Blood Overview of Blood Circulation Blood leaves the

Blood

Overview of Blood Circulation Blood leaves the heart via arteries that branch repeatedly until they become capillaries n Oxygen (O 2) and nutrients diffuse across capillary walls and enter tissues n Carbon dioxide (CO 2) and wastes move from tissues into the blood n

Overview of Blood Circulation Oxygen-deficient blood leaves the capillaries and flows in veins to the heart n This blood flows to the lungs where it releases CO 2 and picks up O 2 n The oxygen-rich blood returns to the heart n

Composition of Blood is a connective fluid tissue n It is composed of liquid plasma and formed elements n Formed elements include: n ¨ Erythrocytes, or red blood cells (RBCs) ¨ Leukocytes, or white blood cells (WBCs) ¨ Platelets n Hematocrit – the percentage of RBCs out of the total blood volume

Components of Whole Blood

Physical Characteristics and Volume Blood is a sticky, opaque fluid with a metallic taste n Color varies from scarlet to dark red n The p. H of blood is 7. 35– 7. 45 n Temperature is 38 C n Blood accounts for approximately 8% of body weight n Average volume: 5– 6 L for males, and 4– 5 L for females n

Functions of Blood n Blood performs a number of functions dealing with: ¨ Substance distribution ¨ Regulation of blood levels of particular substances ¨ Body protection

Distribution n Blood transports: ¨ Oxygen from the lungs and nutrients from the digestive tract ¨ Metabolic wastes from cells to the lungs and kidneys for elimination ¨ Hormones from endocrine glands to target organs

Regulation n Blood maintains: ¨ Appropriate body temperature by absorbing and distributing heat ¨ Normal p. H in body tissues using buffer systems ¨ Adequate fluid volume in the circulatory system

Protection n Blood prevents blood loss by: ¨ Activating plasma proteins and platelets ¨ Initiating clot formation when a vessel is broken n Blood prevents infection by: ¨ Activating complement proteins ¨ Activating WBCs to defend the body against foreign invaders

Blood Plasma n Blood plasma contains over 100 solutes, including: ¨ Proteins – albumin, globulins, clotting proteins, and others ¨ Lactic acid, urea, creatinine ¨ Organic nutrients – glucose, carbohydrates, amino acids ¨ Electrolytes – sodium, potassium, calcium, chloride, bicarbonate ¨ Respiratory gases – oxygen and carbon dioxide

Formed Elements n Erythrocytes, leukocytes, and platelets make up the formed elements ¨ Only WBCs are complete cells ¨ RBCs have no nuclei or organelles, and platelets are just cell fragments Most formed elements survive in the bloodstream for only a few days n Most blood cells do not divide but are renewed by cells in bone marrow n

Components of Whole Blood

Erythrocytes (RBCs) Biconcave discs, anucleate, essentially no organelles n Filled with hemoglobin (Hb), a protein that functions in gas transport n Contain the plasma membrane protein spectrin and other proteins that: n ¨ Give erythrocytes their flexibility ¨ Allow them to change shape as necessary

Erythrocytes (RBCs)

Erythrocytes (RBCs) Erythrocytes are an example of the complementarity of structure and function n Structural characteristics contribute to its gas transport function n ¨ Biconcave shape has a huge surface area relative to volume ¨ Erythrocytes are more than 97% hemoglobin ¨ ATP is generated anaerobically, so the erythrocytes do not consume the oxygen they transport

Erythrocyte Function n n RBCs are dedicated to respiratory gas transport Hb reversibly binds with oxygen and most oxygen in the blood is bound to Hb Hb is composed of the protein globin, made up of two alpha and two beta chains, each bound to a heme group Each heme group bears an atom of iron, which can bind to one oxygen molecule Each Hb molecule can transport four molecules of oxygen

Structure of Hemoglobin

Hemoglobin (Hb) n Oxyhemoglobin – Hb bound to oxygen ¨ Oxygen loading takes place in the lungs Deoxyhemoglobin – Hb after oxygen diffuses into tissues (reduced Hb) n Carbaminohemoglobin – Hb bound to carbon dioxide n ¨ It binds to globin’s amino acids ¨ Carbon dioxide loading takes place in the tissues

