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Blood Physiology Hana Derseh (BSc, MSc) Addis Ababa University ,College of Health Science School of Medicine, Department of Physiology 7/24/2024 Blood Physiology 1  Objectives At the end of this lesson the stude...

Blood Physiology Hana Derseh (BSc, MSc) Addis Ababa University ,College of Health Science School of Medicine, Department of Physiology 7/24/2024 Blood Physiology 1  Objectives At the end of this lesson the students are expected to: 1. Understand the four major functions of blood: transport, hemostasis, homeostasis, and immunity 2. Explain the components of whole blood. 3. Describe the principles and general uses of different laboratory test associated with blood. 4. Discuss about the clinical usefulness of blood typing 5. Clarify the process of hemostasis. 7/24/2024 Blood Physiology 2  Outlines Introduction Blood composition Functions of blood Blood plasma Formed elements (cells) in blood Human blood types (group) Hemostasis 7/24/2024 Blood Physiology 3  Introduction Blood, is a connective tissue in fluid form Considered as the ‘fluid of life’, ‘fluid of growth’ and ‘fluid of health’. – provides nourishment to all body organs & tissues & carries away waste materials. – “the river of life”, blood is pumped from heart through network of blood vessels, circulatory system. 7/24/2024 Blood Physiology 4  Introduction … Adult human has about 5-6 liters of blood, 7- 8% of total body weight. Infants & children have comparably lower volumes of blood, – roughly proportionate to their smaller size. The volume of blood in individual fluctuates. – Hypovolemia can occur during dehydration, running a marathon, hemorrhage, water loss or sodium depletion… – Hypervolemia can occur due to renal failure, excessive sodium intake, or pregnancy, when the mother’s blood needs to carry extra oxygen and nutrients to the baby... 7/24/2024 Blood Physiology 5  Physical Characteristics & Volume Blood is sticky, opaque fluid with metallic taste. Color varies from scarlet (oxygen-rich) to dark red (oxygen- poor). The pH of blood is 7.35 – 7.45, which is slightly alkaline Temperature is 37C(98.60 F), which is similar to “normal” body temperature. Average volume of blood is 5-6 L for males, and 4-5 L for females. Viscosity: Blood is five times more viscous than water. It is mainly due to red blood cells and plasma proteins. 7/24/2024 Blood Physiology 6 Composition of Whole Blood Blood is the body’s only fluid tissue composed of: – liquid plasma (55%) and – formed elements (45%) Formed elements include: 1. Erythrocytes = Red blood cells (RBCs) 2. Leukocytes = White blood cells (WBCs) 3. Thrombocytes = Platelets 7/24/2024 Blood Physiology 7 Composition of Blood… Plasma (55% of whole blood) Buffy coat: leukocyctes 1 Withdraw blood 2 Centrifuge platelets Formed elements and place in tube (45% of whole blood) Erythrocytes 7/24/2024 Blood Physiology 8 7/24/2024 Blood Physiology 9 Composition of Blood… 7/24/2024 Blood Physiology 10  Function of Blood 1. Distribution/transportion of substance. 2. Homeostasis(Regulation) of pH, temperature & fluid volume. 3. Protection of blood loss & infection. 7/24/2024 Blood Physiology 11 Function of Blood… Distribution/transportation.  Blood is the primary means of long-distance transport in the body.  It carries an abundance of important substances from one area of the body to another,  including antibodies, acids and bases, ions, vitamins, cofactors, hormones, nutrients, lipids, pigments, metabolites, and minerals. 7/24/2024 Blood Physiology 12  Distribution… Blood transports: 1. Oxygen from the lungs & nutrients from the digestive tract. 2. Metabolic wastes from cells to the lungs & to kidneys for elimination. 3. Hormones from endocrine glands to target organs. 7/24/2024 Blood Physiology 13 Function of Blood… Hemostasis(arrest of bleeding)  Blood prevents blood loss by:  Activating plasma proteins & platelets.  Initiating clot formation when a vessel is broken.  The failure to stop bleeding after injury is called hemorrhage and can quickly lead to bleeding to death. 7/24/2024 Blood Physiology 14 Function of Blood… Immunity Blood leukocytes are involved in the body’s battle against infection by microorganism Blood prevents infection by: 1. actually destroying invading bacteria or viruses by phagocytosis and 2. forming antibodies and sensitized lymphocytes that may destroy or inactivate the invader In most cases, the blood’s defense system is efficient enough to eliminate the pathogens or to prevent their spreading before they can cause substantial bodily harm. 7/24/2024 Blood Physiology 15 Function of Blood… Homeostasis.  