Blood Lectures PDF - Bernard Leung - AY2024

The Blood – Lecture I I. Blood Composition and Function II. Hemoglobin, Erythropoiesis, and Anemia III. Blood Group Systems Bernard Leung [email protected] HSC1007, AY2024 Zoom#: 999 6999 5721 Passcod...

The Blood – Lecture I I. Blood Composition and Function II. Hemoglobin, Erythropoiesis, and Anemia III. Blood Group Systems Bernard Leung [email protected] HSC1007, AY2024 Zoom#: 999 6999 5721 Passcode: 172060  Highlights Blood Circulation in The Adult Lecture 1 - Blood composition and function - Red blood cells - Hemoglobin - Erythropoiesis & anemia - Blood Groups and transfusion reaction Lecture 2 - Platelets and Hemostasis - Coagulation Pathways - Leukocytes References: Ch19. Fundamentals of Anatomy & Physiology, 10/11th Edition, F Martini; Ch11. Introduction to Human Physiology, 9th Edition, L Sherwood.  Learning Objectives Physical characteristics of the blood. What are the major functions of blood? What are the various elements in blood? Generation and functions of red blood cells. Erythrocyte dysfunction. Basis of blood groups & blood transfusion reaction.  Blood Functions Primary means of long-distance transport in the body: - Respiratory gases: O2 and CO2 - Nutrients, electrolytes, vitamins, hormones, lipids, and wastes. Regulation (homeostasis, optimal environment for cell function): - Body temperature: Re-distribution of heat. - pH, ion concentrations and osmolality. - Hormones: Transport from glands to target organ. Hemostasis: Complex and efficient pathways to prevent blood loss from a damage blood vessel and tissue repair. Platelets and coagulation. Immunity: Blood leukocytes against infectious agents.  Physical Characteristics of Blood Blood is the body’s only fluid tissue. Formed elements (cellular components): red & white blood cells, platelets. Plasma: liquid components of blood. Blood accounts for approximately 8% of body weight; 5 times more viscous as water, dissolved proteins and formed elements. Average adult 5L of whole blood; 5-6L in men & 4.5-5.5L in women. pH of blood is 7.35 - 7.45; 38°C, slightly above ‘normal’ body temperature.  Plasma Composition Plasma proteins 7% OTHER SOLUTES Electrolytes Normal extracellular fluid ion Other solutes 1% composition essential for vital cellular activities. Water 92% Transport Ions contribute to osmotic pressure of body fluids. PLASMA PROTEINS Major plasma electrolytes are Na+, K+, Ca2+, Mg2+, Cl–, HCO3– Albumins Major contributors to osmotic HPO4–, SO42– (60%) pressure of plasma; transport lipids, steroid hormones Organic Used for ATP production, Globulins Transport ions, hormones, nutrients growth, and maintenance of (35%) lipids; immune function cells; include lipids (fatty acids, cholesterol, glycerides), Fibrinogen Essential component of clot- carbohydrates (primarily (4%) ting system; can be converted glucose), and amino acids to insoluble fibrin Organic Carried to sites of breakdown Regulatory Enzymes, proenzymes, wastes or excretion; include urea, proteins hormones uric acid, creatinine, bilirubin, (99% of formed (cellular) elements in blood - RBC constitute ~ 45% of blood volume - Men: 4.5 – 6.5 x 109/ml - Women: 3.9 – 5.6 x 109/ml - RBC life span is 100 – 120 days. Stack formation in capillaries RBC is Hb carrier, content >97%Hb Men: 14 - 17Hb g/dl (deciliter, 100ml) Women: 12 - 16Hb g/dl  RBC – Lack of Nucleus and Organelles Key Facts: - More hemoglobin (Hb) ééO2 transport capacity. - Less work for heart as a pump, the heart pumps approximately 3 kg of erythrocytes per minute. - Lacking mitochondria, RBCs rely on glycolysis (anaerobic) for ATP to fuel active transport mechanisms in maintaining ionic concentrations within the cell. No consumption of transported O2 - Carbonic Anhydrase, convert CO2 into bicarbonate (HCO3), primary form in CO2 in blood. CO2 + H2O H2CO3 H+ + HCO3- - Homeostasis of blood pH, Hb binds to H+ ions (more on respiratory system!). - No nucleus/ribosomes, ✗✗repairs or divide/synthesis cellular proteins/enzymes, lifespan: ~100-120 days. - Requires vast new replacement cell production (Erythropoiesis).  