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BLOOD 2 RED BLOOD CELLS JAUNDICE ANEMIA & POLYCYTHEMIA

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1 BLOOD 2 RED BLOOD CELLS JAUNDICE ANEMIA & POLYCYTHEMIA

2 CONTENT RED BLOOD CELLS (RBC) COUNT, FUNCTIONS, STRUCTURE
HEMOGLOBIN (Hb): CHEMISTRY, REACTIONS, FUNCTIONS, CONCENTRATION ERYTHROPOIESIS, CONTROL OF ERYTHROPOIESIS DESTRUCTION OF RBC, METABOLISM OF Hb AND IRON. HEMOSIDEROSIS JAUNDICE ERYTHROCYTE SEDIMENTATION RATE TYPES OF ANEMIA, SICKLE CELL DISEASE POLYCYTHEMIA

3 OBJECTIVES Describe the functional consequence of the lack of a nucleus, ribosomes, and mitochondria for a) protein synthesis and b) energy production within the red blood cell. Relate the three red blood cell concentration estimates, red blood cell count, hematocrit, and hemoglobin concentration. Know the importance of MCV and be able to calculate the mean corpuscular volume. Describe the structure of hemoglobin (Hb). Describe the differences between the major normal types of Hb (adult A and A2, glucosilated, fetal). Predict the changes in Hb types present in blood when synthesis of beta chains of globin is deficient. Describe the abnormal types of Hb (Hb S, thalassemias). Describe the normal and abnormal Hb reactions (oxyHb, MetHb, carboxyHb). Calculate the mean corpuscular Hb concentration and the mean corpuscular Hb. Identify the site of erythropoietin production, the adequate stimulus for erythropoietin release, and the target tissue for erythropoietin action. Describe the role of vitamin B12 & folic acid, and various hormones in regulation of RBC formation. Describe the dietary requirements for RBC production. Relate the rate of red blood cell production and the percentage of immature reticulocytes in the blood. Describe the metabolism of iron in the body. Describe the metabolism of Hb (pre-hepatic, hepatic, post-hepatic). Describe the three types of jaundice (pre-hepatic, hepatic and post-hepatic). Compare and contrast the laboratory findings and urine/stool color in the three types of jaundice. Describe physiological jaundice of the newborn. Discuss the normal balance of red blood cell synthesis and destruction, including how imbalances in each lead to anemia or polycythemia. Compare and contrast the main types of anemia (nutritional, hemolytic, aplastic, hemorrhagic). Be able to describe different types of anemia in terms of MCV and MCHC. Describe the main effects of anemia and polycythemia on body functions.

4 RBC: Functions Transport of O2 from the lungs to the tissues and CO2 in the opposite direction Hemoglobin Carbonic anhydrase Catalyses the reaction H2O + CO2 ↔ H2CO3 Maintenance of pH homeostasis (globin, phosphate and bicarbonate buffers)-hemoglobin in the cells is an excellent acid-base buffer Contribution to the blood viscosity ↓ blood oncotic P (by keeping Hb-protein inside the cells)

5 RBC COUNT Normal values
Adult males: – /mm3 (5.4million/mL) Adult females: – /mm3 (4.8million/mL) Abnormally high count – polycythemia Abnormally low count – anemia

6 STRUCTURE OF THE MATURE RBC
Small size Excess of the plasma membrane & specific shape RBC - biconcave discs with central depression on each side High surface-to-volume ratio Deformation of the cells without stretching the plasma membrane Rapid diffusion of respiratory gases to and from the cell Easy passage through the small capillaries The RBC is a bag, which can be deformed into almost any shape.

7 Red Blood Cells Figure 16-5

8 STRUCTURE OF THE MATURE RBC (cont.)
Membrane contains special proteins and polysaccharides that differ from person to person – blood groups Lack of the nucleus and organelles Cannot undergo mitosis Generate ATP anaerobically → do not use oxygen they transport Can not synthesize new cellular components to replace damaged ones Life span days Contain a red pigment, hemoglobin (red color of the blood) Occupies 1/3 of cellular volume 280 million Hb molecules/RBC

9 MEAN CORPUSCULAR VOLUME
MCV: fL Mean volume of a RBC Values Normal range 82 – 99 femtolitre (fL) Low volume in microcytic anemia High volume in macrocytic anemia Calculation of the MCV Hematocrit x 10 RBC count (in millions/mL blood) Sample calculation: Htc = 40, RBC count = 5 (x 106/mL) MCV = (40 x 10)/5 = 80 fl fL= L

10 RBC Morphology In a normal individual RBCs show minimal anisocytosis(Excessive variation in the size of cells )and poikilocytosis(irregularly shaped erythrocytes). Larger than average RBCs are macrocytic (left), while those smaller than average are microcytic (right).