is a steady state that provides an optimal internal environment for cell function.  The blood system plays a crucial role in preserving homeostasis:  By maintaining body temperature, pH, ion conc., osmolality, nutrient supply, and vascular integrity.  Homeostasis is the result of normal functioning of the blood’s transport, immune, and hemostatic systems. 7/24/2024 Blood Physiology 16 Genesis of Blood Cells (Hematopoiesis) Before birth: – first occurs in yolk sac of embryo & – During the middle trimester of gestation, occurs in liver, spleen, thymus & lymph nodes of fetus. Last 3 months before birth, red bone marrow – becomes 1ry site & continues as the source of blood cells after birth & throughout life. Red bone marrow is highly vascularized spongy bone tissue present chiefly in bones of; – axial skeleton, pectoral & pelvic girdles & proximal epiphyses of humerus & femur. 7/24/2024 Blood Physiology 17  Hematopoiesis… Red bone marrow of essentially all bone produces blood cells until a person is 5 years old. After the age 20yrs, red marrow of long bones becomes quite fatty (yellow marrow) & produces no more blood cells, - exceptions: proximal portions of humeri, femur & tibiae. After 20yrs blood cells are produced in marrow of membranous bones of; – cranium, vertebrae, sternum, ribs & pelvic bones. Fig. 3. Changes in red bone marrow cellularity in various bones with age. 7/24/2024 Blood Physiology 18  Pluripotent hematopoietic stem cell(PHSC) Single type of cell from which all the cells of the circulating blood are eventually derived. Capable to reproduce and develop into: – myeloid stem cells & lymphoid stem cells. Myeloid stem cells begin their development in red bone marrow & differentiate into; – RBCs, platelets, granulocytes( eosinophils, basophils, neutrophils ) & monocytes. Lymphoid stem cells begin their development in red bone marrow, complete in lymphatic tissues & differentiate into; – T and B lymphocytes. 7/24/2024 Blood Physiology 19 7/24/2024 Blood Physiology 20  Erythrocytes (RBCs) Biconcave discs, anucleate, essentially no organelles. Filled with hemoglobin (Hb), – protein that functions in gas transport. Plasma membrane is comprised of flexible proteins – allow them to change shape as necessary. 7/24/2024 Blood Physiology 21  Erythrocytes (RBCs)… Are example of how structure drives function, structural characteristics contribute to its gas transport function: Biconcave shape that has huge surface area relative to volume. Discounting water content, about 95% of the erythrocytes are composed of hemoglobin. ATP is generated anaerobically, erythrocytes do not consume the oxygen they transport. 7/24/2024 Blood Physiology 22  Erythrocyte Function 1. Transports respiratory gases – O2 & CO2 2. Hemoglobin serve as a buffer – pH balance 3. Carbonic anhydrase (CA) – enzyme located in RBC membrane CA CO2 + H2O H2CO3 HCO-3 + H+ – CA increases the rate of this reaction 5000 fold 7/24/2024 Blood Physiology 23  Erythropoiesis (Production of Erythrocytes) Fig. Major steps in erythrocyte production (erythropoiesis) 7/24/2024 Blood Physiology 24 Regulation & Requirements for Erythropoiesis The total volume of circulating erythrocytes remains remarkably constant because of reflexes that regulate bone marrow’s production of these cells. – Too many RBCs causes blood viscosity. – Too few RBCs leads to tissue hypoxia. Erythropoiesis is hormonally controlled & depends on adequate supplies of: iron, vita B12 & folic acid – animal products, green vegetables, fruits, liver, meat. 7/24/2024 Blood Physiology 25  Tissue Oxygenation is the most essential regulator of Red Blood Cell production.  Conditions that decrease oxygen transported to the tissues ordinarily increase the rate of RBC production. Thus,  Anemia as a result of hemorrhage or any other condition,  Various diseases that decrease tissue blood flow, like prolonged cardiac failure and lung diseases  very high altitudes, where the quantity of oxygen in the air is greatly decreased. all these conditions cause low oxygen supply to tissue, stimulating the kidney for the secretion of Erythropoietin(EPO) 7/24/2024 Blood Physiology 26  Hormonal Control of Erythropoiesis Normally, about 90% of all EPO is formed in the kidneys, and the remainder is formed mainly in the liver EPO production by the kidneys is triggered by hypoxia due to: 1. Decreased RBCs count. 