1. Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. Chapter 18 APR Enhanced Lecture PowerPoint To run the animations you must be in Slideshow View. Use the buttons on the animation to play, pause, and turn audio/text on or off. Please Note: Once you have used any of the animation functions (such as Play or Pause), you must first click in the white background before you can advance to the next slide. 18-1

2. 18-2 The Circulatory System: Blood Introduction Erythrocytes Blood types Leukocytes Platelets and Hemostasis – The Control of Bleeding

3. 18-3 Circulatory System circulatory system consists of the heart, blood vessels and blood cardiovascular system refers only to the heart and blood vessels hematology – the study of blood functions of circulatory system –transport O 2, CO 2, nutrients, wastes, hormones, and stem cells –protection inflammation, limit spread of infection, destroy microorganisms and cancer cells, neutralize toxins, and initiates clotting –regulation fluid balance, stabilizes pH of ECF, and temperature control

4. Cardiovascular System Overview 18-4 Please note that due to differing operating systems, some animations will not appear until the presentation is viewed in Presentation Mode (Slide Show view). You may see blank slides in the “Normal” or “Slide Sorter” views. All animations will appear after viewing in Presentation Mode and playing each animation. Most animations will require the latest version of the Flash Player, which is available at http://get.adobe.com/flashplayer.

5. 18-5 Components and General Properties of Blood adults have 4-6 L of blood a liquid connective tissue consisting of cells and extracellular matrix –plasma – matrix of blood a clear, light yellow fluid –formed elements - blood cells and cell fragments red blood cells, white blood cells, and platelets

6. 18-6 Components and General Properties of Blood seven kinds of formed elements –erythrocytes - red blood cells (RBCs) –platelets cell fragments from special cell in bone marrow –leukocytes - white blood cells (WBCs) five leukocyte types divided into two categories: granulocytes (with granules) –neutrophils –eosinophils –basophils agranulocytes (without granules) –lymphocytes –monocytes

7. 18-7 Formed Elements of Blood Neutrophil Erythrocyte Eosinophil Monocyte Neutrophil Basophil Neutrophil Platelets Monocyte Small lymphocyte Young (band) neutrophil Small lymphocyte Large lymphocyte Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. Figure 18.1

8. 18-8 Separating Plasma From Formed Elements of Blood hematocrit - centrifuge blood to separate components –erythrocytes are heaviest and settle first 37% to 52% total volume –white blood cells and platelets 1% total volume buffy coat –plasma the remainder of volume 47% - 63% complex mixture of water, proteins, nutrients, electrolytes, nitrogenous wastes, hormones, and gases Figure 18.2 Centrifuge Withdraw blood Plasma (55% of whole blood) Buffy coat: leukocytes and platelets (<1% of whole blood) Erythrocytes (45% of whole blood) Formed elements Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display.

9. 18-9 Plasma and Plasma Proteins plasma – liquid portion of blood –serum – remaining fluid when blood clots and the solids are removed identical to plasma except for the absence of fibrinogen 3 major categories of plasma proteins –albumins – smallest and most abundant contributes to viscosity and osmolarity, influences blood pressure, flow and fluid balance –globulins (antibodies) provide immune system functions alpha, beta and gamma globulins –fibrinogen precursor of fibrin threads that help form blood clots plasma proteins formed by liver –except globulins ( produced by plasma cells)

10. 18-10 Nonprotein Components of Plasma nitrogenous compounds –free amino acids from dietary protein or tissue breakdown –nitrogenous wastes (urea) toxic end products of catabolism normally removed by the kidneys nutrients –glucose, vitamins, fats, cholesterol, phospholipids, and minerals dissolved O 2, CO 2, and nitrogen electrolytes –Na + makes up 90% of plasma cations

11. 18-11 Properties of Blood viscosity - resistance of a fluid to flow, resulting from the cohesion of its particles –whole blood 4.5 - 5.5 times as viscous as water –plasma is 2.0 times as viscous as water important in circulatory function osmolarity of blood - the total molarity of those dissolved particles that cannot pass through the blood vessel wall –if too high, blood absorbs too much water, increasing the blood pressure –if too low, too much water stays in tissue, blood pressure drops and edema occurs –optimum osmolarity is achieved by bodies regulation of sodium ions, proteins, and red blood cells.

