytes) appear on the blood smear as cigar or pencil-shaped forms and target cells, and the erythroid marrow becomes increasingly ineffective. Consequently, with severe prolonged iron deficiency anemia, erythroid hyperplasia of the marrow develops rather than hypoproliferation.
The manifestations of iron-deficiency anemia are related to lack of hemoglobin and impaired oxygen transport. Depending on the severity of the anemia, fatigability, palpitations, dyspnea, angina, and tachycardia may occur. Epithelial tissue atrophy is common and results in waxy pallor, brittle hair and nails, smooth tongue, sores in the corners of the mouth, and sometimes dysphagia and decreased acid secretion. A poorly understood symptom that sometimes is seen is pica, the bizarre compulsive eating of ice, dirt, or other abnormal substances.
Clinical manifestations of iron-deficiency anemia.
Anemic syndrome.
Easy fatigability, tachycardia, palpitations, tachypnea on exertion, pallor, malaise, weakness, light-headedness, vertigo, and tinnitus, as well as palpitations, angina, and the symptoms of congestive failure.
In the anemic patient, physical examination may demonstrate a forceful heartbeat, strong peripheral pulses, and a systolic “flow” murmur. The skin and mucous membranes may be pale if the hemoglobin is <80 to 100 g/L (8 to 10 g/dL).
Sideropenic syndrome.
Cheilosis (fissures at the corners of the mouth), fever and koilonychia (spooning of the fingernails) are signs of advanced tissue iron deficiency.
Iron deficiency causes skin and mucosal changes, including a smooth tongue, brittle nails. Dysphagia because of formation of esophageal webs also occurs. Many iron-deficient patients develop pica, craving for specific foods, ofteot rich in iron.
Diagnostic criteria include anemia, hypochromic and microcytic red cell indices, low serum ferritin and serum iron levels, low transferrin saturation, increased total iron-binding capacity, and, ultimately, response to iron therapy.
Erythrocytes in severe iron deficiency.The large area of central pallor (anulocytes) is typical. The erythrocytes are flat, small, and appear pale
The treatment of iron-deficiency anemia is directed toward controlling chronic blood loss, increasing dietary intake of iron, and administering supplemental iron. Ferrous sulfate, which is the usual oral replacement therapy, replenishes iron stores in several months. Parenteral iron (iron dextran) therapy may be used when oral forms are not tolerated or are ineffective. Caution is required because of the possibility of severe hypersensitivity reactions.
B12-(folate)deficiency anemia.
Cobalamine (vitamin B12) must be taken up by humans in their food (daily requirement:3 – 5 µg). About a thousand times this amount is stored in the liver. Bound to different proteins, it is transported inside the organism from food to the site of its action where, in the form of methylcobalamine, it serves as coenzyme in demethylating N5-methyltetrahydrofolate. Among possible causes of cobalamine deficiency are:
– Too little uptake with food(e.g., a strict vegetarian diet);
– Intrinsic factor (IF) deficiency (in atrophic gastritis etc.)
– IF is essential for the binding and absorption of cobalamine. It is freed from its binding to salivary proteins in the lumenof the smallintestine;
– Competition for cobalamine and splitting of IF from bacteria (blind-loop syndrome;, or broad fish tapeworms in the intestinal lumen;
– Absence (congenital, after resection) or inflammation of the terminal ileum, i.e., at the site of absorption of cobalamine);
– Defective transcobalamine II (TCII), which is responsible for cobalamine transport in plasma and for its uptake into cells.
Because of the great store of cobalamine in the liver, the symptoms of cobalamine deficiency (pernicious anemia, neurological abnormalities) occur only after years of blocked supply.
Deficiency of vitamin B12 results in development of the frustration connected with formation disorder of its two coenzyme forms: methylcobalamine and 5-desoxyadenosilcobalamine. In a red bone marrow erythroblastic type of hemopoiesis is replaced on megaloblastic, inefficient erythropoesis increases, life expectancy of erythrocytes is shortened. The anemia with the expressed degenerate shifts not only in a bone marrow, but also in blood develops. Changes in cells of myeloid and megacariocytic lines are shown by reduction of leukocytes quantity and thrombocytes, expressed by atypia of cells (huge neutrophils, megacaryocytes with degenerative changes in a nucleus). Occurrence of atypic mitosis and huge cells of epithelium digestive tract results in development of inflammatory-atrophic processes in mucous membrane of its parts (glossitis, stomatitis, esophagitis, achylic gastritis, enteritis). As a result of the second coenzyme forms insufficiency of vitamin B12 – 5-desoxyadenosilcobalamine in organism propionic and methylmalonic acids, which are toxic for nervous cells. Besides fatty acids with the changed structure are synthesised iervous fibres results in disorder formation of myeline and to damage of axones. The degeneration of back and lateral columns of a spinal cord develops (funicular myelosis), cranial and peripheral nerves are damaged.
Occurrence in blood and red bone marrow of pathological regeneration cells – megaloblasts, megalocytes is the most typical feature of this anemia. the color index is increased, that is explained by the big saturation of cells by hemoglobin. The phenomenon of degeneration erythrocytes is typical: anisocytosis (macrocytosis), poikilocytosis (occurrence of the oval form cells), pathological inclusions (Jolly’s bodies, Cabot’s rings). The maintenance granulocytes (especially neutrophils) and thrombocytes in blood is reduced. Huge neutrophils with the hypersegmented nucleus are found out.
B12-(folate)deficiency anemia is characterized by:
1. Hematologic syndrome: а) anemia; b) leukopenia; c) thrombocytopenia. The hematologic manifestations are almost entirely the result of anemia, although very rarely purpura may appear, due to thrombocytopenia. Symptoms of anemia may include weakness, light-headedness, vertigo, and tinnitus, as well as palpitations, angina, and the symptoms of congestive failure. On physical examination, the patient with florid cobalamin deficiency is pale, with slightly icteric skin and eyes. Elevated bilirubin levels are related to high erythroid cell turnover in the marrow. The pulse is rapid, and the heart may be enlarged; auscultation will usually reveal a systolic flow murmur.