2. Decreased oxygen availability. 3. Increased tissue demand for oxygen. EPO stimulate the proliferation of erythrocyte progenitor cells and their differentiation into mature erythrocytes, which finally increase – Number of RBC in circulating blood and – Oxygen carrying capacity of the blood and restoring O 2 delivery to the tissues. 7/24/2024 Blood Physiology 27  Figure. Decreased oxygen delivery to the kidneys increases erythrocyte production via increased erythropoietin secretion 7/24/2024 Blood Physiology 28 7/24/2024 Blood Physiology 29  Hemoglobin Reversibly binds with most O2 in the blood. Composed of 4 protein globin chains of each bound to heme group, – each heme bears an atom of iron, which can bind to one O2 molecule. – each Hb molecule can transport 4 molecules of O2. 7/24/2024 Blood Physiology 30  Hemoglobin structure Fig. A hemoglobin molecule consists of four highly folded polypeptide chains and four iron- containing heme groups. In the lungs, hemoglobin picks up oxygen, which binds to the iron ions, forming oxyhemoglobin. The bright red, oxygenated hemoglobin travels to the body tissues, In the tissue, where it releases some of the oxygen molecules, becoming darker red deoxyhemoglobin, sometimes referred to as reduced hemoglobin. 7/24/2024 Blood Physiology 31  Fate & Destruction of Erythrocytes The life span of an erythrocyte is 100–120 days. Old erythrocytes become rigid and fragile, and their hemoglobin begins to degenerate. Dying erythrocytes are engulfed by macrophages. Heme & globin are separated & the iron is salvaged for reuse: – Heme : broken down into iron and bilirubin – Globin : a reusable protein 7/24/2024 Blood Physiology 32 7/24/2024 Blood Physiology 33 7/24/2024 Blood Physiology 34  Clinically important lab tests cont’d… Hemoglobin concentration (Hb) – amount of Hb in a given volume of blood (g/dl), important to diagnose anemia – vary according to age, gender & altitude.  Normal hemoglobin reference range (guideline figures) – Children ---» at birth = 13.5 - 19.5 g/dl 2 - 5 years = 11 - 14 g/dl 6 - 12years = 11.5 - 15.5 g/dl – Adult ------» men = 13 - 18 g/dl women (non pregnant) = 12 - 15 gm/dl pregnant women = 11 - 13.8 gm/dl  Hb level less than the lower cut off point is anemia. 7/24/2024 Blood Physiology 35  Clinically important lab tests cont’d… Packed cell volume (PCV)/ Hematocrit (Hct) Percentage of RBC in given volume of whole blood. Hct can be determined by centrifugation of anticoagulated blood within small capillary tube.  clinically significant to diagnosis anemia On average it is about 45% – in adult male: 39%- 54% – in adult women: 36%- 45% – pregnant women: 33% - 42% Approximately it is the hemoglobin value times 3 Hct below the lower cut off point indicates anemia. 7/24/2024 Blood Physiology 36 Fig. (a) Normal hematocrit. (b) The hematocrit is lower than normal in anemia, because of too few circulating erythrocytes; and (c) above normal in polycythemia, because of excess circulating erythrocytes. (d) The hematocrit can also be elevated in dehydration when the normal number of circulating erythrocytes is concentrated in a reduced plasma volume 7/24/2024 Blood Physiology 37  Clinically important lab tests cont’d… Complete blood count(CBC) is a more definitive test for blood disorders complete blood count ( full blood count), is part of a routine medical examination. The CBC includes the following tests,  red blood cell (RBC) count,  Hgb, and Hct,  RBC indices;  total white blood cell (WBC) count  differential WBC count;  platelet count and mean platelet volume  Usually done using an automated CBC counting Machine. 7/24/2024 Blood Physiology 38  Clinically important lab tests cont’d Erythrocyte sedimentation rate (ESR) ESR is the rate at which uncoagulated blood (RBC) settles down when allowed to stand in a tube. Erythrocytes have a slightly higher density than the suspending plasma, so that they slowly settle out of whole blood Caused by rouleaux formation- pilling of RBC like coins together This test is performed by placing anticoagulated blood in an upright tube (Westegren's or wintrobe’s tube), – at the end of some specific time(usaually 1hr), rate of RBC sedimentation is measured – High ESR indicate the present of inflammation. 