Production of Erythrocytes Hematopoiesis – blood cell formation n Hematopoiesis occurs in the red bone marrow of the: n ¨ Axial skeleton and girdles ¨ Epiphyses of the humerus and femur n Hemocytoblasts give rise to all formed elements

Production of Erythrocytes: Erythropoiesis A hemocytoblast is transformed into a proerythroblast n Proerythroblasts develop into early erythroblasts n

Production of Erythrocytes: Erythropoiesis n n The developmental pathway consists of three phases ¨ 1 – ribosome synthesis in early erythroblasts ¨ 2 – Hb accumulation in late erythroblasts and normoblasts ¨ 3 – ejection of the nucleus from normoblasts and formation of reticulocytes Reticulocytes then become mature erythrocytes ¨ 1 -2% of RBC in health people

Production of Erythrocytes: Erythropoiesis

Regulation and Requirements for Erythropoiesis n Circulating erythrocytes – the number remains constant and reflects a balance between RBC production and destruction ¨ Too few RBCs leads to tissue hypoxia ¨ Too many RBCs causes undesirable blood viscosity n Erythropoiesis is hormonally controlled and depends on adequate supplies of iron, amino acids, and B vitamins

Hormonal Control of Erythropoiesis n Erythropoietin (EPO) release by the kidneys is triggered by: ¨ Hypoxia due to decreased RBCs or hemoglobin content ¨ Decreased oxygen availability ¨ Increased tissue demand for oxygen n Enhanced erythropoiesis increases the: ¨ RBC count in circulating blood ¨ Oxygen carrying ability of the blood

Erythropoietin Mechanism Start Homeostasis: Normal blood oxygen levels Stimulus: Hypoxia due to decreased RBC count, decreased amount of hemoglobin, or decreased availability of O 2 Increases O 2 -carrying ability of blood Reduces O 2 levels in blood Enhanced erythropoiesis increases RBC count Erythropoietin stimulates red bone marrow Kidney (and liver to a smaller extent) releases erythropoietin

Dietary Requirements of Erythropoiesis n n Erythropoiesis requires: ¨ Proteins, lipids, and carbohydrates ¨ Iron, vitamin B 12, and folic acid The body stores iron in Hb (65%), the liver, spleen, and bone marrow Intracellular iron is stored in protein-iron complexes such as ferritin and hemosiderin Circulating iron is loosely bound to the transport protein transferrin

Fate and Destruction of Erythrocytes The life span of an erythrocyte is 100– 120 days n Old RBCs become rigid and fragile, and their Hb begins to degenerate n Dying RBCs are engulfed by macrophages n Heme and globin are separated and the iron is salvaged for reuse n

Fate and Destruction of Erythrocytes Heme is degraded to a green pigment biliverdin n Biliverdin is converted to a yellow pigment called bilirubin n The bilirubin is picked up by the liver and secreted into the intestines as bile n

Fate and Destruction of Erythrocytes The intestines metabolize it into urobilinogen and stercobilinogen n These degraded pigments leave the body in feces and urine, in a pigment called stercobilin and urobilin n

Fate and Destruction of Erythrocytes Globin is metabolized into amino acids and is released into the circulation n Hb released into the blood is captured by haptoglobin and phagocytized n

Low O 2 levels in blood stimulate kidneys to produce erythropoietin. 1 2 3 Erythropoietin levels rise in blood. Erythropoietin and necessary raw materials in blood promote erythropoiesis in red bone marrow. 4 5 Aged and damaged red blood cells are engulfed by macrophages of liver, spleen, and bone marrow; the hemoglobin is broken down. Hemoglobin New erythrocytes enter bloodstream; function about 120 days.

