Physiology of Blood PDF

PHYSIOLOGY OF PAGE 100 BLOOD 0 Composition and Properties of the Blood  Blood a suspension solution of blood cells in plasma circulating through the cardiovascular system. 0  Composition cellular portion (formed eleme...

PHYSIOLOGY OF PAGE 100 BLOOD 0 Composition and Properties of the Blood  Blood a suspension solution of blood cells in plasma circulating through the cardiovascular system. 0  Composition cellular portion (formed elements) fluid portion (plasma). 0  Physical properties of the blood Colour: – Arterial blood is bright while venous blood is dark red.. Specific gravity: – Blood: 1.060, plasma: 1.030, cells: 1.090. Viscosity: – Whole blood is about 4.5-5.5 times as viscous as water – Important in peripheral resistance. Osmotic pressure: – Colloid osmotic pressure (created by albumin) – Crystalloid osmotic pressure (created by Na+ ). 0  Function of blood Transport function. Defensive function. Hemostatic function. Homeostatic function. 0  Plasma Straw-colored liquid consisting of water and dissolved solutes. Sodium ion is the major solute of the plasma in terms of its concentration. In addition to Na+, plasma contains many other salts and ions, as well as organic molecules such as metabolites, hormones, enzymes, antibodies, and other proteins. 0  Plasma Proteins (6-8gm%) – constitute 7-9% of the plasma Albumins (60% - 80%) (3.5-5gm%) Produced by the liver Provide the osmotic pressure(colloid) and necessary to maintain blood volume and pressure. Effective Filtration Pressure = (capillary pressure + interstitial osmotic pressure) – (plasma colloid osmotic pressure + interstitial hydrostatic pressure) 0 Globulins (2-3.5gm), divided into three types: Alpha and beta globulin, produced by the liver and function to transport lipids and fat soluble vitamins in the blood. Gamma globulins are antibodies produced by lymphocytes and function in immunity. Fibrinogen (400mg%) Prothrombin 0(10mg%)  Plasma pH: 7.35 – 7.45 Maintained in a very narrow range through numerous mechanisms. Acids in the blood are buffered by bicarbonate The lungs aid acid –base balance through elimination of carbon dioxide, which regulates the amount of carbonic acid in the blood. The kidneys participate in acid – base balance by excreting H+ and retaining plasma bicarbonate. 0  Function of plasma protein: Specific function: 1. Osmotic pressure 2. Defensive functions 3. Viscosity of the plasma 4. Clotting of blood Non specific function: 5. Carrier function 6. Protein reserve 0  Site of haemopoiesis Fetus 0-2 months (yolk sac) 2-7 months (liver, spleen) 5-9 months (bone marrow) Infants Bone marrow (practically all bones) Adults Vertebrae, ribs, sternum, skull, sacrum and pelvis, proximal ends of femur RED BLOOD CELLS ERYTHOCYTE  II. Blood Cells red blood cells (erythrocytes) white blood cells (leucocytes) platelets (thrombocytes). 0 0 0  Red cells (Erythrocytes) Number: 5 to 5.5 million in males and 4.5 to 5 million in females per milliliter blood. Shape: flat, biconcave discs, about 7 um in diameter and 2.2 um thick. Importance of the biconcave shape: provides an increased surface area through which gas can diffuse. 0 EM of normal red blood cells 0  Life Span of Red Cells Erythrocytes lack a nucleus (they get energy from anaerobic (but not aerobic) respiration. Life span: about 120 days destroyed by phagocytic cells in the liver, spleen and bone marrow. 0  Physical and Chemical Properties of the Red Cells Hematocrit Function Material for the production Erythropoiesis 0  Hematocrit Concept: The percentage of blood volume occupied by the packed red blood cell volume Normal range: man, 40% - 50%, Women 37% - 48% 0  Function: To transport oxygen from the lungs to the tissue (function of hemoglobin) To transport carbon dioxide in blood. The arterial and venous red cell 0  Material for the production. The protein and iron are used for hemoglobin synthesis. Both vitamin B12 and folic acid are necessary co-factors for DNA synthesis, 0  Early Intermediate Late Proerythroblast Polychromatophilic Reticulocyte (Pronormoblast) Normoblast Basophilic Orthochromatophilic Erythrocyte Normoblast Normoblast 0  Importance of the Erythropoiesis Maintain the number of the red cells remarkable constant Anemia Decrease rate of erythropoiesis or increased rate of red cells destruction Reticulocytes represents only 1% of total RBCs count. Increase in reticulocyte indicate increase in erythropoiesis indicate hemolysis. 0  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. 