PATHOPHYSIOLOGY OF THE HEMOSTASIS SYSTEM

RBC PATHOLOGY 1) Classification of anemia according to their pathogenesis. 3 periods of life cycle of anemia: a) Anemia of impaired erythropoiesis b) Anemia of blood loss (acute; chronic) c) Anemia of shortening of life span (hemolytic anemia) (hereditary; acquired) 2) Classification of anemia according to MCV, MCHC a) Mean Corpuscular Volume (MCV) - A measure of the average RBC volume aka "how big" that is reported as part of a standard complete blood count i. Normocytic (80<MCV<100)- red cell size unchanged ii. Microcytic (MCV<80)- red cells are smaller than normal iii. Macrocytic (MCV>100)- red cells are larger than normal b) Mean Cell Hb Conc. (MCHC) - A measure of the concentration of Hb in a given volume of packed RBC i. Normochromic (usually normocytic) ii. Hyperchromic (usually macrocytic) iii. Hypochromic (usually microcytic) 3) Classification of anemia according to bone marrow regenerative ability and type of hematopoiesis a) Bone marrow regenerative ability i. hypo/ aregenerative ii. hyperregenerative depends on no. of reticulocytes (preformed RBC) in periphery.

b) Type of hematopoiesis i. Normoblastic ii. Megaloblastic - Common in fetus

Only in absence of vitamin B12 and folate

4) Examples of anemia connected with impaired red cell production a) Disturbance of proliferation and differentiation of stem cells: aplastic anemia, pure RBC aplasia, anemia of renal failure, anemia of endocrine disorders b) Disturbance of proliferation and maturation of erythroblasts i. Defective DNA synthesis: deficiency/impaired utilization of vitamin B12 and folic acid (megaloblastic anemias) ii. Defective Hb synthesis o Deficient heme synthesis: iron deficiency o Deficient globin synthesis: thalassemias iii. Unknown/multiple mechanisms: sideroblastic anemia, anemia of chronic inflammation, myelophthisic anemias due to marrow infiltrations 1

5) Iron-deficiency anemia; its causes and pathogenesis. a) Causes: i. Alimentary in childhood ii. No balance between request and real consumption of organism iii. Period of intense growth (children, teenagers) iv. Pregnancy and breastfeeding v. Chronic blood loss vi. Achylia (absence of gastric juice/ other digestive secretion) vii. Diseases of GIT (hypoacidic, malabsorption syndrome/diarrhea, etc.) b) Pathogenesis: of stored iron ( ferritin and stainable iron in bone marrow) circulating iron (with low level of serum iron and serum transferring iron-binding capacity) Hb, myoglobin, and other iron compounds brain fx, immunocompetence, etc (hypoxia) 6) Alterations in the peripheral blood and bone marrow of the patients with iron deficiency anemia. a) Bone marrow i. Insufficiency of Hb saturation by eryth. ii. ineffective erythropoesis iii. no.of sideroblast b) Peripheral blood i. Hypochromic i. Hyporegenerative ii. Microcytic 7) a) i. ii. iii. iv. v. b) Iron blood indices in patient with iron deficiency and sideroblastic anemia. Iron deficiency : Decreasing Hb Decreasing HCT Decreasing serum iron Increasing TIBC Decreasing MCV

ii) Sideroblastic anemia : i. Hypochromic of eryth. ii. coefficient of transferring saturation iii. TIBC

8) Common clinical features characteristics of iron-deficiency anemia and their pathogenesis. Principles of therapy. a) Common clinical features: i. Tachycardia ii. Fatigue iii. Dyspnoea iv. Angular stomatitis v. Koilonychias(spoon-shaped deformity of the fingernails/ spoon nail) vi. Atropic changes in gastric mucous vii. Pica chloratica viii. Intestinal malabsorption 2

ix. Alopecia(loss of hair; baldness) b) Pathogenesis i. Disturbance in hemoglobulinisation (formation of Hb) ii. As Hb is protein transport O2,this will lead to hypoxia c) Principles of therapy i. Replacement ii. Good food 9) B12 (folate) deficiency and folate deficiency anemias, their causes and common ways of the pathogenesis. a) Causes of B12 (folate) deficiency: i. Malabsorption -result from gastrectomy ii. Severe vegetarian diet (strict) iii. Inadequate production or function of intrinsic factor iv. Resection of ileum v. Metastases of neoplasm in bone marrow Pathogenesis: i) o o o that o ii) o B12 deficiencystop formation of metamelonic aciddestruction of myelindisorder in placed where myelin is stored eg:nerve fiberdefect in nervous functionneurological syndrome b) Causes of folate deficiency anemias: i. Folate poor diet eg: in alcoholism ii. folate requirements eg: in pregnancy iii. Malabsorption resection of jejunum iv. Some drugs-anti metabolites Pathogenesis: - lack of folate lead to decreasing of conversion desoxyuridylate desoxythymidylate that necessary in DNA synthesis 10) Morphology of the bone marrow and alterations in the peripheral blood in patients with B12-(folate) or folate-deficiency anemias. a) Bone marrow: -megaloblastic type of erythropoiesis (EP) i. EP rate is higher than leucopoiesis ii. Epithelium:regeneration in short time(3-4 days) iii. RBC: No.is ,in GIT:must be impaired b) Peripheral blood:- Hyperegeneration - No of RBC is lower - In RBC: 3

B12 the form of matacobalamine convert hemocysteinmethione Lack of it no activation of folic acid & in conversion of tetrahydrofolate This tetrahydrofolate needed to convert desoxyuridylatedesoxythymidylate necessary in DNA synthesis * lack of metachobalamine DNA synthesis retardation

- If cell is immature:nucleus is difficult to disappear -we can see jollys howell body,kabos ring - Microcytic, hypochromic ,megaloblastics ,hyperegenerative - Normablastic replaced by megaloblastic (partially) - Macrocytes with poikilocytes WBC- hypersegmented neutrophils n its no. 11) Difference in clinical features between B12-folate deficiency and folate deficiency anemias.

Folate Deficiency Anemia Pallor, easy fatigability Diarrhea Loss of appetite Weakness Sore tongue Headache Heart palpitation Pregnant women likely to give birth to low birth weight & premature infant In child, can slow the growth rate NO neurological abnormalities

B12-folate Deficiency Pallor, easy fatigability Mild jaundice ( destruction of erythroid progenitors) Neurochanges: numbness, tingling, loss of position sense.

