Medical Physiology For Dentistry Students MNU PDF

MEDICAL PHYSIOLOGY General and Blood Physiology For Dentistry student 1st Year Code: GPHM-11 BY Dr/ Elshymaa Abdel-Hady Abdel-Hakeem Medical Physiology Department Faculty of Medicine, Minia Universit...

MEDICAL PHYSIOLOGY General and Blood Physiology For Dentistry student 1st Year Code: GPHM-11 BY Dr/ Elshymaa Abdel-Hady Abdel-Hakeem Medical Physiology Department Faculty of Medicine, Minia University 1  INTRODUCTION TO HUMAN PHYSIOLOGY Physiology is a Latin word divided into 2 parts:  Physio = means Function.  Logy = means Science. Definition of Human Physiology: The science which deals with the functions of human body under different external and internal environmental conditions in order to maintain life. Organization of the Human Body: The cell. Is The basic living unit of the body Is formed of Cells of the same shape and function arranged The tissue. side by side. Is formed of more than one tissue performing a special The organ function; e.g. the stomach digests and the kidney excretes…etc. Is formed of more than one organ having complementary A system functions. The sum of these functions will determine the role of the system in human life.  The human body consists of a group of systems, each plays a specific and different role from the others and the sum of these roles maintain human life. Examples of different systems of human body: * The endocrine system. * The digestive system. * The nervous system. * The excretory systems. * The cardiovascular system. * The reproductive system. * The respiratory system. * The musculoskeletal system. 2  Figure: different body systems Human Body is composed CHEMICALLY of:  Water (60%).  Solids (40%); either; a. Organic (protein 18% - fat 15%). b. Inorganic (minerals 7%). BODY WATER The Total Body Water & its Distribution:  The total body water is normally about 60% of the body weight in young adult males.  Therefore, in a young adult male weighing 70 Kg, the total body water is normally about 42 litres, and it is distributed as follows: (1) Intracellular fluid (ICF): this constitutes about 2/3 of the total body water i.e. about 40% of the body weight (~28 L). (2) Extracellular fluid (ECF): this constitutes about 1/3 of the total body water i.e. about 20% of the body weight (~ 14 L), and it includes the following subdivisions: (a) Intravascular fluid (i.e. plasma): This is normally about 1/4 of the ECF volume. (b) Extravascular fluid: This is normally about 3/4 of the ECF volume. It includes;  Interstitial fluid: the fluid in spaces between the tissue cells 3  Transcellular fluids: fluid present in closed spaces surrounded by epithelium as cerebrospinal fluid, intraocular fluids, and the fluids in the pleura, joints, peritoneum, etc. Figure: Body fluid distribution. 4 Functions of Body Water: 1. It is the medium for the chemical and enzymatic reactions. 2. It is the medium for the physical processes e.g. diffusion and filtration. 3. It is an ionizing medium (regulating pH and body fluid osmolarity). 4. It regulates the body temperature through heat absorption, distribution and evaporation. 5. It is a lubricant in the joints and potential spaces (e.g. the pleura). 6. It is a refractive medium in the eye. 7. The cerebrospinal fluid is a mechanical buffer that protects the brain. 8. It is the medium for exchange of O2 and CO2 in the lungs and tissues. Normal Composition of the ECF and ICF: Table 1: Normal composition of ECF and ICF. ECF ICF Na+ (142 mEq/L) & K (4 K+ (140mEq/L) & Main mEq/L) Mg2+ cation small amounts of Ca2+ and small amounts of Na+ Mg2+ very little Ca2+ Cl- HPO4 & protein. Main small amounts of: HCO-3, Small amounts of Cl-, anion proteins, and HPO4 HCO3 and SO4 About 7 due to low pH About 7.4 HCO-3 Osmolarity The same The same 5  THE HUMAN CELL Definition: The building (structural) unit of the human body (figure 3). Figure: Structure of the Human Cell. 6  THE CELL MEMBRANE  Functions: 1. It forms the outer boundary surrounding the cell and protects it from the external environment. 2. Selective permeability; it allows certain substances to pass through and prevents others.  Chemically: It is formed of phospholipids & proteins. a. Phospholipids: Each phospholipid molecule in the cell membrane is formed of: 1. Water soluble (hydrophilic) phosphate part. 2. Fat soluble (hydrophobic) lipid part containing cholesterol. - The plasma membrane is formed of two layers (bilayer) of phospholipid molecules with their hydrophilic phosphate heads directed outwards and inwards and their hydrophobic lipid tails directed to the interior of the membrane. b. Proteins: - Cell membrane proteins are formed of peptide chains of amino acids. - Chemically, they are either; 1. Pure proteins. or 2. Conjugated proteins with carbohydrates (glycoproteins) or with lipids (lipoproteins). - According to their site; Proteins are either; 1. Peripheral proteins on the outer or inner surfaces. 