Hemoglobin: Complex Quaternary Structure Globin portion: 4 folded polypeptide chains, 2 a + 2 b chains (subunits), each chain contains a single heme molecule. Resemble myoglobin in skeletal and cardiac muscle cells. Heme molecule: pigment complex, 1 iron (Fe):1 O2 molecule Weak and Reversible binding. Each Hb molecule can transport four molecules of O2 O2-carrying capacity of blood ~ 150 g Hb/L blood X 1.34 ml O2 /g Hb = ~ 200 ml O2 /L blood Most oxygen in blood is bound to Hb (>98%).  Erythropoiesis - No nucleus, DNA/RNA, ribosomes, ✗✗repairs or divide/synthesis cellular proteins/enzymes, lifespan: ~100-120 days. - RBC plasma membrane becomes fragile and prone to rupture – hemolyze. - Requires vast new replacement cell production (Erythropoiesis). - Replacement rate 2 - 3 x 106 RBCs / second. (106 = million) Sites of Erythropoiesis: Fetus: yolk sac, developing liver and spleen. Children: most bones are filled with red bone marrow. Cellularity Adults: bone marrow in ribs, sternum, vertebrae, pelvis & upper end of long bones. Erythropoiesis – Bone marrow  Erythropoiesis Hematopoietic stem cells in the bone marrow give rise to proerythroblasts. Proerythroblasts develop into erythroblasts in 3 steps: 1: Ribosome synthesis in early erythroblasts; 2: Hb accumulation in late erythroblasts & normoblasts; 3: Ejection of the nucleus from normoblasts and formation of reticulocytes. Reticulocytes continue Hb synthesis, leave the bone marrow and complete differentiation to mature RBCs in the blood. Reticulocyte count (normal range 0.8 – 1.5%) is indicative of erythropoiesis. Erythropoiesis requires: Proteins, lipids, and carbohydrates. Iron, vitamin B12, and folic acid.  Iron Essential trace element, concentration required is very low. A small paperclip is about 1 gram (1000mg). Constituent of all body cells, and an important component of haemoglobin and myoglobin. Normal diet provides 10 to 15 mg/day; 10% absorbed. Amount absorbed depends on dietary iron and the state of iron sufficiency in the body). 0.5 to 1.0 mg daily loss for males (greater for females due to monthly blood loss from menstruation, pregnancy - transfer 300mg of iron to the fetus). Iron supplement: Fe2+, folic acid and vitamin B12 for treating anemia.  Vitamin B12 & Folate Vitamin B12 Recommended dietary intake: 2 microgram (µg)/day. Dietary source: foods of animal origin, especially liver, kidney. Well-stored vitamin: 0.8 – 11 mg in body, mainly in liver. Folate Related compounds of folic acid. Minimum daily requirement: 50 µg. Dietary source: green leafy vegetables, fruits, yeast, liver, kidney and dairy products. Total body stores about 5 - 10mg. Both vitamin B12 and Folate are necessary for the synthesis of thymidylate, the nucleotide of thymine that is found in DNA but not in RNA. Deficiency of vitamin B12 and Folate leads to maturation failure of healthy RBCs (macrocytic anemia). FYI (DNA): Adenine , Guanine, Cytosine & Thymine Regulation of Erythropoiesis: Erythropoietin (EPO) Reduced numbers of red blood cells due to hemorrhage (bleeding) or excessive RBC destruction Insufficient hemoglobin per RBC (as in iron deficiency) Reduced availability of oxygen (high altitude/hypoxia)  Erythropoietin (EPO) Erythropoietin release by the kidneys is triggered by: Hypoxia due to decreased RBC number or function. Decreased oxygen availability. Increased tissue demand for oxygen. Hemorrhage or anemia. Reduced blood flow to kidney. - is a peptide hormone. - stimulates hematopoietic stem cells to form proerythroblasts. - enhances proliferation rate of proerythroblasts and erythroblasts. - enhances Hb synthesis. - can increase RBC production approximately 10-fold. - about 90% is secreted by the kidneys, and about 10% by the liver. Androgen (but not estrogen) contributes to erythropoiesis. Therefore, men have higher RBC concentrations than women. Recycling of RBC Components & Turnover  Anemia Below normal O2-carrying capacity of the blood (200ml O2/L) - decreased rate of erythropoiesis, excessive loss of RBCs. - reduced hemoglobin (Hb) in RBCs. Some examples of anemia: - Microcytic anemia (RBCs are smaller than normal) – lack of Iron, required for erythropoiesis. - Macrocytic anemia (Bigger than normal RBCs, but lacking Hb) - lack of vitamin B12 or folate, veganism. - Aplastic anemia - failure of the bone marrow to make adequate numbers of RBCs even though all ingredients are available (e.g. radiation damage or chemotherapy).  