0  Regulation of Erythropoiesis B. Other hormones stimulate erythropoiesis Adrenal cortical steroids, Pituitary growth hormone, Parathyroid hormone Androgen (testosterone) most important C. Estrogen – inhibit erythropoiesis 0  Nutritional factors: 1. Proteins : for hemoglobin synthesis “essential amino acids “ 2. Iron 3. Vitamins 4. Copper and Cobalt 0  Tissue hypoxia Any condition causes decrease in O2 tissue delivery “ hypoxia” cause increase RBCs formation. High altitude, respiratory diseases, cardiac disease , anemia and bleeding Why ??? 0 0  Function of RBCs The main function of RBCs is transport of HB 1)- Function of Hb: Gases transport Buffering function 2)- Function of RBC membrane: Plastic : allows change shape and size Biconcave: a maximal surface for gas exchange Semipermeable: allowing anions only to pass as HCO3- and CL- but not cations. Contains the antigens of blood groups. Contains carbonic anhydrase. 0  Hemoglobin The normal hemoglobin concentration in blood is on average of 13-16 gm. in adult men and 12-15 gm. in adult women ?? In new born about 18-19 gm. Consist of heme+ globin 0  HB structure 0  Types of hemoglobin HB A HB F HB A2 Structure A2B2 A2G2 A2 D2 Normal % 96 – 98 0.5 – 0.8 1.5 – 3.2  Abnormal forms of HB Hemoglobin-S (Hb-S): contain 2 abnormal B chain Glutamic acid in position 8 is replaced by valine This make Hb less soluble→ sickling shape (common in African people) Hemoglobin-H (Hb-H): mutation in three α gene → α thalassemia. In B thalassemia→ the B chain are absent and Hb contain 4α chains. 0 Alpha Thalassemia: There are 4 genes encoding for α chain synthesis: If 1 gene is missing α thalassemia trait asymptomatic If 2 genes are missing α thalassemia trait (also) microcytic picture If 3 genes are missing Hb H disease moderate anemia and splenomegaly If 4 genes are missing α thalassemia major can’t carry oxygen Hydrops Fetalis (the baby die ) 0  Reaction of hemoglobin: A. Normal forms: 1. Oxyhemoglobin 2. Carbaminohemoglobin B. Abnormal forms: 1. Carboxyhemoglobin 2. Met hemoglobin: 0 0 0  Fate of old RBCs Old RBCs destroyed in tissue macrophage (reticuloendothelial system) Hemoglobin → – Globulin: used for protein synthesis – Heme: Fe++ used for Hb synthesis Bilirubin (unconjugated in plasma) – In the liver conjugated with glucoronic acid forming conjugated bilirubin) – In the intestine converted to stercobilinogen » 1⁄3 is reabsorbed » 2⁄3 pass with stool 0  iron 0 0  Iron requirement for male 10 mg/day Iron requirement for female 10 mg/day Some people need more iron e.g pregnant woman and growth people 0 0 0 Vitamin B12 & Folic acid 0 0 0 0 0  anemia 0 Causes of anemia 0 0 General signs include pallor of mucous membranes which occurs. Specific signs e.g. koilonychia 'spoon nails' with iron deficiency, Jaundice haemolytic or megaloblastic anaemias, leg ulcers with sickle cell and other haemolytic anaemias  Types of anemia 1. Normocytic normochromic anemia: RBCs size is normal (MCV) Hb content of RBCs is normal Causes: 1.Hemolysis of RBCs as in:. Intracorpauscular causes:(Hereditary) Cell membrane defect: e.g. hereditary spherocytosis Hb defect: e.g sickle cell anemia Enzyme defect: glucose 6 phosphate dehydrogenase deficiency 0 Extracorpauscular causes: (Acquired) Chemical: arsenic and lead Drugs: sulphonamides Bacterial toxins Snake venoms Antibodies against RBCs Acute blood loos Bone marrow depression 0 2. Microcytic hypochromic anemia I - Iron deficiency anemia II - Anaemia of chronic disorders III - Thalassaemia 0  (Iron deficiency anemia) may be due to: Diminished intake (malnutrition and starvation) Decreased absorption Decrease storage Increase requirement Chronic blood loss.  II - Anaemia of chronic disorders decreased release of iron from macrophages to plasma  Iron overload Iron overload can occur in disorders associated with excessive absorption or chronic blood transfusion.  Sideroblastic anaemia This is a refractory anaemia increased marrow iron; it is defined by the presence of many pathological ring sideroblasts in the bone marrow  Thalassaemia These are a heterogeneous group of genetic disorders that result from a reduced rate of synthesis of A or B chains 3. Macrocytic anemia: (megaloblastic anemia) It is due to folic acid or vit B12 deficiency Causes of vit B12 deficiency Deficient intake Increase requirements Decrease absorption Decrease storage  Macrocytic anaemia (pernicious) anaemia There is an immune reaction against the gastric parietal cells, Leading to absent intrinsic factor(IF) which is important in Vit B12 absorption..  Causes of folic acid deficiency:. Decrease intake. Decrease absorption. Decrease storage. Increase requirements 0  Physiological effect of anemia: 1. On CVS: A. Decreased blood viscosity: B. Increase venous retain: C. Increase pulse pressure: D. Increase heart rate: 2. Hypoxia: 3. Jaundice: in case of hemolytic anemia 4. Subacute combined degeneration of spinal cord: in pernicious anemia. 