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PATHOPHYSIOLOGY OF THEHEMOSTASIS SYSTEM

RBC PATHOLOGY

1) Classification of anemia according to their pathogenesis.

3 periods of life cycle of anemia:a) Anemia of impaired erythropoiesisb) Anemia of blood loss (acute; chronic)c) Anemia of shortening of life span (hemolytic anemia) (hereditary; acquired)

2) Classification of anemia according to MCV, MCHCa) 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 unchangedii. 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 hematopoiesisa) Bone marrow regenerative ability

i. hypo/ aregenerativeii. hyperregenerative

- depends on no. of reticulocytes (preformed RBC) in periphery.

b) Type of hematopoiesisi. Normoblastic

ii. Megaloblastic - Only in absence of vitamin B12 and folate- Common in fetus

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 erythroblastsi. Defective DNA synthesis: deficiency/impaired utilization of vitamin B12 and folic acid

(megaloblastic anemias)ii. Defective Hb synthesis

o Deficient heme synthesis: iron deficiencyo Deficient globin synthesis: thalassemias

iii. Unknown/multiple mechanisms: sideroblastic anemia, anemia of chronic inflammation, myelophthisic anemias due to marrow infiltrations

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5) Iron-deficiency anemia; its causes and pathogenesis.a) Causes:

i. Alimentary in childhoodii. No balance between request and real consumption of organism

iii. Period of intense growth (children, teenagers)iv. Pregnancy and breastfeedingv. 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 marrowi. Insufficiency of Hb saturation by eryth.

ii. ↑ ineffective erythropoesisiii. ↓ no.of sideroblast

b) Peripheral bloodi. Hypochromici. Hyporegenerative

ii. Microcytic

7) Iron blood indices in patient with iron deficiency and sideroblastic anemia.

a) Iron deficiency :i. Decreasing Hb

ii. Decreasing HCT iii. Decreasing serum ironiv. Increasing TIBCv. Decreasing MCV

b) ii) Sideroblastic anemia :i. Hypochromic of eryth.

ii. ↑ coefficient of transferring saturationiii. ↓ TIBC

8) Common clinical features characteristics of iron-deficiency anemia and their pathogenesis. Principles of therapy.a) Common clinical features:

i. Tachycardiaii. Fatigue

iii. Dyspnoeaiv. Angular stomatitisv. Koilonychias(spoon-shaped deformity of the fingernails/ spoon nail)

vi. Atropic changes in gastric mucousvii. Pica chloratica

viii. Intestinal malabsorptionix. Alopecia(loss of hair; baldness)

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b) Pathogenesisi. Disturbance in hemoglobulinisation (formation of Hb)

ii. As Hb is protein transport O2,this will lead to hypoxia

c) Principles of therapyi. 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 factoriv. Resection of ileumv. Metastases of neoplasm in bone marrow

Pathogenesis:i)o B12 the form of matacobalamine convert hemocystein→methioneo Lack of it→ no activation of folic acid & in conversion of tetrahydrofolateo This tetrahydrofolate needed to convert desoxyuridylate→desoxythymidylate that

necessary in DNA synthesiso * lack of metachobalamine → DNA synthesis retardation

ii) o B12 deficiency→stop formation of metamelonic acid→destruction of

myelin→disorder in placed where myelin is stored eg:nerve fiber→defect in nervous function→neurological syndrome

b) Causes of folate deficiency anemias:i. Folate poor diet eg: in alcoholism

ii. ↑ folate requirements eg: in pregnancyiii. Malabsorption –resection of jejunumiv. 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:

- If cell is immature:nucleus is difficult to disappear

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-we can see jolly’s howell body,kabo’s 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 B12-folate Deficiency 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

Pallor, easy fatigability Mild jaundice (↑ destruction of

erythroid progenitors) Neuro- changes: 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 Anemiao ALA synthetase deficiency

iii. Toxin Exposure o Alcohol Abuse o Lead exposure

iv. Drugso Isoniazid (INH)

Chloramphenicolv. Nutritional:

o pyridoxine deficiency o copper deficiency

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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 δ-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) Aplastic anemia: its classification and major causes.

a) Hereditary form – Fancali’s Syndrome (autosomal recessive)b) Acquired form

i. In 80% of the causes – cause is unknown (idiopathic)ii. Chemotherapy

iii. Total ionization (whole body irradiation): x-ray diseaseiv. Some chemical intoxication (Benzine, chloramphenicol)v. Some drug (alkylating agents → secondary aplastic anemia)

vi. Infection with certain viruses (especially those causing viral hepatitis, as well as Epstein-Barr virus, parvovirus, and HIV, the virus which can cause AIDS)

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17) Theories of aplastic anemia pathogenesis.

a) Immunologically mediated suppressionb) 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) Morphology and function of the bone marrow and alterations in blood in aplastic anemia.

