blood enormous importance in the practice of medicine clinicians examine it more often than any...

BLOOD Enormous importance in the practice of medicine Clinicians examine it more often than any other tissue when trying to determine the cause of disease in their patients

BLOOD COMPOSITION AND FUNCTIONS Components: Although blood appears to be a thick, homogeneous liquid, the microscope revels that it has both cellular and liquid components Blood is a specialized connective tissue consisting of living cells, called formed elements, suspended in a nonliving fluid matrix, blood plasma The collagen and elastic fibers typical of other connective tissues are absent from blood, but dissolved fibrous proteins become visible as fibrin strands during blood clotting

WHOLE BLOOD Blood that has been centrifuged separates into three layers: Erythrocytes: 42 to 47% Red blood cells that transport oxygen Buffy coat: less than 1% Thin, whitish layer Leukocytes: WBC Platelets: cell fragments that help stop bleeding Plasma: 55% The blood hematocrit represents the percentage of erythrocytes in whole blood Male: 47% +/- 5% Female: 42% +/- 5%

PHYSICAL CHARACTERISTICS BLOOD Sticky, opaque fluid with a characteristic metallic taste (salty taste) Color: Oxygen-rich: scarlet Oxygen-poor: dark red Higher density and viscosity than water, due to the presence of formed elements Blood is slightly basic (alkaline): pH= 7.35-7.45 Temperature: 38 0 C or 100.4 0 F Always slightly higher than body temperature

BLOOD VOLUME/WEIGHT Accounts for about 8% of body weight Average volume in healthy adult: Male: 5-6 L (about 1.5 gallons) Female: 4-5 L (about 1.2 gallons) About 7% to 8% of the body weight Human of about 150 lbs: 11 pounds of blood

BLOOD FUNCTIONS Distribution: Distribution functions of blood include: Medium for delivery of oxygen (from lungs) and nutrients (from digestive system) Removal of metabolic wastes from cells to elimination sites (to the lungs for elimination of carbon dioxide, and to the kidneys for disposal of nitrogenous wastes in urine) Transporting hormones from the endocrine organs to their target organs

BLOOD FUNCTIONS Regulation: Regulatory functions of blood include: Maintaining appropriate body temperature by absorbing and distributing heat throughout the body and to the skin surface to encourage heat loss Water has a high specific heat Maintaining normal pH in body tissues Many blood proteins and other bloodborne solutes act as buffers to prevent excessive or abrupt changes in blood pH that could jeopardize normal cell activities Acts as the reservoir for the bodys alkaline reserve of bicarbonate atoms Maintaining adequate fluid volume in the circulatory system Salts and blood proteins act to prevent excessive fluid loss from the blood into tissues Fluid volume in the blood vessels remains ample to support efficient blood circulation to all parts of the body

BLOOD FUNCTIONS Protection: Protective functions of blood include: Preventing blood loss: When a blood vessel is damaged, platelets and plasma proteins initiate clot formation, halting blood loss (clotting mechanism) Preventing infection: Drifting along in blood are antibodies, complement proteins, and white blood cells, all of which help defend the body against foreign invaders such as bacteria and viruses (immune system)

BLOOD PLASMA Straw-colored, sticky fluid Mostly water (90%) Contains over 100 different dissolved solutes including nutrients, gases, hormones, wastes, products of cell activity, ions, and proteins Plasma proteins account for 8% of plasma solutes Except for hormones and gamma globulins, most plasma proteins are produced by the liver Serve a variety of functions They are NOT taken up by cells to be used as fuels or metabolic nutrients as are most other plasma solutes, such as glucose, fatty acids, and oxygen Albumin accounts for some 60% of plasma protein Acts as a carrier of certain molecules Contributes to the osmotic pressure (pressure that helps to keep water in the bloodstream) Sodium ions are the other major solute contributing to blood osmotic pressure Kept relatively constant by various homeostatic mechanisms Example: When blood protein drops, the liver makes more protein When blood becomes too acidic (acidosis), both the respiratory system and the kidneys are called into action to restore plasmas normal, slightly alkaline pH

FORMED ELEMENTS Erythrocytes, leukocytes, and platelets, have some unusual features 1. Two are not even true cells Erythrocytes have no nuclei or organelles Platelets are cell fragments Only leukocytes are complete cells 2. Most survive in the bloodstream for only a few days 3. Most blood cells do not divide They are continuously renewed by division of cells in bone marrow, where they originate

STAINED BLOOD WRIGHTS STAIN

A stained smear of human blood under the microscope: Disc-shaped red blood cells Spherical white blood cells Scattered platelets that look like debris

ERYTHROCYTES Red blood cells (RBC): Small cells that are biconcave discsflattened discs with depressed centers Thin centers appear lighter in color than their edges They lack nuclei (anucleate) and most organelles, and contain mostly hemoglobin (Hb) Hemoglobin is an oxygen- binding protein pigment that is responsible for the transport of most of the oxygen in the blood Hemoglobin is made up of the protein globin bound to the red heme pigment

ERYTHROCYTES Red Blood Cell: Other proteins act as antioxidant enzymes that rid the body of harmful oxygen radicals Most of the other proteins function mainly to maintain the plasma membrane or promote changes in RBC shape Spectrin: Flexible network of proteins that maintains the shape of RBC Gives flexibility to change shape as needed (twisting and turning as RBC passes through capillaries with diameters smaller than RBC)