The megaloblastic anemias are disorders caused by impaired DNA synthesis. Cells primarily affected are those having relatively rapid turnover, especially hematopoietic precursors and gastrointestinal epithelial cells. Cell division is sluggish, but cytoplasmic development progresses normally, so megaloblastic cells tend to be large, with an increased ratio of RNA to DNA. Megaloblastic erythroid progenitors tend to be destroyed in the marrow. Thus, marrow cellularity is often increased but production of red blood cells (RBC) is decreased, an abnormality termed ineffective erythropoiesis.
Megaloblastic anemias are characterized by ineffective erythropoiesis. In a severely megaloblastic patient, as many as 90% of the RBC precursors may be destroyed before they are released into the bloodstream, compared with 10 to 15% iormal individuals. Enhanced intramedullary destruction of erythroblasts results in an increase in unconjugated bilirubin and lactic acid dehydrogenase (isoenzyme 1) in plasma. Abnormalities in iron kinetics also attest to the presence of ineffective erythropoiesis, with increased iron turnover but low incorporation of labeled iron into circulating RBCs.
2. Neurologic manifestations.
The neurologic manifestations often fail to remit fully on treatment. They begin pathologically with demyelination, followed by axonal degeneration and eventual neuronal death; the final stage, of course, is irreversible. Sites of involvement include peripheral nerves; the spinal cord, where the posterior and lateral columns undergo demyelination; and the cerebrum itself. Signs and symptoms include numbness and paresthesia in the extremities (the earliest neurologic manifestations), weakness, and ataxia. There may be sphincter disturbances. Reflexes may be diminished or increased. The Romberg and Babinski signs may be positive, and position and vibration senses are usually diminished. Disturbances of mentation will vary from mild irritability and forgetfulness to severe dementia or frank psychosis. It should be emphasized that neurologic disease may occur in a patient with a normal hematocrit and normal RBC indexes. Although it has many benefits, folate supplementation of food
The clinical features of cobalamin deficiency involve the blood, the gastrointestinal tract, and the nervous system.
3. Gastrointestinal manifestations.
The gastrointestinal manifestations reflect the effect of cobalamin deficiency on the rapidly proliferating gastrointestinal epithelium. The patient sometimes complains of a sore tongue, which on inspection will be smooth and beefy red. Anorexia with moderate weight loss may also be evident, possibly accompanied by diarrhea and other gastrointestinal symptoms. These latter manifestations may be caused in part by megaloblastosis of the small intestinal epithelium, which results in malabsorption.
The characteristic of hemolytic anemias
Anemias which arise after destruction (hemolysis) of erythrocytes are called hemolytic.
Hemolytic anemia is characterized by the (1) premature destruction of red cells, (2) retention in the body of iron and the other products of hemoglobin destruction, and (3) marked increase in erythropoiesis within the bone marrow.
According to the mechanism of development hemolysis anemias may be: 1) anemias with intravascular hemolysis; 2) anemias with endocellular hemolysis.
Intravascular hemolysis arises in blood vessels under the action of factors that damage erythrocytes. These factors are called hemolytic. They include:
а) Factors of physical nature (mechanical trauma, ionizing radiation, ultrasound, temperature);
b) Chemical agents (hemolytic poisons);
c) Biological factors (causative agents of infectious diseases, toxins, enzymes);
d) Immune factors (antibodies).
Intravascular hemolysis it is accompanied by an output of hemoglobin from cells to blood plasma where it partially connects with protein haptoglobin.
Endocellular hemolysis develops after absorption and digestion of erythrocytes by macrophages. In its basis the following reasons may lay: а) occurrence of defective erythrocytes. b) occurrence on surface of erythrocytes the chemical groups capable to cooperate specifically with receptors of macrophages. In this case antibodydependent phagocytosis of erythrocytes is activated; c) hypersplenism – increase of phagocytic activity of spleen macrophages.
Acquired hemolytic anemias
Depending on the reasons of development is allocated the following kinds of acquired hemolytic anemias.
1. Toxic hemolytic anemias.
2. Immune hemolytic anemias.
3. The anemias caused by mechanical damage of erythrocytes.
4. Acquired membranopathy.
Mechanical hemolysis of erythrocytes arises at prosthetics vessels or valves of heart traumas of erythrocytes in capillaries of foot during a long march (marching hemoglobinuria), at their collision with strings of fibrin (microangiopathic hemolytic anemia of DIC-syndrome).
Immune hemolytic anemias arise due to participation of specific immune mechanisms. They are caused by interaction of humoral antibodies with the antigenes fixed on a surface of erythrocytes. Their reason may be: а) receipt from the outside antibodies against own of erythrocytes (hemolytic desease of newborn); b) receipt into organism of erythrocytes which in plasma there are antibodies (the blood transfusion, not compatible on groups AB0 or Rh); c) fixing on a surface of erythrocytes foreing antigenes (haptens), in particular, medical products (antibiotics, sulfanilamides), viruses; d) formation of antibodies against own erythrocytes.
Toxic hemolytic anemia may be caused by:
а) exogenous chemical agents: phenylhydrasin, lead, copper salts, arsenous hydrogen etc.;
b) endogenous chemical factors: bile acids, products formed at burn desease, uraemia;
c) poisons of biological origin: snake, beer, poison of some kinds of spiders, aumber of infectious agents, in particular, hemolytic streptococcus, malarial plasmodium, toxoplasma, leishmania.
Acquired membranopathy arise due to the acquired defects of erythrocytes membranes. As an example may be paroxysmal noctural hemoglobinuria. This disease as a results of a somatic mutation erythropoietic cells with defects of membrane. It is considered that disorders of membranes are connected with changes of ratio of fat acids which are part of their phospholipids. Erythrocytes of abnormal population get ability to fix complement and hemolyse.
