BLOOD

1. 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

2. 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

3. 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%

4. PHYSICAL CHARACTERISTICSBLOOD • 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: 380C or 100.40F • Always slightly higher than body temperature

5. 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

6. 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

7. 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 body’s “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

8. 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)

9. 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 plasma’s normal, slightly alkaline pH

10. 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

11. STAINED BLOODWRIGHT’S STAIN

12. STAINED BLOODWRIGHT’S 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

13. ERYTHROCYTES • Red blood cells (RBC): • Small cells that are biconcave discs—flattened 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

14. 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)

15. 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

16. ERYTHROCYTES

17. ELECTRON MICROGRAPHofERYTHROCYTES

18. 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/mm3) • 1 ml / cc / cm3 = 1,000 mm3 • 4.3 to 5.2 billion/ml • Male: • 5.1 to 5.8 million/cubic millimeter (million/mm3) • 1 ml / cc / cm3 = 1,000 mm3 • 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

19. 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

20. HEMOGLOBIN

21. HEMOGLOBIN • Made up of the protein globin bound to the red heme pigment • Globin consists of four polypeptide chains—two alpha and two beta—each 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

22. 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

23. 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

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

25. HEMOGLOBIN

26. 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

27. ERYTHROPOIESIS

28. 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 B12 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

29. 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

30. ERYTHROPOIETIN MECHANISM

31. 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)

32. 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

33. 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 athletes—particularly 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

34. Dietary RequirementsforErythropoiesis • Raw materials required for erythropoiesis include the usual nutrients and structural material—proteins, lipids, and carbohydrates • Iron is essential for hemoglobin synthesis • 65% of the body’s iron supply is in hemoglobin • Remainder is stored in the liver, spleen, and bone marrow • Because free iron ions (Fe2+, Fe3+) 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 vitamins—vitamin B12 and folic acid—are necessary for normal DNA synthesis • Even slight deficits jeopardize rapidly dividing cell populations, such as developing erythrocytes

35. Fate and DestructionofErythrocytes • 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)

36. LIFE CYCLE OF RED BLOOD CELLS

37. Fate and DestructionofErythrocytes • 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

38. ERYTHROCYTES DISORDERSANEMIAS • 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

39. ERYTHROCYTES DISORDERSANEMIAS • An insufficient number of red blood cells due to: • Blood loss • Excessive RBC destruction • Bone marrow failure

40. ERYTHROCYTES DISORDERSANEMIAS • 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

41. ERYTHROCYTES DISORDERSANEMIAS • 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) • Athlete’s 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 B12 • 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 B12 to be absorbed by intestinal cells • Treatment with vitamin B12

42. ERYTHROCYTES DISORDERSANEMIAS • 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

43. ERYTHROCYTES DISORDERSANEMIAS: 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

44. ERYTHROCYTES DISORDERSANEMIAS: 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

45. SICKEL CELL ANEMIA

46. 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

47. BLOOD DOPING • Practiced by some athletes • Artificially induced polycythemia: • Athelete’s 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

48. LEUKOCYTESGeneral 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/mm3 • 4.8-10.8 million/ml (cc)(cm3) • Leukocytes are critical to our defense against disease: • Protect the body from damage by bacteria, viruses, parasites, toxins, and tumor cells

49. LEUKOCYTESGeneral Structural and Functional Characteristics • WBCs have the ability to slip out of the capillary blood vessels—process called diapedesis—and 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

50. LEUKOCYTESGeneral 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