ERYTHROCYTES Pick up oxygen in the capillary beds of the lungs and releases it to tissue cells across other capillaries throughout the body Transports some 20% of the carbon dioxide released by tissue cells back to the lungs Structural characteristic contributes to its gas transport functions: 1. Small size and biconcave shape provide a huge surface area relative to volume (30% more surface area than comparable spherical cells Because no point within its cytoplasm is far from the surface, the biconcave disc shape is ideally suited for gas exchange 2. Discounting water content, an erythrocyte is over 97% hemoglobin, the molecule that binds to and transports respiratory gases 3. Because erythrocytes lack mitochondria and generate ATP by anaerobic mechanisms, they do not consume any of the oxygen they are transporting, making them very efficient oxygen transporters

ERYTHROCYTES

ELECTRON MICROGRAPH of ERYTHROCYTES

ERYTHROCYTES Major factor contributing to blood viscosity (state of being sticky, gummy, gelatinous): Women typically have a lower RBC count than men Female: 4.3 to 5.2 million/cubic millimeter (million/mm 3 ) 1 ml / cc / cm 3 = 1,000 mm 3 4.3 to 5.2 billion/ml Male: 5.1 to 5.8 million/cubic millimeter (million/mm 3 ) 1 ml / cc / cm 3 = 1,000 mm 3 5.1 to 5.8 billion/ml When the number of RBC increases beyond the normal range, blood viscosity rises and blood flows more slowly When the number of RBC drops below the lower end of the range, the blood thins and flows more rapidly

HEMOGLOBIN Protein that makes RBC bind easily and reversible with oxygen Most oxygen carried in the blood is bound to hemoglobin Normal values are: 14-20 grams per 100 ml of blood (14-20g/100 ml) in infants 13-18 g/100 ml in adult males 12-16 g/100 ml in adult females

HEMOGLOBIN

Made up of the protein globin bound to the red heme pigment Globin consists of four polypeptide chainstwo alpha and two betaeach bound to a ringlike heme group Each heme group bears an atom of iron set like a jewel in its center Since each iron atom can combine reversibly with one molecule of oxygen, a hemoglobin molecule can transport 4 molecules of oxygen A single RBC contains about 250 million hemoglobin molecules, so each of these tiny cells can transport about 1 billion molecules of oxygen

HEMOGLOBIN The fact that hemoglobin is contained in erythrocytes, rather than existing free in plasma, prevents it: 1. From breaking into fragments that would leak out of the bloodstream (through the rather porous capillary membranes) 2. From contributing to blood viscosity and osmotic pressure

HEMOGLOBIN In the lungs, oxygen binds to iron, the hemoglobin, now called oxyhemoglobin, assumes a new three-dimensional shape and becomes ruby (bright) red In the tissues, oxygen detaches from iron, hemoglobin resumes its former shape, and the resulting deoxyhemoglobin, or reduced hemoglobin, becomes dark red

HEMOGLOBIN About 20% of the carbon dioxide transported in the blood combines with hemoglobin Binds to globins amino acids rather than with the heme group forming carbaminohemoglobin Occurs more readily when hemoglobin is in the reduced state (dissociated from oxygen)

HEMOGLOBIN

PRODUCTION OF ERYTHROCYTES Hematopoiesis, or blood cell formation, occurs in the red bone marrow: Bones of the axial skeleton and girdles, and in the proximal epiphyses of the humerus and femur Erthropoiesis, the formation of erythrocytes, begins when a myeloid stem cell is transformed to a proerythroblast, which develops into mature erythrocytes Process takes about 5-7 days On average, the marrow turns out an ounce of new blood containing some 100 billion new cells each and every day

ERYTHROPOIESIS

Regulation and Requirements for Erythropoiesis Number of circulating erythrocytes is remarkably constant and reflects a balance between red blood cell production and destruction: Balance is important because: Too few erythrocytes leads to tissue hypoxia (oxygen deprivation) Too many makes the blood undesirably viscous To ensure that the number of erythrocytes in blood remains within the homeostatic range, new cells are produced at the incredibly rapid rate of more than 2 million per second in healthy people Erythrocyte production is controlled by the hormone erythropoietin Dietary requirements for erythrocyte formation include iron, vitamin B 12 and folic acid, as well as proteins, lipids, and carbohydrates Blood cells have a short life span due to the lack of nuclei and organelles; destruction of dead or dying blood cells is accomplished by macrophages

Hormonal Controls for Erythropoiesis Direct stimulus for erythrocyte formation is provided by erythropoietin (EPO), a glycoprotein hormone: Normally, a small amount of EPO circulates in the blood at all times and sustains red blood cell production at a basal rate The liver produces some EPO The kidneys play the major role in EPO production When kidney cells become hypoxic (inadequate oxygen), they accelerate their release of erythropoietin The male sex hormone testosterone also enhances EPO production by the kidneys Because female sex hormones do not have similar stimulatory effects, testosterone may be at least partially responsible for the higher RBC counts and hemoglobin levels seen in males A wide variety of chemicals released by leukocytes, platelets, and even reticular cells stimulates bursts of RBC production

ERYTHROPOIETIN MECHANISM

Hormonal Controls for Erythropoiesis The drop in normal blood oxygen levels that triggers EPO formation can result from: 1. Reduced numbers of RBC due to hemorrhage or excess RBC destruction 2.Reduced availability of oxygen, as might occur at high altitudes or during pneumonia 3.Increased tissue demands for oxygen (common in those who engage in aerobic exercise)

Hormonal Controls for Erythropoiesis Too many erythrocytes or excessive oxygen in the bloodstream depresses erythropoietin production It is NOT the number of erythrocytes in blood that controls the rate of erythropoiesis Control is based on their ability to transport enough oxygen to meet tissue demands Hypoxia (oxygen deficit) does NOT activate the bone marrow directly Instead it stimulates the kidneys, which in turn provide the hormonal stimulus that activates the bone marrow

