Chapter Notes for Lecture: E.N. Marieb, HUMAN ANATOMY & PHYSIOLOGY,5^TH Edition, , Benjamine Cummings Publisher, 2001

Prepare from : V.A. Austin’s PowerPpoint Presentation (ISBN: 0-8053-5469-7), CD ROM: Pearson Education, Inc. , 2003.ter 19

Blood

Overview of Blood Circulation

• Blood leaves the heart via arteries that branch repeatedly until they become capillaries

• Oxygen (O₂) and nutrients diffuse across capillary walls and enter tissues

• Carbon dioxide (CO₂) and wastes move from tissues into the blood

• Oxygen-deficient blood leaves the capillaries and flows in veins to the heart

• This blood flows to the lungs where it releases CO₂ and picks up O₂

• The oxygen-rich blood returns to the heart

Composition of Blood

• Blood is the body’s only fluid tissue

• It is composed of liquid plasma and formed elements

• Formed elements include:

• Erythrocytes, or red blood cells (RBCs)

• Leukocytes, or white blood cells (WBCs)

• Platelets

• Hematocrit – the percentage of RBCs out of the total blood volume

Physical Characteristics and Volume

• Blood is a sticky, opaque fluid with a metallic taste

• Color varies from scarlet (oxygen-rich) to dark red (oxygen-poor)

• The pH of blood is 7.35–7.45

• Temperature is 38°C, slightly higher than “normal” body temperature

• Blood accounts for approximately 8% of body weight

• Average volume of blood is 5–6 L for males, and 4–5 L for females

Functions of Blood

• Blood performs a number of functions dealing with:

• Substance distribution

• Regulation of blood levels of particular substances

• Body protection

Distribution

• 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

• Blood maintains:

• Appropriate body temperature by absorbing and distributing heat

• Normal pH in body tissues using buffer systems

• Adequate fluid volume in the circulatory system

Protection

• Blood prevents blood loss by:

• Activating plasma proteins and platelets

• Initiating clot formation when a vessel is broken

• Blood prevents infection by:

• Synthesizing and utilizing antibodies

• Activating complement proteins

• Activating WBCs to defend the body against foreign invaders

Blood Plasma

• Blood plasma contains over 100 solutes, including:

• Proteins – albumin, globulins, clotting proteins, and others

• Nonprotein nitrogenous substances – lactic acid, urea, creatinine

• Organic nutrients – glucose, carbohydrates, amino acids

• Electrolytes – sodium, potassium, calcium, chloride, bicarbonate

• Respiratory gases – oxygen and carbon dioxide

Formed Elements

• 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

• Most blood cells do not divide but are renewed by cells in bone marrow

Erythrocytes (RBCs)

• Biconcave discs, anucleate, essentially no organelles

• Filled with hemoglobin (Hb), a protein that functions in gas transport

• Contain the plasma membrane protein spectrin that:

• Gives erythrocytes their flexibility

• Allows them to change shape as necessary

• Erythrocytes are an example of the complementarity of structure and function

• Structural characteristics that contribute to its gas transport function are:

• Biconcave shape that has a huge surface area to volume ratio

• Discounting water content, erythrocytes are 97% hemoglobin

• ATP is generated anaerobically, so the erythrocytes do not consume the oxygen they transport

Erythrocyte Function

• Erythrocytes are dedicated to respiratory gas transport

• Hemoglobin reversibly binds with oxygen and most oxygen in the blood is bound to hemoglobin

• Hemoglobin 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 one to oxygen molecule

• Each hemoglobin molecule can transport four molecules of oxygen

Hemoglobin (Hb)

• Oxyhemoglobin – hemoglobin bound to oxygen

• Oxygen loading takes place in the lungs

• Deoxyhemoglobin – hemoglobin after oxygen diffuses into tissues (reduced Hb)

• Carbaminohemoglobin – hemoglobin bound to carbon dioxide

• Carbon dioxide loading takes place in the tissues

Production of Blood Cells

• Hematopoiesis – blood cell formation

• Hemopoiesis occurs in the red bone marrow of the:

• Axial skeleton and girdles

• Epiphyses of the humerus and femur

• Hemocytoblasts give rise to all formed elements

Production of Erythrocytes: Erythropoiesis

• A hemocytoblast is transformed into a committed cell called the proerythroblast