11 Normal peripheral blood RBCs are normochromic normocytic.
Pale cells (central pallor >1/3 dia) are referred to as hypochromic (right), while cells without central pallor are called hyperchromic (left). Normal peripheral blood RBCs are normochromic normocytic.

12 HEMOGLOBIN: Chemistry
Protein – globin 4 polypeptide chains Normal adult Hb – HbA, Hbα2β2 A pair of α chains (141 AA) A pair of β chains (146 AA) Adult Hb – HbA2 (2.5% of Hb), Hbα2δ2 β chains are replaced by δ chains Fetal Hb – HbF, Hbα2γ2 β chains are replaced by γ chains (146 AA) Adult Hb glucosilated – HbAIc Has a glucose attached to each β chain Nonprotein pigment bound to each of the 4 chains – hem Each hem ring has 1 iron ion (Fe2+) that can combine reversibly to 1 O2 molecule Each Hb molecule can bind 4 O2 molecules Adult Hb – HbA, Hbα2β2 red, oxygen-carrying pigment in the red blood cells of vertebrates is hemoglobin, a protein with a molecular weight of 64,450. Hemoglobin is a globular molecule made up of four subunits (Figure 32–6). Each subunit contains a heme moiety conjugated to a polypeptide. Heme is an iron-containing porphyrin derivative (Figure 32–7). The polypeptides are referred to collectively as the globin portion of the hemoglobin molecule. There are two pairs of polypeptides in each hemoglobin molecule. In normal adult human hemoglobin (hemoglobin A), the two polypeptides are called chains, each of which contains 141 amino acid residues, and chains, each of which contains 146 amino acid residues. Thus, hemoglobin A is designated 22.,Formation of glucosilated Hb increases in untreated diabetes mellitus → abnormal dissociation of HbO2 and tissue hypoxia. Hb A HbA2 HbF

13 SICKLE CELL DISEASE Inherited disease
High prevalence in the malaria belt Mutation causes formation of HbS instead of HbA HbS precipitates into long crystals when oxygen tension is low (hypoxia) → cell elongation (sickling) and damage to the cell membrane → hemolysis → hypoxia (vicious cycle) Rigid sickled RBCs occlude the microvasculature leading to vaso-occlusive crisis. HbS – HbαA2βS2 The production of each type of globin chain is controlled by an individual structural gene with five different loci. Mutations, which can occur anywhere in these five loci, have resulted in the production of over 550 types of abnormal hemoglobin molecules, most of which have no known clinical significance. Mutations can arise from a single substitution within the nucleic acid of the gene coding for the globin chain, a deletion of the codons, or gene rearrangement as a result of unequal crossing over between homologous chromosomes. Sickle-cell anemia, for example, results from the presence of sickle-cell hemoglobin (HbS), which differs from normal adult hemoglobin A because of the substitution of a single amino acid in each of the two chains. -Note. The gene responsible for sickle cell disease alters the permeability of the RBC membrane → ↑ leakage of K+ from the RBC →↑ resistance to malaria parasites. Negatively charged glutamate is substituted for nonpolar valine at position 6 in the β chain)

14 HEMOGLOBIN: Reactions
Oxyhemoglobin: Hb + 4 O2 (O2 attaches to Fe2+ in hem) Is produced in the lungs (oxygen loading) Reduced Hb (deoxyHb) Is produced in tissue capillaries after dissociation of O2 (oxygen unloading) Combines with H+ - acts as a buffer Combines with CO2 → Carbaminohemoglobin: Hb + CO2 (CO2 binds to globin, not to hem) OxyHb O2 carrying function CO2 carrying function Buffering function Oxyhemoglobin (HbO2), the oxygen-saturated form of hemoglobin, transports oxygen from the lungs to tissues, where the oxygen is released. When oxygen is released, HbO2 becomes reduced hemoglobin (Hb). While oxygensaturated hemoglobin is bright red, reduced hemoglobin is bluish-red, accounting for the difference in the color of blood in arteries and veins. The affinity of hemoglobin for O2 is affected by pH, temperature, and the concentration in the red cells of 2,3-bisphosphoglycerate (2,3-BPG). 2,3-BPG and H+ compete with O2 for binding to deoxygenated hemoglobin, decreasing the affinity of hemoglobin for O2 by shifting the positions of the four peptide chains (quaternary structure). COOH/COO- NH-COO- NH2/NH3+