Polycythemia An excess in circulating RBCs -> elevated hematocrit (normal Hct 37-54%). Primary polycythemia is caused by a tumor or tumor-like condition of the bone marrow. 7–11x109 RBCs/ml, Hct 70-80%. (Normal 4-6.5) Secondary polycythemia is an erythropoietin-induced, adaptive mechanism to improve the oxygen-carrying capacity of the blood. e.g. in people living at high altitudes. 6–8x109 RBCs/ml. Relative polycythemia: dehydration can elevate the hematocrit, RBCs is not changed but drop in plasma volume. Polycytemia causes 5-7x more viscous than normal conditions, éé total peripheral resistance, blood pressure and workload of the heart. Polycythemia  MCHC = MCH/MCV, amount of Hb/volume of erythrocyte For Your Info!  Erythrocyte Sedimentation Rate (ESR) Erythrocytes sediment faster with increased plasma protein concentration. RBCs stack like coins, sediment faster and elevate ESR, normal range 15-20 mm/hr. Inexpensive way for monitoring infection, autoimmune and inflammatory diseases.  Type A Type B Type AB Type O Type A blood has RBCs with Type B blood has RBCs with Type AB blood has RBCs with Type O blood has RBCs lacking surface antigen A only. surface antigen B only. both A and B surface antigens. both A and B surface antigens. Surface Surface antigen A antigen B If you have type A blood, your If you have type B blood, your If you have type AB blood, If you have type O blood, your plasma contains anti-B plasma contains anti-A your plasma has neither plasma contains both anti-A antibodies, which will attack antibodies, which will attack anti-A nor anti-B antibodies. and anti-B antibodies. type B surface antigens. type A surface antigens. a Blood type depends on the presence of surface antigens (agglutinogens) on RBC surfaces. The plasma contains antibodies (agglutinins) that will react with foreign surface antigens. Donor cells Recipient antibodies  Blood Transfusion Reaction Donor’s RBCs are being attacked by the recipient’s plasma agglutinins (antibodies).  Blood Group Systems Blood types A, B, AB, and O are based on distinct antigens on RBCs. Rh factor first observed in rhesus monkeys; antigens: C (c), D (d) & E (e). Rh-D is responsible for majority transfusion reactions – Rh-D positive (Rh+), and rest are Rh negative (Rh-). Blood type with ABO and Rh status, O negative (O-), AB positive (AB+). +ve/-ve blood group please Ignore! https://www.youtube.com/watch?v=cKnEdvrmHK4 Red Cell Compatibility – ABO group  Learning Objectives Physical characteristics of the blood. What are the major functions of blood? What are the various elements in blood? Generation and functions of red blood cells. Erythrocyte dysfunction. Basis of blood groups & blood transfusion reaction.  The Blood – Lecture II I. Blood Group Systems II. Platelets and Hemostasis III. White Blood Cells Bernard Leung [email protected] HSC1007, AY2024 Zoom#: 910 5610 3252 Passcode: 602843  Learning Objectives How is blood loss minimized? Functions of platelets & coagulation cascade. Regulation of blood clotting and fibrinolysis. Types and functions of leukocytes.  Hemostasis Hemostasis, cessation of bleeding and halts the blood loss of damaged vessels – first step of tissue repair. Homeostasis* – balance of physiology process.  Vasoconstriction/Vascular Phase Endothelial cells contract, expose the underlying Basal Lamina to bloodstream. Lasts for ~ 30 min, provides time for platelet and coagulation phase. Endothelial cells begin releasing chemical factors and local hormones, ie tissue factor, ADP*, and thromboxane A2. stimulates smooth muscle contraction and vasoconstriction; stimulates division of smooth muscle cells, endothelial cells & fibroblasts for tissue repair. Endothelial cell membranes become sticky – partial seal. Slow blood flow & reduces blood loss. *Adenosine DiPhosphate  Platelets Fragments of megakaryocytes, 4 x 1 µm, 1.5 – 3 x 108 / ml, lifespan