7/24/2024 Blood Physiology 39  Erythrocyte sedimentation rate (ESR)… Reference range – adult females 0-20 mm/hr – adult males 0-15 mm/hr Increased ESR may be due to: – pregnancy, inflammation, cancer. Decreased ESR may be due to : – polycythemia, sickle cell anemia, hereditary spherocytosis, congestive heart failure. 7/24/2024 Blood Physiology 40  Clinically important lab tests cont’d… Osmotic fragility test(OFT)- a test to measure red blood cells (RBC) resistance to hemolysis when exposed to hypotonic solutions. Cells like RBC shrink or swell in solutions of osmotic pressure greater or less than that of normal plasma.  OFT measure the ability of erythrocytes to take up fluid without lysing. A 0.9% NaCl solution is isotonic with plasma. 7/24/2024 Blood Physiology 41  Osmotic fragility test... To maintain viable cells in vivo/vitro the cells must be suspended in a solution with an osmotic conc. relatively equal to their interior osmotic conc. RBC gets - swell then hemolyzed in hypotonic (0.9% NaCl) solution. – the sooner hemolysis occurs, the greater is osmotic fragility of RBC 7/24/2024 Blood Physiology 42 Cont’d When osmotic fragility test is normal, ― Hemolysis of normal RBC begins at saline conc. of 0.50 – 0.55% ― 50% RBC lyse( MCF) occur at saline conc. of 0.40%- 0.45% ― Complete hemolysis occur at saline conc. of < 0.35% 7/24/2024 Blood Physiology 43  Clinical significance of OFT Useful in diagnosis of different types of hereditary hemolytic anemia. Increased osmotic fragility – hereditary spherocytosis Decreased osmotic fragility – Thalassemia, sickle cell anemia, iron deficiency anemia 7/24/2024 Blood Physiology 44  Human Blood Groups/types Grouping depends on: presence/absence of antigens/ agglutinogens on surface of RBCs. Agglutinogens- protein present on the RBC membrane with antigenic effect(ability to cause the production of antibody against it or ability to bind specific antibody molecules ) Agglutinins/antibodies – are proteins produced against agglutinogens/antigen  Agglutination –reaction between these two Major blood groups are: – ABO blood group & Rh system 7/24/2024 Blood Physiology 45 ABO blood grouping/typing Two antigens(type A and type B) present on the surfaces of RBCs in a large proportion of human beings Karl Landsteiner's Law − If an antigen present on the RBC’s of an individual, the corresponding antibody must be absent from the plasma. − If an antigen is absent on the RBC’s of an individual, the corresponding antibody must be present in the plasma. Blood type Agglutinogen on RBC Agglutinin in plasma A A Anti-B B B Anti-A AB A and B None O None Anti- A and Anti B 7/24/2024 Blood Physiology 46  ABO Blood Group summary on the characteristics of the blood types in the ABO blood group. 7/24/2024 Blood Physiology 47  Importance of Knowing Blood groups For blood transfusion Hemolytic disease of the newborn Paternity dispute Susceptibility to various diseases(blood group O- peptic ulcer, group A –gastric cancer) 7/24/2024 Blood Physiology 48  Rh Factor (Rh blood group) It was first worked out on Rhesus monkey to the name Rh- system. individual grouped as Rh+ & Rh- based on + of agglutinogen D on the surface of RBCs:  Presence of agglutinogen D on RBCs = Rh+  Missing agglutinogen D on RBCs = Rh- Agglutinin (anti-D antibodies) are not normally present in the serum, – produced 2ry to exposure of Rh- blood to Rh+ blood (antigen-D). 7/24/2024 Blood Physiology 49  ABO/Rh blood grouping in Lab…. Report as  Slide1 A-, Slide 2 B+,  Slide 3 AB-, Slide 4 O+  Erythroblastosis Fetalis/HDFN Incompatibility of Rh blood groups b/n fetus & mother  Antibodies produced by Rh -- mother destroy RBCs of Rh+ fetus. occurs when Rh- mother marries Rh+ father & conceives Rh+ fetus. During delivery, there could be leakage of Rh+ blood from fetus to circulation of mother. – Rh+ blood induces production of anti-D antibodies in circulation of mother. During 2nd conception of Rh+ fetus, anti-D antibodies cross placenta & attack RBCs of fetus.(Rh incompatibility rxn occur) Most population in the world (85%) is Rh+ Treatment : Rho Gam injection after 1st birth blocks mother from forming anti-Rh antibody [Limits risk for subsequent births]. 