15 HEMOGLOBIN: Reactions (cont.)
Methemoglobin (MetHb): Hb iron is oxidized from the ferrous (Fe2+) to the ferric state (Fe3+) Is incapable of carrying O2 and has a bluish color → cyanosis Limited amount of metHb can be converted back to Hb by methemoglobin reductase present in the RBCs In normal state, 1.5% of Hb is in MetHb state Methemoglobinemia: Met-Hb > 1.5% (results from oxidation by nitrates, drugs like phenacetin or sulfonamides and congenital deficiency of methemoglobin reductase). Carboxyhemoglobin: Hb + CO(carbon monoxide) → cherry-red color of the skin and mucous membranes CO has times the affinity to Hb as does O2 → HbCO is a very stable molecule CO ↓ the functional Hb concentration HbCO is unavailable for O2 transport → CO poisoning, acute onset anemia Certain chemicals readily block the oxygen-transporting function of hemoglobin. For example, carbon monoxide (CO) rapidly replaces oxygen in HbO2, resulting in the formation of the stable compound carboxyhemoglobin (HbCO). The formation of HbCO accounts for the asphyxiating properties of CO. Nitrates and certain other chemicals oxidize the iron in Hb from the ferrous to the ferric state, resulting in the formation of methemoglobin (metHb). MetHb contains oxygen bound tightly to ferric iron; as such, it is useless in respiration. Cyanosis, the darkblue coloration of skin associated with anoxia, becomes evident when the concentration of reduced hemoglobin exceeds 5 g/dL. Cyanosis may be rapidly reversed by oxygen if the condition is caused only by a diminished oxygen supply. However, cyanosis caused by the intestinal absorption of nitrates or other toxins, a condition known as enterogenous cyanosis, is due to the accumulation of stabilized methemoglobin and is not rapidly reversible by the administration of oxygen alone.

16 HEMOGLOBIN: Concentrations
Concentration per unit volume of whole blood Mean corpuscular Hb concentration - concentration of Hb per unit packed cell volume MCHC = Hb amount / Volume of packed RBC Hb concentration = Hb amount (g)/Volume of whole blood (dL, L) Plasma Calculation: MCHC = Hb concentration x 100 Htc Sample calculation: [Hb] = 14.5 g/dL, Htc = 45 mL/dL MCHC = (14.5/45) x 100 = 32.2 g/dL packed cells Males – 16.0±2.0 g/dL Females – 14.0±2.0 g/dL RBC Normal range: 31-37 g/dL packed cells ↓ value – hypochromia (i.e., Hb deficiency) ↑ value – hyperchromia (i.e., spherocytosis)

17 Hb CONCENTRATION: Mean corpuscular Hb (MCH)
Is the total Hb content of a RBC Values Normal range – pg ↓ value – hypochromia (i.e., iron deficiency anemia) ↑ value – hyperchromia (i.e., vit B12 deficiency) Calculation MCH = Hb in grams/100 mL blood x 10 RBC count in million/L blood Sample calculation: [Hb] = 12 g/dL, RBC count = 4 x 106/mL MCH = 12/4 x 10 = 30 pg MCH

18 RBC CHARACTERISTICS: SUMMARY

19 Erythropoiesis Concept: The production of new red blood cells to replace the old and died ones In the adult, all the red cells are produced in bone marrow

20 Erythropoiesis- Pluripotent stem cells
in the bone marrow can produce any type of blood cells. is capable of both self-replication and differentiation to committed precursor cells that can produce only a specific cell line. CFU:colony-forming unit

21 Erythropoiesis-CPU-E
the committed red cell precursor undergoes several divisions. The daughter cells becomes progressively smaller, the cytoplasm changes color from blue to pink as hemoglobin is synthesized, the nucleus becomes small and dense and then extruded. Proerythroblast (Pronormoblast) Basophilic Normoblast Polychromatophilic Orthochromatophilic Reticulocyte Erythrocyte Early Intermediate Late

22 Erythropoiesis-CPU-E
The resulting non-nucleated cells is termed a reticulocyte since it still contains RNA. Within a few days of entering the circulation, the reticulocytes lose their RNA and becomes mature red cells Proerythroblast (Pronormoblast) Basophilic Normoblast Polychromatophilic Orthochromatophilic Reticulocyte Erythrocyte Early Intermediate Late

23 Regulation of Erythropoiesis
A. Erythropoietin, a glycoprotein released predominantly from the kidneys in response to tissue hypoxia. also produced by reticuloendothelial system of the liver and spleen. Effect: a, Stimulates the proliferation and differentiation of the committed red cell precursor b, Accelerates hemoglobin synthesis c, Shortens the period of red cell development in the bone marrow.