HOMEOSTATIC IMBALANCE Renal dialysis patients whose kidneys have failed produce too little erythropoietin (EPO) to support normal erythropoiesis They routinely have RBC counts less than half that of healthy individuals Genetically engineered (recombinant) EPO has helped such patients immeasurably and has also become a substance of abuse in athletesparticularly in professional bike racers and marathon runners seeking increased stamina and performance Consequence could be deadly: By injecting EPO, healthy athletes increase their normal RBC volume from 45% to as much as 65% Then, with dehydration that occurs in a long race, the blood concentrates even further, becoming a thick, sticky sludge that can cause clotting, stroke, and even heart failure

Dietary Requirements for Erythropoiesis Raw materials required for erythropoiesis include the usual nutrients and structural materialproteins, lipids, and carbohydrates Iron is essential for hemoglobin synthesis 65% of the bodys iron supply is in hemoglobin Remainder is stored in the liver, spleen, and bone marrow Because free iron ions (Fe 2+, Fe 3+ ) are toxic Iron is stored in cells as protein-iron complexes such as ferritin and hemosiderin In blood, iron is transported loosely bound to a transport protein called transferrin Small amounts of iron are lost each day in feces, urine, and perspiration Male: 0.9 mg/daily Female: 1.7mg/daily In woman, the menstrual flow accounts for the additional losses Two B-complex vitaminsvitamin B 12 and folic acidare necessary for normal DNA synthesis Even slight deficits jeopardize rapidly dividing cell populations, such as developing erythrocytes

Fate and Destruction of Erythrocytes The anucleate condition of erythrocytes carries with it some important limitations RBCs: Are unable to synthesize new proteins, to grow, to divide Become old as they lose their flexibility and become increasingly rigid and fragile, and their contained hemoglobin begins to degenerate Useful life span of 100 to 120 days, after which they become trapped and fragment in smaller circulatory channels, particularly in those of the spleen (RBC graveyard)

LIFE CYCLE OF RED BLOOD CELLS

Fate and Destruction of Erythrocytes Dying RBC are engulfed and destroyed by macrophages Heme of their hemoglobin is split off from globin Iron is salvaged, bound to protein (as ferritin or hemosiderin), and stored for reuse Balance of the heme group is degraded to bilirubin, a yellow pigment that is released to the blood and binds to albumin for transport: Picked up by the liver cells, where it is metabolized to urobilinogen Most of this degraded pigment leaves the body in feces, as a brown pigment called stercobilin The protein (globin) part of hemoglobin is metabolized or broken down to amino acids, which are released to the circulation

ERYTHROCYTES DISORDERS ANEMIAS Condition in which the blood has abnormally low oxygen-carrying capacity Inadequate to support normal metabolism It is a symptom of some disorder rather than a disease in and of itself Individuals are fatigued, often pale, short of breath, and chilly

ERYTHROCYTES DISORDERS ANEMIAS An insufficient number of red blood cells due to: Blood loss Excessive RBC destruction Bone marrow failure

ERYTHROCYTES DISORDERS ANEMIAS Hemorrhagic anemias: Results from blood loss Acute: Blood loss is rapid (stab wound) Chronic: Blood loss is slight but persistent Ulcer, hemorrhoids Hemolytic anemias: Erythrocytes rupture, or lyse, prematurely Hemoglobin abnormalities, transfusion of mismatched blood, certain bacterial and parasitic infections Aplastic anemia: Destruction or inhibition of the red marrow by certain bacterial toxins, drugs, and ionizing radiation Because marrow destruction impairs formation of all formed elements, anemia is just one of its signs Defects in blood clotting and immunity are also present Blood transfusions are a temporary solution until a marrow transplant or umbilical stem cell tranfusion can be performed

ERYTHROCYTES DISORDERS ANEMIAS Low hemoglobin content: when hemoglobin molecules are normal, but erythrocytes contain fewer than the usual number, a nutritional anemaia is always suspected Iron-deficiency anemia: Generally a secondary result of hemorrhabic anemias Could also result from inadequate intake of iron-containing foods and impaired iron intake Resulting erythrocytes produced are called microcytes (small and pale) Athletes anemia: temporary due to vigorous exercise, blood volume can increase diluting the blood Quickly reverse in a day or so Pernicious anemia: Deficiency of vitamin B 12 Because meats, poultry, and fish provide ample amounts of the vitamin, diet is rarely the problem except for strict vegatarians Deficient Intrinsic factor: A substance called intrinsic factor, produced by the stomach mucosa, must be present for vitamin B 12 to be absorbed by intestinal cells Treatment with vitamin B 12

ERYTHROCYTES DISORDERS ANEMIAS Abnormal hemoglobin: usually a genetic basis Thalassemias: People of Mediterranean ancestry One of the globin chains is absent or faulty Erythrocytes are thin, delicate, and deficient in hemoglobin RBC count low Monthy transfusions

ERYTHROCYTES DISORDERS ANEMIAS: Abnormal Hemoglobin Sickle-cell anemia: results from a change in just 1 of the 287 amino acids in a beta chain of the globin molecule Shape of the hemoglobin changes resulting in the RBC becoming crescent shaped Any form of exercise: Stiff, deformed erythrocytes rupture easily and tend to dam up in small vessels Low oxygen delivery, leaving victim gasping and in pain Standard treatment: transfusion

