Hematology & lymph system Block ------2nd Physiology Lecture Plasma and Red Blood cells

By

Dr. Eman Elbassuoni Professor of Physiology ------

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Blood Blood is the vital fluid tissue that circulates inside blood vessels. It represents 8% of body weight (5.6 L). Ø Functions of blood: § Transport function (O2, CO2, nutrients, waste products, and hormones). § Defensive function (WBs & antibodies). § Hemostasis (stoppage of bleeding). § Homeostasis: keeping internal environment (extracellular fluid) of the body constant for optimum function of the cell (PH, osmotic pressure, volume, gases, minerals, temperature, and nutrients). Composition of Blood

1- Blood Tissue (45% of the blood)

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2- Blood Plasma (55% of the blood): Plasma is a yellow clear fluid consisting of: ▪ 91 % water. ▪ 7 % : - Albumin - Globulin - Fibrinogen - Prothrombin ▪ 2 % other substances: - Ions (Na+, Ca++, Cl– and other ) - Nutrients - Waste products - Gases - Regulatory substances (hormones & vitamins ) Plasma Proteins

Type Concentration Function Site of formation Albumin 4 gm/100 ml plasma - Colloidal osmotic Liver. (Highest Concentration) pressure due to its highest concentration. - Transport of some substances. Globulins 2.5 gm/100 ml plasma - Defensive function (γ (α, β, γ): in the liver. (α, β, γ) globulins). (γ): in the liver as well - Transport of some the plasma cells (Reticuloendothelial substances. system (R.E.S)) Fibrinogen 0.4 gm/100 ml plasma - Blood clotting. Liver. (Highest MW) - Plasma viscosity due to its highest MW. Prothrombin 10 mg/100 ml plasma - Blood clotting. Liver.

• The Albumin/Globulin (A/G) Ratio: This is the ratio between albumin and globulin concentration in blood = 1.2 – 1.7 Albumin = 1.2 – 1.7 Globulin

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Ø Significances of A/G ratio: Decreases in: Liver disease due to decreased formation of albumin. ↓↓↓ Albumin ↓ Globulin Kidney disease due to loss of albumin in urine. ↓↓↓ Albumin ↓ Globulin Infection due to increase globulin concentration. Albumin ↑↑↑Globulin

Ø Functions of plasma proteins: Plasma is essential to life. Death occurs when plasma proteins decrease to 1-2 gm %. Plasma proteins have the following functions: 1. Blood clotting: prothrombin & fibrinogen. 2. Regulate blood volume: mainly by albumin due to its highest concentration. 3. Plasma viscosity: Fibrinogen is responsible for plasma viscosity due its highest molecular weight. Viscosity is important for the maintenance of arterial blood pressure especially diastolic blood pressure. 4. Buffering function of blood: responsible for 15% of buffering power of the blood. 5. Defensive function of blood: gamma globulin. 6. Capillary permeability; plasma proteins are essential for normal permeability of capillaries by closing the capillaries pores. 7. Plasma proteins carry and transport important elements as iron, copper, and hormones; forming complexes to conserve it and prevent its loss in urine. 8. It can be used by tissues to supply proteins during starvation (Reserve ).

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Red Blood Corpuscles (Erythrocytes) • These are non-nucleated circular biconcave discs containing the red respiratory pigment () and have an average life span of 120 days.. • The concentration of hemoglobin in R.B.Cs is 34%. The chief ion inside R.B.Cs is potassium (K+) also contains carbonic anhydrase enzyme & glucose-6-phosphate dehydrogenase (G-6-PD).

Ø R.B.Cs Count: • In adult males 5-6 million per cubic mm (due to androgen hormone that stimulate its formation & increase male musculature which need more oxygen). • In adult females 4-5 million per cubic mm (due to menstruation). • In newly born: 7 million per cubic mm (due to intra-uterine oxygen lack & to increase the iron coming from the damaged RBCs that can be used for recycling and reformation of new RBCs due to poor iron in the milk). Ø Functions of R.B.Cs:

1. Hemoglobin carry O2 to and take CO2 from tissues. 2. Hemoglobin has buffering action (85% of blood buffering action).

3. R.B.Cs contain carbonic anhydrase enzyme which is important for CO2 carriage. The biconcave shape of R.B.Cs increases the surface area and helps the exchange of gases between R.B.Cs and tissues.

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5- R.B.Cs membrane keeps hemoglobin inside them that prevents: a- the increase in the load on the which can lead to heart failure; since free hemoglobin increase blood viscosity, and increase in blood volume due to increase plasma colloidal osmotic pressure. b- obstruction of the renal tubules by the free hemoglobin which can lead to renal failure.

6- R.B.Cs membrane contains the specific agglutinogens that determine blood group.

7- The plastic nature of R.B.Cs membrane giving it a high degree of flexibility that allows RBCs to compress passing in the narrow capillaries and then resume their normal shape on leaving these capillaries without rupture. Ø Hemoglobin: • It is the red oxygen-carrying pigment. Protein in nature, made up of four subunits. Each unit is formed of (Iron protoporphyrin) and (polypeptide chain). • In each molecule of hemoglobin, there are four atoms of iron (ferrous state) and two pairs of polypeptides. Ø Types of hemoglobin: I- Normal types of hemoglobin: § Adult hemoglobin (Hb A): about 15.5 gm% in adult male and 13.5 gm% in adult female. ; its globin consists of 2 α chains and 2 β chains. § (Hb F): (2 α & 2γ) It is present in fetal blood and its affinity to oxygen is greater than Hb A to be able to take oxygen from the mother that have HbA. It is replaced by adult type within 6-8 months after birth.