* Different of both is in Neurological Abnormalities. 12) Sideroblastic anemia; its classification & causes. a) A term used to describe a group of rare blood disorders characterized by the bone marrow's inability to manufacture normal red blood cells. b) Classification (2): i. Inherited (Congenital X-linked, Autosomal dominant & recessive) ii. Acquired (Drugs, Toxins, Nutritional) c) Causes: i. Neoplasm or inflammatory disease o Carcinoma Leukemia o Lymphoma o Rheumatoid Arthritis ii. X-Linked recessive Sideroblastic Anemia o ALA synthetase deficiency iii. Toxin Exposure o Alcohol Abuse o Lead exposure iv. Drugs o Isoniazid (INH) Chloramphenicol v. Nutritional: o pyridoxine deficiency o copper deficiency 4

13)

Pathogenesis of sideroblastic anemia. a) As a hypochromic anemia, with total body iron is increased, enhanced transferrin saturation & high concentration of ferritin. b) There is erythropoiesis due to haemosynthesis disturbance. c) In the peripheral blood, presence sideroblasts - a normocyte that contains the non-hemoglobin iron. d) Mitochondria are localized around the nucleus forming the typical ringlet of sideroblasts. Sideroblasts are regarding the hemoglobin content hypochromic. (They are smaller than the mature erythrocytes). e) Hereditary sideroblastic anemia o Due to the impaired activity of -aminolevulic acid (ALA) synthetase, an enzyme that acts at the beginning of haem biosynthesis. This type of anemia can often be successfully treated with high doses of pyridoxine. f) Acquired sideroblastic anemia o Can be induced by isoniazide application or by excessive alcohol intake. In both cases induced disturbance of pyridoxine metabolism is involved. o In lead intoxication the haem synthesis is impaired.

14) Disturbance in bone marrow activity and corresponding alterations in the blood of patients with sideroblastic anemia. a) Ring sideroblasts in the bone marrow (abnormal normoblasts with excessive accumulation of iron in the mitochondria) b) The blood smear sometimes reveals basophilic stippling, hypochromia and microcytosis. c) Normocytosis and macrocytosis are also possible (in myelodysplastic syndromes). d) A dimorphic red cell population is characteristic of female carriers of the hereditary conditions. 15) Clinical features of sideroblastic anemia & their pathogenesis. a) Patients have the usual symptoms of anemia including fatigue, decreased tolerance to physical activity, and dizziness. b) Other symptoms not related to anemia can also be present and may point to a cause of the condition (e.g. alcoholism). 16) a) b) i. ii. iii. iv. v. vi. Aplastic anemia: its classification and major causes. Hereditary form Fancalis Syndrome (autosomal recessive) Acquired form In 80% of the causes cause is unknown (idiopathic) Chemotherapy Total ionization (whole body irradiation): x-ray disease Some chemical intoxication (Benzine, chloramphenicol) Some drug (alkylating agents secondary aplastic anemia) Infection with certain viruses (especially those causing viral hepatitis, as well as Epstein-Barr virus, parvovirus, and HIV, the virus which can cause AIDS) 5

17)

Theories of aplastic anemia pathogenesis. a) Immunologically mediated suppression b) Intrinsic abnormality of stem cells Some studies suggest that aplastic anemia result most commonly from suppression of stem cell by activated T-cell. It is postulated that stem cell are first antigenically altered by exposure to drugs, infectious agents or other unidentified environmental insult.

18) aplastic anemia.

Morphology and function of the bone marrow and alterations in blood in

Morphology a) The bone marrow is typically marked hypocellular, with greater than 90% of the intratrabecular space being occupied by fat b) This changes are better appreciated in a bone marrow biopsy specimen than in marrow aspirates, which often yield a dry tap because of hypocellularity. c) In marrow biopsy specimens, small foci of lymphocytes and plasma cell maybe seen. d) A number of secondary changes may accompany marrow failure. e) Hepatic fatty changes may result from anemia, and thrombocytopenia and granulocytopenia may give rise to hemorrhages and bacterial infections, respectively. f) Multiple transfusions may cause hempsiderosis. 19) Main clinical features of aplastic anemia and their pathogenesis. a) Lack of stem cells acquired - congenital b) Autoimmune death - under viruses - HIV infection - CD8+ against CD4+ c) Disturbing in micro surrounding of stem cell Fibroblast, mph, endothelial cell (cytokines produces) Via them, stem cell get cytokines (CSF, il-1,3,5,6 this is growth factor) Stem cell cant accept growth factor and they are transform into fat cell and fibrous tissues In aplastic anemia, replacement of parenchymal by fat cell and fibrous tissue. 20) treatment. Main causes of death from aplastic anemia and modern principles of its

a) Main causes of death i. The worst-prognosis type of aplastic anemia is one associated with very low numbers of a particular type of white blood cell. ii. If white blood cells (specifically, neutrophils) are lacking, resistance to infection is much lowered and infection becomes the major cause of death. iii. When platelets are very low, bleeding may be severe. b) Treatment i. In younger patient allogeneic bone marrow transplantation 6

ii. In older patient or patient without suitable donors often respond well to immunosuppressive therapies (antithymocyte globulin and cyclosporine) iii. Medical therapy of aplastic anemia often includes a short course of anti-thymocyte globulin (ATG or anti-lymphocyte globulin) and several months of treatment with cyclosporin to modulate the immune system. iv. Mild chemotherapy with agents such as cyclophosphamide and vincristine may also be effective. Antibodies therapy, such as ATG, targets T-cells, which are believed to attack the bone marrow. Steroids are generally ineffective. 21) Anemia of acute blood loss, its major causes. Possible hemodynamic disturbances and erythropoiesis at different stages of this type of anemia. a) Cause: i. Blood loss from the vascular space.(e.g. :trauma) ii. Normocytic - normochromic Hemodynamic disturbances and erythropoiesis: i.If blood loss is severe, manifestations are related to blood volume rather than loss of Hb. ii.Vol. loss leads to reduces mean systemic filling pressure, resulting in decrease venous return. iii.If blood loss is not severe, recovery is possible. iv.Anemia associated with blood loss is the direct result of the decrease in circulating red blood cells (RBCs). v.The average adult has a total blood volume of approximately 5,000 to 6,000 ml (milliliters) and can usually lose 500 ml of blood without serious or lasting effects; vi.But, if the loss reaches 1,000 ml or more, serious acute consequences may result. 22) Possible changes in hematocrit and MCHC within one hour or two days after massive blood loss. a) Within 24 hours of blood loss, lost plasma is replaced by mobilizing water and electrolytes from tissues and interstitial spaces into the vascular system. b) The hemodilution that results lowers the hematocrit: concurrently, there is often rapid elevation of circulating neutrophils and platelets. c) Neutrophils can rise to level btwn10000 to 30000/L within a few hours as a result of a shift of marginated leukocytes into the circulation and release of the leukocyte from the bone marrow. d) The platelet count can rise to level of about 1000000/L. e) In severe hemorrhage , more immature cell- metemyelocyte, myelocytes and nucleated RBC may enter the circulation. f) Tissue oxygenation reduction stimulates production of erythropoietin, and the bone marrow responds by increasing production of RBCs (reticulocytes). g) A normal erythrocyte count is usually evident within four to six weeks, but hemoglobin restoration can take up to eight weeks in acute blood loss MCHC maybe normal or low. 23) Anemia of chronic blood loss: its possible causes and pathogenesis. Specificity of hematopoiesis and blood film. a) i. Causes: Lesions of GIT : 7