0  Clinical effect of anemia Pallor Palpitation Fatigue Fainting Headache Blurred vision 0  polycythemia Definition: abnormal increase in RBCs count Types and causes: 1. Primary polycythemia (polycythemia Vera) 2. Secondary polycythemia: A. Physiological: e.g. in high altitude B. Pathological: heart failure and chronic lung disease 0  polycythemia Effect on CVS: A.↑ blood viscosity→ ↑in peripheral resistance→↑ blood pressure→ ↑ work of the heart may lead to heart failure B.↑ viscosity → ↓ blood flow to tissue→ stagnant hypoxia  jaundice 0 Hemolytic jaundice and obstruction jaundice 0  Platelets (thrombocyte) 150.000- 350.000⁄ mm3 Non-nucleated irregularly shaped minute round cells 2-4 µm in diameter. 0  Platelets (thrombocyte) Produced in the bone marrow and Budded off from the cytoplasm of the megakaryocytes 0  Platelets (thrombocyte) have an average life span of 7 to 14 days and are removed and destroyed by reticuloendothelial cells in the liver and spleen. 0  Function of Platelets (thrombocyte) Play a key role in hemostasis. Assist in maintaining the integrity of vascular endothelium by quickly repairing the minor breaks in the endothelium. 0  How platelets play important role in hemostasis Platelet release vasoconstrictor substance as serotonin and thromboxane A2. Platelet plug formation: it involve 4 steeps: 1. Platelet adhesion: Injured blood vessel→ release of subendothelial collagen fiber. Platelet adhere to subendothelial collagen (depends on von willebrand factor) This factor has two binding site one for platelet membrane other for subendothelial collagen. 0  2. Platelets release: Platelet adhesion→ platelet enzymes will be activated→ formation of thromboxane A2 →stimulates the releae of the contents of platelets granules (ADP, Ca2+ and serotonin).. Stimulate growth of vascular wall to repair site of injury through release of platelet growth factor present in specific granules.  3. Platelets aggregation: ADP and thromboxane A2 (from primary activated platelet) → acting on nearby platelet to activate them. The newly activated platelet become sticky and adhere to primary activated platelet. Activated platelet→ release ADP and thromboxane A2 → activate more platelet and result in platelets aggregation. Vicious cycle→ platelet plug that can close small injury. 0  4. Help blood clot formation: Platelet membrane phospholipids act as a surface for activation of clotting factors as F XII and F X. Platelet release some clotting factors as fibrinogen and F VIII. 0 Hemostasis, Blood Coagulation and Fibrinolysis  Hemostasis The process to arrest the bleeding 0  Mechanisms of Hemostasis vascular constriction (neural, myogenic and humoral) formation of a platelet plug; formation of a blood clot as a result of blood coagulation 0  1. Vascular Constriction Nervous reflex; Local myogenic spasm Local humoral factors from the traumatized tissue and blood platelets. Such as 5-HT, endothelin and thromboxane A2. 0  Vascular Constriction Tissue Factor 0  Vascular Constriction Last for many minutes or even hours, 0  2. Formation of the Platelet Plug Platelet adhesion: First phase of platelet aggregation Platelet Release. Second phase of aggregation 0  Platelet adhesion Adhere to the damaged vascular wall, such as the collagen fibers in the vascular wall or even damaged endothelial wall 0  First phase of platelet aggregation ADP released from the damaged tissue the platelet adhere together loosely Reversible aggregation 0  Platelet Release After the first phase (reversible) of aggregation the contractile proteins in the platelet contract forcefully and cause the release of granules that contain multiple active factors including the ADP and thromboxane A2 0  Second phase of aggregation ADP and thromboxane A2 in turn act on nearby platelets Cause the platelets to adhere to the originally activated platelets. Irreversible aggregation 0  3. Blood Coagulation in the Ruptured Vessel The clot begins to develop in 15 to 20 seconds if the trauma of the vascular wall is severed in 1 to 2 minutes if the trauma is minor. With 3 to 6 minutes after rupture, if the vessel opening is not too large, the entire opening or broken end of the vessel is filled with clot. Bleeding time, 1-5min 0  General Mechanism of Blood Coagulation Formation of prothrombin activator Activation of thrombin Activation of fibrinogen 0  Two pathways of the Formation of prothrombin activator Extrinsic pathways: begins with trauma of the vascular wall and surrounding tissues Intrinsic pathways begin in