24 CONTROL OF ERYTHROPOIESIS: Hypoxia
Hypoxia stimulates production of EPO by the kidneys - the tubular epithelial cells and juxtaglomerular cells (90% of EPO) & the liver Biological effects of EPO: 1. ↑ production of proerythroblasts from hematopoietic stem cells 2. ↑ speed of erythropoietic stages Tissue oxygenation is the most powerful regulator of the RBC production (but not the RBC count in the blood) Note. The liver is an important source of EPO in the fetus and neonates but it is less sensitive to hypoxia than kidneys → smaller response to hypoxia. Erythropoietin is a very powerful stimulator of the RBC production. A significant increase in the erythropoietin secretion can rise the rate of RBC production 10 or more times.

25 ERYTHROPOIESIS Morpho-functional changes (proerythroblast → RBC)
Appearance of Hb Some Hb is present in the early erythroblasts Late erythroblasts are saturated with Hb Degeneration of the cell organelles Progressive ↓ in the cell size Degeneration of the nucleus Starts in the late erythroblast stage Disappeared by the reticulocyte stage Note that mature RBCs do not have nucleus and organelles. Reticulocytes contain remnants of RNA and cell organelles – reticulum or network of black spots in the cytoplasm. Reticulocytes enter the blood and within 1-2 days develop into mature RBC. Only mature RBC and reticulocytes are present in the blood

26 RETICULOCYTES & ERYTHROPOIESIS RATE
Normal reticulocytes count in the blood 1-4% of the circulating RBC in adults 2-6% in newborns ↑ reticulocytes count – indicator of rapid RBC production (i.e., hypoxia, hemorrhage, stress, effective therapy of anemia) ↓ reticulocytes count - ↓ erythropoiesis (↓ EPO production, ↓ ability of red bone marrow to respond to EPO, nutritional anemia, etc.)

27 CLINICAL FOCUS: BLOOD DOPING AND EPO
Beneficial effects of EPO ↑ RBC count and O2 carrying capacity of the blood → ↑ O2 delivery to tissues, ↑ muscular performance, ↓ muscular fatigue Recombinant EPO (rhEPO) is used for treatment of anemias associated with chronic renal failure, AIDS and cancer chemotherapy Dangers of excessive EPO Genetically engineered EPO (i.e., darbepoetin) has increased life time ↑ Htc → ↑ blood viscosity, ↑ peripheral resistance, ↑ blood pressure, ↓ heart rate (secondary to increased blood pressure), ↑ blood clotting Genetically engineered EPO often cause production of antibodies against natural EPO and destruction of the RBC

28 CONTROL OF ERYTHROPOIESIS: Vitamin B12 and folic acid
Are required for maturation of the RBC ↑ Synthesis of DNA (synthesis of thymidine triphosphate – DNA building block) → rapid proliferation of the erythroblastic cells Vitamin B12 (cyanocobolamin) Is required for action of folic acid on erythropoiesis Dietary B12 Parietal/oxyntic cells of gastric mucosa produce intrinsic factor (IF) B12+IF B12 binds with the IF – protection from digestion by GIT secretions Complex of Vit B12 +IF complex binds to the mucosal receptors in the ileum → transport across mucosa Dietary deficiency of the Vit B12 occurs partially in vegetarians because vegetables and fruits contain very little vitamin B12. Folic acid is easily destroyed during cooking. Note that macrocytes have normal oxygen carrying capacity. Release of B12 into the portal blood freed of IF Binding to the plasma globulins (transcobolamin I, II and III) → red bone marrow or storage in the liver (very large quantities – 3-4 years reserve)

29 CONTROL OF ERYTHROPOIESIS: Other factors
Testosterone Stimulates the release of EPO Adrenal cortical steroids and ACTH In physiological concentrations stimulate EPO production Large doses are inhibitory

30 DESTRUCTION OF THE RBC Sites of destruction Senescent RBC
Circulating blood (10% of senescent RBCs) Macrophage system (spleen and liver) Senescent RBC ↓ metabolic rate → ↑ fragility → rupture of the membrane when RBC pass through tight spots of the circulation (i.e., red pulp of the spleen)

31 METABOLISM OF Hb Prehepatic Takes places in the macrophages
Results in formation of bilirubin – a bile pigment Hepatic Takes place in the liver (hepatocytes) Conjugation of bilirubin with glucuronic acid – bilirubin mono- or bi-glucuronide and secretion of conjugated bilirubin into the bile Posthepatic Takes place in the GI and kidneys Formation of urobilinogen and stercobilinogen and excretion