12. 18-12 Starvation and Plasma Proteins hypoproteinemia –deficiency of plasma proteins extreme starvation liver or kidney disease severe burns kwashiorkor –children with severe protein deficiency fed on cereals once weaned –thin arms and legs –swollen abdomen

13. 18-13 Hemopoiesis adult production of 400 billion platelets, 200 billion RBCs and 10 billion WBCs every day hemopoiesis – the production of blood, especially its formed elements hemopoietic tissues produce blood cells –yolk sac produces stem cells for first blood cells colonize fetal bone marrow, liver, spleen and thymus –liver stops producing blood cells at birth –spleen remains involved with lymphocyte production –red bone marrow produces all seven formed elements pluripotent stem cells (PPSC) –formerly called hemocytoblasts or hemopoietic stem cells colony forming units – specialized stem cells only producing one class of formed element of blood myeloid hemopoiesis – blood formation in the bone marrow lymphoid hemopoiesis – blood formation in the lymphatic organs

14. Hemopoiesis 18-14 Please note that due to differing operating systems, some animations will not appear until the presentation is viewed in Presentation Mode (Slide Show view). You may see blank slides in the “Normal” or “Slide Sorter” views. All animations will appear after viewing in Presentation Mode and playing each animation. Most animations will require the latest version of the Flash Player, which is available at http://get.adobe.com/flashplayer.

15. 18-15 Erythrocytes two principal functions: –carry oxygen from lungs to cell tissues –pick up carbon dioxide from tissues and bring to lungs insufficient RBCs may kill in few minutes due to lack of oxygen to tissues Figure 18.4c Erythrocytes (c) 7 µm Capillary wall Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. © Dr. Don W. Fawcett/Visuals Unlimited

16. 7.5 µm 2.0 µm Sectional view(a) Surfaceview 18-16 Erythrocytes (RBCs) disc-shaped cell with thick rim –7.5  M diameter and 2.0  m thick at rim –lose nearly all organelles during development lack mitochondria –anaerobic fermentation to produce ATP lack of nucleus and DNA –no protein synthesis or mitosis –blood type determined by surface glycoprotein and glycolipids –cytoskeletal proteins (spectrin and actin) give membrane durability and resilience stretch and bend as squeeze through small capillaries Figure 18.4a Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display.

17. 18-17 RBC Form and Function gas transport - major function –increased surface area/volume ratio due to loss of organelles during maturation increases diffusion rate of substances –33% of cytoplasm is hemoglobin (Hb) 280 million hemoglobin molecules on one RBC O 2 delivery to tissue and CO 2 transport to lungs –carbonic anhydrase (CAH) in cytoplasm produces carbonic acid from CO 2 and water important role in gas transport and pH balance

18. 18-18 Hemoglobin (Hb) Structure each Hb molecule consists of: –four protein chains – globins –four heme groups heme groups –nonprotein moiety that binds O 2 to ferrous ion (Fe 2+ ) at its center globins - four protein chains –two alpha and two beta chains –5% CO 2 in blood is bound to globin moiety adult vs. fetal hemoglobin Figure 18.5 a-b (a) (b) C CH 3 C C C C C C C C C C C N N NN CH CH 2 COOH CH 3 CH 2 COOH CH 2 CH 3 HC C CC C Fe 2+ CH 2 Beta Alpha Beta Heme groups Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display.

19. 18-19 Erythrocytes and Hemoglobin RBC count and hemoglobin concentration indicate amount of O 2 blood can carry –hematocrit (packed cell volume) – percentage of whole blood volume composed of red blood cells men 42- 52% cells; women 37- 48% cells –hemoglobin concentration of whole blood men 13-18g/dL; women 12-16g/dL –RBC count men 4.6-6.2 million/  L; women 4-2-5.4 million/  L values are lower in women –androgens stimulate RBC production –women have periodic menstrual losses –hematocrit is inversely proportional to percentage of body fat

20. 18-20 Erythrocyte Production (Erythropoiesis) 2.5 million RBCs are produced per second average lifespan of about 120 days development takes 3-5 days –reduction in cell size, increase in cell number, synthesis of hemoglobin and loss of nucleus first committed cell - erythrocyte colony forming unit –has receptors for erythropoietin (EPO) from kidneys erythroblasts (normoblast) multiply and synthesize hemoglobin nucleus discarded to form a reticulocyte –named for fine network of endoplasmic reticulum –0.5 to 1.5% of circulating RBCs are reticulocytes Figure 18.6 ErythrocyteErythrocyte CFUErythroblastReticulocyte Pluripotent stem cell Colony-forming unit (CFU) Precursor cells Mature cell Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display.