the blood itself 0  Intrinsic Pathway Extrinsic Pathway Collagen XII XIIa HMW Kinogen Tissue factor XI XIa Factor III Ca++ HMW Kinogen IX IXa pf3 VIIa VII Ca++ VIII Xa Ca++ X X pf3 V XIII Prothrombin Thrombin XIIIa stable Fibrinogen fibrin fibrin (monomer polymer polymer) 0  Activation of Factor XI, Smaller letter “a” indicate the activated form XIIa Inactive XI Active XIa + 0  Intrinsic Pathway (1)Blood trauma causes 1) activation of XII 2) release of platelet phospholipids (platelet factor) 0  Blood trauma or contact with collagen XII XIIa PL HMW kininogen prekallikrein XI XI a Ca2 + IX IXa VIIIa, Ca2+, PL X X a 0  Intrinsic Pathway (2)Activation of factor XI. Besides the activated XII (XIIa), this process requires high-molecular-weight (HMW) kininogen is accelerated by prekallikrein (co-factor) 0  Blood trauma or contact with collagen XII XIIa PL HMW kininogen prekallikrein XI XI a Ca2 + IX IXa VIIIa, Ca2+, PL X X a 0  Intrinsic Pathway (3) Activation of factor IX 0  Blood trauma or contact with collagen XII XIIa PL HMW kininogen prekallikrein XI XI a Ca2 + IX IXa VIIIa, Ca2+, PL X X a 0  Intrinsic Pathway (4) Activation of factor X. This reaction needs VIIIa, Ca2+ (factor IV) and platelets phospholipids. 0  Blood trauma or contact with collagen XII XIIa PL HMW kininogen prekallikrein XI XI a Ca2 + IX IXa VIIIa, Ca2+, PL X X a 0 0  Intrinsic Pathway (5) Action of activated factor X to form prothrombin activator. Together with Factor V, Ca2+ and platelets phospholipids. Xa, V, Ca2+, PL Prothrombin Thrombin 0 II IIa  Extrinsic Pathway (1) Release of tissue factor. Traumatized tissue release a complex of several factors called tissue factor or thromboplastin. 0  Extrinsic Pathway (2) Activation of factor X. Tissue factor complexes with blood coagulation factor VII and , in the presence of calcium ions, acts enzymatically on Factor X to form Xa. 0  VII Ca2+, PL a X Xa + Tissue Factor (TF) Tissue Damage Vessel wall Cell particles II IIa (prothrombin) (thrombin) Initial Tissue Factor Pathway Activation of Hemostasis 0 0  Conversion of Prothrombin (Factor II) to Thrombin (Factor IIa) After prothrombin activator has been formed, it then, in the presence of sufficient amounts of Ca2+ ions causes conversion of prothrombin (Factor II) to thrombin (Factor IIa). 0  Conversion of Fibrinogen to Fibrin The thrombin (IIa) acts on fibrinogen (Factor I) to form a molecule of fibrin monomer (Factor Ia) that has the automatic capability to polymerize with other fibrin monomer molecules into long fibrin fibers that form the reticulum of the clot 0 0  Conversion of Fibrinogen to Fibrin The clot is composed of a meshwork of fibrin fibers running in all directions and entrapping blood cells, platelets and plasma It becomes adherent to any vascular opening and thereby prevents blood loss. 0. 0  Clot Contraction Within a few minutes after a clot is formed, it begins to contract (contractile fibers in platelets) and usually expresses most of the fluid from the clot within 20 to 60 minutes The fluid expelled is called serum, in which all fibrinogen and most of the other clotted factors have been removed. In this way, serum differs from plasma. Serum can not clot because of lack of these factors. 0 0  Role of Calcium Ions Calcium ions are required for promotion or acceleration of all the blood-clotting reactions. Except for the first two steps in the intrinsic pathway, Therefore, in the absence of calcium ions, blood clotting by either pathway does not occur. 0  Role of Calcium Ions In the living body, the calcium ion concentration seldom falls low enough to affect significantly the kinetics of blood clotting. When blood is removed from a person, it can be prevented from clotting by reducing the calcium ion concentration below the threshold level for clotting, either by deionizing the calcium by causing it to react with substances such as citrate ion and oxalate ion 0 0  Intravascular Anticoagulants  Antithrombin III Present in a concentration of 30mg/dl in the plasma It is a serine protease inhibitor combine with active centers of the clotting factors IIa, VII, IXa, Xa and XIIa, blocks the effect of these factors and then inactivates them within a few minutes. 0  Heparin Produced by mast cells and located in connective tissue basophil cells of the blood. A large quantities of the heparin is present in the areas of the liver and lungs. 0  Heparin By itself, it has little or no anticoagulant property, but when it combines with antithrombin III, it increases a hundred-fold the effectiveness of antithrombin III thus acts as an anticoagulant. Heparin is widely used in medical practice to prevent intravascular clotting. 