1 Low O 2 levels in blood stimulate kidneys to produce erythropoietin. 2 Erythropoietin levels rise in blood. 3 Erythropoietin and necessary raw materials in blood promote erythropoiesis in red bone marrow. 4 New erythrocytes enter bloodstream; function about 120 days. 5 Aged and damaged red blood cells are engulfed by macrophages of liver, spleen, and bone marrow; the hemoglobin is broken down. Hemoglobin Heme Globin Bilirubin Iron stored as ferritin, hemosiderin Amino acids Iron is bound to transferrin and released to blood from liver as needed for erythropoiesis Bilirubin is picked up from blood by liver, secreted into intestine in bile, metabolized to stercobilin by bacteria and excreted in feces Circulation Food nutrients, including amino acids, Fe, B 12, and folic acid are absorbed from intestine and enter blood 6 Raw materials are made available in blood for erythrocyte synthesis.

Erythrocyte Disorders n n Anemia Low RBC count or Hemoglobin content ¨Low oxygen-carrying capacity ¨It is a symptom rather than a disease itself ¨Blood oxygen levels cannot support normal metabolism ¨Signs/symptoms include fatigue, paleness, shortness of breath, and chills

Anemia: Insufficient Erythrocytes Hemorrhagic anemia – result of acute or chronic loss of blood n Hemolytic anemia – prematurely ruptured RBCs n Aplastic anemia – destruction or inhibition of red bone marrow n

Anemia: Decreased Hemoglobin Content n n n Iron-deficiency anemia results from: ¨ A secondary result of hemorrhagic anemia ¨ Inadequate intake of iron-containing foods ¨ Impaired iron absorption Pernicious anemia results from: ¨ Deficiency of vitamin B 12 ¨ Lack of intrinsic factor needed for absorption of B 12 Treatment is intramuscular injection of B 12

Anemia: Abnormal Hemoglobin n Thalassemias – absent or faulty globin chain in Hb ¨ RBCs n are thin, delicate, and deficient in Hb Sickle-cell anemia – results from a defective gene coding for an abnormal Hb called hemoglobin S (Hb. S) ¨ Hb. S has a single amino acid substitution in the beta chain ¨ This defect causes RBCs to become sickleshaped in low oxygen situations

Polycythemia – excess RBCs that increase blood viscosity n Three main polycythemias are: n ¨ Polycythemia vera ¨ Secondary polycythemia ¨ Blood doping

Leukocytes (WBCs) n Leukocytes, the only blood components that are complete cells: ¨ Are less numerous than RBCs ¨ Make up 1% of the total blood volume ¨ Can leave capillaries via diapedesis ¨ Move through tissue spaces

Leukocytes (WBCs) n Leukocytosis – WBC count over 11, 000 / mm 3 ¨ Normal response to bacterial or viral invasion n Leukopenia – WBC count under 4, 000/mm 3

Percentages of Leukocytes

Granulocytes n Granulocytes – neutrophils, eosinophils, and basophils ¨ Contain cytoplasmic granules that stain specifically (acidic, basic, or both) with Wright’s stain ¨ Are larger and usually shorter-lived than RBCs ¨ Have lobed nuclei ¨ Are all phagocytic cells

Neutrophils n Neutrophils have two types of granules that: ¨ Take up both acidic and basic dyes ¨ Give the cytoplasm a lilac color ¨ Contain peroxidases, hydrolytic enzymes, and defensins (antibiotic-like proteins) n Neutrophils are our body’s bacteria slayers ¨ Respiratory burst – by metabolizing oxygen they produce substances that pierce holes in the germ’s membrane

Eosinophils n Eosinophils account for 1– 4% of WBCs ¨ Have red-staining, bilobed nuclei connected via a broad band of nuclear material ¨ Have red to crimson (acidophilic) large, coarse, lysosome-like granules ¨ Lead the body’s counterattack against parasitic worms ¨ Lessen the severity of allergies by phagocytizing immune complexes

Basophils n Account for 0. 5% of WBCs and: ¨ Have U- or S-shaped nuclei with two or three conspicuous constrictions ¨ Have large, purplish-black (basophilic) granules that contain histamine n Histamine – inflammatory chemical that acts as a vasodilator and attracts other WBCs (antihistamines counter this effect) ¨ Mast cells n Are functionally similar to basophils

Agranulocytes n Agranulocytes – lymphocytes and monocytes: ¨ Lack visible cytoplasmic granules ¨ Are similar structurally, but are functionally distinct and unrelated cell types ¨ Have spherical (lymphocytes) or kidneyshaped (monocytes) nuclei