b)

o o o o ii.

peptic ulcers colonic cancer hemorrhoids hookworm disease

Gynecologic disturbances. o Menorrhagia o Metrorrhagia o cancers

b)

Pathogenesis: i. With chronic blood loss, iron stores are gradually depleted. ii. Iron is essential for Hb synthesis and effective erythropoiesis, and its deficiency thus leads to a chronic anemia of underproduction. Hematopoiesis and blood film: i. RBCs are microcytic and hypochromic( due to reduced MCV and MCHC) ii. Increase in platelets count iii. Extramedullary hematopoiesis is uncommon. Iron metabolism indices in anemia of chronic blood loss.

c)

24) a) b) c) d) e) 25)

Low serum ferritin Low serum iron levels Low transferring saturation Increase total iron binding capacity Response to iron therapy Hemolytic anemia, its classification.

a) intrinsic(intracorpuscular) abnormalities of RBCs i. Hereditary o Disorder of RBC membrane cytoskeleton (spherocytosis, elliptocytosis) o RBC enzyme deficiency Glycolytic enzymes: pyruvate kinase Enzyme of hexose monophosphate shunt: glucose 6 phosphate dehydrogenase o Disorder of hemoglobin synthesis. Deficient globin synthesis: thalassemia Structurally abnormal globin synthesis: sickle cell anemia

ii. Acquired o Membrane defect: paraxosymal nocturnal hemoglobinuria. b) Extrinsic (extracorpuscular ) abnormalities i. Ab mediated o Isohemoglutinin: transfusion reaction, erythroblastosis fetalis 8

ii. iii.

o Autoantibodies:SLE Mech trauma to RBC o Microangiopathic hemolytic anemias: DIC Infections: malaria

26)

Common clinical and laboratory features of hemolytic anemia a) Hemolytic anemia:anemia associated with decrease of RBC life span (normal 120 days) It is cause by : 1) Inherent (intracorpuscular) 2) External (extracorpuscular) b) Characteristic: 1) Increase rate of RBC destruction 2) Compensatory increase in erythropoesis into reticulocytosis 3) Retention by body of products of RBC destruction(including iron) - Associated with marked erythroid hyperplasia within marrow and increase reticulocyte count in peripheral blood. - If severe develop extramedullary hematopoesis in spleen,liver and lymph nodes. c) Clinical features: i. Hypoxia ii. Non special signs-paleness,fatigue,tachycardia,dizziness iii. Special signs-dyspnoe, koilonichia d) 2 types of hemolytic anemia: i. Intravascular hemoylsis o Destruction of RBC within vascular compartment o Occurs when subjected to mechanical trauma or physical, biochemical agents o Results in:hemoglobinemia, hemoglobinuria and hemosiderinuria ii. Extravascular hemolysis o Within cells of mononuclear phagocyte or reticulocytes o Phagocytes remove RBC that injured or altered o Results in jaundice and formation of bilirubin rich gallstone (pigment stone) o Serum haptoglobulin decrease(because Hb escapes into plasma) o Hyperplasia of mononuclear system splenomegaly

27)

Hereditary spherocytosis, its molecular pathology a) Characterised by ineherited(intrinsic)defect in RBC membrane tht renders the RBC spheroidal, less deformable,vulnerable to splenic sequestration and destruction. b) Transmited as autosomal dominant trait 9

c) Hereditary spherocytosis is caused by a variety of moleculardefects in the genes tht code for spectrin,ankyrin,protein 4.1,and other erythrocyte membrane protein. d) Spectrin linked at 2 points: i. Through ankyrin to intrinsic membrane protein band 3 ii. Through band 4.1 to intrinsic membrane protein glycophorin e) These proteins are necessary to maintain the normal shape of erythrocyte which is biconcave disk f) Protein that is most commonly defective is ankyrin.

28) Typical clinical course of hereditary spherocytosis.The mechanism of the shortened life span of erythrocytes in this pathology. a) Clinical course: i. Anemia, splenomegaly and jaundice ii. RBC are spheroidal, there is a little margin for expansion of volume when cells exposed to hypotonic salt solution (increase osmotic fragility is a characteristic finding that is helpful in diagnostic). b) Mechanism of shortened life span of erythrocytes: i. More or less stable clinical course maybe punctuated by an aplastic crisis which is triggered by Parvovirus infection of developing erythroblasts in the marrow(associated with transient cessation of RBC production) ii. Because of shortened life span of HS cells the failure of erythropoisis for even a few days results in a rapid worsening of anemia accompanied by reticulocytopenia 29) Peripheral blood, bone marrow activity and laboratory data characteristic of hereditary sperocytosis. a) Peripheral blood: o Many of RBC will appear abnomally small and will lack the central pallor (lighter area in the middle of RBC) b) Bone marrow: o Immature RBC or reticulocytes counts will appear elevated 30) Pathogenesis of the main symptoms of hereditary spherosytosis.Possibility of surgical treatment in this disesase. a) Pathogenesis: i. Primary abnormal resides in protein tht form skeleton of RBC membrane. ii. Major protein is spectrin which form meshlike network on intracellular face of cell membrane. iii. RBC has decrease membrane stability and loses membrane fragments after their release into periphery. iv. Results; surface area to volume ratio of hereditary spherocytosis cells decrease until they assume the smallest possible diameter for a given volume sphere 10

b) Possibility of surgical treatment : i. There is no treatment for HS ii. In those who are symptomatic, splenectomy is beneficial because the major site of RBC destruction is removed(however splenectomy must be weighed against risk of increased susceptibility to infections, particularly in children)