The picture of blood of acquired hemolytic anemias is characterized by reduction of erythrocytes quantity and hemoglobin. The color index iorm, however may be higher than 1 unit that is connected with extraerythrocytic hemoglobin. In blood smear the significant amount regenerative forms of erythrocytes is found out: reticulocytes, polychromatophils, normocytes.
Hereditary hemolytic anemias
All hereditary caused hemolytic anemias are subdivided into three groups.
1. Membranopathies. Defects of erythrocytes membranes are in basis of this anemias group.
2. Enzymopathies. Anemias of this group are caused by disorder of erythrocytes enzymes .
3. Hemoglobinopathies. Arise after qualitative changes of hemoglobin.
Hereditary membranopathies may be caused by two groups of defects erythrocytic membranes:
1) membranopathies, caused by disorders of membrane proteins: а) microspherocytic anemia Minkovsky-Shoffar’s; b) ovalocytic hemolytic anemia;
Anemia Minkovsky-Shoffar’s is hereditary, endoerythrocytic (membranopathy) hemolytic anemia with endocellular hemolysis. Type of inheritance – autosomal dominant. Hereditary defect mentions membrane proteins of erythrocytes, in particular spectrin. Therefore permeability of erythrocytic membranes for ions sodium is considerably increased. Sodium and water pass from plasma inside of erythrocytes. In spleen they lose part of erythrocytes membrane and turn into microspherocytes. Life expectancy of erythrocytes decreases untill 8-12 days instead of 120.
Hereditary enzymopathies arise due to defect of erythrocytes fermental systems:
1) deficiency of enzymes pentose cycle. The most widespread enzymopathy is glucose-6-phosphatedehydrogenase deficiency anemia, caused by absence or significant decrease(reduction) of glucose-6-phosphatedehydrogenase activity;
2) deficiency of enzymes of glycolysis. The most widespread is deficiency of pyruvatekinase which results to disorders of energy provision Na-K-pumps of plasmatic membranes. Erythrocytes thus turn into spherocytes which are exposed to phagocytosis by macrophages;
3) deficiency of enzymes of glutathion cycle (glutathionsynthetase, glutathionreductase, glutathionperoxidaza) results in oppression antioxidant systems of erythrocytes, barrier properties of erythrocytic membranes to ions and osmotic hemolysis;
4) deficiency of utilization АТP enzymes. An example is deficiency of albuminous components Na-K-pump of erythrocytic membranes. Thus concentration of sodium that results them to hemolysis is increased in a cell.
Qualitative and quantitative changes of hemoglobin lay in basis of development of hereditary hemoglobinopathies. The most widespread clinical form is sickle-cell anemia at which in β-chain of a molecule of hemoglobin glutamine acid is replaced on valine (HbS.) HbS is crystallized easily, erythrocyte loses its shape and cells of red blood get the sickle-like form.
Hemolytic syndrome.
The hematologic manifestations are almost entirely the result of anemia, although very rarely purpura may appear, due to thrombocytopenia. Symptoms of anemia may include weakness, light-headedness, vertigo, and tinnitus, as well as palpitations, angina, and the symptoms of congestive failure. On physical examination, the patient with florid cobalamin deficiency is pale, with slightly icteric skin and eyes. Elevated bilirubin levels are related to high erythroid cell turnover in the marrow. The pulse is rapid, and the heart may be enlarged; auscultation will usually reveal a systolic flow murmur.
Hemolytic anemias present in different ways. Some appear suddenly as an acute, self-limited episode of intravascular or extravascular hemolysis, a presentation pattern often seen in patients with autoimmune hemolysis or with inherited defects of the Embden-Myerhof pathway or the glutathione reductase pathway. Patients with inherited disorders of the hemoglobin molecule or red cell membrane generally have a lifelong clinical history typical of the disease process. Those with chronic hemolytic disease, such as hereditary spherocytosis, may actually present not with anemia but with a complication stemming from the prolonged increase in red cell destruction such as aplastic crisis, symptomatic bilirubin gallstones, or splenomegaly.
Aplastic anemias
Aplastic anemia is pancytopenia with bone marrow hypocellularity. Acquired aplastic anemia is distinguished from iatrogenic marrow aplasia, the common occurrence of marrow hypocellularity after intensive cytotoxic chemotherapy for cancer. Aplastic anemia can also be constitutional: the genetic disease Fanconi’s anemia, while frequently associated with typical physical anomalies and the development of pancytopenia early in life, can also present as marrow failure iormal-appearing adults. Acquired aplastic anemia is often stereotypical in its manifestations, with the abrupt onset of low blood counts in a previously well young adult; seronegative hepatitis or a course of an incriminated medical drug may precede the onset. The diagnosis in these instances is uncomplicated. Sometimes blood count depression is moderate or incomplete, resulting in anemia, leukopenia, and thrombocytopenia in some combination. Aplastic anemia is related to both paroxysmal nocturnal hemoglobinuria (PNH; Chap. 108)
The origins of aplastic anemia have been inferred from several recurring clinical associations; unfortunately, these relationships are neither a reliable guide in an individual patient nor necessarily etiologic. In addition, while most cases of aplastic anemia are idiopathic, little other than history separates these cases from those with a presumed etiology such as a drug exposure.
The acquired forms may be caused by the following reasons:
1) physical factors (ionizing radiation);
2) chemical agents (benzene, lead, steams of mercury, medical products: cytostatic agents, chloramphenicol, sulfanilamids);
3) biological factors (virus of hepatites).
Essential forms of anemia, which reason is not established belongs to acquired anemias.
Bone marrow failure results from severe damage to the hematopoietic cell compartment. In aplastic anemia, replacement of the bone marrow by fat is apparent in the morphology of the biopsy specimen and magnetic resonance imaging of the spine; cells bearing the CD34 antigen, a marker of early hematopoietic cells, are greatly diminished; and in functional studies, committed and primitive progenitor cells are virtually absentѕin vitro assays have suggested that the stem cell pool is reduced to ^1% of normal in severe disease at the time of presentation. Qualitative abnormalities, such as limited number of operating stem cell clones or shortened telomere length, may follow from the quantitative deficiency, reflecting the shrunken and stressed state of hematopoiesis. An intrinsic stem cell defect exists for constitutional aplastic anemia, as cells from patients with Fanconi’s anemia exhibit chromosome damage and death on exposure to certain chemical agents, but there is no convenient mechanism for the propagation of an acquired genetic abnormality that would produce a hypoproliferative (as opposed to neoplastic) disease. Aplastic anemia does not appear to result from defective stroma or growth factor production.