Lymphocytes n Account for 25% or more of WBCs and: ¨ Have large, dark-purple, circular nuclei with a thin rim of blue cytoplasm ¨ Are found mostly enmeshed in lymphoid tissue (some circulate in the blood) n There are two types of lymphocytes: T cells and B cells ¨T cells function in the immune response ¨ B cells give rise to plasma cells, which produce antibodies

Monocytes n Monocytes account for 4– 8% of leukocytes ¨ They are the largest leukocytes ¨ They have abundant pale-blue cytoplasms ¨ They have purple-staining, U- or kidneyshaped nuclei ¨ They leave the circulation, enter tissue, and differentiate into macrophages

Macrophages n Macrophages: ¨ Are highly mobile and actively phagocytic ¨ Activate lymphocytes to mount an immune response

Leukocytes

Summary of Formed Elements 51

Summary of Formed Elements 52

Production of Leukocytes n Leukopoiesis is stimulated by interleukins and colony-stimulating factors (CSFs) ¨ Interleukins are numbered (e. g. , IL-1, IL-2), whereas CSFs are named for the WBCs they stimulate (e. g. , granulocyte-CSF stimulates granulocytes) Macrophages and T cells are the most important sources of cytokines n Many hematopoietic hormones are used clinically to stimulate bone marrow n

Formation of Leukocytes All leukocytes originate from hemocytoblasts n Hemocytoblasts differentiate into myeloid stem cells and lymphoid stem cells n Myeloid stem cells become eosinophilic, basophilic and neutrophilic myeloblasts or monoblasts n Lymphoid stem cells become lymphoblasts n

Formation of Leukocytes The myeloblasts develop into eosinophils, neutrophils, and basophils n Monoblasts develop into monocytes n Lymphoblasts develop into lymphocytes n

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Leukocytes Disorders: Leukemias n n Leukemia refers to cancerous conditions involving WBCs Leukemias are named according to the abnormal WBCs involved ¨ Myelocytic leukemia – involves myeloblasts ¨ Lymphocytic leukemia – involves lymphocytes Acute leukemia involves blast-type cells and primarily affects children Chronic leukemia is more prevalent in older people

Leukemia n n n Immature WBCs are found in the bloodstream in all leukemias Bone marrow becomes totally occupied with cancerous leukocytes The WBCs produced, though numerous, are not functional Death is caused by internal hemorrhage and overwhelming infections Treatments include irradiation, antileukemic drugs, and bone marrow transplants

Platelets n n Platelets are fragments of megakaryocytes with a blue-staining outer region and a purple granular center Their granules contain serotonin, Ca 2+, enzymes, ADP, and platelet-derived growth factor (PDGF) Platelets function in the clotting mechanism by forming a temporary plug that helps seal breaks in blood vessels Platelets not involved in clotting are kept inactive by NO and prostacyclin

Genesis of Platelets The stem cell for platelets is the hemocytoblast n The sequential developmental pathway is as shown. n Stem cell Hemocytoblast Developmental pathway Megakaryoblast Promegakaryocyte Megakaryocyte Platelets

Hemostasis A series of reactions for stoppage of bleeding n During hemostasis, three phases occur in rapid sequence n ¨ Vascular spasms – immediate vasoconstriction in response to injury ¨ Platelet plug formation ¨ Coagulation (blood clotting)

Hemostasis n Vascular spasms because of: ¨ Direct injury to the smooth muscle layer of the blood vessel ¨ Chemicals released by the platelet and endothelial cells ¨ Reflexes initiated by local pain receptors

Hemostasis n n n Platelet Plug Formation Platelets do not stick to each other or to blood vessels in normal conditions Upon damage to blood vessel endothelium the exposed collagen will cause platelets to swell and become sticky : ¨ With the help of von Willebrand factor (VWF) secreted by the endothelial cells. ¨ Stick to exposed collagen fibers and form a platelet plug

Hemostasis ¨ Release n serotonin and ADP, which attract still more platelets and promote vascular spam ¨ Release thromboxane A 2 that promotes further platelet aggregation The platelet plug is limited to the immediate area of injury by prostacyclin secreted by endothelial cells