7/24/2024 Blood Physiology 51  Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. – – – – ––– ––– – – – – – – – – – – –– – – –– – – – – – – – – – – – – – –– – –– – – – – – – – – – – – – – – –– – – –– – – – – – – – – – – –– – – –– – – – – – – – – – – – – – – –– – – – – –– – – – – – – –– – – – – – –– – – – – – – – – – – –– – – –– – –– – – –– – – – – – – ++ + – – – – – – – – – – – – ++ – – – – – – – – – – + – + – – – + – – – – + + + + – – – – – – + + + – + + + + – – – – – + + + – + – – + – + – – – + – + – – – – + – – + – – – – – – – – – Rh-negative Cells from Woman In the next woman with Rh-positive becomes Sensitized, Rh-positive Rh-positive fetus enter produce antibodies to pregnancy, woman’s fight Rh-positive maternal antibodies fetus bloodstream blood cells attack fetal RBCs 7/24/2024 Blood Physiology 52  Blood Transfusions Giving blood of one person to another when there is a need. It can be: 1. RBC/ Packed red cells transfusion cells with plasma removed, are used to treat anemia. 2. Platelet Transfusions Platelets stops the body from bleeding. Often patients suffering from leukemia, or other types of cancer, have lower platelet counts as a side effect of their chemotherapy treatments. 3. Plasma Transfusions Contains important proteins and other substances crucial to one’s overall health Used for patients with liver failure, severe infections, and serious burns. 7/24/2024 Blood Physiology 53 7/24/2024 Blood Physiology 54  Transfusion Reactions Occur when mismatched blood is infused. Donor blood cells are attacked by the recipient’s plasma: – Diminished oxygen-carrying capacity. – Clumped cells impede blood flow. – Ruptured RBCs release free hemoglobin into the bloodstream  Circulating Hg precipitates in kidneys & causes renal failure. Recipients Serum Donor's Cells A B AB O Compatibility b/n Recipient’s Serum Donor's Cells & A  Х  Х B Х   Х AB Х Х  Х O      = No Agglutination , Х = Agglutination [clumping of RBCs in the presence of antibody] 7/24/2024 Blood Physiology 55  Precautions to be taken while blood donation or transfusion Should be Health, Screened for – AIDS, viral Hepatitis, malaria, syphilis Age- 17- 60Yrs, weigh over 50kg Hg and PCV should be normal During transfusion- only compatible blood must be transfused. – Both major & minor cross matching of recipient & donor blood must be done.  Major - Donor’s RBC + Recipient plasma  Minor – Donor’s plasma +Recipient RBC Rh compatibility must be confirmed(Rh+ blood never be transfused to Rh –ve person) Contraindicated in pregnant and lactating mothers 7/24/2024 Blood Physiology 56  Leucocyte/WBCs 7/24/2024 Blood Physiol 57  Leucocyte/WBCs Play an important role in the immune system identifying, destroying, and removing pathogens, damaged cells, cancer cells, and foreign matter from the body. produced within bones by bone marrow and some then mature in the lymph nodes, spleen, or thymus gland. The only blood components that are complete cells. – contain nucleus, and other organelles Less numerous than RBCs and platelets. 7/24/2024 Blood Physiol 58  Leukocytes (WBCs)… WBC count : – Normal (4,000-11,000cell/mm3), Average (7,000 cell/mm3)  Decrease in WBC count = Leukopenia – A low WBC count may be due to disease, radiation exposure, or bone marrow deficiency  Increase in WBC count = Leukocytosis  a normal, protective response to bacterial or viral invasion. A high WBC count may indicate the presence of an infectious or inflammatory disease, leukemia, stress or tissue damage. 7/24/2024 Blood Physiology 59  Leukocytes (WBCs)… 1% of blood, but play vital role in the body’s immune system. defense against invading bacteria, viruses, fungi & parasites by: 1. Direct attack [phagocytosis]. – identifying invading organism as foreign, attaching & destroying. 2. Produce antibodies into circulating blood to target & attach to foreign organisms.  neutralize organism  elicit help from other immune system cells to destroy foreign substance. 7/24/2024 Blood Physiology 60  Leukocytes (White Blood Cells) Granular leukocytes Agranular leukocytes PMN-cells: Neutrophils Lymphocytes Eosinophils Monocytes Basophils WBC differential count  Neutrophils: 60-70% (62%), 3000-7000/mm3  Eosinophils: 1-4% (2.4%), 100-440/mm3  Basophils: 0.3-0.5% (0.4%), 20-50/mm3  Monocytes: 2-8% (5.3%), 100-700/mm3  Lymphocytes: 20-40% (30%), 1500-3500/mm3 7/24/2024 Blood Physiology 61  Characteristics of WBCs  Mobility: highly mobile & reach tissue fluids. Diapedesis – squeezing out of WBC b/n capillary endothelial cells in to interstitial space. Amoeboid motion – movement of WBC through tissue spaces by forming pseudopodia & reach microbes in tissues. Chemotaxis – attraction of WBC towards injured or inflamed/infected area by chemicals or toxins produced by the microbe or inflamed tissues.  