Appearence of hypoplastic anemias are connected with reduction of three kinds formation of form blood elements: erythrocytes, granulocytes and thrombocytes. It characterized by Cytopenic syndrome.
Aplastic anemia can appear with seeming abruptness or have a more insidious onset. Bleeding is the most common early symptom; a complaint of days to weeks of easy bruising, oozing from the gums, nose bleeds, heavy menstrual flow, and sometimes petechiae will have been noticed. With thrombocytopenia, massive hemorrhage is unusual, but small amounts of bleeding in the central nervous system can result in catastrophic intracranial or retinal hemorrhage. Symptoms of anemia are also frequent, including lassitude, weakness, shortness of breath, and a pounding sensation in the ears. Infection is an unusual first symptom in aplastic anemia (unlike in agranulocytosis, where pharyngitis, anorectal infection, or frank sepsis occur early). A striking feature of aplastic anemia is the restriction of symptoms to the hematologic system, and patients often feel and look remarkably well despite drastically reduced blood counts. Systemic complaints and weight loss should point to other etiologies of pancytopenia. History of drug use, chemical exposure, and preceding viral illnesses must often be elicited with repeated questioning
LEUКЕМІА
Blood cell development. A blood stem cell goes through several steps to become a red blood cell, platelet, or white blood cell
The leukemias are malignant neoplasms of cells originally derived from hematopoietic stem cells. They are characterized by diffuse replacement of bone marrow with unregulated, proliferating, immature neoplastic cells. In most cases, the leukemic cells spill out into the blood, where they are seen in large numbers. The term leukemia (i.e., “white blood”) was first used by Virchow to describe a reversal of the usual ratio of red blood cells to white blood cells. The leukemic cells may also infiltrate the liver, spleen, lymph nodes, and other tissues throughout the body, causing enlargement of these organs.
The causes of leukemia are unknown. The incidence of leukemia among persons who have been exposed to high levels of radiation is unusually high. The number of cases of leukemia reported in the most heavily exposed survivors of the atomic blasts at Hiroshima and Nagasaki during the 20-year period from 1950 to 1970 was nearly 30 times the expected rate. An increased incidence of leukemia also is associated with exposure to benzene and the use of antitumor drugs (i.e., mechlorethamine, procarbazine, cyclophosphamide, chloramphenicol, and the epipodophyllotoxins). Leukemia may occur as a second cancer after aggressive chemotherapy for other cancers, such as Hodgkin’s disease. The existence of a genetic predisposition to acute leukemia is suggested by the increased leukemia incidence among a number of congenital disorders, including Down syndrome, von Recklinghausen’s disease, and Fanconi’s anemia. In individuals with Down syndrome, the incidence of acute leukemia is 10 times that of the general population. In addition, there are numerous reports of multiple cases of acute leukemia occurring within the same family.
nLeukemia, like other cancers, result from somatic mutations in the DNA which activate oncogenes or deactivate tumor suppressor genes, and disrupt the regulation of cell death, differentiation or division. These mutations may occur spontaneously or as a result of exposure to radiation or carcinogenic substances and are likely to be influenced by genetic factors.
nViruses have also been linked to some forms of leukemia. For example, certain cases of ALL are associated with viral infections by either the human immunodeficiency virus (HIV, responsible for AIDS) or human T-lymphotropic virus (HTLV-1 and -2, causing adult T-cell leukemia/lymphoma).
nFanconi anemia is also a risk factor for developing acute myelogenous leukemia.
nUntil the cause or causes of leukemia are found, there is no way to prevent the disease.
On modern conception, leukemia arise on genetic, mutational basis. The speech does about specific of bloodforming cells mutations, which result to superexpression of cells oncogenes, or protooncogenes. These genes are an integral part of cells genome and answer for proliferation of cells. Cells oncogenes vitally are necessary. Without them would become impossible fill of the cells, worn out and lost during vitality. At the same time cells oncogenes, as has appeared, have latent blastomogenic potentions. Excessive expression them the regeneratioormal of bone marrow cells in leucosis stipulates.
To major etiological factors, which are capable to transform protooncogenes in active oncogenes, the chemical agents, ionising rays and retroviruses concern. There are some mechanisms of the cell oncogenes activation: point mutation, chromosomal aberrations, virus transduction, insertion of provirus, genes amplification.
Classification
The leukemias commonly are classified according to their predominant cell type (i.e., lymphocytic or myelogenous) and whether the condition is acute or chronic. Biphenotypic leukemias demonstrate characteristics of both lymphoid and myeloid lineages. A rudimentary classification system divides leukemia into four types: acute lymphocytic (lymphoblastic) leukemia, chronic lymphocytic leukemia, acute myelogenous (myeloblastic) leukemia, and chronic myelogenous leukemia.
The lymphocytic leukemias involve immature lymphocytes and their progenitors that originate in the bone marrow but infiltrate the spleen, lymph nodes, CNS, and other tissues. The myelogenous leukemias, which involve the pluripotent myeloid stem cells in bone marrow, interfere with the maturation of all blood cells, including the granulocytes, erythrocytes, and thrombocytes.
nLeukemia is clinically and pathologically split into its acute and chronic forms
Acute leukemia is a rapidly progressing disease that affects mostly cells that are unformed or immature (not yet fully developed or differentiated). These immature cells cannot carry out their normal functions.
nAcute forms of leukemia can occur in children and young adults. (In fact, it is a more common cause of death for children than any other type of malignant disease.)
nImmediate treatment is required in acute leukemias due to the rapid progression and accumulation of the malignant cells, which then spill over into the bloodstream and spread to other organs of the body. If left untreated, the patient will die within months or weeks.