2. Through & through proteins (i.e. transmembrane or integral proteins) 7  Figure: Chemical structure of the cell membrane. Functions of Cell Membrane Proteins: 1. Surface proteins act as receptors or surface recognition sites (self-antigens) ------ very important for immune system to differentiate between what is self and non-self (foreign) ------ thus preventing the body from attacking itself (i.e. autoimmune diseases). 2. Act as active Pumps e.g. Na+-K+ pump. 3. Act as Receptors for; a. Hormones. b. Chemical transmitters. 4. Act as Enzymes e.g. adenylate cyclase enzyme ------ which catalyzes the formation of cyclic AMP (cyclic AMP) from ATP. 5. Act as Carriers; helping transport of substances through the cell membrane. Types of carriers: 1. Uniport: Transport one substance in one direction. 2. Symport: Cotransport more than one substance at a time in only one direction. 3. Antiport: transport one substance in one direction in exchange for another in opposite direction e.g. Na+-K+ pump carrier --- it transports 3 Na+ out of the cell in exchange with 2 K+ into the cell. 8  Figure: Types of cell membrane carrier proteins. 6. Act as Channels: through which water soluble substances can pass through the cell membrane. Types of cell membrane channels: 1. Non gated channels: they are channels that are open all the time allowing passage of ions all the time. Sometimes they are called “leak channels”. 2. Gated channels: these channels are classified into: a. Voltage gated channels: they open or close in response to changes in membrane potential. b. Ligand gated channels: they open or close in response to binding to a chemical substance called (ligand), which may be either: i. External ligands; binds to the outer surface of the cell membrane as neurotransmitters and hormones. ii. Internal ligands; binds to the inner surface of the cell membrane as ca+2 and cyclic AMP. c. Mechanical gated channels: they open or close in response to mechanical stretch or pressure. 9  Figure: Types of channels Transport Mechanisms through Cell Membrane Essential and continuous parts of the life of a cell are the taking in of nutrients and the expelling of wastes. All of these must pass through the cell membrane. Transport through cell membrane may be active or passive as shown in the following table: Passive transport Active Transport No need for energy Needs Energy Energy (ATP) No ATP used ATP is used Diffusion Examples Osmosis Active transport Filtration I. Diffusion Definition:  It is the free movement of substance molecules through the cell membrane caused by their kinetic energy. It does not need energy. It is caused by the kinetic energy of the diffusing molecules. 11 Factors affecting the rate of diffusion:  The rate of diffusion is directly proportional to: 1. Concentration difference of the substance across the cell membrane. 2. Temperature of the solution. 3. The surface area of the membrane.  The rate of diffusion is inversely proportional to: 1. The thickness of the membrane (i.e. distance of diffusion). 2. The square root of M.W. of the substance. √ Figure: Simple diffusion. II. Facilitated diffusion: It is a special type of diffusion that occurs when the substance can NOT pass by simple diffusion through membrane phospholipid bilayer either due to its high Molecular Weight and/or poor lipid solubility. So it diffuses through transmembrane proteins such as: 1. Channels: These are channels or pores for substances with poor lipid solubility (i.e. water soluble such as ions), provided that:  The molecular size of the diffusing molecule is less than that of the channel. 11   The electric charge allows diffusion including; a. The charge lining the channels. b. The charge on the opposite side to the direction of diffusion. The rule is :“opposite charges attract and enhance while similar charges repel and oppose diffusion. The greater the hydration energy of the molecule, the thicker is the water jacket around and the slower is the diffusion rate. 2. Carriers: These are membrane proteins (carriers) that facilitate transport of substances with relatively high molecular size bigger than the size of the pores or electrically not fit to pass through membrane channels. e.g. all sugars as Glucose diffuse by means of carriers. Mechanism: A substance (S) combines with a transmembrane protein carrier (C) on one side …. Forming a C-S complex … resulting in conformational change … thus, the C- S complex changes its position to the opposite side of the membrane …… then the substance leaves the carrier …. The carrier restores its original conformation …… binding of another molecule of (S) and so on … Properties of Facilitated Diffusion: 1. Passive mechanism (i.e. NO energy from ATP is needed). 