Phagocytosis: engulfing & destroying microorganisms. 7/24/2024 Blood Physiology 62  Functions of WBCs 1. Neutrophils The most abundant(60-70%) & the first line of defense. Phagocytic cells (ingest bacteria or fungi), lysozome. High number indicates bacterial infection. 2. Monocytes The largest WBCs & highly phagocytic cells. High count may indicate viral/fungal infections, autoimmune disorder.  Leave circulation, enter tissue & differentiate into macrophages: 7/24/2024 Blood Physiology 63  The tissue macrophage system (reticuloendothelial system) Monocytes are formed in the bone marrow enter the circulation leave the circulation & enter the tissue ↑size, ↑lysosomal activities become tissue macrophages Lungs Skin Liver Brain Bone Spleen Alveolar Histocytic Kupffer Microglial Lymph nodes Osteoclastes macrophage cells cells cells reticular cells 7/24/2024 Blood Physiology 64  Functions of WBCs... 3. Basophils(least abundent) Liberate heparin, histamine & serotonin in allergic reactions that intensify overall inflammatory response. 4. Eosinophils Absorb histamine during allergic conditions so that lessen severity of allergies. Produce hydrolytic enzymes to kill big parasites. Increase in number during parasitic infection. – Eosinophilia 7/24/2024 Blood Physiology 65  Functions of WBCs... 5. Lymphocytes Are responsible for specific/ acquired immunity. Of 2 types; B and T lymphocytes An important cell class in the immune system that produces antibodies: – to attack infected & cancerous cells, and – to reject foreign tissue. 10-12µm Their number increases in viral infections. 7/24/2024 Blood Physiology 66 7/24/2024 Blood Physiology 67 FIGURE :Normal blood cellular elements and typical human blood cell count. 7/24/2024 Blood Physiology 68  Platelets Smallest fragment of cells in blood designed for coagulation – forming clot whenever Inactive platelets blood vessel is broken. As soon as artery/vein is injured, – platelets in area of injury begin to clump together & stick to edges of the cut. Active platelets 7/24/2024 Blood Physiology 69  General Characteristics Have granules which releases chemicals up on stimulation; – serotonin, thromboxane, ADP, Ca++, PDGF Contractile proteins actin & myosin help platelets to contract. Residuals of ; ER, Golgi apparatus , Mitochondria – synthesize enzymes, ATP & ADP Cell membrane has surface coat of glycoproteins : – repulses adherence to normal endothelium – adherence to injured endothelial cells (exposed collagen). Eliminated from circulation by tissue macrophage system. 7/24/2024 Blood Physiology 70  Hemostasis Process of forming clots in the walls of damaged blood vessels and preventing blood loss. Involves a series of reactions of plasma coagulation factors & substances released by platelets & injured tissues  Can be organized into four separate but interrelated events: 1. Compression and vasoconstriction; 2. Formation of a temporary loose platelet plug ( primary hemostasis); 3. Formation of the more stable fibrin clot ( secondary hemostasis), 4. Clot retraction and dissolution 7/24/2024 Blood Physiology 71 Hemostasis. The blood’s response to blood vessel injury can be viewed as four interrelated steps. 7/24/2024 Blood Physiology 72 Cont’d…. 7/24/2024 Blood Physiology 73  Vascular spasm Occurs immediately after blood vessel has ruptured. Local vasoconstriction that results from: 1. Local myogenic contraction of vascular wall. – trauma to vessel wall causes smooth muscle in the wall to contract, instantaneously reduces flow of blood from the ruptured vessel. 2. Vasoconstrictor chemicals released by damaged tissues (endothelin) & platelets([thromboxane A2, serotonin]. 3. Neuronal reflex initiated by pain nerve impulses. 7/24/2024 Blood Physiology 74  Platelet Plug Formation 1ry hemostasis, temporarily seals the break in the vessel wall. Injury to a vessel disrupts the endothelium and exposes the underlying connective-tissue collagen fibers. platelets adhere to collagen fibers with the help of adherence proteins (integrins) and large plasma protein (Von Willebrand Factor (VWF) VWF enhances platelet adhesion to the endothelium by forming a bridge b/n platelet surface receptors and collagen. When platelet binds injured endothelial cells & collagen they will undergo changes: – begins to swell, become sticky – contract forcefully to release multiple active factors(ADP, serotonin & thromboxane A2 ) Serotonin - vasoconstrictor ADP - attracts more platelets to the