ERYTHROCYTES DISORDERS ANEMIAS: Abnormal Hemoglobin Sickle-cell anemia occurs chiefly in black races who live in the malaria belt of Africa and among their descendents: Malarian parasite does not survive in a sickle cell since these cells loss potassium an essential element for parasite survival Genetic recessive trait Since RBCs do not sickle in fetus: Genetic engineering trying to reverse the gene back to its infancy (before it activates) and block it

SICKEL CELL ANEMIA

ERYTHROCYTES DISORDERS Polycythemia is characterized by an abnormal excess of RBCs Increase viscosity Most often a result of bone marrow cancer Secondary Polycythemias: results when less oxygen is available or erythropoietin production increases Appears in individuals living at high altitudes Normal physiological response to the reduced atmospheric pressure and lower oxygen content of the air

BLOOD DOPING Practiced by some athletes Artificially induced polycythemia: Atheletes red blood cells are drawn off and then reinjected a few days before event: Because the erythropoietin mechanism is triggered shortly after blood removal, the erythrocytes are quickly replaced Then, when the stored blood is reinfused, a temporary polycythemia results Since red blood cells carry oxygen, the additional infusion should translate into increased oxygen-carrying capacity due to a higher hematocrit, and hence greater endurance and speed Other than problems that might derive from increased blood viscosity, such as, temporary high blood pressure or reduced blood delivery to body tissues, blood doping seems to work Banned in OLYMPICS

LEUKOCYTES General Structural and Functional Characteristics White blood cells, are the only formed elements that are complete cells, with nuclei and the usual organelles and make up less than 1% of total blood volume Less numerous than red blood cells 4800-10,800 WBCs/mm 3 4.8-10.8 million/ml (cc)(cm 3 ) Leukocytes are critical to our defense against disease: Protect the body from damage by bacteria, viruses, parasites, toxins, and tumor cells

LEUKOCYTES General Structural and Functional Characteristics WBCs have the ability to slip out of the capillary blood vesselsprocess called diapedesisand the circulatory system is simply their means of transport to areas of the body where they are needed to mount inflammatory or immune responses Once out of the bloodstream, leukocytes move through the tissue spaces by amoeboid motion Whenever WBC are mobilized for action, the body speeds up their production and twice the normal number may appear in the blood within a few hours

LEUKOCYTES General Structural and Functional Characteristics Group into two major categories on the basis of structural and chemical characteristics: Granulocytes contain obvious membrane-bound cytoplasmic granules Agranulocytes lack obvious granules Most abundant to the least abundant: Never let monkeys eat bananas Neutrophils, lymphocytes, monocytes, eosinophils, basophils

LEUKOCYTES General Structural and Functional Characteristics Granulocytes are a main group of leukocytes characterized as large cells with lobed nuclei (rounded nuclear masses connected by thinner strands of nuclear material) and visibly staining granules, all are phagocytic Larger and much shorter lived than erythrocytes Their membrane-bound cytoplasmic granules stain specifically with Wrights stain

TYPES OF LEUKOCYTES

GRANULOCYTES NEUTROPHILS(a) Most numerous type of leukocyte (50%- 70%) Twice as large as erythrocytes Called neutrophils because their granules take up both basic (blue) and acidic (red) dyes They are chemically attracted to sites of inflammation and are active phagocytes: Especially partial to bacteria and some fungi Killing bacteria is promoted by a process called respiratory burst Oxygen is actively metabolized to produce potent germ-killer oxidizing substances such as bleach (calcium hypochlorite) and hydrogen peroxide, and defensin-mediated lysis occurs Defensins form protein spears that pierce holes in the membrane of the ingested foe

GRANULOCYTES EOSINOPHILS(b) Account for 2% to 4% of all leukocytes and are approximately the size of neutrophils Deep red nucleus usually resembles an old- fashioned telephone receiver (two lobes connected by a broad band of nuclear material) Cytoplasmic Granules affinity for acid dye (eosin) Most important role is to attack parasitic worms, such as flatworms (tapeworms and flukes) and roundworms (pinworms: rectal area eggs/bedding and hookworms: lungs/ intestines) that are too large to be phagocytized These worms are ingested in food (especially raw fish) or invade the body via the skin and then typically burrow into the intestinal or respiratory mucosae Release enzymes from their cytoplasmic granules onto the parasites surface, digesting it away Lessen the severity of allergies by phagocytizing immune (antigen-antibody) complexes involved in allergy attacks and inactivating certain inflammatory chemicals released during allergic reactions

GRANULOCYTES BASOPHILS(c) Rarest WBC: 0.5% to 1% Slightly smaller than neutrophil Histamine-containing granules have affinity for basic dyes (basophil) Inflammatory chemical that acts as a vasodilator (makes blood vessels dilate) and attracts other WBC to the inflamed site Drugs called antihistamines counter this effect Granulated cells (mast cells) similar to basophils are found in connective tissue Both bind to a particular antibody (immunoglobin E) that causes the cells to release histamine

TYPES OF LEUKOCYTES a: Neutrophil b: Eosinophil c: Basophil d: Small Lymphocyte e: Monocyte

AGRANULOCYTES Main group of lymphocytes that lack visibly cytoplasmic staining granules Although they are similar structurally, they are functionally distinct and unrelated cell types: T lymphocytes directly attack viral-infected and tumor cells; B lymphocytes produce antibody cells Monocytes become macrophages and activate T lymphocytes