• Proerythroblasts develop into early erythroblasts

• The developmental pathway consists of three phases

• Phase 1 – ribosome synthesis in early erythroblasts

• Phase 2 – hemoglobin accumulation in late erythroblasts and normoblasts

• Phase 3 – ejection of the nucleus from normoblasts and formation of reticulocytes

• Reticulocytes then become mature erythrocytes

• Circulating erythrocytes – the number remains constant and reflects a balance between RBC production and destruction

• Too few red blood cells leads to tissue hypoxia

• Too many red blood cells causes undesirable blood viscosity

• Erythropoiesis is hormonally controlled and depends on adequate supplies of iron, amino acids, and B vitamins

Hormonal Control of Erythropoiesis

• Erythropoietin (EPO) release by the kidneys is triggered by:

• Hypoxia due to decreased RBCs

• Decreased oxygen availability

• Increased tissue demand for oxygen

• Enhanced erythropoiesis increases the:

• RBC count in circulating blood

• Oxygen carrying ability of the blood increases

Erythropoiesis: Nutrient Requirements

• Erythropoiesis requires:

• Proteins, lipids, and carbohydrates

• Iron, vitamin B₁₂, 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

• Old erythrocytes become rigid and fragile, and their hemoglobin begins to degenerate

• Dying erythrocytes are engulfed by macrophages

• Heme and globin are separated and the iron is salvaged for reuse

Fate of Hemoglobin

• Heme is degraded to a yellow pigment called bilirubin

• The liver secretes bilirubin into the intestines as bile

• The intestines metabolize it into urobilinogen

• This degraded pigment leaves the body in feces, in a pigment called stercobilin

• Globin is metabolized into amino acids and is released into the circulation

Life Cycle of Red Blood Cells

Erythrocyte Disorders

• Anemia – blood has abnormally 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

• Hemolytic anemia – prematurely ruptured erythrocytes

• Aplastic anemia – destruction or inhibition of red bone marrow

Anemia: Decreased Hemoglobin Content

• 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 B₁₂

_• Often caused by lack of intrinsic factor needed for absorption of B₁₂

Anemia: Abnormal Hemoglobin

• Thalassemias – absent or faulty globin chain in hemoglobin

• Erythrocytes are thin, delicate, and deficient in hemoglobin

• Sickle-cell anemia – results from a defective gene coding for an abnormal hemoglobin called hemoglobin S (HbS)

• HbS has a single amino acid substitution in the beta chain

• This defect causes RBCs to become sickle-shaped in low oxygen situations

Polycythemia

• Polycythemia – excess RBCs that increase blood viscosity

• Three main polycythemias are:

• Polycythemia vera

• Secondary polycythemia

• Blood doping

Leukocytes (WBCs)

• 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

• Leukocytosis – WBC count over 11,000 per cubic millimeter

• Normal response to bacterial or viral invasion

Classification of Leukocytes: Granulocytes

• 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

• 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)

• Neutrophils are our body’s bacterial slayers

Eosinophils

• Eosinophils account for 1–4% of WBCs

• Have red-staining, bi-lobed 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

• Account for 0.5% of WBCs and:

• Have U- or S-shaped nuclei with two or three conspicuous constrictions

• Are functionally similar to mast cells

• Have large, purplish-black (basophilic) granules that contain histamine

• Histamine – inflammatory chemical that acts as a vasodilator and attracts other WBCs

Agranulocytes

• Agranulocytes – lymphocytes and monocytes:

• Lack visible cytoplasmic granules

• Are similar structurally, but are functionally distinct and unrelated cell types

• Have spherical (lymphocytes) or kidney-shaped (monocytes) nuclei

Lymphocytes

• Have large, dark-purple, circular nuclei with a thin rim of blue cytoplasm

• Found mostly enmeshed in lymphoid tissue (some circulate in the blood)

• 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

• Monocytes account for 4–8% of leukocytes

• They are the largest leukocytes

• They have abundant pale-blue cytoplasms

• They have purple staining, U- or kidney-shaped nuclei

• They leave the circulation, enter tissue, and differentiate into macrophages

• Macrophages:

• Are highly mobile and actively phagocytic

• Activate lymphocytes to mount an immune response

Production of Leukocytes

• Leukopoiesis is hormonally stimulated by two families of cytokines (hematopoetic factors) – 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

• Many hematopoietic hormones are used clinically to stimulate bone marrow

Formation of Leukocytes

• All leukocytes originate from hemocytoblasts

• Hemocytoblasts differentiate into myeloid stem cells and lymphoid stem cells

• Myeloid stem cells become myeloblasts or monoblasts

• Lymphoid stem cells become lymphoblasts

• Myeloblasts develop into eosinophils, neutrophils, and basophils

• Monoblasts develop into monocytes

• Lymphoblasts develop into lymphocytes

Leukocyte Disorders: Leukemias

• Leukemia refer to cancerous conditions involving white blood cells

• Leukemias are named according to the abnormal white blood cells 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

• Immature white blood cells are found in the bloodstream in all leukemias

• Bone marrow becomes totally occupied with cancerous leukocytes

• The white blood cells 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

• Platelets are fragments of megakaryocytes with a blue-staining outer region and a purple granular center

• The granules contain serotonin, Ca²⁺, 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

Genesis of Platelets

• The stem cell for platelets is the hemocytoblast

• The sequential developmental pathway is hemocytoblast, megakaryoblast, promegakaryocyte, megakaryocyte, and platelets

Hemostasis

• A series of reactions designed for stoppage of bleeding

• During hemostasis, three phases occur in rapid sequence

• Vascular spasms – immediate vasoconstriction in response to injury

• Platelet plug formation

• Coagulation (blood clotting)

Platelet Plug Formation

• Platelets do not stick to each other or to the endothelial lining of blood vessels

• Upon damage to a blood vessel, platelets:

_• Are stimulated by thromboxane A₂

• Stick to exposed collagen fibers and form a platelet plug

• Release serotonin and ADP, which attract still more platelets

_• The platelet plug is limited to the immediate area of injury by PGI₂

Coagulation

• A set of reactions in which blood is transformed from a liquid to a gel

• Coagulation follows intrinsic and extrinsic pathways

Coagulation

• The final thee steps of this series of reactions are:

• Prothrombin activator is formed

• Prothrombin is converted into thrombin

• Thrombin catalyzes the joining of fibrinogen into a fibrin mesh

Detailed Reactions of Hemostasis

Coagulation Phase 1: Two Pathways to Prothrombin Activator

• 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

• Once factor X has been activated, it complexes with calcium ions, PF₃, and factor V to form prothrombin activator

Coagulation Phase 2: Pathway to Thrombin

• Prothrombin activator catalyzes the transformation of prothrombin to the active the enzyme thrombin

Coagulation Phase 3: Common Pathways to the Fibrin Mesh

• Thrombin catalyzes the polymerization of fibrinogen into fibrin

• Insoluble fibrin strands form the structural basis of a clot

• Fibrin causes plasma to become a gel-like trap

• Fibrin in the presence of calcium ions activates factor XIII that:

• Cross-links fibrin

• Strengthens and stabilizes the clot

Clot Retraction and Repair

• Clot retraction – stabilization of the clot by squeezing serum from the fibrin strands

• Repair

• Platelet-derived growth factor (PDGF) stimulates rebuilding of blood vessel wall

• Fibroblasts form a connective tissue patch

• Endothelial cells multiply and restore the endothelial lining

Factors Limiting Clot Growth or Formation

• Two homeostatic mechanisms prevent clots from becoming large

• Swift removal of clotting factors

• Inhibition of activated clotting factors

Inhibition of Clotting Factors

• Fibrin acts as an anticoagulant by binding thrombin and preventing its:

• Positive feedback effects of coagulation

• Ability to speed up the production of prothrombin activator via factor V

• Acceleration of the intrinsic pathway by activating platelets

• Thrombin not absorbed to fibrin is inactivated by antithrombin III

• Heparin, another anticoagulant, also inhibits thrombin activity

Factors Preventing Undesirable Clotting

• Unnecessary clotting is prevented by the structural and molecular characteristics of endothelial cells lining the blood vessels

• Platelet adhesion is prevented by:

• The smooth endothelial lining of blood vessels

• Heparin and PGI₂ secreted by endothelial cells

• Vitamin E quinone, a potent anticoagulant

Hemostasis Disorders: Thromboembolytic Disorders

• Thrombus – a clot that develops and persist in an unbroken blood vessel

• Thrombi can block circulation, resulting in tissue death

• Coronary thrombosis – thrombus in blood vessel of the heart

• 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

• Substances used to prevent undesirable clots include:

• Aspirin – an antiprostaglandin that inhibits thromboxane A₂

• Heparin – an anticoagulant used clinically for pre- and postoperative cardiac care

• Warfarinin – used for those prone to atrial fibrillation

• Flavonoids – substances found in tea, red wine, and grape juice that have natural anticoagulant activity

Hemostasis Disorders: Bleeding Disorders

• Thrombocytopenia – condition where the number of circulating platelets is deficient

• Patients show petechiae (small purple blotches on the skin) due to spontaneous, widespread hemorrhage

• Caused by suppression or destruction of bone marrow (e.g., malignancy, radiation)

• Platelet counts less than 50,000/mm³ is diagnostic for this condition

• Treated with whole blood transfusions

Hemostasis Disorders: Bleeding Disorders

• 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

• 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 – results from a deficiency of factor IX

• Hemophilia C – mild type, caused by a deficiency of factor XI

• Symptoms include prolonged bleeding and painful and disabled joints

• Treatment is with blood transfusions and the injection of missing factors

Blood Transfusions

• Transfusions are necessary:

• When substantial blood loss occurs

• In certain hemostatis disorders

• Whole blood transfusions are used:

• When blood loss is substantial

• In treating thrombocytopenia

• Packed red cells (cells with plasma removed) are used to treat anemia

Human Blood Groups

• RBC membranes have glycoprotein antigens on their external surfaces

• These antigens are:

• Unique to the individual

• Recognized as foreign if transfused into another individual

• Promoters of agglutination and are referred to as agglutinogens

• Presence/absence of these antigens are used to classify blood groups

• Humans have 30 varieties of naturally occurring RBC antigens

• The antigens of the ABO and Rh blood groups cause vigorous transfusion reactions when they are improperly transfused

• Other blood groups (M, N, Dufy, Kell, and Lewis) are mainly used for legalities

ABO Blood Groups

• 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)

• An individual with ABO blood may have various types of antigens and spontaneously preformed antibodies

• Agglutinogens and their corresponding antibodies cannot be mixed without serious hemolytic reactions

Rh Blood Groups

• There are eight different Rh agglutinogens, three of which (C, D, and E) are common

• Presence of the Rh agglutinogens on RBCs is indicated as Rh⁺

• Anti-Rh antibodies are not spontaneously formed in Rh^– individuals

• However, if an Rh^– individual receives Rh⁺ blood, anti-Rh antibodies form

• A second expose to Rh⁺ blood will result in a typical transfusion reaction

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

• Rh^– mother become sensitized when Rh⁺ blood (from a previous pregnancy of an Rh⁺ baby or a Rh⁺ transfusion) causes her body to synthesis Rh⁺ antibodies

• The drug RhoGAM can prevent the Rh^– mother from becoming sensitized

• Treatment of hemolytic disease of the newborn involves pre-birth transfusions and exchange transfusions after birth

Transfusion Reactions

• Transfusion reactions occur when mismatched blood is infused

• Donor’s cells are attacked by the recipient’s plasma agglutinins causing:

• Diminished oxygen-carrying capacity

• Clumped cells that impede blood flow

• Ruptured RBCs that release free hemoglobin into the bloodstream

• 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

• Positive reactions indicate agglutination

Plasma Volume Expanders

• When shock is imminent from low blood volume, volume must be replaced

• Plasma or plasma expanders can be administered

• 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

• 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

• Microscopic examination:

• Variations in size and shape of RBCs – predictions of anemias

• Type and number of WBCs – diagnostic of various diseases

• 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

• By the 7^th month, red bone marrow is the primary hematopoietic area

• Blood cells develop from mesenchymal cells called blood islands

• The fetus forms HbF, which has a higher affinity for oxygen than adult hemoglobin

Developmental Aspects

• Age-related blood problems result from disorders of the heart, blood vessels, and the immune system

• Increased leukemias are thought to be due to the waning deficiency of the immune system

• Abnormal thrombus and embolus formation reflects the progress of atherosclerosis