0  Heparin mechanism of action Heparin Antithrombin III Thrombin 0  Coumarins (e.g. warfarin) Mode of action: – Compete with vitamin K on active sites for synthesis of coagulation factors X, IX, VII and II Mode of administration: – Givens as oral tablets Onset of action: – Needs three days to reach full effect 0 Differences between heparin and coumarines “warfarin” Heparin Dicumarol “ Warfarin” From animal origin From plant origin Rapid action Slow action Action last for few hours Action last for days Given by injection Given orally Acts by increase activity of Acts by competitive antithrombin III and inhibition of Vitamin “K” Inactivate active “IX,X,XI depending factors  Protein C activated by thrombin. plays a powerful role to prevent clotting by inactivating the factors V and VIII, blocking the activation of X and II increasing the process of fibrinolysis due to stimulating the release of plasminogen activators. 0  TFPI:Tissue Factor Pathway Inhibitor 1.5-3.4 nmol/L in the plasma Release from the endothelial cell of small vessels Glycoprotein Inhibit Xa and inactivate VIIa-TF complex 0  Tissue factor pathway inhibitor VII a X Xa + Tissue Factor (TF) Tissue Damage Vessel wall Cell particles II IIa (prothrombin) (thrombin) Initial Tissue Factor Pathway Activation of Hemostasis 0 FIBRINOL YSIS  Concept The fibrin formed within blood vessels is gradually dissolved to restore the fluidity of the blood. The process of liquefaction or lysis of the fibrin is called fibrinolysis. 0  FIBRINOLYSIS Tissue damage release TPA & Plasminogen Extrinsic Intrinsic TPA & Urokinase XII & Kallikrein Streptokinase Plasminogen Plasmin  General Process Plasminogen Activator Plasminogen Plasmin Fibrin and Fibrinogen Fibrin Degradation Products (FDP) 0  Activation of Plasminogen to Form Plasmin – Plasminogen Activator There are two types of plasminogen activator Vessel activator. Some clotting factors in the intrinsic pathway, such as XIIa, XIa, prekallikrein , HMW kininogen, IIa (thrombin). Tissue activator. Released by the injured tissue and endothelium tissue-type plasminogen activator (t-PA) urokinase synthesized by the kidney 0  Plasminogen t-PA PG Plasmin t-PA FDPs PG PL Fibrin 0  Degradation of the fibrin Plasmin is a most powerful proteolytic enzyme. digest the fibrin, fibrinogen, Factor V, VIII, prothrombin and Factor XII. whenever plasmin is formed in a blood clot, it can cause lysis of the clot and destruction of many of the clotting factors, 0  Plasminogen t-PA PG Plasmin t-PA FDPs PG PL Fibrin 0  Degradation of the fibrin Human t-PA is produced by recombinant DNA technique and available for clinical use. lyses clots in the coronary arteries if given to patients soon after the onset of myocardial infarction. Streptokinase and urokinase are also fibrinolytic enzymes used in the treatment of early myocardial infarction 0 0  Other role of platelets in hemostasis: Maintenance of the Integrity and Repair of the Vascular Endothelium 0  Disorders of hemostasis: A. Disseminated intravascular coagulation (DIC) Definition: spontaneous formation of blood clots inside blood vessels. Causes: 1.Venous causes 2.Arterial causes 3.Blood causes: A. Polycythemia B. Thrombocytosis C. Deficiency of antithrombin III 0  1- Vascular disorders 2- Platelets Characterized by spontaneous skin purpura and mucosal haemorrhage 1- Decrease in the number of platelets 2- Disorders of platelet function 3- Defective coagulation  Disorders of hemostasis B. Hemorrhagic disease 1.purpura: disease characterized by small punctate hemorrhages under the skin resulting from spontaneous bleeding from small vessels 2.Hemophilia: Hereditary disease characterized by sever bleeding inherited as sex linked recessive Types: 1. Hemophilia A -‫ ـــــــــــــــ‬Factor VIII 2. Hemophilia B ‫ ــــــــــــــــ‬Factor IX 3. Hemophilia C ‫ ــــــــــــــــ‬Factor XI 0  Disorders of hemostasis C. Vitamin K deficiency: Vitamin K deficiency → deficiency of prothrombin group Causes: 1.Sterility of intestine 2.Failure of absorption 3.Competitive inhibition of vitamin K D. Von willbrand’s disease: 0  Factor VIII and Hemophilia Factor VIII is the factor that is missing in a person who has classic hemophilia Factor VIII is called antihemophilic factor 0  Tests of hemostasis Platelet count Bleeding time clotting time (coagulation time) PT (prothrombin time) PTT (partial thromboplastin time)  PLATELET COUNT (CBC) NORMAL 150,000 - 400,000 CELLS/MM3 < 150,000 Thrombocytopenia 50,000 - 100,000 Mild Thrombocytopenia < 50,000 Sever Thrombocytopenia  BLEEDING TIME Provides assessment of platelet count and function NORMAL VALUE 2-5 minutes  Clotting Time - Slide Method The surface of the glass tube initiates the clotting process. This test is sensitive to the factors involved in the intrinsic pathway The expected range for clotting time is 5-10 min.  