2. Obey the same rules of simple diffusion. 3. Require a carrier protein (the number of carriers is a limiting factor). N.B. The carrier for glucose is regulated by insulin hormone. 12  Figure: facilitated diffusion III.Osmosis: Definition:  It's the free movement of the solvent molecules through a semipermeable membrane from the compartment of lower concentration to the compartment of higher concentration of the solution.  Or it’s the diffusion of water through a semi- permeable membrane from an area of high conc. of water to an area of low conc. of water.  It is a passive mechanism (no energy needed)  For only solvent molecules (e.g. water)  It depends on the number of particles in the solution rather than its concentration.  The measuring unit of osmosis is called; Osmole = 1000 mosmole N.B. Osmole is the number of particles present in one mole of undissociated substance. Mole is the molecular weight of a substance in grams. 13  Figure: Osmosis. The Osmotic Pressure: It is the pressure required to stop osmosis. The osmotic pressure is dependent on the number of particles/unit volume and not on the weight of the substance in grams. ↑ [solute] ------↑ osmotic pressure of the solution Figure: Osmotic pressure. 14 Normal plasma osmolarity = ~ 290 mosmol/L. Plasma osmolarity can be calculated from this equation; Plasma osmolarity = 2 (Na+) + 0.055 (glucose) + 0.36 (urea) mosmole/L mEq/L mg % mg% Factors affecting plasma osmolarity: 1. Plasma Na+ conc. (~ 142 mEq/L). 2. Plasma glucose conc. (~ 126 mg %). 3. Plasma urea conc. (~ 20 - 40 mg %). 4. Plasma protein conc. (~ 7 gm %). 15 Tonicity: It is the osmolarity of the solution relative to that of plasma. Solutions compared to Plasma Osmolarity are 3 types: 1. Isotonic: Tonicity is equal to that of plasma osmolarity. They are the only solutions allowed to be given to the patient parenterally (i.v.) Ex.: Glucose 5% - NaCl 0.9% = (saline) 2. Hypotonic: Tonicity is less than that of plasma osmolarity. If given i.v. -------- it causes Shift of water into the cells ---------- leading to Cell swelling or edema ---------- cell rupture. Ex.: Water. 3. Hypertonic: Tonicity is more than that of plasma osmolarity. If given i.v. ----- it causes Shift of water out of cells ---------- leading to Cell shrinkage. Solutions compared to Plasma Osmolarity are 3 types 1. Isotonic 2. Hypertonic 3. Hypotonic  Tonicity is equal to that of Tonicity is more than Tonicity is less than plasma osmolarity. that of plasma that of plasma osmolarity. osmolarity. They are the only solutions allowed to be given to the If given i.v. -------- it If given i.v. ------ it patient parenterally (i.v.) causes Shift of water causes Shift of from cells into the water into the cells - Ex. blood ------------- ------- leading to 1. Glucose 5% leading to Cell Cell swelling or 2. NaCl 0.9% = (saline) shrinkage edema 16  Figure: Types of solutions relative to plasma osmolarity. Test yourself: 17 Filtration: Definition;  It means forcing a fluid to pass through a semipermeable membrane by creating a pressure difference (gradient).  It is a passive mechanism (no energy needed) Importance: 1. Filtration of plasma to form tissue fluid. 2. Filtration of plasma in the kidney  urine formation. Active Transport::  Transport of a substance against electric or concentration gradients.  Requires energy from (ATP) either direct or indirect.  Requires a carrier protein. Types of Active transport:  Primary Active Transport: Energy is supplied directly from ATP. ATP → ADP + Pi + energy Example: Sodium-Potassium pump (Na+ - K+ pump): 18  It's present in all cell membranes. Transports 3 Na+ out and 2 K+ in. Figure: Na+ - K+ pump (primary active transport).  Secondary Active Transport:  It is a transport of one or more solutes against an electrochemical gradient, coupled to the transport of another solute down its electrochemical gradient (e.g. Na).  The energy is supplied indirectly from 1ry active transport.  It may be either co-transport or counter transport. 19 In this figure: Na+ is actively pumped out of the cell by Na+-K+ pump creating a concentration gradient for Na+ (high outside and low inside the cell). A cotransport (or antiport) carrier binds both Na+ and substance X or substance Y. Na+ moves from outside to inside according to its concentration gradient, while both of substance X and substance Y move against their concentration gradient ( from outside to inside for substance X and from inside to outside for substance Y). The transport of both X and Y is called secondary active transport because it occurs against concentration gradient making use of the energy derived from the concentration gradient of Na+ that is created by the active Na+-K+ pump. Types of 2ry active transport: a) 2ry Active Co-transport: b) 2ry Active Counter transport: Na+ is moving to the interior causing other All solutes move in the same direction substance to move out. “e.g. inside cell” Ex.: Ex.: 1. Na+ – glucose Co-transport. 