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II—Abnormal types of hemoglobin:

§ Hemoglobin A1c: Hb A reacts with glucose to form . Normally it account about 5 % of adult hemoglobin and it increases if blood glucose level increased and remain elevated for several days so it's used in diabetic persons follow up. § Carboxy-hemoglobin (HbCO): Hb reacts with carbon monoxide to form carboxy-hemoglobin. The affinity of Hb to CO is about 200 times its affinity to oxygen, it combine with the Hb iron competing with oxygen. N.B. Co2 combine with the a.a. of the Hb polypeptide chain, so it is not compete with O2.

Met-hemoglobin (MetHb): Normally small amount of Hb are oxidized to met-hemoglobin (blue in color & can’t carry O2 due to oxidation of ferrous iron to ferric). An enzyme ( reductase) is present inside R.B.Cs. It changes MetHb back to Hb, congenital absence of this enzyme → increase the amount of MetHb in R.B.Cs.

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HbS: Abnormality in β chain with normal α chain. At low oxygen tension, red cell becomes sickled shape, they break down prematurely, the result is a severe hemolytic anemia (Sickle cell anemia).

Formation of R.B.Cs (Erythropoiesis) q Sites of R.B.Cs formation; • In the fetus, they are formed in liver and spleen. • In the last three months of fetal life and after birth, they are formed in bone marrow of all bone until adolescent. • By the age of 20, they are formed by the bone marrow of upper parts of humerus and femur and of membranous bones. • After the age of 20 years, they are formed in bone marrow of membranous bone as skull, vertebra, sternum and ribs. • Rate of erythropoiesis must be equal to the rate of RBCs destruction to maintain normal RBCs count. After 120 days (life span) due to loss of flexibility, RBCs are engulfed and hemolysed by reticulo-endothelial cells mainly spleen. q Factors affecting erythropoiesis: 1. Oxygen supply to tissues: Hypoxia occurs in hemorrhage (due to RBCs loss), high altitude (due to decrease O2 tension around) and heart failure (blood don’t reach tissue properly).

• O2 lack (hypoxia) → releases erythropoietin hormone from the kidney mainly → stimulates bone marrow → increase production of R.B.Cs (↑ erythropoiesis rate). 2. Diet: Erythropoiesis requires: § Protein; of high biological value containing essential amino acids that essential for formation of globin of hemoglobin.

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§ Iron; Average daily intake of iron is 20 mg. Most of the diet iron is in ferric state. However ferric iron poorly absorbed & ferrous iron is better absorbed than it. • So, ferric iron is reduced to ferrous in the stomach by HCl and vitamin C. Ferric iron (Fe 3+) HCl & Vitamin C→ Ferrous iron (Fe 2+) • The intestinal epithelial cells contain Apoferritin protein that combines with the ferrous iron to form ferritin. Iron is absorbed in this form from the upper part of small intestine (duodenum). Ferrous iron(Fe2+) + Apoferritin → Ferritin (the form in which the iron absorbed) • The blood containing transferrin protein which carries iron to bone marrow to form a part of R.B.Cs hemoglobin or to the liver to be stored. • Excessive oxalates, phytic acids and phosphates in diet precipitate iron and decrease its absorption. § Vitamins;

Ø Vitamin B12: - It is called extrinsic factor and is important for RBC nuclear maturation and cell division. In addition, it is responsible for myelination of the nerves and integrity of digestive system mucosa. - It unites with intrinsic factor, secreted by mucous membrane of the stomach forming intrinsic factor-Vit B12 complex. (intrinsic factor + Vit B 12 → intrinsic factor-Vit B12 complex )

- Intrinsic factor protects vitamin B12 from digestion by gastric enzymes and facilitates its absorption in lower part of ileum.

- Vitamin B12 is stored in large amount in liver and released slowly from liver as needed by bone marrow for formation of new red cells.

Ø Folic acid: as importance as vitamin B12, important for RBC nuclear maturation and cell division.. Ø Vitamin C: stimulates tissue growth and metabolism in general including the bone marrow. § Trace elements: copper and cobalt act as cofactors for hemoglobin formation. 3. Hormones: • Specific: Erythropoietin hormone. • Non-specific: thyroid hormones (↑ metabolism in general) • Male sex hormones (Androgen), increase erythropoietin hormone and hence stimulate erythropoiesis.

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4. Healthy organs: A-Bone marrow; A healthy bone marrow is essential for normal erythropoiesis (site for formation). B- Liver: is important for erythropoiesis as:

• Acts as a store for vitamin B12 & iron. • Formation of globin of hemoglobin. • Secretes 15% of erythropoietin hormone. C- Kidney: It secretes 85% of erythropoietin hormone in response to hypoxia, anemia and androgen hormone. 5. N.B. Patients with renal diseases or failure develop severe anemia because erythropoietin production by liver cannot compensate for the inability of the kidney to produce the hormone. D- Stomach: - Gastric HCl is needed to convert ferric iron to ferrous.

- Intrinsic factor secreted by gastric mucosa is essential for vitamin B12 absorption.

E- Small intestine: It is the site of iron and vitamin B12 absorption.

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