32 PREHEPATIC METABOLISM OF Hb
RBC or remnant Macrophages Cell remnants Hemoglobin Hem Globin Pigment Fe++ CO Biliverdin Bilirubin Exhaled Blood Albumin Bilirubin-albumin Fe++ pool Protein pool Liver Conversion of the hem pigment into the bile pigment biliverdin + CO → bilirubin → blood plasma Removal of the globin from Hb in macrophages → protein pool of the body In the plasma water insoluble bilirubin combines with albumin to form water soluble complex → liver

33 HEPATIC & POSTHEPATIC METABOLISM OF BILIRUBIN
In the liver Replacement of albumin with glucuronic acid – bilirubin mono- or bi-glucuronide (water soluble) Excretion of conjugated bilirubin into the small intestine via the bile In the small intestine Conversion of bilirubin to urobilinogen by the intestinal bacteria Conversion to stercobilinogen → oxidation and excretion in the feces as stercobilin Absorption from the small intestine & either re-excretion by the liver or oxidation & excretion by the kidneys as urobilin. Transport of bilirubin from plasma into the hepatocytes Liver Glucuronic acid Albumin Bilirubin-glucuronide Urobilinogen (in the small intestine) Reabsorption Stercobilinogen Re-excretion in bile Excretion as urobilin in urine Excretion as stercobilin in feces

34 BILIRUBIN: Concentration in plasma
Concentration in plasma, mg/dL Free bilirubin = unconjugated bilirubin 0.1 – 1 Conjugated bilirubin 0 – 0.3 Total bilirubin 0.3 – 1.2

35 JAUNDICE Refers to the yellow color of the skin, conjunctivae and mucous membranes caused by the presence of excessive bilirubin in the plasma and body fluids (jaune (French) = yellow) Blood bilirubin level must exceed three times the normal values, for the coloration to be easy visible Types of jaundice: Pre-hepatic – the pathology occurs prior to the liver Hepatic – the pathology is located in the liver Post-hepatic – the pathology occurs after the conjugation of bilirubin in the liver

36 PRE-HEPATIC JAUNDICE N
Excessive hemolysis of the RBCs – hemolytic jaundice  bilirubin production ↑ unconjugated (indirect) bilirubin Capacity of the liver to conjugate bilirubin is exceeded (saturation of enzyme glucuronyl transferase) Normal conjugated (direct) bilirubin N Note that unconjugated bilirubin can enter the brain  toxic effect in neonates. The yellowish discoloration is less marked than in hepatic and posthepatic jaundice. In infants urobilinogen formation is not increased because gut flora is not developed.  urobilinogen formation   urobilinogen → dark urine ↑ stercobilinogen → dark feces

37 HEPATIC JAUNDICE Results from infective or toxic damage to the liver cells (hepatocellular damage) Uptake, conjugation and/or excretion of bilirubin is affected ↑ unconjugated bilirubin Normal/decreased conjugated bilirubin ↑ urobilinogen in blood (↓ enterohepatic circulation and hepatic extraction of blood urobilinogen by damaged hepatocytes) In obstructive jaundice, serum level of cholesterol is also elevated. Patients often complain of severe itching or "pruritus". In posthepatic and hepatic jaundice fecal fat increases and liver function tests are impaired. ↑ urobilinogen filtration and excretion in urine Pale/N stool Dark urine

38 POSTHEPATIC JAUNDICE N ↓ or absent urobilin in urine
Results from obstruction of the bile ducts by stones, tumors, etc. Functioning of the hepatic cells is normal N Normal unconjugated bilirubin  plasma level of conjugated bilirubin due to the bile entry into the blood from ruptured congested canaliculi and ↑ total bilirubin  urobilinogen formation Conjugated bilirubin in urine (kidney can excrete small quantities of highly soluble conjugated bilirubin) → dark urine ↓ or absent urobilin in urine ↓ stercobilin content in feces → pale feces

39 PHYSIOLOGICAL JAUNDICE OF THE NEWBORN
Hemolysis of the excess RBC when the infant is suddenly exposed to a high oxygen environment and hence does not need so many RBC as in the uterus Immaturity of the liver (inability to conjugate significant quantities of bilirubin with glucuronic acid for excretion into the bile) to handle the excess bilirubin (especially in premature babies) ↑ plasma total bilirubin concentration (less than 1 mg/dL → 5 mg/dL) Mild jaundice (yellowness) of the infant’s skin and the sclerae for 1-2 weeks Is observed in 60% of normal babies during the first 1-2 weeks.