area Txa A2 - promotes platelet aggregation & vasoconstriction 7/24/2024 Blood Physiology 75  Mechanism of Platelet aggregation , positive feedback adhesion activation aggregation 7/24/2024 Blood Physiology 76 7/24/2024 Blood Physiology 77  Blood coagulation 2ry hemostasis , slow but long lasting effect to stop bleeding is the transformation of blood from a liquid form into a solid gel by fibrin. Formation of a clot on top of the platelet plug strengthens and supports the plug, reinforcing the seal over a break in a vessel. The fundamental reaction is conversion of the soluble plasma protein fibrinogen to insoluble fibrin by thrombin. Regulated by the sequential activation of coagulation factors in events called the coagulation cascade. 7/24/2024 Blood Physiology 78  Mechanism of blood coagulation More than 50 important substances that cause or prevent blood coagulation have been found in the blood and in the tissues. Factor that promote coagulation called procoagulants, and factor that inhibit coagulation, called anticoagulants. Coagulation depends on balance between these two groups of substances. Anticoagulants predominate in intact vessel, so the blood does not coagulate while its circulate in the blood vessels. When vessel is ruptured, procoagulant activity increases dramatically & clot formation begins. 7/24/2024 Blood Physiology 79  Clotting factor/procoagulant Numbered I - XIII according to order of their discovery. – hence the numerical order does not reflect the reaction sequence. Most of these factors are plasma proteins synthesized in the liver and circulate in inactive form in blood until mobilized. Vitamin K is not directly involved in coagulation, but required for synthesis of 4 procoagulants made by liver. (Factor II, VII, IX, X) 7/24/2024 Blood Physiology 80  0 7/24/2024 Blood Physiology 81  Coagulation is divided into two pathways that eventually merge into one. 1. An intrinsic pathway (Slower) begins when damage to the tissue exposes collagen. triggered by proteins already present in the plasma. – Trauma to blood or blood contact with damaged endothelium/collagen/testtube initiates intrinsic pathway, causing activation of Factor XII Factor XII activates factor XI which in turn activates factor IX , require high-molecular-weight kininogen and is accelerated by prekallikrein). Activated factor IX joins with factor VIII, Ca++, platelet phospholipids to activate factor X. 7/24/2024 Blood Physiology 82  2. An extrinsic pathway (faster) starts when damaged tissues releases a tissue factor or tissue thromboplastin(factor III). Tissue factor activates factor VII to begin the extrinsic pathway The lipoprotein complex of tissue factor further complexes with Factor VIIa to activate Factor X (Xa ).  requires ionic calcium The activated Factor X combines with Factor V, to form the complex called prothrombin activator in the presence of Ca++ and tissue/platelet phospholipids 7/24/2024 Blood Physiology 83 Common pathway The two pathways unite at the common pathway to create thrombin, the enzyme that converts fibrinogen into insoluble fibrin polymers. These fibrin fibers become part of the clot It is initiated by the conversion of inactive clotting factor X to its active form, factor Xa Activated factor X complexes with Ca++, platelet phospholipids & factor V to form prothrombin activator. – Process of forming prothrombin activator is the slowest step of blood clotting process. Prothrombin activator converts prothrombin to its active form thrombin. 7/24/2024 Blood Physiology 84  Common pathway … Thrombin is a protein enzyme that remove 4 peptides from fibrinogen forming insoluble fibrin monomer. Fibrin monomers spontaneously assemble into ordered fibrous arrays of fibrin strands forming a highly organized and firm network(web),  which traps more platelets, red blood cells, and leukocytes at the site of vascular damage, thereby forming a stable blood clot. A plasma enzyme, fibrin stabilizing factor (factor XIII), catalyzes the formation of covalent bonds b/n strands of polymerized fibrin, stabilizing and tightening the blood clot 7/24/2024 Blood Physiology 85 7/24/2024 Blood Physiology 86  Conversion of prothrombin to thrombin & polymerization of fibrin fibers 7/24/2024 Blood Physiology 87 7/24/2024 Blood Physiology 88  Clot retraction & repair Clot retraction Further stabilization of clot by squeezing serum from fibrin strands. after clot is formed, it begins to contract (platelets) & usually expresses most of fluid (serum) from the clot. as clot retracts, ruptured edges of the blood vessel slowly brought together again to repair the damage. 