of about 10 days before being removed by phagocytes (spleen). Thrombopoiesis lack nuclei. contain contractile proteins (actin and myosin). contain granules: ADP, Ca2+ and growth factors (PDGF, VEGF)*. contain factor XIII (13, Fibrin stabilizing factor). *PDGF = platelet derived growth factor, VEGF = vascular endothelial growth factor  Platelet Phase Non-activated platelets do not adhere to normal endothelial cells due to ‘repulsive’ glycoproteins on platelet surface. Actin and myosin contract, forcing out the contents of platelet granules, strengthen the platelet plug. Degranulated platelets secrete: - Thromboxane A2 (enhance vascular spasms). - ADP* (enhances platelet aggregation and secretion). Further release of ADP & thromboxane A causing secondary platelet aggregation (Positive feedback loop). - Calcium (essential for blood clotting) - PDGF (fibroblasts) - VEGF (vascular endothelial cells) - Factor XIII (FSF) - convert fibrin polymer to stable fibrin. *Adenosine DiPhosphate Formation of Platelet Plug Think of Velcro! A large plasma protein called von Willebrand factor stabilizes bound platelets by forming a bridge between collagen and platelets. Platelets swell, form spiked processes, become stickier, and release chemical messengers ADP, serotonin & thromboxane A2. Sherwood Textbook of Physiology Platelet and Coagulation Phase Erythrocytes trapped in fibrin of meshwork of a clot Intrinsic, Extrinsic & Common Pathway Common pathway  Tissue Factor and Factor VIIa/Vll in Hemostasis Tissue Factor (TF, Thromboplastin/Factor III) is a transmembrane receptor for VII(7)/Vlla. The endothelium physically separates this potent “activator” from circulating VIIa. Triggered by exposing blood to a factor found in tissues underneath the damaged endothelium. This factor is called tissue factor (TF) or factor III. Faster because it bypasses several steps of the intrinsic pathway. In severe tissue trauma, it can form a clot in 15 seconds. Tissue factor (TF, brown colour) expression in the arteriole wall. Purple colour – endothelial cells.  The Coagulation Factors Amplification – 1 XIa (11a) molecule through sequential activation of Factors IX, X & II may generate up to 2x108mol of fibrin. Almost all factors, except Tissue Factor and Factor (IV, Calcium) are produced by the Liver. Factor X (10), IX (9), VII (7) & II (2) – require Vitamin K.  Role of Thrombin (IIa) in Hemostasis Thrombin (Factor IIa) - Converting fibrinogen to fibrin. - Factor XIII(13) activation (stabilization of fibrin mesh). - release of PF3 from platelets (enhancement of intrinsic pathway). - release of tissue factor (enhancement of extrinsic pathway). - enhances platelet aggregation. - enhances its own generation (Positive feed back loop). Clot Dissolution - Fibrinolysis During clot formation plasminogen is trapped inside the clot. Plasminogen is a plasma protein, made by the liver, and cleaved to plasmin by proteases including tPA, thrombin, Factor XII(12). The surrounding tissue and vascular endothelial cells slowly release tissue plasminogen activator (tPA) which cleaves the inactive plasminogen to the protease plasmin. Plasmin digests fibrin, thereby dissolving the clot. Phagocytic white blood cells remove the remains of the clot.  Regulation of Blood Clotting Balance between pro/anti-coagulants: abnormal or excessive clot within blood vessels can compromise blood flow to vital organs.  Thromboembolism Inappropriate clotting, e.g. roughened surface of a vessel, endothelial cell damage, ie post-operation. Thrombi - solid masses/plugs form in the circulation from blood constituents, with platelets and fibrin form the basic structure. Thrombi can block circulation, resulting in tissue death (deep vein thromboisis, DVT). Coronary thrombosis – a thrombus in a blood vessel of the heart, ie atherosclerosis of the arterial wall, plaque rupture and endothelial collagen and tissue factor. Embolus – a thrombus freely floating in the blood stream. Pulmonary emboli can impair the ability of the body to obtain oxygen Cerebral emboli can cause strokes.  Blood Clotting Disorders Thrombocytopenia Circulating platelets is too low (