31) Hemolytic changes due to glucose-6-phosphate dehydrogenase (G6PD) deficiency. Possible provoking agents and the mechanism of hemolysis. a) The erythrocyte and its membrane are vulnerable to injury by endogenous and exogenous oxidants. Abnormalities of enzymes that participate in the hexose monophosphate shunt or glutathione metabolism reduce the ability of RBCs to protect themselves from oxidative injury and lead to hemolytic anemias. The most prevalenceof these anemias is caused by a deficiency of G6PD. b) Possible provoking agents: o This disorder produces no symptoms unless the RBCs are subjected to oxidant injury by exposure to certain drugs, toxins or infections. The drugs incriminated include antimalarials (primaquine) , sulfonamides, nitrofuratoin, phanecetin, aspirin (in large doses) and vitamin K derivatives. o More important are the infections that presumably trigger hemolysis, awing to release of free radicals from phagocytotic cells. c) Mechanism of hemolysis: o The effect of these offending agents is to cause oxidation of reduced glutathione (GSH) to oxidized gluthatione (GSSG) through the production of hydrogen peroxide. Because regeneration of GSH impaired in G6PD-deficient cells, hydrogen peroxide accumulates and denatures globin chains by oxidation of sulfhydryl groups. Denatured Hb is precipitated within the RBCs in the form of inclusions called Heinz bodies. These precipitates of denatured Hb may damage the cell membrane sufficiently to cause intravascular hemolysis. 32) Variants of hemoglobinopathies; their common clinical features and characteristics of erythropoiesis. The clinically important hemoglobinopathies are classified into five categories on the basis of the underlying defect. The defects are as follows: a) Hemoglobin tends to gel or crystallize (e.g., sickle cell anemia or hemoglobin C disease). b) Hemoglobin is unstable (e.g., the congenital Heinz body anemias). c) Hemoglobin has abnormal oxygen-binding properties (e.g., the disorder caused by hemoglobin Chesapeake). d) Hemoglobin is readily oxidized to methemoglobin (e.g., methemoglobinemia). e) Hemoglobin chains are synthesized at unequal rates (e.g., the thalassemias 33) Possible complications hemoglobinopathies. and causes 11 of death of homozygous patients with

a) Pain episodes b) Strokes c) Increased infections d) Leg ulcers e) Bone damage f) Yellow eyes or jaundice g) Early gallstones h) Lung blockage i) Kidney damage and loss of body water in urine j) Painful erections in men (priapism) k) Blood blockage in the spleen or liver (sequestration) l) Eye damage m) Low red blood cell counts (anemia) n) Delayed growth 34) Sickle cell anemia; its molecular pathology and pathogenesis. a) Molecular pathology: i. Sickle-cell anemia is caused by a missense mutation in the -globin chain of hemoglobin, replacing the amino acid glutamic acid with the less polar amino acid valine at the sixth position of the chain . The association of two wild type -globin subunits with two mutant -globin subunits forms hemoglobin S, which polymerises under low oxygen conditions causing distortion of red blood cells and a tendency for them to lose their elasticity. ii. New erythrocytes are quite elastic, which allows the cells to deform to pass through capillaries. Often a cycle occurs because as the cells sickle, they cause a region of low oxygen concentration which causes more red blood cells to sickle. Repeated episodes of sickling causes loss of this elasticity and the cells fail to return to normal shape when oxygen concentration increases. These rigid red blood cells are unable to flow through narrow capillaries, causing vessel occlusion and ischemia. b) Pathogenesis: i. Under deoxy conditions, Hb S undergoes marked decrease in solubility, increased viscosity, and polymer formation at concentrations exceeding 30 g/dL. It forms a gellike substance containing Hb crystals called tactoids. The gel-like form of Hb is in equilibrium with its liquid-soluble form. A number of factors influence this equilibrium, including the following: ii. Oxygen tension o Polymer formation occurs only in the deoxy state. o If oxygen is present, the liquid state prevails. iii. Concentration of hemoglobin S o The normal cellular Hb concentration is 30 g/dL. o Gelation of Hb S occurs at concentrations greater than 20.8 g/dL. iv. The presence of other hemoglobins o Normal adult hemoglobin (Hb A) and fetal hemoglobin (Hb F) have an inhibitory effect on gelation. o These and other Hb interactions affect the severity of clinical syndromes. Hb SS produces a more severe disease than sickle cell Hb C (Hb SC), Hb SD, Hb SO Arab, and Hb with one normal and one sickle allele (Hb SA). 35) Clinical form of sickle cell anemia. Blood film and erythropoiesis in patients with this type of hemoglobinopathies. 12

a) Sickle-cell disease is a general term for a group of genetic disorders caused by sickle hemoglobin (Hgb S or Hb S). In many forms of the disease, the red blood cells change shape, usually looking much like that of a banana, upon deoxygenation because of polymerization of the abnormal sickle hemoglobin. b) Patients with sickle cell anaemia have an anaemia that varies in severity, with typical hemoglobin levels of 6-9 g/dl. Reticulocyte counts are elevated, reflecting new red blood cells replacing the rapidly destroyed older cells red blood cell life span is markedly reduced in this disease. Often, the white blood cell and platelet counts are elevated, and these cells may contribute to vaso-occlusion. 36) Clinical features of sickle cell anemia and their pathogenesis. a) Clinical features Heterozygotes do not normally show clinically significant phenotypic abnormalities (sickle cell trait). ii. Homozygotes in whom there is no normal haemoglobin A show a clinical phenotype (sickle cell disease) of differing grades of severity. i. Pathogenesis i. A substitution of thymine for adenine in the 6th codon of the chain gene results in the substitution of of valine for glutamic acid. ii. This causes deoxygenated HbS to polymerize and this causes sickling. iii. Sickled red cells are more adherent to endothelium and macrophages contributing to hemolytic anemia. iv. The flow patterns of sickled red cells are different with the result that there is obstruction of small vessels and ischemic tissue damage.

b)

37) Thalassemia syndromes. Alpha and beta thalassemia, minor and major forms. Molecular abnormalities characteristic of different types of thalassemia. a) The thalassemias are a heterogeneous group of genetic disorders of Hb synthesis characterized by a lack of or decreased synthesis of globin chains. b) In -thalassemia, -chain synthesis is reduced. c) In -thalassemia, -globin chain synthesis is either absent (designated thalassemia) or markedly deficient (+ thalassemia) Cinical Nomenclature -thalassemias thalassemia major