AGRANULOCYTES LYMPHOCYTES (d) Account for 25% of WBC Second most numerous leukocytes in the blood Only a small proportion of them (mostly the small lymphocytes) are found in the bloodstream Most are in lymphoid tissue (lymph nodes, spleen, etc.), where they play a crucial role in immunity Large, dark-purple nucleus that occupies most of the cell volume T lymphocytes (T cells) function in the immune response by acting directly against virus-infected cells and tumor cells B lymphocytes (B cells) give rise to plasma cells, which produce antibodies (immunoglobulins) that are released to the blood

AGRANULOCYTES MONOCYTES (e) Account for about 3% to 8% of WBCs Largest leukocytes Nucleus distinctively U or kidney shaped When circulating monocytes leave the bloodstream and enter the tissues, they differentiate into highly mobile macrophages with prodigious appetites: Actively phagocytic Crucial in the bodys defense against viruses, certain intracellular bacterial parasites, and chronic infections such as tuberculosis Important in activating lymphocytes to mount the immune response

Production and Life Span of Leukocytes Leukopoiesis, the formation of white blood cells Is hormonally stimulated These hormones, released mainly by macrophages and T lymphocytes, are glycoproteins that fall into two families of hematopoietic factors, interleukins and colony-stimulating factors (CSFs) Interleukins are numbered ( e.g., IL-3, IL-5) Most CSFs are named for the leukocyte population they stimulate Example: Granulocyte-CSF (G-CSF) stimulates production of granulocytes Many of these hematopoietic hormones (erythropoietin (EPO) and several of the CSFs) are used clinically to stimulate the bone marrow in: Cancer patients who are receiving chemotherapy (which suppresses the marrow) Marrow transplants AIDS patients

Production and Life Span of Leukocytes Leukopoiesis involves differentiation of hemocytoblasts along two pathways: Lymphoid stem cells which produce lymphocytes Myeloid stem cells which give rise to all other formed elements Bone marrow stores mature granulocytes and usually contains 10 to 20 times more granulocytes than are found in the blood The normal ratio of granulocytes to erythrocytes produced is about 3:1 Reflects the much shorter life span (0.5 to 9.0 days) of the granulocytes, most of which die combating invading microorganisms

LEUKOCYTE FORMATION

Production and Life Span of Leukocytes Despite their similar appearances, the two types of agranulocytes have very different lineages Like granulocytes, monocytes diverge from common myeloid stem cells Lymphocytes derive from the lymphoid stem cell

Leukocyte Disorders Leukopenia is an abnormally low white blood cell count Commonly induced by drugs, particularly glucocorticoids and anticancer agents

Leukocyte Disorders Leukemia: refers to a group of cancerous conditions involving white blood cells Leukemias are clones of a single white blood cell that remain unspecialized and divide out of control, impairing normal bone marrow function The leukemias are named according to the abnormal cell type primarily involved: Example: Myelocytic leukemia involves myeloblast descendants Lymphocytic leukemia involves the lymphocytes Leukemia is: Acute (quickly advancing) if it derives from blast-type cells like lymphoblast Primarily affect children Chronic (slowly advancing) if it involves proliferation of later cell stages like myelocytes Seen more often in elderly people Without therapy, all leukemias are fatal; only the time course differs

Leukocyte Disorders In all leukemias, the bone marrow becomes almost totally occupied by cancerous leukocytes and immature WBCs flood into the bloodstream Because the other blood cell lines are crowded out, severe anemia and bleeding problems also result Other symptoms include fever, weight loss, and bone pain Although tremendous numbers of leukocytes are produced, they are nonfunctional and cannot defend the body in the usual way The most common causes of death are internal hemorrhage and overwhelming infections Irradiation and administration of antileukemic drugs to destroy the rapidly dividing cells have successfully induced remissions (symptom-free periods) lasting from months to years Bone marrow or umbilical cord blood transplants are used in selected patients when compatible donors are available

Leukocyte Disorders Infectious mononucleosis: Once called the kissing disease Highly contagious viral disease most often seen in children and young adults Caused by the Epstein-Barr virus Excessive numbers of agranulocytes, many of which are atypical Tired and achy, and has a chronic sore throat and a low-grade fever No cure, but with rest the condition typically runs its course to recovery in a few weeks

PLATELETS Platelets are not complete cells, but fragments of large cells called megakaryocytes Platelets are critical to the clotting process, forming the temporary seal when a blood vessel breaks Formation of platelets involves repeated mitosis of megakaryocytes without cytokinesis

STAINED BLOOD WRIGHTS STAIN

PLATELETS The granules contain an impressive array of chemicals that act in the clotting process, including serotonin, Ca 2+, a variety of enzymes, ADP, and platelet-derived growth factor (PDGF) Anucleate, they age quickly and degenerate in about 10 days if they are not involved in clotting Circulate freely, kept mobile but inactive by molecules (nitric oxide, prostaglandin I 2 ) secreted by endothelial cells lining the blood vessels

PLATELET FORMATION Regulated by a hormone called thrombopoietin Progeny of the hemocytoblast and the myeloid stem cell Repeated mitoses (pl) of the megakaryoblast occur, but cytokinesis does not: Final result is the megakaryocyte, a bizarre cell with a huge, multilobed nucleus and a large cytoplasmic mass Presses up against capillaries in the marrow and sends cytoplasmic extensions into the bloodstream Extensions rupture, releasing the platelet fragments seeding the blood with platelets Plasma membrane associated with each fragment quickly seal around the cytoplasm to form the grainy, roughly disc-shaped platelets 150,000-400,000 platelets/mm 3 150,000,000-400,000,000 platelets/cc (cm 3 ) (ml)