1. Ca²+ – Na+ exchange. 2. Na+ – amino acid Co-transport. 2. Na+ – H+ exchange in the kidney. 21 Summary of the difference between active and passive transport  Bulk transport: This is a specialized mechanism for transport of large molecular sized substances, including; a. Endocytosis: Mechanism: the cell extends cytoplasmic processes (pseudopodia) around the substance which become enclosed as a food vacuole within the cytoplasm. Endocytosis includes:  Phagocytosis (cell eating), if the substance is solid.  Pinocytosis (cell drinking) if the substance is liquid. 21  Figure: endocytosis b. Exocytosis: Mechanism: The vesicle enclosing the substance fuses with the cell membrane from the inner surface, and then becomes lysed with expulsion of the substance out of the cell. It is called cytopempesis or cell vomiting. Figure: exocytosis ************************************************************ 22  BLOOD Blood is a fluid tissue that circulates inside blood vessels. It represents 8% of total body weight (~5.6 L). Composition of blood: Blood is composed of two main parts: blood cells & plasma (fluid part): I. Blood cells: 45% of total blood II.Plasma: 55% of TBV. volume (TBV). Includes: Plasma is a yellow clear fluid consisting 1. Red blood corpuscles (RBCs): ~ 5 5 of: million /mm3. Their decrease is called 1. 90 % water. anemia and their increase is called polycythemia. 2. 10 % solids, either: 2. White blood cells (WBCs): 4000- a. Organic substances; as 11000 per cubic mm. Their decrease is plasma proteins = 7.1% of called leucopenia and their increase is its volume. called leukocytosis Urea, uric acid, 3. Platelets: hormones& vitamins= 2 %. 250000 to 500000 / mm3. Their b. Inorganic substances such as; decrease is called thrombocytopenia Na+, Ca++, Cl– and others = 0.9 %. and their increase is called thrombocytosis. Figure: Composition of Blood. 23 Functions of blood: 1. Transport function (O2, CO2, nutrients, waste products, hormones). 2. Defensive function (WBs & antibodies). 3. Hemostasis (stoppage of bleeding). 4. Homeostasis: keeping internal environment (i.e. extracellular fluid) of the body constant for optimum function of the cell (PH, osmotic pressure, volume, gases, minerals, temperature, nutrients, …..). 24  Plasma Proteins  Concentration: 6-8 gm with an average 7 gm/100 ml blood. Types and Functions of plasma proteins: Type Concentration Function Site of formation 1. Albumin 4 gm/100 ml - Osmotic pressure → Liver. plasma blood volume. - Transport of some substances as hormones. 2. Globulin 2.5 gm/100 ml - Defensive function (γ Reticuloendothelial (α, β, γ) plasma globulins) → form system (R.E.S) e.g. antibodies. liver, spleen, lymph - Transport of some nodes and bone substances. marrow. 3. Fibrinogen 0.4 gm/100 ml - Blood clotting. Liver. plasma - Blood viscosity. 4. Prothrombin 10 mg/100 ml - Blood clotting. Liver. plasma The Albumin/Globulin (A/G) Ratio:  This is the ratio between albumin and globulin concentration in blood.  It equals (1.2 – 1.7). Significances of A/G ratio: Determination of A/G ratio helps in the diagnosis of diseases as it decreases in: 1. Liver diseases Due to decreased formation of albumin 2. Kidney diseases Due to loss of albumin in urine (due to its smaller molecular size). 3. Infection & allergic diseases Due to increased formation of γ globulins. And it increases in: cases of immunosuppressive diseases as in AIDS. 25  Red Blood Corpuscles (Erythrocytes) (RBCs)  RBCs are non-nucleated circular biconcave discs containing the red respiratory pigment (haemoglobin).  Its average life span is about ~ 120 days.  Erythrocytes have no mitochondria. Therefore, they obtain their energy requirements from anaerobic glycolysis. The energy is needed mainly for the operation of Na+-K+ pump.  The concentration of hemoglobin in R.B.Cs is 34%.  The main cation inside R.B.Cs is potassium (K+). It also contains carbonic anhydrase (CA) enzyme & glucose-6-phosphate dehydrogenase (G-6-PD).   Figure: Red Blood corpuscle  RBCs Count: 1-In adult males: 5.5 million/ mm3 (due to androgen hormone). 2-In adult females 4.8 million/ mm3 (due to menstruation). 3-In newly born 7 million/ mm3 (due to intra-uterine oxygen lack)  Haematocrit value: It is the volume of RBCs in 100 ml blood. It is about 45% in adult male.  Functions of RBCs: 1. Haemoglobin is essential to carry oxygen to and take CO2 from tissues. 