Genotype Homozygous -th (/); homozygous +- th (+/+)

Disease Severe, requires blood transfusions regularly)

Molecular Genetics Rare gene deletions in / Defects in transcription processing, or translation of globin messenger RNA Same

Thalassemia minor

/ +/

Asymptomatic with mild or no anemia; RBC 13

abnormalities seen -thalassemia silent carrier -th trait HbH disease -/ -/ -/- Asymptomatic; no RBC abnormality Asymptomatic; like the minor Severe anemia, tetramers of -globin (HbH) formed in RBCs Lethal in utero Gene deletions mainly Same Same

Hydrops fetails

-/-

Same

38)

Clinical course, alterations in the peripheral blood and erythropoiesis in thalassemia. a) Thalassemia major i. Manifests itself postnatal as HbF synthesis diminishes. ii. Affected children fail to develop normally, and their growth is retarded almost from birth. iii. They are sustained only by repeated blood transfusions, which improve the anemia and reduce the skeletal deformities associated with excessive erythropoiesis. iv. With transfusion alone, survival into the second or third decade is possible, but gradually systemic iron overload develops. v. Both iron present in transfused RBCs and iron inappropriately taken up from the gut (somehow related to ineffective erythropoiesis) contribute to iron overload. vi. Unless patients are treated aggressively with iron chelators, cardiac failure from secondary hemochromatosis commonly occurs and often causes death in the second or third decade of life. vii. When feasible, bone marrow transplantation at an early age is the treatment of choice. b) Thalassemia minor i. Usually only a mild microcytic hypochromic anemia, and in general these patients have a normal life expectancy. ii. Because iron deficiency anemia is associated with a similar RBC appearance, it should be excluded by appropriate laboratory tests iii. The diagnosis of -thalassemia minor is made by HbA (22), the level of HbA2 (22) is increased iv. The peripheral blood shows a severe microcytic hypochromic anemia, with marked variation in cell shapes (poikilocytosis) v. The reticulocyte count is increased vi. Hb electrophoresis shows profound reduction or absence of HbA and increased levels of HbF vii. The HbA2 level may be normal ar increased viii. Prenatal diagnosis of both forms of thalassemia can be made by DNA analysis

39)

Aplastic crises in thalassemia; their possible causes, clinical course and complications.

Viral infections 14

a) Many types of viral infections can suppress bone marrow activity. The most important etiologic agent in transient aplastic crisis is parvovirus B19 b) In patients with hemolytic anemia, parvovirus B19 supresses bone marrow erythropoietic activity, leading to transient aplastic crisis. c) Parvovirus B19 infections can also produce serious complications in patients who are immune compromised. d) can develop pure red cell aplasia, in which suppression of erythroid precursors is permanent. e) a person with sickle cell disease or thalassemia may turnover 10% of their red cells each day f) Transient aplastic crisis usually is self-limiting and requires only supportive measures. g) Immunoglobulin treatment, which is dramatically effective in reversing the aplasia.

40) Acquired form of hemolytic anemia. Possible causes of non-immune anemia and their pathogenesis. a) Hemolytic anemia (HA) is anemia due to hemolysis, the abnormal breakdown of red blood cells either in the blood vessels (intravascular hemolysis) or elsewhere in the body (extravascular). Causes of hemolytic anemia can be acquired or genetic. b) Two forms of acquired hemolytic anemia: i. Immune-mediated (direct Coomb test +ve) [question 42] ii. Non-immune mediated (direct Coombs test is negative) o Causes: - Drugs (i.e., some drugs and other ingested substances lead to haemolysis by direct action on RBCs) - Toxins (e.g., snake venom) - Mechanical (heart valves, extensive vascular surgery, microvascular disease) - Infections: malaria - Membrane disorders o Example pathogenesis: Paroxysmal nocturnal hemoglobinuria (PNH) - Due to membrane disorder - Rare acquired clonal disorder of red blood cell surface proteins - Some erythrocytes ( derived from somatically mutated stem cell ) have increased complement sensitivity due to lack of membrane protein needed to synthesis membrane anchor - Membrane anchor limits the spontaneous activation of complement on surface of RBC - Without membrane anchor, complement will be activated and lead to perforation (menebuk) of the erythrocytes membrane. - Lead to hemolytic anemia 41) Immune form of hemolytic anemia (immunohemolytic anemia). Possible causes and different models of immune hemolysis. a) b) Immune-mediated (direct Coombs test +ve) Causes: i. Caused by antibodies that react against normal or altered RBC membranes. 15

ii. Anti-RBC antibodies arise from o Autoimmune o Drug induced immune iii. +ve result from Coombs test indicates that patients RBC are coated with human antibodies that can react with antihuman Ig ( malaria, drug) c) Models: i. Warm antibody type Presence of IgG active at 37C leads to opsonization of RBC and phagocytosis by splenic macrophage o Primary (idiopathic) belong to autoimmune disease o Secondary ( induced by drugs-methldopa, quinidine, penicillin) [tgh soklan test control RBC no.16] ii. Cold antibody type Presence of IgM that bind to RBC membrane at 30C but not lead to lysis. When the antibody and complement coated-cell travel to warmer area, the weak bond of IgM is released and cell is left with coating of C3b (opsonin). The cell is later phagocytosed by mononuclear phagocyte system. 42) Types of antibodies involved in immune reaction and method of their detection. a) Type of antibodies i. IgG ii. IgM b) Method of detection: Coombs antiglobulin test (direct) i. Based on capacity of antibodies raised in animal against human Ig to agglutinate RBC. ii. +ve indicates that patients RBC are coated with human antibodies that can react with antihuman Ig ( malaria, drug) 43) Characteristic symptoms of acute or chronic hemolytic anemia a) Acute: trauma, normocytic normochromic, recovery by rise in erythropoietin level b) Chronic: lesions of GIT, gynecologic disturbances, iron deficiency