40 IRON METABOLISM Dissociation of Fe from the hem → plasma → binding to transferrin, transport in the blood → Detachment from transferrin & storage in the liver, muscle cells & macrophages attached to ferritin or hemosiderin → Release from the storage sites, transport in the blood by transferrin Transport into the RBC precursor cells by receptor mediated endocytosis → Hem synthesis 2 1 3 4 ↓ quantities of transferrin → ↓ Hb content in the RBC – hypochromic anemia Note that transferrin strongly binds to receptors on the erythroblasts plasma membrane and is transported inside the cell by endocytosis. In the cell the transferrin delivers iron to the site of hem synthesis – mitochondria. Note that intestinal absorption of non-hem iron is facilitated by ascorbic acid. Synthesis of transferrin increases with iron deficiency but decreases with any type of chronic disease.

41 FORMS OF IRON IN THE BODY
Recommended daily intake - 15 – 18 mg ( μmol) Minimal absorption to balance iron loss Adult males - 35 μmol Adult females μmol Distribution of body iron in an average man Hb, 2100 mg Ferritin - water soluble protein-iron complex , 700 mg (in the liver, spleen, marrow and plasma) Hemosiderin - water insoluble complex (macrophages of the liver and bone marrow), 300 mg Myoglobin - local oxygen reserve, 200 mg Tissue (heme and nonheme) enzymes, 150 mg Transport-iron compartment in plasma (transferrin), 3 mg. Note that ferrous iron (Fe2+) is absorbed much readily than ferric iron (Fe3+); reducing substances such as ascorbic acid facilitate iron absorption. Ferritin is also present in the plasma and its plasma concentration is an excellent indicator of the iron stored in the body, because of a dynamic balance, which exists between intra- and extracellular ferritin iron and iron used. Insoluble hemosiderin tends to form large clusters in the cells that can be observed microscopically.

42 HEMOCHROMATOSIS Reasons
Primary - one of the most common autosomal recessive genetic disorders characterized by excessive absorption of dietary iron resulting in a pathological increase in total body iron stores Failure to reduce iron reabsorption in response to increased iron level in the body Secondary – is not genetic (results from anemia, alcoholism, transfusion iron overload –hemosiderosis, etc.) Consequences Deposition of iron in the body tissues (liver, heart, pancreas, pituitary, joints, and skin) initially as ferritin and than as hemosiderin Toxic action on organs and damage of cells due to action as a pro-oxidant (↑ formation of free radical formation, i.e., the hydroxyl radical and the superoxide radical) → DNA cleavage, impaired protein synthesis, and impairment of cell integrity and cell proliferation, leading to cell injury and fibrosis. Cirrhosis, hyperpigmentation of skin, diabetes mellitus, impotence, joint diseases, etc. Normally only 10% of iron from diet is reabsorbed in the GI. In hemochromatosis, up to 30% of iron is reabsorbed. Over time, the patients absorb and retain between five to 20 times more iron than the body needs. Because the body has no natural way to rid itself of the excess iron, it is stored in body tissues, specifically the liver, heart, and pancreas.

43 ERYTHROCYTE SEDIMENTATION RATE (ESR)
Specific weight of the RBC is higher than that of the plasma  in a stabilized blood, RBC slowly sink towards the bottom of the test tube -sedimentation Factors increasing ESR ↓ Htc, ↓ blood viscosity ↑ concentration of fibrinogen (i.e., pregnancy, vascular diseases, heart diseases), haptoglobulin, lipoproteins, immunoglobulins Macrocytic RBC Extreme elevation of WBC count (leukemia) Factors decreasing ESR ↑ Htc Change in the RBC shape (i.e., sickle-cell anemia, poikilocytosis – nonuniformity of shape) ↑ albumin concentration Males – 3-6 mm/h Females – 8-10 mm/h ESR Clumps of RBCs Gathering of the RBCs into clumps increases ESR. Negative charge of the RBC membrane prevents clamps formation.

44 ANEMIA Deficiency of blood Hb due to
↓ RBC count (too rapid loss or/and too slow production) ↓ Hb quantity in the RBC WHO's Hemoglobin thresholds used to define anemia (1 g/dL =  mmol/L) Age or gender group Hb threshold (g/dl) Hb threshold (mmol/l) Children ( yrs) 11,0 6,8 Children (5-12 yrs) 11,5 7,1 Children (12-15 yrs) 12,0 7,4 Women, non-pregnant (>15yrs) Women, pregnant Men (>15yrs) 13,0 8,1 Note that under normal conditions about 1% of the RBCs are destroyed daily and equal numbers are produced.