PROTHROMBIN TIME l Measures Effectiveness of the Extrinsic Pathway NORMAL VALUE 10-15 SECS  Prothrombim time The prothrombin time: is the time required for the plasma to clot after an excess of thromboplastin and an optimal concentration of calcium have been added. Measures the function of the extrinsic Pathway and the common pathways. Sensitive to Factors I, II,III,IV, V, VII, X. The PT evaluates patients suspected of having an inherited or acquired deficiency in these pathways.  An elevated prothrombin time may indicate the presence of: Vitamin K deficiency (Vitamin K is needed to make prothrombin and other clotting factors) DIC liver disease a deficiency in one or more of the following factors: I, II, III, IV, V, VII, X. Anticoagulant (warfarin)  PARTIAL THROMBOPLASTIN TIME Measures Effectiveness of the Intrinsic Pathway NORMAL VALUE 25-40 SECS  APTT is a performance indicator measuring the efficacy of both the "intrinsic" and the common coagulation pathways. Normal PTT times require the presence of the following coagulation factors: I, II, IV, V, VIII, IX, X, XI, & XII.  Prolonged APTT may indicate: use of heparin. coagulation factor deficiency : e.g hemophilia DIC Liver disease  Partial Platelet Bleeding Prothrombin thromboplastin Condition count time time time unaffected prolonged prolonged unaffected Von Willebrand disease Vitamin K deficiency or unaffected unaffected prolonged prolonged Warfarin unaffected unaffected prolonged unaffected Haemophilia unaffected unaffected prolonged prolonged Factor V deficiency Unaffected prolonged unaffected unaffected Aspirin Decreased prolonged unaffected unaffected Thrombocytopenia decreased prolonged prolonged prolonged End-stage Liver failure Blood Group and Transfusion  Blood Groups the types of special antigens on the surface of the red blood cells Two particular groups of antigens are more likely than the others to cause blood transfusion reactions. ABO system Rh system, 0  ABO Blood classifications depend on the presence or absence of the agglutinogens (antigens) on the surface of the red cell means 0  Agglutinogens Two antigens- type A and type B occur on the surface of the red blood cells. These antigens are called agglutinogens because they often cause blood cell agglutination, causing blood transfusion reactions Group Group Group Group B AB O A 0  Agglutinins The agglutinins are gamma globulin in the plasma. When type A agglutinogen is not present in a person’s red blood cells, antibodies known as anti-A agglutinins develop in the plasma. when type B agglutinogen is not present in the blood cells, antibodies known as anti-B agglutinins develop in the plasma. 0  Major types of ABO blood group The bloods are normally classified into four major types, depending on the presence or absence of the two agglutinogens, A and B 0  BLOOD GROUPS Red blood cells (rbc’s) can contain surface A & B antigens. There are four principal blood groups in humans: O, A, B and AB anti-A Group O Group B anti-A anti-B Group O rbc’s have no surface A & B antigens: antibodies anti-A Group B rbc’s have surface & anti-B are present in the plasma antigen B and antibody A. Group A anti-B Group AB Group A rbc’s have surface Group AB rbc’s have surface antigen A and antibody 0 B. antigens A & B and no antibodies.  ABO blood group Two genes, one on each of two paired chromosomes, determine the ABO blood groups. They are allelomorphic genes that can be any one of three types but only one type on each chromsome: type O, A, B. The type O gene is either functionless or almost functionless, so that it causes no significant type O agglutinogen on the cells. the type A and type B genes do cause strong agglutinogens on the cells. 0 Blood Type Agglutinogen Agglutinin O -- Anti-A, Anti-B A A Anti - B B B Anti-A AB A and B -- 0  Agglutination and hemolysis in transfusion reaction When bloods are mismatched so anti-A or anti-B plasma agglutinins are mixed with red blood cells that contain A or B agglutinogens respectively, agglutinins will make the red cells adhere to each other – agglutination. The clumps of red cells will plug small blood vessels throughout the circulatory. 0  Group Group anti-B B B a a nt nt i- i- B Group B Group anti-B B B 0 0  Agglutination and hemolysis in transfusion reaction During the ensuring few hours to a few days, either physical distortion of the cells or attack by phagocytic white cells destroys the agglutinated cells, releasing hemoglobin into the plasma, which is called “hemolysis” of the red blood cells. 