PLATELET FORMATION

HEMOSTASIS ARREST OF BLEEDING A break in a blood vessel stimulates hemostasis, a fast, localized response to reduce blood loss through clotting: Involves many blood coagulation factors normally present in plasma as well as some substances that are released by platelets and injured tissue cells During hemostasis, three phases occur in rapid sequence: 1.Vascular spasms are the immediate vasoconstriction response to blood vessel injury 2.Platelet Plug Formation 3.Coagulation (blood clotting)

Hemostasis Vascular Spasms The immediate response to blood vessel injury is constriction of the damaged blood vessel (vasoconstriction) Factors that trigger this vascular spasm include: Direct injury to vascular smooth muscle Chemicals released by endothelial cells and platelets Reflexes initiated by local pain receptors The value of the spasm response is obvious: A strongly constricted artery can significantly reduce blood loss for 20-30 minutes, allowing time for platelet plug formation and blood clotting to occur

Hemostasis Platelet Plug Formation Platelets play a key role in hemostasis by forming a plug that temporarily seals the break in the vessel wall They also help to orchestrate subsequent events that lead to blood clot formation As a rule, platelets do not stick to each other or to the smooth endothelial linings of blood vessels: When endothelium is damaged and underlying collagen fibers are exposed, platelets, with the help of a large plasma protein called von Willebrand factor (VWF) synthesized by endothelial cells, adhere tenaciously to the collagen fibers and undergo some remarkable changes They swell, form spiked processes, and become sticky

Hemostasis Platelet Plug Formation Once attached, the platelets are activated by the enzyme thrombin and their granules begin to break down and release several chemicals: Serotonin: enhances the vascular spasm (vessel constriction) Adenosine diphosphate (ADP): potent aggregating agents that attract more platelets to the area and cause them to release their contents Thromboxane A 2 : short-lived prostaglandin derivative that is generated and released, stimulates both previous events Thus, a positive feedback cycle that activates and attracts greater and greater numbers of platelets to the area begins and, within one minute, a platelet plug is built up, which further reduces blood loss

BLOOD CLOTTING

Hemostasis Coagulation (Blood Clotting) Blood is transformed from a liquid to a gel Final three phases: 1. A complex substance called prothrombin activator is formed 2. Prothrombin activator converts a plasma protein called prothrombin into thrombin, an enzyme 3. Thrombin catalyzes the joining of fibrinogen molecules present in plasma to a fibrin mesh, which traps blood cells and effectively seals the hole until the blood vessel can be permanently repaired

Hemostasis Coagulation (Blood Clotting) Coagulation, or blood clotting, is a multi-step process in which blood is transformed from a liquid to a gel Over 30 different substances are involved Factors that promote clotting are called clotting factors, or procoagulants Although vitamin K is not directly involved in coagulation, this fat-soluble vitamin is required for the synthesis of four of the procoagulants made by the liver Factors that inhibit clot formation are called anticoagulants Whether or not blood clots depends on a delicate balance between these two groups of factors

Hemostasis Coagulation (Blood Clotting) The procoagulants are numbered I to XIII according to the order of discovery; hence the numerical order does not reflect the reaction sequence Tissue factor (III) and Ca 2+ (IV) are usually indicated by their names, rather than by numerals Most of these factors are plasma proteins made by the liver that circulates in an inactive form in blood until mobilized

BLOOD CLOTTING

Coagulation (Blood Clotting) Phase 1 Two Pathways to Prothrombin Activator Clotting in the body may be initiated by either the intrinsic or extrinsic pathway Clotting in a test tube (outside the body) is initiated only by the intrinsic mechanism Each pathway requires ionic calcium and involves the activation of a series of procoagulants, each functioning as an enzyme to activate the next procoagulant in the sequence Each pathway cascades toward a common intermediate, factor X Once factor X has been activated, it complexes with calcium ions, PF 3, and factor V to form prothrombin activator This step is usually the slowest step of the blood clotting process, but once prothrombin activator is present, the clot forms in 10 to 15 seconds

Coagulation (Blood Clotting) Phase 2 Common Pathway to Thrombin Prothrombin activator catalyzes the transformation of the plasma protein prothrombin to the active enzyme thrombin

Coagulation (Blood Clotting) Phase 3 Common Pathway to the Fibrin Mesh Thrombin catalyzes the polymerization of fibrinogen (another plasma protein made by the liver) Fibrinogen molecules align into long, hair-like, insoluble fibrin strands They glue the platelets together and make a web that forms the structural basis of the clot In the presence of fibrin, plasma becomes gel-like and traps formed elements that try to pass through it

Coagulation (Blood Clotting) Phase 3 Common Pathway to the Fibrin Mesh In the presence of calcium ions, thrombin also activates factor XIII (fibrin stabilizing factor), a cross-linking enzyme that binds the fibrin strands tightly together and strengthens and stabilizes the clot Clot formation is normally complete within 3 to 6 minutes after blood vessel damage Extrinsic pathway is more rapid: In cases of severe trauma it can promote clot formation within 15 seconds

Clot Retraction and Repair Clot retraction is a process in which the contractile proteins (actin and myosin) within platelets contract and pull on neighboring fibrin strands, squeezing serum (plasma minus the clotting proteins) from the clot and pulling damaged tissue edges together Even as clot retraction is occurring, vessel healing is taking place Repair is stimulated by platelet-derived growth factors (PDGF) Released by platelets: stimulates smooth muscle and fibroblasts to divide and rebuild the wall restoring the endothelial lining