Morphologya) The bone marrow is typically marked hypocellular, with greater than 90% of the intratrabecular

space being occupied by fatb) 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 can’t 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) Main causes of death from aplastic anemia and modern principles of its treatment.

a) Main causes of deathi. 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) Treatmenti. In younger patient → allogeneic bone marrow transplantation

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.

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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

b) 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/µL 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/µL.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) Causes: i. Lesions of GIT :

o peptic ulcerso colonic cancero hemorrhoidso hookworm disease

ii. Gynecologic disturbances.

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o Menorrhagiao Metrorrhagiao 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.

c) Hematopoiesis and blood film:i. RBCs are microcytic and hypochromic( due to reduced MCV and MCHC)

ii. Increase in platelets countiii. Extramedullary hematopoiesis is uncommon.

24) Iron metabolism indices in anemia of chronic blood loss.

a) Low serum ferritinb) Low serum iron levelsc) Low transferring saturationd) Increase total iron binding capacitye) Response to iron therapy

25) Hemolytic anemia, its classification.

a) intrinsic(intracorpuscular) abnormalities of RBCs

i. Hereditaryo 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. Acquiredo Membrane defect: paraxosymal nocturnal hemoglobinuria.

b) Extrinsic (extracorpuscular ) abnormalities

i. Ab mediatedo Isohemoglutinin: transfusion reaction, erythroblastosis fetaliso Autoantibodies:SLE

ii. Mech trauma to RBCo Microangiopathic hemolytic anemias: DIC

iii. Infections: malaria

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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,dizzinessiii. Special signs-dyspnoe, koilonichia

d) 2 types of hemolytic anemia:

i. Intravascular hemoylsiso Destruction of RBC within vascular compartmento Occurs when subjected to mechanical trauma or physical, biochemical

agentso Results in:hemoglobinemia, hemoglobinuria and hemosiderinuria

ii. Extravascular hemolysiso Within cells of mononuclear phagocyte or reticulocyteso Phagocytes remove RBC that injured or alteredo 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 traitc) 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 3ii. Through band 4.1 to intrinsic membrane protein glycophorin

e) These proteins are necessary to maintain the normal shape of erythrocyte which is biconcave diskf) Protein that is most commonly defective is ankyrin.

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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

b) Possibility of surgical treatment :

i. There is no treatment for HSii. 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)

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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 and causes of death of homozygous patients with hemoglobinopathies.

a) Pain episodesb) Strokesc) Increased infectionsd) Leg ulcerse) Bone damagef) Yellow eyes or jaundiceg) Early gallstonesh) Lung blockagei) Kidney damage and loss of body water in urine

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j) Painful erections in men (priapism)k) Blood blockage in the spleen or liver (sequestration)l) Eye damagem) 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 β-globin chain of

hemoglobin, replacing the amino acid glutamic acid with the less polar amino acid valine at the sixth position of the β chain . The association of two wild type α-globin subunits with two mutant β-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 gel-like 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.

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

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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 featuresi. 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.

b) Pathogenesisi. A substitution of thymine for adenine in the 6th codon of the β 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.

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 α-thalassemia, α-chain synthesis is reduced.c) In β-thalassemia, β-globin chain synthesis is either absent (designated β° thalassemia) or

markedly deficient (β+ thalassemia)

Cinical Nomenclature

Genotype Disease Molecular Genetics

β-thalassemiasthalassemia major

Thalassemia minor

α-thalassemiasilent carrier

α-th trait

HbH disease

Hydrops fetails

Homozygous β°-th (β°/β°); homozygous β+- th (β+/β+)

β°/ββ+/β

-α/αα

-α/αα

-/-α

-/-

Severe, requires blood transfusions regularly)

Asymptomatic with mild or no anemia; RBC abnormalities seen

Asymptomatic; no RBC abnormality

Asymptomatic; like the minor

Severe anemia, tetramers of β-globin (HbH) formed in RBC’s

Lethal in utero

Rare gene deletions in β°/β°Defects in transcription processing, or translation of β-globin messenger RNA

Same

Gene deletions mainly

Same

Same

Same

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38) Clinical course, alterations in the peripheral blood and erythropoiesis in thalassemia.

a) Thalassemia majori. 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 RBC’s 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 minori. 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 testsiii. The diagnosis of β-thalassemia minor is made by HbA (α2β2), the level of HbA2

(α2δ2) is increasediv. 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 increasedviii. 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

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 dayf) Transient aplastic crisis usually is self-limiting and requires only supportive measures.g) Immunoglobulin treatment, which is dramatically effective in reversing the aplasia.