0  Agglutination During severe hemolytic reaction, fever, chills and shock may occur. One of the most lethal effects of transfusion reactions is kidney shutdown, which can begin within few minutes to a few hours. If the shutdown is complete and fails to open up, the patient die of renal failure. 0  RH blood group Depending on present or absent of Rh antigen (Agglutinogen D ) or D antigen Anti D antibodies are not present normally, in contrast to ABO system antibodies, it developed after exposure Rh negative person to Rh positive blood“ sensitization” 0 0  Side effect of blood transfusion Allergic transfusion reactions: “mild mismatch”: fever, flushing, shivering, itching, rash,…..etc Hemolysis “sever mismatch”: anemia, low blood pressure, acute renal failure, dark urine, disseminated intravascular coagulation. Transmission of infections: bacteria, parasites “malaria”, viral “ Hepatitis and HIV” Circulatory overload “large amount of blood” Increase K+, citrate,…etc. Iron overload “multiple blood transfusion with time ” 0  Rh + blood mismatch When an Rh negative blood person is injected with Rh positive RBCs “Rh factor”, anti Rh agglutinin “ anti Rh antibody” develop very slowly and cause sensitization, the severity of immune reaction is occurs depending on amount of antibodies level “ amount of injected RBCs”!! The maximum concentration of agglutinins occurs 2-4 months later 0  Hemolytic disease of the newborn “Erythroblastosis foetalis” When the mother is Rh negative and father is Rh positive, so if the fetus has inherited Rh positive antigen from the father, at delivery, small amount of fetal blood may leak into maternal circulation, mother may develop significant amounts of anti Rh agglutinins after 2-4 months, so, first baby usually born normally. During next pregnancy, the mother anti Rh agglutinins diffuse through placenta into the fetus, if he is Rh positive blood, the sever immune reaction occurs causing hemolysis of fetal RBCs and the infant may die in the uterus or may develop erythroblastosis foetalis 0  Erythroblastosis foetalis Destruction of fetal blood causing: 1. Sever hemolysis causing sever anemia leading to heart failure and generalized edema. 2. Sever hemolysis of RBCs cause increase of Bilirubin lead to “Jaundice”, because of blood brain barrier still not well mature in the newborn, the Bilirubin may pass to brain and cause permanent damage of brain cell “ Kernicterus” leading to mental retarded baby 3. Sever hemolytic anemia stimulate erythropoiesis cause erythroblast “ immature RBCs” in the baby blood and cause extramedullary erythropoiesis (extra bone marrow) cause hepatosplenomegaly. Erythroblastosis foetalis 0  II. The Principles of Blood Transfusion Blood typing Transfusing the Same Type of Blood (ABO) Cross-Match test 0 0  White blood cells (leucocytes) Leukocytes contain nuclei and mitochondria and can move in an amoeboid fashion, so they can squeeze through pores in capillary and get to a site of infection. Number, 5000 to 10000/ mm3 Classification: Granular leukocytes Agranular (or nongranular) leukocytes 0 0  Granular Leukocytes- Neutrophils 50 % - 70%. nonspecific cellular immunity : After attracted by chemical substances (chemotaxis) released by bacteria, They engulf and digest the bacteria or other foreign substances by means of phagocytosis. 0  Granular Leukocytes-Eosinophils 0.5-5%. Function: Limit the action of basophils in the rapid allergic reactions (through release of prostaglandin E and histamine oxidase) Participate in the immune response to parasites 0  Granular Leukocytes- Basophils less than 1%, release heparin and histamine that are responsible for the allergic reaction. 0 0  Agranular Leukocytes- Monocytes 3% - 8%. Wander into the tissue and become fixed in the tissue and swell to become fixed tissue macrophages. During the inflammation, they can divide and form more macrophages 0  macrophages 0  Agranular Leukocytes- Lymphocytes 20% - 40% T (thymus dependent) lymphocytes, responsible for the cellular immunity B lymphocytes, responsible for the humoral immunity. 0 0  Immunity Definition: It is ability of the body to defense and protect it self from forging antigen or harmful event ". Immune response: Reactions of the body against harmful event. Antigen: Any substance cause immune response Antibody: Substance against antigen that protect our body. 0  Types of immunity Innate immunity (natural immunity) – Doesn't need previous exposure to antigen – Non specific – Doesn't need time to develops Acquired immunity (adaptive immunity) – Needs previous exposure to antigens – Specific – Needs time to develops 0  Innate immunity 1. Phagocytosis 2. HCL and gastrointestinal secretion 3. Skin protection against microorganism 4. Certain blood compounds for example A. Lysozymes B. The complement system 5. Natural killer lymphocyte 0  Acquired immunity Types of acquired immunity. 