7/24/2024 Blood Physiology 89  Vessel Repair Once blood clot has formed it is invaded by fibroblasts (form a tissue patch). This is promoted partially by growth factor secreted by platelets Platelet derived growth factors(PDGF) stimulates smooth muscle cells, vascular endothelial cells & fibroblasts to divide & rebuild the wall. 7/24/2024 Blood Physiology 90  Clot dissolution Once the wall of damaged blood vessel is repaired, the blood clot is removed by lysis. Fibrinolysis removes unneeded clots when healing has occurred without fibrinolysis, blood vessels would gradually become completely blocked. fibrinolysis begins within 2 days & continues slowly over several days until the clot is finally dissolved. 7/24/2024 Blood Physiology 91  Plasmin cause clot dissolution Plasmin (fibrinolysin)“fibrin splitting” enzyme, dissolve the clot. Plasmin is a plasma protein produced by the liver and present in the blood in an inactive precursor form, plasminogen. Plasminogen activators include: – Factor XII (Hageman Factor), tissue plasminogen activator (tPA) from vascular endothelial cells & thrombin. Plasmin gets trapped in clot & slowly dissolves it by breaking down the fibrin meshwork. Phagocytic white blood cells gradually remove the products of clot dissolution. 7/24/2024 Blood Physiology 92  Fibrinolysis 7/24/2024 Blood Physiology 93  Prevention of unwanted intravascular clotting 1. Smoothness of endothelial cell surface – prevents contact activation of intrinsic clotting system 2. Layer of glycocalyx on vascular endothelium – repels platelets & clotting factors 3. Presence of thrombomodulin which binds thrombin – removes thrombin 4. Heparin – inactivate thrombin, IXa, Xa, XIa – activate other anticoagulants (anti-thrombin III) 5. Antithrombin III, inactivates thrombin and several other clotting factorsBlood Physiology 7/24/2024 94 6. Nitric oxide & prostacyclin – released by intact vascular endothelial cells, prevents platelet aggregation. 7. Plasmin /fibrinolysin break down fibrin into fibrinogen, lysis the clotted ones digest fibrin & other clotting factors (fibrinogen, prothrombin, V,VIII,XII) important in the blood to avoid occlusion 7/24/2024 Blood Physiology 95  Abnormal intravascular clotting Thromboembolic Conditions Thrombus – clot that develops & persists in uninjured blood vessel Thrombi can block flow in the circulation, resulting in tissue death & organ failure. Coronary thrombosis – thrombus in blood vessel of heart e.g. Myocardial infarction (heart attack) Embolus - thrombus (blood clot) freely floating in the blood Pulmonary emboli can impair the ability of the body to obtain oxygen. Cerebral emboli can cause strokes. 7/24/2024 Blood Physiology 96  Cause of Thromboembolic Conditions ; – A roughened endothelial surface of a vessel—as may be caused by arteriosclerosis, infection, or trauma – Sluggishness of blood flow. – Increase in viscosity of blood due to high platelet or high RBC count. – Widespread clotting is occasionally triggered by the release of tissue thromboplastin into the blood from large amounts of traumatized tissue.  Similar widespread clotting can occur in septicemia, in which bacteria or their toxins(endotoxin) initiate the clotting cascade 7/24/2024 Blood Physiology 97  Erythrocyte Disorders I. Anemia Insufficient Erythrocytes, decreased hemoglobin content. – blood has abnormally low O2 carrying capacity. Blood O2 levels can not support normal metabolism. II. Polycythemia Excess RBCs production, of 2 types: 1. Primary polycythemia (polycythemia Vera) – bone marrow abnormality. 2. Secondary polycythemia – mostly physiologic, 2ry to hypoxia (higher altitude, EPO) 7/24/2024 Blood Physiology 98  Leukocytes Disorders I. Leukemia Abnormal increase of white blood cells. Cancerous conditions causing proliferation of immature WBCs II. Leukopenia (leukocytopenia) Decrease number of WBCs (leukocytes), which places individuals at increased risk of infection. 7/24/2024 Blood Physiology 99  Bleeding disorders Inability to synthesize procoagulants (clotting factors) by liver results in severe bleeding disorders. Bleeding can be caused by:  Hepatitis/cirrhosis  Vitamin K deficiency  Hemophilia  Thrombocytopenia (platelet deficiency)  purpura 7/24/2024 Blood Physiology 100 7/24/2024 Blood Physiology 101