Fibrinolysis A clot is not a permanent solution to blood vessel injury Process called fibrinolysis removes unneeded clots through the action of the fibrin-digesting enzyme plasmin (clot buster) Because small clots are formed continually in vessels throughout the body, this cleanup detail is crucial Without fibrinolysis, blood vessels would gradually become completely blocked Most plasmin activity is confined to the clot, and any plasmin that strays into the plasma is quickly destroyed by circulating enzymes Begins within two days and continues slowly over several days until the clot is finally dissolved

Factors Limiting Clot Growth or Formation Normally, two homeostatic mechanisms prevent clots from becoming unnecessarily large: 1. Swift removal of clotting 2. Inhibition of activated clotting factors Rapidly moving blood disseminates clotting factors before they can initiate a clotting cascade Thrombin that is not bound to fibrin is inactivated by antithrombin III and protein C, as well as heparin Heparin, the natural anticoagulant contained in basophil and mast cell granules and also produced by endothelial cells, is ordinarily secreted in small amounts into the plasma It inhibits thrombin by enhancing the activity of antithrombin III Like most other clotting inhibitors, heparin also inhibits the intrinsic pathway

Disorders of Hemostasis Thromboembolytic Results from conditions that cause undesirable clotting, such as roughening of vessel endothelium, slow-flowing blood, or blood stasis (stoppage of normal flow) A clot that develops and persist in an unbroken blood vessel is called a thrombus If large enough, it may block circulation If it breaks away from the vessel wall and floats freely in the bloodstream, it becomes an embolus Usually no problem until it encounters a blood vessel too narrow for it to pass through (then it becomes an embolism, obstructing the vessel) Pulmonary embolisms Cerebral embolisms (stroke) Coronary arteries (heart attack) Conditions that roughen the vessel endothelium, such as arteriosclerosis, severe burns, or inflammation, cause thromboembolytic disease by allowing platelets to gain a foothold Slowly flowing blood or blood stasis (stoppage) is another risk factor, particularly in bedridden patients and those taking a long flight in economy-class seats Clotting factors are NOT washed away as usual and accumulate so that clot formation finally becomes possible

Disorders of Hemostasis Poor Clotting Arise from abnormalities that prevent normal clot formation, such as a deficiency in circulating platelets, lack of synthesis of procoagulants, or hemophilia Aspirin is an antiprostaglandin drug that inhibits thromoboxane A 2 formation Hence, it blocks platelet aggregation and platelet plug formation Anticoagulant drugs: Dicumarol: Warfarin sodium Heparin: used for preoperative and postoperative cardiac patients and those receiving blood transfusions Warfarin (Coumadin): interferes with the action of vitamin K in the production of some procoagulants Rat poison Treatment of patients prone to atrial fibrillation (blood pools in the heart) Reduce stroke

Disorders of Hemostasis Homeostatic Imbalance Disseminated intravascular coagulation: widespread clotting occurs in intact blood vessels and the residual blood becomes unable to clot Blockage of blood flow accompanied by severe bleeding follows: Common in: Complicated pregnancy Result of septicemia (presence of pathogenic microorganisms in the blood) Incompatible blood transfusions

Disorders of Hemostasis Bleeding Disorders Thrombocytopenia: Condition in which the number of circulating platelets is deficient Spontaneous bleeding from small blood vessels all over the body Even normal movement leads to widespread hemorrhage, evidenced by many small purplish blotches, called petechiae, on the skin Etiology: Condition that suppresses or destroys bone marrow Bone marrow malignancy, exposure to ionization radiation, or certain drugs

Disorders of Hemostasis Bleeding Disorders Impaired Liver Function: When the liver is unable to synthesize its usual supply of procoagulants, abnormal, and often severe, bleeding occurs Cause may range: From an easily resolved vitamin K deficiency Common in newborns After taking systemic antibiotics Fat absorption impairment (vitamin K is fat-soluble) Bacterial problem in colon (bacteria synthesize vitamin K) To nearly total impairment of liver function Hepatitis Cirrhosis Lack of bile production (required for fat and vitamin K absorption)

Disorders of Hemostasis Bleeding Disorders Hemophilias: Several different hereditary bleeding disorders Hemophilia A (classical hemophilia): Deficiency of factor VIII (antihemophilic factor) Sex-linked (primarily males) Hemophilia B: Deficiency of factor IX Sex-linked (primarily males) Hemophilia C: Deficiency of factor XI Less severe form seen in both sexes

Blood Loss The body can compensate for only so much blood loss: 15-30% cause pallor and weakness Loss of more than 30% of blood volume results in severe shock, which can be fatal

TRANSFUSION AND BLOOD REPLACEMENT Transfusion of whole blood is routine when blood loss is substantial, or when treating thrombocytopenia Humans have different blood types based on specific antigens on RBC membranes ABO blood groups are based on the presence or absence of two types of agglutinogens Preformed antibodies (agglutinins) are present in blood plasma and do not match the individuals blood The Rh factor is a group of RBC antigens that are either present in Rh + blood, or absent in Rh - blood A transfusion reaction occurs if the infused donor blood type is attacked by the recipients blood plasma agglutinins, resulting in agglutination and hemolysis of the donor cells Plasma and blood volume expanders are given in cases of extremely low blood volume

Transfusion of Whole Blood Routine when blood loss is substantial and when treating thrombocytopenia Infusions of packed red cells (whole blood from which most of the plasma has been removed) are preferred to treat anemia Usual blood bank procedure involves collecting blood from a donor and then mixing it with an anticoagulant, such as certain citrate or oxalate salts, which prevents clotting by binding with calcium ions Shelf life of the collected blood at 4 o C is about 35 days When freshly collected blood is transfused, heparin is the anticoagulant used

Human Blood Groups RBC plasma membranes, like those of all body cells, bear highly specific glycoproteins (antigens) at their external surfaces, which identify each of us as unique from all others Since RBC antigens promote agglutination, they are more specifically called agglutinogens At least 30 varieties of naturally occurring RBC antigens are common in humans The presence or absence of each antigen allows each persons blood cells to be classified into several different blood groups (ABO, Rh, M, N, Duffy, Kell, Lewis, etc.)