2. Haemoglobin helps in the regulation of blood pH and in producing blood viscosity which is essential for maintenance diastolic blood pressure. 3. R.B.Cs contain carbonic anhydrase enzyme which is important for CO2 carriage. 4. R.B.Cs membrane keeps haemoglobin inside them and prevents its loss in urine. 5. R.B.Cs membrane contains the specific agglutinogens that determine blood group. 26  6. The biconcave shape of R.B.Cs increases the surface area and helps the exchange of gases between R.B.Cs and tissues. 7. The plastic nature of R.B.Cs membrane allows RBCs to pass through narrow capillaries easily. Formation of RBCs (Erythropoiesis):  Sites of RBCs formation: In the foetus RBCs are formed in liver and spleen. In the last three months of fetal life and RBCs are formed in bone marrow of all after birth bones until adolescent. By the age of 20 RBCs are formed by the bone marrow of upper parts of humorous and femur and of membranous (flat) bones. After the age of 20 years RBCs are formed in bone marrow of membranous bone as skull, vertebra, sternum and ribs. N.B. the rate of erythropoiesis must be equal to the rate of RBCs destruction (hemolysis) to maintain normal RBCs count. After 120 days (life span) due to loss of their flexibility, RBCs are engulfed and hemolysed by reticuloendothelial (RES) cells mainly spleen. Factors affecting erythropoiesis: I. Oxygen supply to tissues: O2 lack (hypoxia) → releases erythropoietin hormone from the kidney → stimulates bone marrow → increase production of RBCs (↑erythropoiesis). Hypoxia occurs in hemorrhage, high altitude and heart failure. II. Diet: Erythropoiesis requires: 1. Proteins: Proteins of high biological value (animal protein), containing essential amino acids are more essential for formation of globin part of Hb. 2. Minerals: mainly iron & trace elements A. Iron:  Average daily intake of iron is 20 mg/day.  About 70% of iron is present in hemoglobin, 3% is present in myoglobin and 27% is stored mainly in the liver. 27   It is essential for formation of haemoglobin.  Ferrous salts are better absorbed than ferric salts.  Most of the diet iron is in ferric state which is reduced to ferrous in the stomach by HCl and vitamin C then absorbed in the upper part of small intestine (duodenum).  The intestinal epithelial cells contain apoferritin that combines with iron to form ferritin increasing its absorption.  Ferritin is the main storage form of iron.  It is present in the liver and intestinal mucosal cells. When the life cycle of the mucosal cells ends, they are shed into the lumen of the intestine and pass in stools with their content of ferritin.  Transferrin:  The blood containing transferrin which carries iron to bone marrow to form a part of RBCs hemoglobin.  When the quantity of iron in the plasma falls low, some of the iron in the ferritin storage pool is removed easily and transported in the form of transferrin in the plasma to the areas of the body where it is needed  Excess iron in the blood is deposited especially in the liver hepatocytes and less in the reticuloendothelial cells of the bone marrow.  Excessive oxalates, phytic acids and phosphates in diet precipitate iron and decrease its absorption. Factors affecting iron absorption:  Gastric HCl reduces ferric to ferrous → increases its absorption.  Excessive oxalates, phytic acids and phosphates in diet precipitate iron and decrease its absorption.  Duodenal ulcers decrease iron absorption. B. Trace elements: e.g., copper and cobalt act as cofactors for haemoglobin formation. 28  3. Vitamins: including; A. Vitamin B12:  It is called extrinsic factor and is important for nuclear maturation and cell division.  Moreover, it is responsible for myelination of the nerves and ensures integrity of digestive system mucosa.  It unites with intrinsic factor, glycoprotein secreted by mucous membrane of the fundus of the stomach (parietal cells) forming intrinsic factor B12 complex.  Significance: 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 as needed by bone marrow for formation of new red cells. B. Folic acid: the same importance as vitamin B12. C. Vitamin C:  It stimulates tissue growth and metabolism in general including the bone marrow.  It facilitates absorption of iron from stomach. III. Hormones: either; a. Specific: e.g. Erythropoietin hormone. b. Non-specific: e.g. thyroid hormones and male sex hormones (androgen) are required for erythropoiesis. IV. Healthy organs; including: 1. Bone marrow: A healthy bone marrow is essential for normal erythropoiesis. 2. Liver: liver is important for erythropoiesis as: a. It acts as a store for vitamin B12 & iron. b. Responsible for formation of globin part of haemoglobin. c. Secretes 15% of erythropoietin hormone. d. An extramedullary (outside bone marrow) site for erythropoiesis. 