WBC PATHOLOGY 1) Leukocytosis.Classification a) Reactive As a respond to the request b) Pathology Associated with neoplasma with hematopoeitic system - Leukemia 2) Common mechanism of reactive leukocytosis a) Physio leukocytosis i. Myogenic physical exercise ii. Digestive iii. In newborn iv. In pregnancy v. Emotional stress(e.g.: child crying) Mechanism: - Redistributive (from one place to another) to fulfill function - Substance: cathecolamines 16

b) As a respond to same disease i. Neutrophilia ii. Eosinophilia iii. Monocytosis 3) Neutrophilic leukocytosis,its major causes and alterations in the blood, different types of neutrophil nucleus shift a) Neutrophilia granulocytosis Absolute number of neutrophil is increase due to activation of

b) Causes: 1) Acute bacterial infection especially those caused by pyrogenic organisms 2) Sterile inflammation cause by for examples tissues necrosis(myocardial infections, burns) 3) Hemorrhage, neoplasma,ketoacidosis (diaberes mellitus type I) ,stroke c) Neutrophilic nucleus shift: Myeloblast Promyelocyte myelocyte metamyelocyte band neutrophil 4) Eosinophilic leukocytsis, its major causes and mechanism, alteration in the blood. Causes a) Allergic disorders such as hay fever, asthma, allergic skin diseases (e.g.: pemphigus, dermatitis) b) Parasitic infestations (worms, protozoa) c) Drug reactions d) Certain malignancies(e.g.; hodgkin and non hodgkin lymphomas) e) Collagen vascular disorders 5) Absolute and relative lymphocytosis. Its causes and blood features.

Lymphocytosis is increased in no. of lymphocytes. Lymphocyte is 20-40 % of total WBC. But the occurrence of lymphocytosis is translated into increase of overall WBC count. Absolute: an increase in blood lymphocytes above 4, 000/mm3 Causes: cytomegalovirus infection, pertussis, hepatitis,TB, chronic lymphocytic leukemia Relative: an increased percentage of circulating lymphocytes, but the absolute number does not exceed 4, 000/mm3. Causes: infancy, viral infections, connective tissue diseases, Thyrotoxicosis and Addison's disease. 6) Monocytosis. Causes and blood features.

Monocytosis is an increase in the number of circulating monocytes. 950/L is regarded as at the upper limit of normal; monocyte counts above this level are regarded as monocytosis. Causes: i. Infections: tuberculosis, brucellosis, subacute bacterial endocarditis, syphilis, infectious mononucleosis ii. Autoimmune diseases and vasculitis: systemic lupus erythematosus, rheumatoid arthritis and inflammatory bowel disease. 7) 8) Leukopenia. Classification. Main causes of neutropenia and lymphopenia. Myelotoxic and immune forms of agranuloctosis, their main causes 17

Leukopenia is decrease in the peripheral white cell count because of decrease in any specific type of leucocytes. Class: a) Neutopenia (agranulocytosis) - decrease in the number of circulating neutrophil granulocytes, Causes: i. Decreased production in the bone marrow (myelotoxic)- drug, large granular leukemia, marrow failure (aplastic anemia, thrombocytopenia,) ii. Increased destruction of neutrophils (immune mediated)- aminopyrine, bacteria, infections, sequestration of neutrophils by enlarged spleen E.g.: aminopyrine acts as hapten and leads to immune process(hypersensitivity typr II) b) Lymphopenia - low number of lymphocytes in the blood. Causes: i. chemotherapy, such as with cytotoxic agents or immunosuppressive drugs ii. AIDS.

9) Main differences in clinical and hematological symptoms of immune and myelotoxic forms of agranulocytosis a) Involve special triad: leukoppenia, neutropenia and relative lymphocytosis b) It is a common feature for both but c) Differs in myelotoxic, thrombocytopenia and anemia accompany but not in immune 10) Lymphopenia;its main causes and alteration in the blood. a) Lymphopenia is the condition in which there exists an abnormally low number of lymphocytes in the blood. b) Lymphopenia can be caused by various types of chemotherapy, such as with cytotoxic agents or immunosuppresive drugs. Some malignancies in the bone marrow will also cause lymphopenia. c) Lymphopenia is less common; they are acquired in association with specific clinical states, such as HIV infection or treatment with corticosteroids 11) Leukemia. definition and types of classification. Common features of leukemia as hematopoietic neoplasma a) Def: malignant tumors/neoplasma which arises from bone marrow with abnormality in process of proliferation and maturation of hematopoietic cells infiltration with these cells in bone marrow and lymphoid tissue b) Classification: i. According to tissue which differentiate myelogenous leukemia and lympho-leukemia ii. According to grade of maturation; iii. Acute myelo-leukemia iv. Acute lymphoblastic leukemia v. Chronic lympholeukemia 12) Modern theories of etiopathogenesis of leukemia. a) Natural or artificial ionizing radiation, 18

b) Certain kinds of chemicals, c) Some viruses, and d) Genetic predispositions. - Leukemia, 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. Cohort and case-control studies have linked exposure to petrochemicals, such as benzene, and hair dyes to the development of some forms of leukemia. - Viruses 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).

13) Acute myelogenous leukemia. FAB-classification. Morphology of the bone marrow alteration in the blood in patient with this disease. o Background: Acute myelogenous leukemia (AML) is a malignant disease of the bone marrow in which hematopoietic precursors are arrested in an early stage of development. Most AML subtypes are distinguished from other related blood disorders by the presence of more than 20% blasts in the bone marrow. Acute Myelogenous (Non-Lymphoblastic) Leukemia (FAB Classification)

o Lymphocytic leukemias can be subdivided by type of cell surface antigens: 95% are B-cell and 5% are T-cell type. Undifferentiated leukemia (98013) stem cells predominate or cell M0 type unidentified M1 Myeloblastic leukemia without maturation (98723--acute) 19

M2 M3

M4

M5

M6 M7 14)

immature white blood cells predominate Myeloblastic leukemia with maturation (98723--acute) with partial differentiation Promyelocytic leukemia (98663--acute) promyelocytes predominate subdivided M3a without eosinophilia M3b with eosinophilia (98603) Combination myeloblastic-monoblastic leukemia (98723--acute; 98683--chronic) each component constitutes greater than 20% of the blasts in the bone marrow subdivided M4 acute myelomonocytic leukemia M4E0 acute myelomonocytic leukemia with eosinophilia Monoblastic leukemia (98603--monocytic, NOS; 98913--acute; 98603--subacute; 98603--chronic; 98603 aleukemic) monoblasts predominate subdivided M5a acute monocytic leukemia without differentiation (98913--monoblastic) M5b acute monocytic leukemia with differentiation (promonocytic) Erythroleukemia (98403) immature red and white cells predominate Megakayrocytic leukemia (99103--acute) Cytochemical test of acute myelogenous leukemia. Type of anemia M0 M1 M2 M3 M4 M5 M6 M7 Cytochemical reaction All reaction are negative + Myeloperoxidase + Sudan black + PAS-material in diffuse form + Myeloperoxidase + Sudan black + PAS-diffuse form + Myeloperoxidase + Sudan black + PAS-diffuse form + Myeloperoxidase + Non-specific esterase + Non-specific esterase + PAS Antigen of factor vii of clotting system

15) Typical clinical features of acute myelogenous leukemia and their pathogenesis. Main COD of this disease. a) i. ii. iii. iv. v. b) Clinical features: Abrupt stormy onset:patient present within 3 months of the onset of the symptoms Symptoms related to depression of normal marrow functions Bone pain and tenderness Generalized lymphadenopathy, splenomegaly and hepatomegaly CNS manifestation.