Hemostasis n n n Coagulation A set of reactions in which blood is transformed from a liquid to a gel Coagulation follows intrinsic and extrinsic pathways

Coagulation

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Detailed Events of Coagulation

Coagulation n May be initiated by either the intrinsic or extrinsic pathway ¨ Triggered by tissue-damaging events ¨ Involves a series of procoagulants ¨ Each pathway cascades toward factor X

Coagulation Prothrombin is transformed into thrombin n Thrombin converts fibrinogen into fibrin n Fibrin becomes part of the clot n ¨ It causes plasma to become a gel-like trap

Clot Retraction and Repair Clot retraction – stabilization of the clot by squeezing serum from the fibrin strands n Restoration of the blood vessel wall n ¨ Platelet will stimulate n smooth muscle cells mitosis n fibroblast multiplication n endothelial cells division

Fibrinolysis n n The process of removal of clots after healing has occurred Plasminogen is activated by ¨ Tissue plasminogen activator (t. PA) released by many tissues ¨ Thrombin Plasminogen is converted into plasmin Plasmin will then digest the clot

Factors Limiting Clot Growth or Formation n Two homeostatic mechanisms prevent clots from becoming large ¨ Blood flow n Wash away activated clotting factors n Hinder further grow of forming clot

Factors Limiting Clot Growth or Formation ¨ Mechanisms that prevents thrombin action n Fibrin binds thrombin preventing its: ¨Positive feedback effects of coagulation n Fast inactivation of thrombin that escapes into blood circulation by: ¨Antithrombin III

Prevention of clotting in the normal vascular system The presence of a smooth and intact endothelial surface n The presence of circulating antithrombin factors n ¨ Antithrombin III n also inhibits steps of the intrinsic pathway ¨ Protein C n inhibits steps of the intrinsic pathway

Prevention of clotting in the normal vascular system n n Heparin ¨ increases the action of antithrombin III Vitamin E n a potent anticoagulant

Hemostasis Disorders: Thromboembolytic Conditions n Thrombus – a clot that develops and persists in an unbroken blood vessel ¨ Thrombi can block circulation, resulting in tissue death ¨ Coronary thrombosis – thrombus in blood vessel of the heart

Hemostasis Disorders: Thromboembolytic Conditions n 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

Prevention of Undesirable Clots n Substances used to prevent undesirable clots: ¨ Aspirin – an antiprostaglandin that inhibits thromboxane A 2 ¨ Heparin – an anticoagulant used clinically for pre- and postoperative cardiac care ¨ Warfarin – competes with vitamin K in the production of some procoagulants

Hemostasis Disorders Disseminated Intravascular Coagulation (DIC): widespread clotting in intact blood vessels n Residual blood cannot clot n Blockage of blood flow and severe bleeding follows n Most common as: n ¨A complication of pregnancy ¨ A result of septicemia or incompatible blood transfusions

Hemostasis Disorders: Bleeding Disorders n Thrombocytopenia – condition where the number of circulating platelets is deficient ¨ Patients show petechiae due to spontaneous, widespread hemorrhage ¨ Caused by suppression or destruction of bone marrow (e. g. , malignancy, radiation) ¨ Platelet counts less than 50, 000/mm 3 is diagnostic for this condition ¨ Treated with whole blood transfusions

Hemostasis Disorders: Bleeding Disorders n n Inability to synthesize procoagulants by the liver results in severe bleeding disorders Causes can range from vitamin K deficiency to hepatitis and cirrhosis Inability to absorb fat can lead to vitamin K deficiencies as it is a fat-soluble substance and is absorbed along with fat Liver disease can also prevent the liver from producing bile, which is required for fat and vitamin K absorption

Hemostasis Disorders: Bleeding Disorders n Hemophilias – hereditary bleeding disorders caused by lack of clotting factors ¨ Hemophilia A – most common type (83% of all cases) due to a deficiency of factor VIII ¨ Hemophilia B – due to a deficiency of factor IX ¨ Hemophilia C – mild type, due to a deficiency of factor XI