45 ANEMIA: CONSEQUENCES ↓ oxygen-carrying capacity of the blood → hypoxia → vasodilation ↑ in pulse and respiratory rates (effort to supply sufficient oxygen to tissues) ↓ exercise & cold tolerance Pale skin (↓ red colored oxyHb) ↑ fatigue and lassitude ↓ blood viscosity → ↓ peripheral vascular resistance → ↑ blood flow, venous return, cardiac output and work load on the heart

46 ANEMIAS: Classifications
Classification according to etiological ground Nutritional Aplastic Hemorrhagic Hemolytic Anemia: classification according to MCV      Macrocytic anemia (MCV>100)  Normocytic anemia (80<MCV<100)  Microcytic anemia (MCV<80)    Deficiency of vit B12, folic acid, or IF. Hypothyroidism. Alcoholism. Liver diseases. Drugs that inhibit DNA replication (i.e., methotrexate, zidovudine) Hem synthesis defect (i.e., iron deficiency, chronic diseases) Globin synthesis defect (i.e., thalassemia) Sideroblastic defect Acute blood loss, chronic diseases, bone marrow failure, hemolysis Sideroblastic defect. The body has iron available, but cannot incorporate it into hemoglobin. This results in production of sideroblasts, which are nucleated erythrocytes with granules of iron in their cytoplasm.

47 ANEMIA: Nutritional Iron deficiency Is the most common type Reasons
Premenopousal women: Blood loss during menses (20% of all women of childbearing age have iron deficiency anemia, compared with only 2% of adult men) Males and postmenopausal females: Excessive iron loss due to chronic occult bleeding (peptic ulcer, tumor, etc.) Increased iron demands (i.e., pregnancy and lactation) Inadequate iron intake or absorption (i.e., vit. C deficiency) Parasitic infestation (hookworm, amebiasis, schistosomiasis) Chronic intravascular hemolysis (if the amount of iron released during hemolysis exceeds the plasma iron-binding capacity) Iron deficiency anemia develops slowly after the normal stores of iron have been depleted in the body and in the bone marrow. Women, in general, have smaller stores of iron than men and have increased loss through menstruation, placing them at higher risk for anaemia than men. In men and postmenopausal women, anaemia is usually due to gastrointestinal blood loss associated with ulcers or the use of aspirin or nonsteroidal anti-inflammatory medications (NSAIDs). Dietary sources of iron are red meat, liver, and egg yolks. Flour, bread, and some cereals are fortified with iron. If the diet is deficient in iron, iron should be taken orally. During periods of increased requirements such as pregnancy and lactation, increase dietary intake or take iron supplements. Oral iron supplements are in the form of iron salts (ferrous sulphate, gluconate, etc.) or saccharated iron . The best absorption of iron is on an empty stomach, but many people are unable to tolerate this and may need to take it with food. Milk and antacids may interfere with absorption of iron and should not be taken at the same time as iron supplements. Vitamin C can increase absorption and is essential in the production of haemoglobin. Parenteral iron causes the same therapeutic response as oral iron. It is reserved for patients who do not tolerate or who will not take oral iron or for patients who steadily lose large amounts of blood because of capillary or vascular disorders.

48 IRON DEFICIENCY ANEMIA: CONSEQUENCES
Low serum ferritin (serum iron) level Plasma ferritin concentration is an excellent indicator of the iron stored in the body, because of a dynamic balance between intra- and extracellular ferritin iron ↓ bone marrow iron stores (ferritin and hemosiderin) ↓ saturation of transferrin ↓ RBC count & Htc RBC are small and look pale - microcytic hypochromic anemia Abnormal fissuring of the angular (corner) sections of the lips (angular stomatitis). Abnormal craving to eat substances (eg, ice, dirt, paint).

49 DEFICIENCY OF IRON UTILIZATION: SIDEROBLASTIC ANEMIA
Inadequate marrow utilization of iron for Hb synthesis despite the presence of adequate or increased amounts of iron Reasons: Hereditary or acquired, including lead and ethanol toxicity, pyridoxine deficiency Deficient reticulocyte production, intramedullary death of RBCs, and bone marrow erythroid hyperplasia (and dysplasia) Presence of polychromatophilic, stippled RBCs (siderocytes) Hipochromic, microcytic RBCs, variations in RBC size Ring sideroblasts are erythroid precursors whose mitochondria (located around the nucleus) are loaded with nonheme iron.