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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) Immune-mediated (direct Coombs test +ve)b) Causes:

i. Caused by antibodies that react against normal or altered RBC membranes. ii. Anti-RBC antibodies arise from

o Autoimmuneo Drug induced immune

iii. +ve result from Coombs test indicates that patient’s 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

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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. IgGii. 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 patient’s RBC are coated with human antibodies that can react with

antihuman Ig ( malaria, drug)

43) Characteristic symptoms of acute or chronic hemolytic anemiaa) Acute: trauma, normocytic normochromic, recovery by rise in erythropoietin levelb) Chronic: lesions of GIT, gynecologic disturbances, iron deficiency

WBC PATHOLOGY

1) Leukocytosis.Classification

a) Reactive - As a respond to the requestb) Pathology - Associated with neoplasma with hematopoeitic system

- Leukemia

2) Common mechanism of reactive leukocytosis

a) Physio leukocytosisi. Myogenic physical exercise

ii. Digestiveiii. In newborniv. In pregnancyv. Emotional stress(e.g.: child crying)

Mechanism: - Redistributive (from one place to another) to fulfill function - Substance: cathecolamines

b) As a respond to same diseasei. Neutrophilia

ii. Eosinophiliaiii. Monocytosis

3) Neutrophilic leukocytosis,its major causes and alterations in the blood, different types of neutrophil nucleus shift

a) Neutrophilia - Absolute number of neutrophil is increase due to activation of granulocytosis

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

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c) Neutrophilic nucleus shift:Myeloblast Promyelocyte myelocyte metamyelocyte band neutrophil

4) Eosinophilic leukocytsis, its major causes and mechanism, alteration in the blood.

Causesa) Allergic disorders such as hay fever, asthma, allergic skin diseases (e.g.: pemphigus, dermatitis)b) Parasitic infestations (worms, protozoa)c) Drug reactionsd) 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/mm3Causes: 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/μL 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) Leukopenia. Classification. Main causes of neutropenia and lymphopenia.8) Myelotoxic and immune forms of agranuloctosis, their main causes

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 drugsii. AIDS.

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9) Main differences in clinical and hematological symptoms of immune and myelotoxic forms of agranulocytosis

a) Involve special triad: leukoppenia, neutropenia and relative lymphocytosisb) It is a common feature for both butc) 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-leukemiaiv. Acute lymphoblastic leukemiav. Chronic lympholeukemia

12) Modern theories of etiopathogenesis of leukemia.

a) Natural or artificial ionizing radiation,b) Certain kinds of chemicals,c) Some viruses, andd) 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).

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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.

M0Undifferentiated leukemia (98013) stem cells predominate or cell    type unidentified

M1Myeloblastic leukemia without maturation (98723--acute)    immature white blood cells predominate

M2 Myeloblastic leukemia with maturation (98723--acute) with partial    differentiation

M3Promyelocytic leukemia (98663--acute) promyelocytes predominate   subdivided    M3a without eosinophilia                        M3b with eosinophilia (98603)

M4

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

M5 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

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                        differentiation (promonocytic)M6 Erythroleukemia (98403) immature red and white cells predominateM7 Megakayrocytic leukemia (99103--acute)

14) Cytochemical test of acute myelogenous leukemia.

Type of anemia Cytochemical reactionM0 All reaction are negative

M1+ Myeloperoxidase+ Sudan black+ PAS-material in diffuse form

M2+ Myeloperoxidase+ Sudan black+ PAS-diffuse form

M3+ Myeloperoxidase+ Sudan black+ PAS-diffuse form

M4+ Myeloperoxidase+ Non-specific esterase

M5 + Non-specific esteraseM6 + PASM7 Antigen of factor vii of clotting system

15) Typical clinical features of acute myelogenous leukemia and their pathogenesis. Main COD of this disease.

a) Clinical features:i. Abrupt stormy onset:patient present within 3 months of the onset of the symptoms

ii. Symptoms related to depression of normal marrow functionsiii. Bone pain and tendernessiv. Generalized lymphadenopathy, splenomegaly and hepatomegalyv. CNS manifestation.

b) Pathogenesis:i. Block of differentiation and that the neoplastic blasts have prolonged rather than

shortened generation time.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):

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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 ageb) Peak incidence is in the fourth and fifth decades of life.c) Target for neoplastic transformation and hematopoiesis

i. Target: from pleuripotent stem cellii. 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 eosinophilo Philadelphia chromosomeo Anemiao thrombocytopenia

17) Three stages of chronic myelocytic leukemia. Alteration in the blood.

a) Onset of CMLi. Usually slow

ii. Initial symptoms are nonspecificiii. Marked elevation of leukocyte countiv. Circulating cell predominantly neutrophil and myelocytesv. Basophil and eosinophil also prominent

vi. Thrombocytosis

b) Accelerated phasei. 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.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 (sea-

blue 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.