Pathogenesis: i. Block of differentiation and that the neoplastic blasts have prolonged rather than shortened generation time. 20

ii. Thus, accumulation of blasts result from clonal expansion and failure of maturation of the progeny into fxnal mature cell. iii. As blasts accumulate in the marrow, they suppress normal hematopoietic stem cells. c) Cause of death (COD):

16) Chronic myelocytic leukemia (CML) as a variant of chronic myeloproliferative disorder. The target for neoplastic transformation in this disease and characteristic of hematopoiesis. a) Affects adults between 25 to 60 years of age b) Peak incidence is in the fourth and fifth decades of life. c) Target for neoplastic transformation and hematopoiesis i. Target: from pleuripotent stem cell ii. Characteristic o Too much leukocytes(100x10^9 and more) o Myeloblast (less than 10) o Shift to left (presence of all type of neutrophil in peri blood) o Increase basophil and eosinophil o Philadelphia chromosome o Anemia o thrombocytopenia 17) Three stages of chronic myelocytic leukemia. Alteration in the blood. a) Onset of CML i. Usually slow ii. Initial symptoms are nonspecific iii. Marked elevation of leukocyte count iv. Circulating cell predominantly neutrophil and myelocytes v. Basophil and eosinophil also prominent vi. Thrombocytosis b) Accelerated phase i. Increasing anemia and new thrombocytopenia ii. Transformation into a picture resembling acute leukemia( blast crisis) iii. 50% case, blast crisis occur w/out intermediate accelerated phase. c) Phase of extensive bone marrow fibrosis. 21

i. Less commonly progress 18) Characteristic cytogenetic abnormality in the blood and bone marrow cells in patient with chronic myelogenous leukemia a) Bone marrow - Usually consist of 100% cellular (normal: 50% cellular, 50% fat) - Increased number in megakaryocytes often includes small dysplactic form - Present of scattered storage histiocytes with wrinkled green blue cytoplasm (seablue histiocytes) - Increased deposition of retikulin fibers is typical b) Peripheral blood - Circulating cells are predominantly neutrophils, metamyelocytes, and myelocutes with less than 10% myeloblasts. - Patient has thrombocytosis early in the course of their disease - Neoplastic extramedullary hematopoiesis within the splenic red pulp produces marked splenomegaly, often complicated by focal infarction. - Extramedullary hematopoiesis can also lead to hepatomegaly and mild lymphoadenopathy. - Can see cells of different stages. 19) Clinical symptoms of the accelerated phase of chronic myelogenous leukemia and their pathogenesis a) Clinical symptoms: - There are more blast cells in the blood and bone marrow, and fewer normal cells. - 10-19% myeloblasts in the blood or bone marrow - >20% basophils in the blood or bone marrow - Platelet count <100,000, unrelated to therapy - Platelet count >1,000,000, unresponsive to therapy - Cytogenetic evolution with new abnormalities in addition to the Philadelphia chromosome - Increasing splenomegaly or white blood cell count, unresponsive to therapy b) The patient is considered to be in the accelerated phase if any of the above are present. The accelerated phase is significant because it signals that the disease is progressing and transformation to blast crisis is imminent. 20) Acute lymphoblastic leukemia. Types of its classification and common characteristic features. a) A severe blood disorder in which abnormal leukocytes are identified as immature forms of lymphocytes. Also known as lymphoblastic leukemia. b) Classification: i. T form ii. B form Pro B - Pre B iii. Common T and B i. ii. iii. iv. v. c) Common features: Pain behind the sternum Pain in low extremities Neuroleukemia Meningeal syndromes Pneumonia cough (enlarged nodes) 22

21) Specific features of peripheral blood and bone marrow activity in acute lymphoblastic leukemia. a) Blastosis - Subleukemia, aleukemia b) In smear blastosis (> leukocytes) - Prolymphocytes - Lymphocytes - Monocytes - granulocytes c) Bone marrow infiltration with lymphoblast. 22) Cytochemical reactions & phenotyping of immature lymphocytes as the most important test to differentiate acute lymphoblastic leukemia. a) Cytochemical reaction: PAS (+ve) & granular form. b) Phenotyping Precursor T ALL cells: CD3, CD5, CD7, CD2 - Precursor B ALL cells: CD19, CD10

23) Clinical features of acute lymphoblastic anemia and their pathogenesis a) o b) o o c) o d) o e) o Abrupt stormy onset: Patient presents the onset symptoms in few days few weeks. Depression of normal marrow fx: Fatigue due to anemia Fever by infection due to absence mature leukocytes. Bone pain & tenderness: Marrow expansion & infiltration of subperiosteum Generalized lymphadenopathy, splenomegaly, hepatomegaly By neoplastic infiltration. CNS manifestation Headache, vomiting, nerve palsies resulting from meningeal spread.

24) Chronic lymphocytic leukemia (CLL); its clinical features and their pathogenesis. a) Clinical features: i. Age >50 ii. Often symptomatic iii. But when appear symptom:nonspecificesay fatigability,weight loss and aneroxia iv. Lleucocytes count v. Hypogammaglobulinemia( susceptibility to infection) vi. Hyperplastic syndrome with enlarge of liver n spleen i. ii. Pathogenesis Linked to genetic abnormalities and environmental factors Ig genes of some CLL are somatically hypomutated

b)

23

25) leukemia. a) b) i. ii. iii. iv.