Hemostasis Disorders: Bleeding Disorders Symptoms include prolonged bleeding and painful and disabled joints n Treatment is with blood transfusions and the injection of missing factors n

Blood Transfusions n Whole blood transfusions are used: ¨ When blood loss is substantial ¨ In treating thrombocytopenia n Packed red cells (cells with plasma removed) are used to treat anemia

Human Blood Groups RBC membranes have glycoprotein antigens on their external surfaces n These antigens are: n ¨ Unique to the individual ¨ Recognized as foreign if transfused into another individual ¨ Promoters of agglutination and are referred to as agglutinogens n Presence or absence of these antigens is used to classify blood groups

Blood Groups Humans have 30 varieties of naturally occurring RBC antigens n The antigens of the ABO and Rh blood groups cause vigorous transfusion reactions when they are improperly transfused n Other blood groups (M, N, Dufy, Kell, and Lewis) are mainly used for legalities n

ABO Blood Groups n The ABO blood groups consists of: ¨ Two antigens (A and B) on the surface of the RBCs ¨ Two antibodies in the plasma (anti-A and anti-B) ABO blood groups may have various types of antigens and preformed antibodies n Agglutinogens and their corresponding antibodies cannot be mixed without serious hemolytic reactions n

ABO Blood Groups

Rh Blood Groups There are eight different Rh agglutinogens, three of which (C, D, and E) are common n Presence of the Rh agglutinogens on RBCs is indicated as Rh+ n Anti-Rh antibodies are not spontaneously formed in Rh– individuals n However, if an Rh– individual receives Rh+ blood, anti-Rh antibodies form n A second exposure to Rh+ blood will result in a typical transfusion reaction n

Hemolytic Disease of the Newborn Hemolytic disease of the newborn – Rh+ antibodies of a sensitized Rh– mother cross the placenta and attack and destroy the RBCs of an Rh+ baby n Rh– mother becomes sensitized when exposure to Rh+ blood causes her body to synthesize Rh+ antibodies n

Hemolytic Disease of the Newborn The drug Rho. GAM can prevent the Rh– mother from becoming sensitized n Treatment of hemolytic disease of the newborn involves pre-birth transfusions and exchange transfusions after birth n

Transfusion Reactions Transfusion reactions occur when mismatched blood is infused n Donor’s cells are attacked by the recipient’s plasma agglutinins causing: n ¨ Diminished oxygen-carrying capacity ¨ Clumped cells that impede blood flow ¨ Ruptured RBCs that release free hemoglobin into the bloodstream

Transfusion Reactions n Circulating hemoglobin precipitates in the kidneys and causes renal failure

Blood Typing When serum containing anti-A or anti-B agglutinins is added to blood, agglutination will occur between the agglutinin and the corresponding agglutinogens n Positive reactions indicate agglutination n

Blood Typing Blood type being tested RBC agglutinogens Serum Reaction Anti-A Anti-B AB A and B + + B B – + A A + – O None – –

Plasma Volume Expanders When shock is imminent from low blood volume, volume must be replaced n Plasma or plasma expanders can be administered n

Plasma Volume Expanders n Plasma expanders ¨ Have osmotic properties that directly increase fluid volume ¨ Are used when plasma is not available ¨ Examples: purified human serum albumin, plasminate, and dextran n Isotonic saline can also be used to replace lost blood volume

Diagnostic Blood Tests Laboratory examination of blood can assess an individual’s state of health n Microscopic examination: n ¨ Variations in size and shape of RBCs – predictions of anemias ¨ Type and number of WBCs – diagnostic of various diseases n Chemical analysis can provide a comprehensive picture of one’s general health status in relation to normal values

Developmental Aspects Before birth, blood cell formation takes place in the fetal yolk sac, liver, and spleen n By the seventh month, red bone marrow is the primary hematopoietic area n Blood cells develop from mesenchymal cells called blood islands n The fetus forms Hb. F, which has a higher affinity for oxygen than adult hemoglobin n

Developmental Aspects Age-related blood problems result from disorders of the heart, blood vessels, and the immune system n Increased leukemias are thought to be due to the waning deficiency of the immune system n Abnormal thrombus and embolus formation reflects the progress of atherosclerosis n