29  3. Kidney:  It secretes 85% of erythropoietin hormone.  Site of secretion in the kidney: probably by tubular epithelial cells and endothelium of peritubular capillaries in response to hypoxia, anemia and androgen.  N.B. Patients with renal diseases or failure develop severe anaemia because erythropoietin production by liver cannot compensate for the inability of the kidney to produce the hormone. Regulation of erythropoietin secretion: Its secretion is increased by: - Hypoxia is the main stimulus for erythropoietin release. - Alkalosis. - Androgens and cobalt salts. - β- adrenergic stimulation. 4. Stomach:  Gastric HCl is needed to convert ferric iron to ferrous.  Intrinsic factor secreted by gastric mucosa is essential for vitamin B12 absorption. 5. Small intestine:  It is the site of absorption for; a. Iron (upper part). b. Vitamin B12 (lower part). Anaemia: Definition: It is decreased number of RBCs or their haemoglobin content or both. 31 Normal haemoglobin concentration: In males about: 15gm/100mL blood. In females about: 13.5gm/100mL blood. In neonates average about: 20gm/100mL blood Effects of Anaemia:  It leads to decrease of oxygen content which leads to tissue hypoxia and rapid fatigue.  It leads to decrease in the blood viscosity that decreases peripheral resistance and increases venous return and cardiac output →↑↑ work load of the heart producing heart failure. Types and causes of anaemia: I. Normocytic Normochromic Anaemia: including; 1. Haemolytic anaemia; due to excessive haemolysis of RBCs. e.g., 1. Incompatible blood transfusion. 2. Snake venoms. 3. Sensitivity to drugs. 4. Infections as some types of malaria. 5. Antibodies against red blood cells. 6. Increased fragility of RBCs as in spherocytosis, sickle cell anaemia and thalassemia. 7. Deficiency of glucose-6-phosphate in RBCs. 8. Chemical poisons as lead. 9. Hypersplenism, abnormal destruction of blood cells by enlarged spleen 2. Aplastic anaemia; due to bone marrow depression. e.g.; 1. Exposure to radiation such as X-rays. 2. Chemotherapy. 3. Drugs as antibiotics as chloramphenicol. 31  4. Destruction of bone marrow by malignant tumours. 3. Haemorrhagic anaemia; due to acute blood loss (haemorrhage). II. Microcytic Hypochromic Anaemia: 1. Iron deficiency anaemia, either due to: 1. Deficiency in the diet (commonest cause). 2. Failure of iron absorption due to :  Absence or removal of acid producing part of the stomach, e.g. congenital achlorohydra or partial gastrectomy  Excess oxalates, phytic acids and phosphates in diet. 3. Diseases of small intestine (upper part) as duodenal ulcers. 4. Liver disease (site of storage of iron) 5. Chronic blood loss, e.g., bleeding piles and menstruation in females. Treatment: Oral iron or injection (in case of gastric or small intestinal causes) III. Macrocytic (Megaloblastic) Anaemia: it occurs due to deficiency of vitamin B 12 or folic acid. 1. Vitamin B12 deficiency (Pernicious anaemia) due to: 1. Absence of intrinsic factor from the stomach (commonest cause), mostly due to an immune reaction which lead to damage of gastric parietal cells that secrete the intrinsic factor (familial diseases more common in elderly women). 2. Malabsorption due to small intestine diseases (lower part). 3. Liver disease (site of storage). 4. Rarely due to lack of vitamin in diet. Treatment: Vitamin B12 injection for life. It prevents further damage, but cannot correct the damage already present. Therefore, it is called pernicious (destructive) anemia. 2. Causes of folic acid deficiency;  Deficiency of folic acid in diet especially during pregnancy.  Failure of absorption due to small intestine diseases. 32 N.B.  It should be differentiated between the cause of macrocytic anemia whether it is due to vitamin B12 or folic acid deficiency, because: If folic acid is given in a case of vit. B12 deficiency anemia → folic acid shifts vitamin B12 from nervous tissues to the bone marrow leading to correction of anemia but more degeneration in the of nerves of the central nervous system.  While, treatment of folic acid deficiency anemia with vit. B12 injection will be ineffective. Polycythaemia:  Polycythaemia means increased number of RBCs.  It may reach up to 6-8 million/mm3. Effects:  Polycythemia leads to increase blood volume (↑ cardiac output→ ↑ work of heart) and blood viscosity (↑ arterial blood pressure) → increased risk of heart failure. 33  WHITE BLOOD CELLS (i.e. LEUCOCYTES)  Total leucocytic count (TLC): 4000 - 11000/mm3.  The WBCs count in adult females is lower than adult male and show variation in the same individual from day to day and hour to hour. WBCs number increases after meal, with muscular exercise, and emotional stress. Types of white blood cells (WBCs) WBCs are divided into granulocytes and agranulocytes: 34 Summary of the types and functions of WBCs: Types % from Functions TLC I. Granulocytes: Have granules contain myelo-peroxides enzyme that help in killing ingested bacteria. 