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- 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 pathogenesisa) 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

c) Common features:i. Pain behind the sternum

ii. Pain in low extremitiesiii. Neuroleukemiaiv. Meningeal syndromesv. Pneumonia cough (enlarged nodes)

21) Specific features of peripheral blood and bone marrow activity in acute lymphoblastic leukemia.

a) Blastosis - Subleukemia, aleukemiab) In smear - ↑ blastosis (> ½ 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

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23) Clinical features of acute lymphoblastic anemia and their pathogenesis

a) Abrupt stormy onset:o Patient presents the onset symptoms in few days – few weeks.

b) Depression of normal marrow fx:o Fatigue due to anemiao Fever by infection due to absence mature leukocytes.

c) Bone pain & tenderness:o Marrow expansion & infiltration of subperiosteum

d) Generalized lymphadenopathy, splenomegaly, hepatomegalyo By neoplastic infiltration.

e) CNS manifestationo 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 symptomaticiii. But when appear symptom:nonspecific→esay fatigability,weight loss

and aneroxiaiv. Lleucocytes count ↑v. Hypogammaglobulinemia(↑ susceptibility to infection)

vi. Hyperplastic syndrome with enlarge of liver n spleen

b) Pathogenesisi. Linked to genetic abnormalities and environmental factors

ii. Ig genes of some CLL are somatically hypomutated

25) Alterations in the blood and bone marrow in patients with chronic lymphocytic leukemia.

a) Bone marrow:-too much lymphocytes n lymphoblastic

b) Peripheral blood:i. Leucocytes:↑(not < than myeloleukemia but > than acute leukemia)

ii. Lymphocytes: ↑ (~70-80%) iii. Anemia n thrombocytopenia (autoimmune diseases)iv. 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

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- 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) Erythrocytosis. Definition and classification. Common hematological and clinical features.

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:- 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 leftiii. ↑ platelet countiv. ↑ total blood volume and total red cell volumev. ↑ 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 cellsc) Symptoms:

- often asymptomatici. Generalized itching- particularly after exposure to warm water, may be duer to abnormal

histamine release/ prostaglandin production.

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ii. Gouty arthritisiii. 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).

2) List the causes of B12-deficiency anemia.i. Low dietary intake (especially in strict vegetarian).

ii. Gastrectomyiii. Resection of terminal ileumiv. Regional enteritisv. Tropical sprue

vi. Whipple diseasevii. Gastric atrophy (in older person)

3) List the cause of folate deficiency anemiai. Poor diet

ii. Increased metabolism needs(pregnant women and patients with chronic hemolytic anemias)

4) List the causes of aplastic anemiai. Chemotherapy

ii. Total ionization (x- ray disease)iii. Some chemical (benzene)iv. Drugs (alkylating agents)v. Viruses

5) Enumerate the hereditary hemolytic anemias

i. Spherocytosiso Autosomal dominanat trait

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o Defect in rbc membrane that renders the rbc spheroidalo Less deformable & vulnerable to splenic sequestration & destructiono Trapped n splenic cords,phagocytosed by mph

ii. Sickle cell anemiao Mutation in encoding the β-globin chain o Substitution of valine for instead of glutamate at 6 th position of β chain produce

sickle cell hbo In homozygotes all hba is replaced by hbso In heterozygotes half is pelacedo Common in african american n african population

iii. Thalassemiao α-Thalassemia-homozygous(inherited from both parents)o β-Thalassemia-heterozygous(inherited from 1 parent)o Deficiency of β globin chaino Common among mediterranean,african,asian population

6) Name the causes of extravascular eryth. hemolysis:

Occurs within cells of mononuclear phagocytes or reticulocytes of spleeni. 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.

7) The causes of high hematocrit value can be the followings:

i. Dehydration ii. Burns

iii. Diarrheaiv. Other trauma, etc.v. Erythrocytosis (excessive red blood cell production)

vi. Polycythemia Vera

8) The causes of low hematocrit value can be the following

i. Anemiaii. Blood loss (hemorrhage)

iii. Leukemiaiv. Bone marrow failure (e.g., due to radiation, toxin, fibrosis, tumor)v. 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. Low Hb levelsii. Low mean corpuscular volume

iii. Hypochromic microcytic RBCiv. Low serum ferritinv. Low seum iron levels

vi. Increase total iron binding capacity

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10) The typical blood alteration in patients with vitamin B12 deficiency anemia

i. Megaloblasticii. Hyperregenerative

iii. Hypochromiciv. Microcyticv. Macrocytes ???