Chronic leukemia progresses slowly and permits the growth of greater numbers of more developed cells. In general, these more mature cells can carry out some of their normal functions.
Typically taking months to years to progress, the cells are produced at a much higher rate thaormal cells, resulting in many abnormal white blood cells in the blood.
Chronic leukemia mostly occurs in older people, but can theoretically occur in any age group. Whereas acute leukemia must be treated immediately, chronic forms are sometimes monitored for some time before treatment to ensure maximum effectiveness of therapy.
Furthermore, the diseases are classified according to the type of abnormal cell found most in the blood.
When leukemia affects lymphoid cells (lymphocytes and plasma cells), it is called lymphocytic leukemia.
When myeloid cells (eosinophils, neutrophils, and basophils) are affected, the disease is called myeloid or myelogenous leukemia.
Acute leukemias
Acute leukemias are clonal diseases of hematopoietic precursors with molecular genetic abnormalities. All hematopoietic cell lines may be affected. Proliferation of the leukemic cell clone replaces normal hematopoiesis in varying degrees. In acute myeloid leukemia (AML), it is most common for granulocytopoiesis and monocytopoiesis to be affected. Erythropoiesis is less frequently affected, and megakaryopoiesis rarely so. The distribution of the subtypes varies according to age. Acute lymphocytic leukemia (ALL) occurs predominantly in children, while AML has its peak in adults. The involvement of several myeloid cell lines is relatively common, but the simultaneous involvement of myeloid and lymphoid cell lines is very rare (hybrid and bilinear acute leukemias). WHO has recently proposed that the percentage of blasts in the bone marrow must be approximately 20 % to justify a diagnosis of acute leukemia. Examination of the peripheral blood is not essential for diagnosis but can provide important additional information. The diagnosis and classification (subtype assignment) always rely on the bone marrow. The most widely accepted system at present for the classification of AML is based on the criteria of the French-American- British (FAB) Cooperative Group (Table see below) and of the WHO.
The acute leukemias usually have a sudden and stormy onset of signs and symptoms related to depressed bone marrow function. Acute lymphocytic leukemia (ALL) is the most common leukemia in childhood, comprising 80% to 85% of leukemia cases. The peak incidence occurs between 2 and 4 years of age. Acute myelogenous leukemia (AML) is chiefly an adult disease; although it is also seen in children and young adults. The incidence steadily increases after middle age. AML appears to be increasing among the elderly. ALL encompasses a group of neoplasms composed of immature precursor B or T lymphocytes. Most cases (about 85%) of ALL are of pre–B-cell origin. Approximately 90% of persons with ALL have nonrandom chromosome abnormalities. The AMLs are an extremely heterogeneous group of disorders. Some arise from the pluripotent stem cells in which myeloblasts predominate, and others arise from the monocyte-granulocyte precursor, which is the cell of origin for myelomonocytic leukemia. Of all the leukemias, AML is most strongly linked with toxins and underlying congenital and hematologic disorders. It is the type of leukemia associated with Down syndrome.
Clinical Manifestations. Although ALL and AML are distinct disorders, they typically present with similar clinical features. The warning signs and symptoms of acute leukemia are fatigue, pallor, weight loss, repeated infections, easy bruising, nosebleeds, and other types of hemorrhage. These features often appear suddenly in children.
Persons with acute leukemia usually present for medical evaluation within 3 months of the onset of symptoms. Both ALL and AML are characterized by fatigue resulting from anemia; low-grade fever, night sweats, and weight loss caused by the rapid proliferation and hypermetabolism of the leukemic cells; bleeding caused by a decreased platelet count; and bone pain and tenderness caused by bone marrow expansion. Infection results from neutropenia, with the risk of infection becoming high as the neutrophil count falls to less than 500 cells/µL. Generalized lymphadenopathy, splenomegaly, and hepatomegaly caused by infiltration of leukemic cells occur in all acute leukemias but are more common in ALL. In addition to the common manifestations of acute leukemia (e.g., fatigue, weight loss, fever, easy bruising), infiltration of malignant cells in the skin, gums, and other soft tissue is particularly common in the monocytic form of AML.
CNS involvement is more common in ALL than AML, and is more common in children than adults. Signs and symptoms of CNS involvement include cranial nerve palsies, headache, nausea, vomiting, papilledema, and occasionally seizures and coma.
Leukostasis is a condition in which the circulating blast count is markedly elevated (usually 100,000 cells/µL). The high number of circulating leukemic blasts increases blood viscosity and predisposes to the development of leukoblastic em-
boli with obstruction of small vessels in the pulmonary and cerebral circulations. Plugging of the pulmonary vessels leads to vessel rupture and infiltration of lung tissue, resulting in sudden shortness of breath and progressive dyspnea. Cerebral leukostasis leads to diffuse headache and lethargy, which can progress to confusion and coma. Once identified, leukostasis requires immediate and effective treatment to lower the blast count rapidly.
Hyperuricemia occurs as the result of increased proliferation or increased breakdown of purine nucleotides (e.g., one of the compounds of nucleic acid) secondary to leukemic cell death that results from chemotherapy. It may increase before and during treatment. Prophylactic therapy with allopurinol, a drug that inhibits uric acid synthesis, is routinely administered to prevent renal complications secondary to uric acid crystallization in the urine.
Chronic Leukemias
Chronic leukemias have a more insidious onset than do acute leukemias and may be discovered during a routine medical examination by a blood count.