1. Neutrophils. 50-70% Neutrophils: Phagocytosis. 2. Eosinophils 1-4% Eosinophils: 1. Weak phagocytic cells. 2. Related in some ways to allergy and hypersensitivity. 3. Increase with parasitic infection as Ascaris infection. 4. They release pro-fibrinolysin needed for lysis and removal of blood clots. 3. Basophils 0-1% Basophils: 1. No phagocytic action. 2. They contain heparin, histamine and serotonin. 3. Increase with allergy and hyper sensitivity. II. Non-granular leucocyte: Have no granules 3. Lymphocytes. 20-40% Lymphocytes: 1. Formation of antibodies. 2. Can change into highly phagocytic monocytes. 3. Formation of long acting thyroid stimulatory hormone. 4. Monocytes 2-8% Monocytes: 1. Highly phagocytic. 2. Tissue repair after inflammation by taking up dead neutrophils and destroyed tissue remnants. 35  BLOOD PLATELETS (i.e. THROBOCYTES)  Blood platelets are granular, non-nucleated oval bodies.  The average platelet count ~ 250000 – 500000 /mm3.  Their average life span average is 7-12 days (removed by RES especially spleen).  Platelets membrane contain phospholipids (platelet factor 3) ➾ role in blood clotting.  In splenectomy, there is an increase in platelets count not only due to its site of removal, but also 25% of platelets are stored in spleen). Hemostasis (i.e. Stoppage of bleeding): Definition: Hemostasis means stoppage of bleeding. The hemostatic response to vascular injury includes these steps: I. Vasoconstriction (the initial event). II. Platelet reaction & primary hemostatic plug formation (platelets plug) III. Stabilization of platelet plug by fibrin formation (clot formation). IV. Repair of the injured blood vessel. I. Vasoconstriction (the initial event). Immediate vasoconstriction of injured blood vessels & adjacent small arteries caused by: 1. Local myogenic contraction independent of nerve supply or humoral factors. 2. Reflex action due to pain. 3. The vasoconstrictive activity of the released vasoactive amines (serotonin, thromboxane, ADP) released from platelets mainly. Vasoconstriction → slowing blood flow to the injured area to allows contact activation of platelets & coagulation factors. 36 II. Platelets plug formation: It is the main function of platelets. Platelets plug formation occurs through the following steps: 1. Platelet Adhesion; Receptors on the surface of platelets adhere to the injured site of blood vessels due to exposure of subendothelial collagen. This depends on: a. A part of factor VIII (Will brand factor) act as a glue linking platelets to the injured blood vessels and to other platelets. b. The surface membrane ADP (glycoprotein coat of platelets). 2. Platelet activation; the activated platelets swell and develop pseudopodia protruding from their surface and become sticky. 3. Release reaction; Collagen and thrombin activate platelets prostaglandin synthesis → ↑ thromboxane A2 and start the release reaction. They release their contents e.g. ADP, serotonin, fibrinogen, lysosomal enzymes & heparin antagonizing factor. 4. Platelets aggregation (self-propagating process); ADP & thromboxane A2 → ↑ aggregation of platelets to the site of injury → more adhesion & release of ADP & thromboxane A2 → more aggregation → platelet plug is formed. 5. Platelets pro-coagulant activity; after aggregation of platelets, platelet factor3 is exposed for starting blood coagulation. 6. Platelet fusion; High concentration of ADP & enzymes released during release reaction → irreversible fusion of platelets which increased by thrombin and stabilized by fibrin (formed during blood clot formation). 7. Clot retraction (within 5-30 minutes); by contraction of the platelet contractile proteins (actin and myosin, retractozyme) that pull fibrin threads closed together. The 37  growth factor (released from platelets) → stimulates vascular smooth muscle to multiply to accelerate healing after injury. Figure: sequence of platelet plug formation III. Blood coagulation (formation of blood clot): Enzyme cascade theory of blood coagulation suggests that blood coagulation occurs through 4 stages as follows: Stage one; i.e. formation of active thromboplastin (i.e. prothrombin activator) by two systems; Intrinsic system Extrinsic system Platelet factor 3 is the precursor Tissue juice (tissue factor) is the precursor Needs longer duration (4-8 Needs shorter time (12-20 minutes). seconds). Can occur in vivo & vitro Can occur in vivo only A. Intrinsic system (i.e. platelet system of thromboplastin):  It acts within few minutes.  