1. Humeral immunity. 2. Cellular immunity. 0  Characteristics of antigen – Large molecular weight – Found on surface of microorganism, human cell,..etc. 0  Acquired immunity Is mediated by lymphocyte Lymphocyte located in lymph node (mainly) BM, spleen, thymus and submucosa of GIT Usually the invading organism enters to tissue fluid→ lymph node→ lymphoid tissue→ initiate immune response Types of lymphocyte T-lymphocyte: cell mediated immunity B- lymphocyte: humoral immunity 0 Processing of lymphocyte 0 Humoral immunity 0 Cellular immunity 0  Lymphocyte antigen recognition B lymphocyte can recognize antigen directly T lymphocyte only recognize antigen bounds to MHC (major histocompatibility) protein Types of MHC protein – MHCI→ T cytotoxic cell – MHCII →T helper cell 0  Types of T cells 1. helper T cells 2. Cytotoxic T cells 3. Suppressor T cells 0  T helper cell Constitute about 75% of total T cell Serve as a major regulator for almost all immune function→ by forming protein mediators called lymphokines e.g.: 1. Interleukins 2,3,4 and 5 2. Granulocyte- monocyte colony stimulating factors 3. Interferon Ὑ HIV can attack T helper cell (AIDS) 0  Cytotoxic T cells (killer cells) Cytotoxic T cell proteins attached to the antigen of microorganism: Release of perforins Release of cytotoxic substance The attached cell swollen The attached cell dissolve – Some of cytotoxic T cell are specially lethal to Cells infected by viruses Cancer cell Transplanted cell 0 0  Suppressor T cell Causes suppression to cytotoxic T cell and helper T cell Importance 1. Decrease immune tolerance: 2. Decrease the activity of cytotoxic T cell that might damaging to Owen cells 0  Antibodies Are gamma globulins also called immunoglobulin's Constitute 20% of plasma protein Composed of light and heavy polypeptide chains 0 0  Classes of antibodies There are five main classes of antibodies – IgM →primary immune response – IgG →secondary immune response – IgA→localized infection in external secretion – IgD →antigen recognition by B cell – IgE →for allergy IgG: constitutes 75% of all immunoglobulin's 0  Complement system Complement system is made of 11 proteins – C1→C9 – Protein B – Protein D Most of the protein are enzyme precursor The enzyme precursor are normally inactive 0  Effect of complement 1. Opsonization and phagocytosis 2. Lysis 3. Agglutination 4. Chemotaxis 5. Activation of mast cell and basophil 6. Inflammatory effect 0  Immunization Immunization can be done by different ways: 1. Dead organism e.g. Typhoid Diphtheria Whooping cough 2. Toxins treated chemically Tetanus 0  Life attenuated organism (the organism is growing in different culture and muted their toxins have antigen but not toxic to cause a disease e.g. Poliomyelitis Measles Yellow fever Small pox 0  4- Done by infusing antibodies, activated T cell or both Infusing antibodies lasts for 2-3 weeks Activated T cell – If transfused from another person last for few week – If transfused from animals lasts for few hours to few days  Physical and Chemical Properties of the Blood Gravity Suspension Stability of the Red Cells and Erythrocyte sedimentation rate (ESR). Viscosity Plasma Osmotic Pressure 0  Gravity Blood: 1.050-1.060 Plasma: 1.025-1.030 Cells: 1.o90 0  Suspension Stability of the Red Cells The erythrocytes are very stable in suspension due to the repelling force by the same (negative) charge of the red cells. When the blood is anticoagulated and added in a narrow tube, rouleaux of the red cells are formed and then its sediment gradually takes place. The length of sedimentation of the red cells within one hour is termed erythrocyte sedimentation rate (ESR). 0  erythrocyte sedimentation rate (ESR). The normal range – 0 - 10 mm per hour in men, – 0 – 20 mm per hour in women. depends mainly on the relative concentration of the plasma protein (Albumins and Globulins). Globulin and fibrinogen enhances the formation of the rouleaux. Almost all the infections (especially the tuberculosis and rheumatism) that are accompanied by a rise of globulin can accelerate ESR. 0  Viscosity The frictional force between the elements in the blood. The relative viscosity of the blood is 4-5 The higher the red cell concentration and the amount of plasma protein, the greater the viscosity of the blood. Increase of the viscosity can enhance the peripheral blood resistance, decreasing the blood supply to tissue. 0