Chronic lymphocytic leukemia (CLL) is mainly a disorder of older persons; fewer than 10% of those who have the disease are younger than 50 years. Men are affected twice as frequently as women. Chronic myelogenous leukemia (CML) accounts for 15% to 20% of all leukemias in adults. It is predominantly a disorder of adults between the ages of 30 and 50 years, but it can affect children as well. The incidence is slightly higher in men than women. CLL is a disorder characterized by the proliferation and accumulation of relatively mature lymphocytes that are immunologically incompetent. In the United States, more than 95% of cases of CLL are of B-cell origin. The leukemic B cells fail to respond to antigenic stimulation; thus, persons with CLL have hypogammaglobulinemia. Infections remain a major cause of morbidity and mortality. CML is a myeloproliferative disorder that involves expansion of all bone marrow elements. CML is associated in all cases with the presence of the Ph (Philadelphia) chromosome, representing a reciprocal translocation of the long arm of chromosome 22 to the long arm of chromosome 9. In about 5% of persons with CML, the Ph chromosome can be identified in granulocytic, erythroid, and megakaryocytic precursors, as well as B cells, and in some cases, T cells. Although CML originates in the pluripotent stem cells, granulocyte precursors remain the dominant cell type.
Clinical Course. Both CLL and CML have an insidious onset. However, the two types of chronic leukemias differ in their manifestations and clinical course.
CLL typically follows a slow, chronic course. The clinical signs and symptoms are largely related to the progressive infiltration of neoplastic lymphocytes in the bone marrow and extramedullary tissue and to secondary immunologic defects. Affected persons often have no symptoms at the time of diagnosis, and lymphocytosis is noted on a complete blood count obtained for another, unrelated disorder. Fatigue, reduced exercise tolerance, enlargement of superficial lymph nodes, or splenomegaly usually reflect a more advanced stage. As the disease progresses, lymph nodes gradually increase in size and new nodes are involved, sometimes in unusual areas such as the scalp, orbit, pharynx, pleura, gastrointestinal tract, liver, prostate, and gonads. Severe fatigue, recurrent or persistent infections, pallor, edema, thrombophlebitis, and pain are also experienced. As the malignant cell population increases, the proportion of normal marrow precursors is reduced until only lymphocytes remain in the marrow.
Typically CML follows a triphasic course: a chronic phase of variable length, a short accelerated phase, and a terminal blast crisis phase. The onset of the chronic phase is usually slow with nonspecific symptoms such as weakness and weight loss. The most characteristic laboratory finding at the time of presentation is leukocytosis with immature granulocyte cell types in the peripheral blood. Anemia and, eventually, thrombocytopenia develop. Anemia causes weakness, easy fatigability, and exertional dyspnea. Splenomegaly is often present at the time of diagnosis; hepatomegaly is less common; and lymphadenopathy is relatively uncommon. Although persons in the early chronic phase of CML generally have no symptoms, without effective treatment most will enter the accelerated phase within 3 to 5 years. The accelerated phase is characterized by enlargement of the spleen and progressive symptoms. Splenomegaly often causes a feeling of abdominal fullness and discomfort. An increase in basophil count and more immature cells in the blood or bone marrow confirm transformation to the accelerated phase. During this phase, constitutional symptoms such as low-grade fever, night sweats, bone pain, and weight loss develop because of rapid proliferation and hypermetabolism of the leukemic cells. Bleeding and easy bruising may arise from dysfunctional platelets. Generally the accelerated phase is short (6 to 12 months).
The terminal or blast crisis phase represents evolution to acute leukemia and is characterized by an increasing number of myeloid precursors, especially blast cells. Constitutional symptoms become more pronounced during this period, and splenomegaly may increase significantly. Isolated infiltrates of leukemic cells can involve the skin, lymph nodes, bones, and CNS. With very high blast counts (100,000/µL), symptoms of leukostasis may occur. The prognosis for patients who are in the blast crisis phase is poor, with survival rates averaging 2 to 4 months.
Chronic lymphocytic leukemia (CLL) results from an acquired injury to the DNA of a single cell, a lymphocyte, in the marrow. This injury is not present at birth. Scientists do not yet understand what produces this change in the DNA of CLL patients.
This change in the cell’s DNA confers a growth and survival advantage on the cell, which becomes abnormal and malignant (leukemic). The result of this injury is the uncontrolled growth of lymphocytic cells in the marrow, leading invariably to an increase in the number of lymphocytes in the blood. The leukemic cells that accumulate in the marrow in chronic lymphocytic leukemia do not impede normal blood cell production as profoundly as in the case of acute lymphocytic leukemia. This important distinction from acute leukemia accounts for the less severe early course of the disease.
Chronic lymphocytic leukemia (CLL) is a monoclonal disorder characterized by a progressive accumulation of functionally incompetent lymphocytes. It is the most common form of leukemia found in adults in Western countries.
Pathophysiology
The cells of origin in the majority of patients with CLL are clonal B cells arrested in the B-cell differentiation pathway, intermediate between pre-B cells and mature B cells. Morphologically in the peripheral blood, these cells resemble mature lymphocytes. B-CLL lymphocytes typically show B-cell surface antigens, as demonstrated by CD19, CD20, CD21, and CD24 monoclonal antibodies. In addition, they express CD5, which is more typically found on T cells. Because normal CD5+ B cells are present in the mantle zone (MZ) of lymphoid follicles, B-cell CLL is most likely a malignancy of an MZ-based subpopulation of anergic self-reactive cells devoted to the production of polyreactive natural autoantibodies.
B-CLL cells express extremely low levels of surface membrane immunoglobulin, most often immunoglobulin M (IgM) or IgM and immunoglobulin D (IgD). Additionally, they also express extremely low levels of a single immunoglobulin light chain (kappa or lambda).
Recent studies have demonstrated that bcl2, a protooncogene, is overexpressed in B-CLL. The protooncogene bcl2 is a known suppresser of apoptosis (programmed cell death), resulting in a long life for the involved cells. Despite the frequent overexpression of bcl-2 protein, genetic translocations that are known to result in the overexpression of bcl2, such as t(14;18), are not found in patients with CLL.