50 ANEMIA: Nutritional (cont.)
Deficiency of vitamin B12 and/or folic acid Reasons Inadequate intake (a strict vegetarian diet excluding all meat, fish, dairy products, and eggs; chronic alcoholism) Inadequate GI absorption Lack of IF - pernicious anemia Autoimmune destruction of parietal cells (atrophic gastric mucosa) or AB against IF Removal of the functional portion of the stomach, such as during gastric bypass surgery Crohn's disease intestinal malabsorption disorders Resection (or inflammation) of the ileum (site of B12 reabsorption) Consequences Maturation failure Failure of DNA synthesis with preserved RNA synthesis, which result in restricted cell division of the progenitor cells. Production of large precursor cells – megaloblasts and larger irregular oval erythrocytes – macrocytes fully saturated with Hb – macrocytic (megaloblastic) anemia ↑ fragility of the plasma membrane → ↓ life span → anemia Vitamin B12 deficiency only results in peripheral neuropathy and spinal cord degeneration Dietary deficiency of the Vit B12 occurs partially in vegetarians because vegetables and fruits contain very little vitamin B12. Folic acid is easily destroyed during cooking. Note that macrocytes have normal oxygen carrying capacity.

51 ANEMIA: Hemorrhagic Results from abnormal blood loss (mild or severe; acute or chronic) Replacement of lost fluid within 1 – 3 days (much faster than the replacement of lost RBC) → dilution of the RBC Is normocytic Prolonged but mild loss of the blood causes microcytic hypochromic anemia (iron deficiency)

52 ANEMIA: Aplastic Results from suppression or destruction of the bone marrow (i.e., overexposure to ionizing radiation, adverse drug reaction, toxic chemicals, severe infections) Is usually normocytic Panhypoplasia of the marrow is associated with leukopenia and thrombocytopenia

53 ANEMIA: Hemolytic Spherocytosis
Is caused by an abnormally high rate of the RBCs destruction (hemolysis) due to: Structural abnormalities of the RBC (more fragile cells) Hereditary spherocytosis – cells are spherical and can not be compressed Sickle cell anemia – cells have sickle shape → hemolysis Bacterial toxins, parasitic infections (i.e., malaria) Adverse drug reactions Autoimmune reactions The bone marrow is unable to compensate for premature destruction of RBC by increasing their production. Thalassemias (α, β) Hereditary hemolytic anemia Abnormal or nonfunctional genes → globin chains are normal in structure but are produced in reduced amounts Cells are microcytic and hypochromic Spherocytosis

54 ANEMIA OF CHRONIC DISEASE
Occurs as part of a chronic disorder (i.e., infection, inflammatory disease, or cancer) Pathophysiologic mechanisms Shortened RBC survival ↓ EPO production and marrow responsiveness to EPO Impaired intracellular iron metabolism Is microcytic or marginal normocytic

55 POLYCYTHEMIA ↑ RBC count, Htc and Hb concentration Reasons
Hypoxic erythropoietic drive (i.e., high altitudes, chronic pulmonary or cardiac disease) Hemoconcentration - dehydration (i.e., heavy sweating, vomiting or diarrhea) Polycythemia vera or erythremia – uncontrolled RBC production (i.e., neoplastic disease condition of hemocytoblastic cells) Results in ↑ blood viscosity ↑ peripheral resistance → ↓ venous return to the heart ↑ blood volume tends to ↑ venous return ↑ arterial BP Ruddy skin and mucosa membranes with cyanotic tint (sluggish blood flow → ↑ blood deoxygenation in the skin circulation)

56 CLINICAL CASE A 14-year-old girl complained of fatigue and loss of stamina. Her appetite was marginal, as she was very conscious of maintaining her body weight at 96 pounds. Her monthly menstrual flow was always heavy and long from its onset at twelve years of age. Relevant laboratory findings included the following: Hematocrit (Hct) - 28% Hemoglobin (Hgb) - 9 g/dL Iron 16 µg/dL Bone marrow iron - absent Erythrocytes - small and pale Suggested treatment included ferrous sulfate or ferrous gluconate for six months orally between meals, since food may reduce absorption. A well-balanced diet was also suggested, as well as a gynecological examination. Questions. 1. What is the primary disorder of this individual? 2. What does the ferrous sulfate or ferrous gluconate provide? Why is it necessary? 3. What dietary inclusions would you suggest? 4. Why is the gynecological examination important? 5. Why is bone marrow iron an important clinical indicator in this individual?

57 PAST EXAMS QUESTION A 51-year old male complains of generalized weakness and weight loss over the past 6 months. His blood pressure and pulse rate are elevated. Laboratory values revealed a hematocrit of 35% and hemoglobin level of 10.9 g/dL. A blood smear shows hypochromic and microcytic cells. A stool test for occult blood is positive. Which of the following would be the most likely cause of the findings? a. Acute blood loss b. Iron deficiency c. Spherocytosis d. Folic acid deficiency e. Autoimmune reactions B.


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