It is called intrinsic because the factors needed for coagulation are present within the blood. Steps 1. It is initiated by activation of factor XII, when blood is exposed to negative charged surface e.g. glass (in vitro) or to collagen fibers (in vivo). 2. XIIa → activates factor XI (in presence of HMW Kininogen). 3. XIa activates → factor IX (in presence of calcium). 38 4. IXa activates → factor X in the presence of active factor VIII (which is activated by thrombin and calcium. 5. When platelets come in contact with collagen of damaged blood vessels, it gets activated and releases phospholipids. 6. Xa in the presence of Va (which is activated by thrombin) and platelet factor III (platelets phospholipids) form a complex called prothrombin activator. Figure: mechanism of blood clotting 39 B. Extrinsic system (i.e. tissue system of thromboplastin):  It acts within 15 seconds. Steps: 1. This occurs in tissue injury (i.e. in vivo ONLY). 2. Tissue trauma → stimulates release of tissue factor (factor III) which activates → factor VII. 3. The active factor VII will activate → factor X. 4. Activated factor X in the presence of activated factor V and phospholopid form a complex called prothrombin activator. Stage two; Activation of prothrombin → thrombin by tissue & platelets thromboplastin in the presence of calcium. Prothrombin Thromboplastin thrombin Ca2+ Stage three; Conversion of fibrinogen into → soluble fibrin by thrombin. fibrinogen Thrombin fibrin Stage four; stabilization of fibrin by activated factor XIII (fibrin stabilizing factor, that is activated by thrombin) and in presence of calcium converting soluble (loose) fibrin → insoluble (firm) fibrin. Soluble fibrin factor XIIIa insoluble fibrin Ca2+ 41  Physiological limitation of blood coagulation occurs through:- 1- Release of plasma inhibitors which antagonize the active coagulation factors e.g. antithrombin. 2- Inactivation of the active coagulation factors by the liver.  Fibrinolysis:  Means breakdown of fibrin (blood clot) by fibrinolysin enzyme (plasmin).  Plasmin is present in plasma as inactive plasminogen & activated by tissue activators, thrombin & by active factor XII.  Relation of vitamin K to blood clotting; Essential for the formation of factors; II, VII, IX & X in liver, so its deficiency increases the bleeding tendency.  Relation of calcium to blood clotting; 1- Essential for thromboplastin formation. 2. Conversion of prothrombin to thrombin. 3- Stabilization of fibrin. N.B. Blood does NOT clot in the absence of calcium ions. However, decreased calcium in blood does not lead to bleeding tendency because; tetany occurs → laryngeal muscle spasm → Asphyxia & death (i.e. incompatible with life).  Causes of normal fluidity of blood; 1. heparin, 2. fibrinolysin, 3. presence of the clotting factors in inactive form 4. optimal numbers of platelets, 5. optimal rate of blood flow, 6. smooth endothelial lining of blood vessels 7. low fibrinogen content 8. Presence of normal anti-thrombin. 41 Methods of prevention blood coagulation: I. In vitro anticoagulants; 1. Oxalate anticoagulants (precipitate ionized calcium, Calcium oxalate). 2. Citrate anticoagulants (binding of calcium in unionized form, Na salicylates). 3. Collection of blood in siliconized containers which have very smooth inner surface to prevent platelet aggregation. 4. By addition of heparin. 5. Cooling of blood rapidly to zero. II. In vivo anticoagulants; By using heparin & dicumarol (Warfarin). Point Heparin Dicumarol Origin Of animal origin Of plant origin Action: 1- Onset; Acts rapidly (after minutes) Acts slowly (after 1-2 days). 2- Duration; Hours Days 3- Mechanism; Anti-thrombin, Inhibition of factors II, VII, anti-prothrombin, IX & X in liver by anti-thromboplastin competitive inhibition of and anti-thrombocytic vitamin K. Route of Given parentrally (S.C) Given orally administration Use Both in vivo & in vitro Used only in vivo During open heart surgery Given orally 5-7 days after to prevent venous starting heparin therapy to thrombosis. give chance for following In post-operative period to up the response to heparin prevent venous treatment. Once oral thrombosis. dicumarol has started, In laboratories for blood heparin should not be collection. stopped until 4-6 days. Antidote to overdose Protamine sulphate 1% Vitamin K 42 Disorders of Hemostasis and Coagulation: 1. Vitamin K deficiency: Vitamin K deficiency leads to hemorrhage due to inhibition of formation of some of the coagulation factors in liver. 2. Hemophilia: Hereditary sex-linked disease (carried by mother to her male foetus) Cause: Due to deficiency of some coagulation factors (VIII or IX or XI). 3. Thrombocytopenic purpura: Autoimmune disease affects both males and females & usually in young age with no family history. Cause: Decreased platelets count below 40000/mm3 43