An abnormal karyotype is observed in the majority of patients with CLL. The most common abnormality is deletion of 13q, which occurs in more than 50% of patients. Patients showing 13q14 abnormalities have a relatively benign disease that usually manifests as stable or slowly progressive isolated lymphocytosis. The presence of trisomy 12, which is observed in 15% of patients, is associated with atypical morphology and progressive disease. Deletions of bands 11q22-q23, observed in 19% of patients, are associated with extensive lymph node involvement and aggressive disease. More sensitive techniques have demonstrated abnormalities of chromosome 12. Approximately 2-5% of patients with CLL exhibit a T-cell phenotype.
CLL also should be distinguished from prolymphocytic leukemia, in which more than 65% of the cells are morphologically less mature prolymphocytes.
Peripheral blood smear of the patient with CLL
As in the case of most malignancies, the exact cause of CLL is uncertain.
The protooncogene bcl2 is known to be overexpressed, which leads to suppression of apoptosis (programmed cell death) in the affected lymphoid cells.
CLL is an acquired disorder, and reports of truly familial cases are exceedingly rare.
Unlike the other three major types of leukemia, chronic lymphocytic leukemia is not associated with high-dose radiation or benzene exposure. First-degree relatives of patients with the disease have about a threefold greater likelihood of getting the disease than other people. This should be put into perspective, however. For example, the 60-year-old sibling or offspring of a patient with chronic lymphocytic leukemia would have three chances in 10,000 of developing the disease compared with the one chance in 10,000 for a 60-year-old person without a family history of the disease. The disease is very uncommon in individuals under 45 years of age. At the time of diagnosis, 95 percent of patients are over age 50, and the incidence of the disease increases dramatically thereafter.
Symptoms and Signs
Early in the disease, chronic lymphocytic leukemia often has little effect on a person’s well being. The disease may be discovered after finding an abnormal blood count during the course of a periodic medical examination or while the patient is under care for an unrelated condition. The report of an elevated white cell count is the most common clue that leads a physician to consider the diagnosis of chronic lymphocytic leukemia.
The symptoms of chronic lymphocytic leukemia usually develop gradually. Patients tire more easily and may feel short of breath when physically active, as a result of anemia. They may lose weight. The leukemic lymphocytes (white cells) can accumulate in the lymphatic system and the lymph nodes and spleen may become enlarged. Patients may experience infections, sometimes recurrent, of the skin, lungs, kidneys, or other sites.
History
· Patients with CLL present with a wide range of symptoms and signs at presentation. Onset is insidious, and it is not unusual for this disorder to be discovered incidentally after a blood cell count is performed for another reason.
· Predisposition to repeated infections such as pneumonia, herpes simplex labialis, and herpes zoster
· Enlarged lymph nodes
· Early satiety and/or abdominal discomfort related to an enlarged spleen
· Mucocutaneous bleeding and/or petechiae secondary to thrombocytopenia
· Tiredness and fatigue secondary to anemia
Bypass of CLL has three stages:
1. Initial (slight increasing of lymphatic nodes one or two groups, leucocytosis no more than 30 – 50 х 109/l, working capacities preserved.
2. Unrolled (increasing leucocytosis, progressing generalized enlargement of lymph nodes, relapsing infections, and autoimmune cytopenia).
3. Terminal – malignant transformation with expanding of leucosis process out of the borders of hemopoetic system.
Basis of clinical diagnostics of CLL is lymphadenopathy, splenomegaly, hepatomegaly, infiltration by tumoral lymphocytes of pleura, gastrointestinal tract (with simulation of stomach tumor, intestinal polyposis), prostate, bones and joint with development of osteoporosis and osteolisis of vertebra and pelvic bones; perivascular infiltration of retine of eye, middle ear, vestibular apparatus, nervous system (hemiplegia, meningisms, paralysis of cranial nerves), skin (lymphocytic tumoral erythema, macropapules, exematous placodes, rarely – specific skins leukemia’s, erythrodermia, prurigo). From general features – hyperhydrosis, weight loss, undue fatigue.
Physical:
· Localized or generalized lymphadenopathy
o Splenomegaly (30-40% of cases)
o Hepatomegaly (20% of cases)
· Petechiae
· Pallor
Chronic myelogenous leukemia (CML) is a myeloproliferative disorder characterized by increased proliferation of the granulocytic cell line without the loss of their capacity to differentiate. Consequently, the peripheral blood cell profile shows an increased number of granulocytes and their immature precursors, including occasional blast cells. CML is a tumor arisen from one mutate predecessors-cells of mielopoiesis, morphological substrate of which, as a rule, is three- sprouts proliferation, which displays that with prevalent surplus excrescence of cells of granulocytes row, also has a place moderate cell proliferation of erytrocytes and megacariocytes sprouts. This peculiarity is associated with that these sprouts develop from one matter – predecessors-cells of mielopoiesis.
Pathophysiology: CML is an acquired abnormality that involves the hematopoietic stem cell. It is characterized by a cytogenetic aberration consisting of a reciprocal translocation between the long arms of chromosomes 22 and 9; t(9;22). The translocation results in a shortened chromosome 22, an observation first described by Nowell and Hungerford and subsequently termed the Philadelphia (Ph) chromosome after the city of discovery.
The Philadelphia chromosome as seen by metaphase FISH
This translocation relocates an oncogene called abl from the long arm of chromosome 9 to the long arm of chromosome 22 in the BCR region. The resulting BCR/ABL fusion gene encodes a chimeric protein with strong tyrosine kinase activity. The expression of this protein leads to the development of the CML phenotype through processes that are not yet fully understood.
The presence of BCR/ABL rearrangement is the hallmark of CML, although this rearrangement has also been described in other diseases. It is considered diagnostic when present in a patient with clinical manifestations of CML.
Causes:
· The initiating factor of CML is still unknown, but exposure to irradiation has been implicated, as observed in the increased prevalence among survivors of the atomic bombing of Hiroshima and Nagasaki.
· Other agents, such as benzene, are possible causes.
Among etiological factors the most essential are physical and chemical mutagens, viruses, congenital or acquireed defects of immune defense. However in majority of cases (87 %) the cause of beginnings of leucocytosis growth is chromosomal pathology (Philadelphia chromosome).