Alterations in the blood and bone marrow in patients with chronic lymphocytic

Bone marrow: -too much lymphocytes n lymphoblastic Peripheral blood: Leucocytes:(not < than myeloleukemia but > than acute leukemia) Lymphocytes: (~70-80%) Anemia n thrombocytopenia (autoimmune diseases) Humprecht

26) Leukemoid reactions, their possible causes. Common and different signs in comparison with leukemia. a) Leukemoid reactions- transient myeloproliferative disorder, describes an elevated white blood cell count, or leukocytosis, that is a physiologic response to stress or infection (as opposed to a primary blood malignancy, such as leukemia). b) Causes: Hemorrhage - Drugs - Use of glucocorticoids - Use of G-CSF or related growth factors - All-trans retinoic acid (ATRA) - Infections (e.g. tuberculosis, pertussis) - As a feature of Trisomy 21 in infancy (incidence of ~10%) - As a paraneoplastic phenomenon (rare) c) Common and different signs in comparison with leukemia - Leukocytosis exceeding 50,000 WBC/mm3 with a significant increase in early neutrophil precursors - The peripheral blood smear may show myelocytes, metamyelocytes, promyelocytes, and even myeloblasts - There is a mix of early neutrophil precursors with complete maturation, in contrast to the blood smear in acute leukemia 27) features. Erythrocytosis. Definition and classification. Common hematological and clinical

a) Erythrocytosis = a condition in which there is a net increase in the total number of RBC in the body ( so-called Poltcythemia) b) Classification: i. Relative- when there is hemoconcentration caused by plasma volume ii. Absolute when there is in total RBC mass - can be: o primary- when in RBC mass results from autonomous proliferation o of myeloid stem cells o secondary- when RBC progenitors are normal but proliferate in o response to level of erythropoietin. c) Clinical features:

24

- Presentation associated with red cell mass and hyperviscosity and symptoms include headache, dizziness, tinnitus, itching of skin after hot bath, visual disturbances, dyspepsia ( risk of duodenal ulcer), dyspnoe and red skin. Spleen is enlarged and hepatomegaly. d) Lab. Findings (Hematological features): i. red cell count- normal morphology ii. white cell count- myeloid cells commonly show shift to the left iii. platelet count iv. total blood volume and total red cell volume v. blood viscosity (5-10 fold) vi. Hyperuricaemia 28) Polycythemia Vera. Pathogenesis and characteristic blood picture. Symptoms of disease and their pathogenesis. a) Polycythemia vera(PCV)- often called primary polycyhtemia, polycythemia rubra vera (PRV), or erythemia. Occurs when excess RBC are produced as a result of an abnormality of bone marrow. Often, excess WBC and platelets also produced (Myeloproliferative disease) b) Characteristic: in red cell no. as well as other white cells c) Symptoms: - often asymptomatic i. Generalized itching- particularly after exposure to warm water, may be duer to abnormal histamine release/ prostaglandin production. ii. Gouty arthritis iii. Peptic ulcer disease- may be related to susceptibility to infection with ulcer-causing bacterium h. Pylori. iv. Erythromelalgia - A sudden, severe burning pain in hands or feet, usually accompanied by reddish or bluish coloration of skin. - caused by platelet count or platelet stickiness v. Blood clots (thrombosis) vi. A major thrombotic complications (eg. Heart attack, deep venous thrombosis, or Budd-Chiari syndrome) 29) Reactive erythrocytosis; its causes and pathogenesis. Change in hematocrit. a) A form of erythrocytosis that occurs when the concentration of erythrocytes in the circulating blood increases through loss of plasma. b) Causes: Hemoconcentration: diuretics, burns, diarrhea, stress c) Hematocrit: STRUCTURAL Q (HEMATOLOGY) 1) List the causes of iron deficiency anemia. i. Low dietary intake (especially in strict vegetarian). ii. Malabsorbtion may occur with sprue and celiac disease or after gastrectomy. iii. Increased demands not met by normal dietary intake during pregnancy and infancy. iv. Chronic blood loss. May occur from the GIT (e.g. peptic ulcers, colonic cancer, hemorrhoids, hookworm disease or the female genital tract (metrorrhagia, cancers). 25

2) i. ii. iii. iv. v. vi. vii. 3)

List the causes of B12-deficiency anemia. Low dietary intake (especially in strict vegetarian). Gastrectomy Resection of terminal ileum Regional enteritis Tropical sprue Whipple disease Gastric atrophy (in older person)

List the cause of folate deficiency anemia i. Poor diet ii. Increased metabolism needs(pregnant women and patients with chronic hemolytic anemias) i. ii. iii. iv. v. List the causes of aplastic anemia Chemotherapy Total ionization (x- ray disease) Some chemical (benzene) Drugs (alkylating agents) Viruses Enumerate the hereditary hemolytic anemias i. Spherocytosis o Autosomal dominanat trait o Defect in rbc membrane that renders the rbc spheroidal o Less deformable & vulnerable to splenic sequestration & destruction o Trapped n splenic cords,phagocytosed by mph

4)

5)

ii.

iii.

Sickle cell anemia o Mutation in encoding the -globin chain o Substitution of valine for instead of glutamate at 6th position of chain produce sickle cell hb o In homozygotes all hba is replaced by hbs o In heterozygotes half is pelaced o Common in african american n african population Thalassemia o -Thalassemia-homozygous(inherited from both parents) o -Thalassemia-heterozygous(inherited from 1 parent) o Deficiency of globin chain o Common among mediterranean,african,asian population Name the causes of extravascular eryth. hemolysis:

6)

Occurs within cells of mononuclear phagocytes or reticulocytes of spleen i. Phagocytes remove RBC that injured or altered from circulation. ii. Result: jaundice & bilirubin-rich gallstone formation (pigment stone) iii. Serum heptoglobin (because Hb escapes into plasma) iv. Hyperplasia of mononuclear system turns into splenomegaly. 26

7) i. ii. iii. iv. v. vi. 8) i. ii. iii. iv. v.

The causes of high hematocrit value can be the followings: Dehydration Burns Diarrhea Other trauma, etc. Erythrocytosis (excessive red blood cell production) Polycythemia Vera The causes of low hematocrit value can be the following Anemia Blood loss (hemorrhage) Leukemia Bone marrow failure (e.g., due to radiation, toxin, fibrosis, tumor) Deficiency in certain nutrition such as lack of folic acid or vitamin B12

9) The typical blood alterations in patients with iron deficiency anemia are likely to be following: i. ii. iii. iv. v. vi. 10) i. ii. iii. iv. v. Low Hb levels Low mean corpuscular volume Hypochromic microcytic RBC Low serum ferritin Low seum iron levels Increase total iron binding capacity The typical blood alteration in patients with vitamin B12 deficiency anemia Megaloblastic Hyperregenerative Hypochromic Microcytic Macrocytes ???

27