ABO Blood Groups Based on the presence or absence of two agglutinogens, type A and type B A,B dominants O A + B are codominant GenotypePhenotype AOA AAA BOB BBB ABAB OOO

ABO Blood Groups Unique to the ABO blood group is the presence in the plasma of preformed antibodies (agglutinins) The agglutinins act against RBCs carrying ABO antigens that are NOT present on a persons own red blood cell Newborn lacks these antibodies but they form within 2 months Reach peck levels between 8 and 10 Slowly decline throughout life Blood Groups A anti-B B anti-A AB no anti O anti-A and anti-B

Rh Blood Groups There are at least eight different types of Rh agglutinogens, each of which is called an Rh factor Only three of these, the C, D, and E antigens, are fairly common Rh antigen first discovered in the rhesus monkey than in humans 85% Rh + Unlike the ABO system, anti-Rh antibodies are not spontaneously formed in the blood of Rh - individuals However, if an Rh - person receives Rh + blood, the immune system becomes sensitized and begins producing anti-Rh antibodies against the foreign antigen soon after the transfusion Hemolysis does not occur after the first such transfusion because it takes time for the body to react and start making antibodies The second time, and every time thereafter, a typical transfusion reaction occurs in which the recipients antibodies attack and rupture the donor RBCs

HOMEOSTATIC IMBALANCE Important problem related to the Rh factor occurs in pregnant Rh - women who are carrying Rh + babies First such pregnancy usually results in the delivery of a healthy baby But, when bleeding occurs as the placenta detaches from the uterus, the mother may be sensitized by her babys Rh + antigens that pass into her bloodsream She will form anti-Rh antibodies unless treated with RhoGAM before or shortly after she has given birth RhoGAM is a serum containing anti-Rh agglutinins Because it agglutinates the Rh factor, it blocks the mothers immune response and prevents her sensitization

HOMEOSTATIC IMBALANCE Rh Problem If the mother is not treated and becomes pregnant again with an Rh + baby, her antibodies will cross through the placenta and destroy the babys RBCs, producing a condition known as hemolytic disease of the newborn, or erythroblastosis fetalis The baby becomes anemic and hypoxic (oxygen deficiency) Brain damage and even death may result unless transfusions are done before birth to provide the fetus with more erythrocytes for oxygen transport One or two exchange transfusions are done after birth The babys Rh + blood is removed, and Rh - blood infused Within 6 weeks, the transfused Rh - erythrocytes have been broken down and replaced with the babys own Rh + cells

Transfusion Reactions: Agglutination and Hemolysis When mismatched blood is infused, a transfusion reaction occurs in which the donors red blood cells are attacked by the recipients plasma agglutinins (Note: the donors plasma antibodies may also be agglutinating the hosts RBCs, but they are so diluted in the recipients circulation that this does not usually present a serious problem) Results in: The oxygen-carrying capability of the transfused blood cells is disrupted The clumping of RBCs in small vessels hinders blood flow to tissues But more devastating, is the consequence of hemoglobin escaping into the bloodstream Circulating hemoglobin passes freely into the kidney tubules, and in high concentration it precipitates, blocking the kidney tubules and causing renal shutdown If shutdown is complete (acute renal failure), the person may die

Transfusion Reactions: Agglutination and Hemolysis Treatment of transfusion reactions is directed toward preventing damage by infusing alkaline fluids to dilute and dissolve the hemoglobin and wash it out of the body Diuretics, which increase urine output, are also given

Transfusion Reactions: Agglutination and Hemolysis Donors blood is the most important Pooled blood transfusions carry the risk of transfusion reactions and transmission of life-threatening infections Selection of Autologous Transfusions has risen Elective surgery

BLOOD TYPING

Plasma and Blood Volume Expanders Plasma can be administered to anyone without concern about a transfusion reaction because the antibodies it contains become harmlessly diluted in the recipients blood Except for red blood cells, plasma provides a complete and natural blood replacement Plasma expanders: osmotic properties increases the fluid volume of the blood Purified human serum albumin Dextran Isotonic salt solutions (normal saline, multiple electrolytes)

DIAGNOSTIC BLOOD TESTS Changes in some of the visual properties of blood can signal diseases such as anemia, heart disease, and diabetes Differential white blood cell counts are used to detect differences in relative amounts of specific blood cell types Example: high eosinophil: parasitic infection or an allergic response somewhere in the body Prothrombin time, which measures the amount of prothrombin in the blood, and platelet counts evaluate the status of the hemostasis system SMAC (chemistry profile), SMA12-60, and complete blood count (CBC) give comprehensive values of the condition of the blood Provide a comprehensive picture of ones general health status in relation to normal blood values

DEVELOPMENTAL ASPECTS OF BLOOD Prior to birth, blood cell formation occurs within the fetal yolk sac, liver, and spleen, but by the seventh month, red bone marrow is the primary site of hematopoiesis Fetal blood cells form hemoglobin-F, which has a higher affinity for oxygen than adult hemoglobin, hemoglobin-A

blood enormous importance in the practice of medicine clinicians examine it more often than any...

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