In some cases the conditions of “slip out” are created of mutant from under immune control. As a result, happened to be outside of organism control, a mutant cell continues uncontrolledly to “reproductive”, that brings to fast accumulation of tumoral tissues and forcing out healthy haemopoiesis.
· Most patients present in the chronic phase, characterized by splenomegaly and leukocytosis (see Image below) with generally few symptoms. This phase is easily controlled by medication. The major goal of treatment during this phase is to control symptoms and complications resulting from anemia, thrombocytopenia, leukocytosis, and splenomegaly. Newer forms of therapy aim at delaying the onset of the accelerated or blastic phase.
· After an average of 3-5 years, the disease usually evolves into the blast crisis, which is marked by an increase in the bone marrow or peripheral blood blast count or by the development of soft tissue or skin leukemic infiltrates. Typical symptoms are due to increasing anemia, thrombocytopenia, basophilia, a rapidly enlarging spleen, and failure of the usual medications to control leukocytosis and splenomegaly. The manifestations of blast crisis are similar to those of acute leukemia. Treatment results are unsatisfactory, and most patients succumb to the disease once this phase develops. In approximately two thirds of cases, the blasts are myeloid. However, in the remaining one third of patients, the blasts exhibit a lymphoid phenotype, further evidence of the stem cell nature of the original disease. Additional chromosomal abnormalities are usually found at the time of blast crisis, including additional Ph chromosomes or other translocations.
· In many patients, an accelerated phase occurs 3-6 months before the diagnosis of blast crisis. Clinical features in this phase are intermediate between the chronic phase and blast crisis.
Clinical manifestations
· The clinical manifestations of CML are insidious and are often discovered incidentally when an elevated WBC count is revealed by a routine blood count or when an enlarged spleen is revealed during a general physical examination.
· Nonspecific symptoms of tiredness, fatigue, and weight loss may occur long after the onset of the disease. Loss of energy and decreased exercise tolerance may occur during the chronic phase after several months.
· Patients often have symptoms related to enlargement of the spleen, liver, or both.
1. The large spleen may encroach on the stomach and cause early satiety and decreased food intake. Left upper quadrant abdominal pain described as “gripping” may occur from spleen infarction. The enlarged spleen may also be associated with a hypermetabolic state, fever, weight loss, and chronic fatigue.
2. The enlarged liver may contribute to the patient’s weight loss.
· Some patients may have low-grade fever and excessive sweating related to hypermetabolism.
· The disease has 3 clinical phases, and it follows a typical course of an initial chronic phase, during which the disease process is easily controlled; followed by a transitional and unstable course (accelerated phase); and, finally, a more aggressive course (blast crisis), which is usually fatal.
1. Most patients are diagnosed while still in the chronic phase. The WBC count is usually controlled with medication (hematologic remission). This phase varies in duration depending on the maintenance therapy used. It usually lasts 2-3 years with hydroxyurea (Hydrea) or busulfan therapy, but it has lasted for longer than 9.5 years in patients who respond well to interferon alfa therapy. Recently, the addition of imatinib mesylate has dramatically improved the duration of hematologic and indeed cytogenetic remissions.
2. Some patients progress to a transitional or accelerated phase, which may last for several months. The survival of patients diagnosed in this phase is 1-1.5 years. This phase is characterized by poor control of the blood counts with myelosuppressive medication and the appearance of peripheral blast cells (>15%), promyelocytes (>30%) (see Image below), basophils (>20%), and platelet counts less than 100,000 cells/mL unrelated to therapy. Usually, the doses of the medications need to be increased. Splenomegaly may not be controllable by medications, and anemia can worsen. Bone pain and fever, as well as an increase in bone marrow fibrosis, are harbingers of the last phase.
3. Acute phase, or blast crisis, is similar to acute leukemia, and survival is 3-6 months at this stage. Bone marrow and peripheral blood blasts of 30% or more are characteristic. Skin or tissue infiltration also defines blast crisis. Cytogenetic evidence of another Ph-positive clone (double) or clonal evolution (other cytogenetic abnormalities such as trisomy 8, 9, 19, or 21, isochromosome 17, or deletion of Y chromosome) is usually present.
· In some patients who present in the accelerated, or acute, leukemia phase of the disease (skipping the chronic phase), bleeding, petechiae, and ecchymoses may be the prominent symptoms. In these situations, fever is usually associated with infections.
In CML flowing they pick out the next stages initial, unroll and terminal.
· For todays understanding initial stage is that disease stage, when only small part of cells of granulocytes sprout is tumoral, and majority are the cells of normal hemopoiesis. As a rule, this stage has never diagnosed, because specific clinical disease symptoms of disease are absents.
· Unroll stage is manifestation of total generalisation of tumoral cells in marrow with forcing out of healthy haemopoiesis sprout. Clinical symptoms in this stage are crescent general weakness, rapid fatigue, hyperhydrosis, weight loss, increase of temperature, osseous and articulate pains, spleen and livers enlargement which one can be combined into syndrome of tumoral intoxication.
· Terminal stage starts when a monotonously flowing monoclone tumor turns into policlone. Under this sharp there is increase of amount of tumoral cells, that with each following mutation lose ability to differentiatie, the manifestation of what is sharp increasing of cells amount of granulocytes row of different ripening degrees. Metastatic spreading of these cells, adapted to survival for boundary paths of haemopoietic system, brings about appearance of metaplastatic hearths of tumoral growth in liver, skin, bone, lymph node and oth., with clinical features of dysfunctions of these organs and systems. The most threatful features of terminal stage is blastogenic crises. A clinical picture of CML consists from tumoral intoxication syndrome, syndrome of tumoral metaplasy, syndrome of metabolitic distebance. The cells substrate of tumor are leucocytosis for a counting of immature cells of granulocytes row, metaplastic anaemia and tromcytopenia, pletora of marrow for a counting of tumoral granulocytes sprout.
Peripheral blood smear of the patient with CML
Acute phase, or blast crisis of CML
Clinical manifestations of CML