21. 18-21 Iron Metabolism Figure 18.7 leaves 1 2 Gastroferritin 3 45 6 7 Remaining transferrin is distributed to other organs where Fe 2+ is used to make hemoglobin, myoglobin, etc. 8 Blood plasma Transferrin Ferritin Apoferritin Fe 2+ Fe 3+ Fe 2+ binds to apoferritin to be stored as ferritin In liver, some transferrin releases Fe 2+ for storage In blood plasma, Fe 2+ binds to transferrin Gastroferritin transports Fe 2+ to small intestine and releases it for absorption Fe 2+ binds to gastroferritin Stomach acid converts Fe 3+ to Fe 2+ Mixture of Fe 2+ and Fe 3+ is ingested Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display.

22. 18-22 Nutritional Needs for Erythropoiesis iron - key nutritional requirement –lost daily through urine, feces, and bleeding men 0.9 mg/day and women 1.7 mg/day –low absorption rate of iron requires consumption of 5-20 mg/day dietary iron: ferric (Fe 3+ ) and ferrous (Fe 2+ ) –stomach acid converts Fe 3+ to absorbable Fe 2+ –gastroferritin binds Fe 2+ and transports it to small intestine –absorbed into blood and binds to transferrin for transport to bone marrow, liver, and other tissues - bone marrow for hemoglobin, muscle for myoglobin, and all cells use for cytochromes in mitochondria liver apoferritin binds to create ferritin for storage

23. 18-23 Nutritional Needs for Erythropoiesis Vitamin B 12 and folic acid –rapid cell division and DNA synthesis that occurs in erythropoiesis Vitamin C and copper –cofactors for enzymes synthesizing hemoglobin copper is transported in the blood by an alpha globulin called ceruloplasmin

24. 18-24 Erythrocyte Homeostasis negative feedback control –drop in RBC count causes kidney hypoxemia –kidney production of erythropoietin stimulates bone marrow –RBC count increases in 3 - 4 days stimuli for increasing erythropoiesis –low levels O 2 (hypoxemia) –high altitude –increase in exercise –loss of lung tissue in emphysema Figure 18.8 leaves Hypoxemia (inadequate O 2 transport) Sensed by liver and kidneys Secretion of erythropoietin Accelerated erythropoiesis Increased RBC count Increased O 2 transport Stimulation of red bone marrow Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display.

25. 18-25 Erythrocytes Death and Disposal RBCs lyse in narrow channels in spleen macrophages in spleen –digest membrane bits –separate heme from globin globins hydrolyzed into amino acids iron removed from heme –heme pigment converted to biliverdin (green) –biliverdin converted to bilirubin (yellow) –released into blood plasma (kidneys - yellow urine) –liver removes bilirubin and secretes into bile - concentrated in gall bladder: released into small intestine; bacteria create urobilinogen (brown feces)

26. 18-26 Erythrocytes Recycle/Disposal Figure 18.9 Small intestine Globin Heme Iron Biliverdin Bilirubin Bile Feces StorageReuseLoss by menstruation, injury, etc. Amino acids Iron Folic acid Vitamin B 12 Nutrient absorption Erythrocytes circulate for 120 days Expired erythrocytes break up in liver and spleen Cell fragments phagocytized Erythropoiesis in red bone marrow Hemoglobin degraded Hydrolyzed to free amino acids Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display.

27. Please note that due to differing operating systems, some animations will not appear until the presentation is viewed in Presentation Mode (Slide Show view). You may see blank slides in the “Normal” or “Slide Sorter” views. All animations will appear after viewing in Presentation Mode and playing each animation. Most animations will require the latest version of the Flash Player, which is available at http://get.adobe.com/flashplayer.

28. 18-28 Erythrocyte Disorders polycythemia - an excess of RBCs –primary polycythemia (polycythemia vera) cancer of erythropoietic cell line in red bone marrow –RBC count as high as 11 million/  L; hematocrit 80% –secondary polycythemia from dehydration, emphysema, high altitude, or physical conditioning –RBC count up to 8 million/  L dangers of polycythemia –increased blood volume, pressure, viscosity can lead to embolism, stroke or heart failure

29. 18-29 Anemia causes of anemia fall into three categories: –inadequate erythropoiesis or hemoglobin synthesis kidney failure and insufficient erythropoietin iron-deficiency anemia inadequate vitamin B 12 from poor nutrition or lack of intrinsic factor (pernicious anemia) hypoplastic anemia – slowing of erythropoiesis aplastic anemia - complete cessation of erythropoiesis –hemorrhagic anemias from bleeding –hemolytic anemias from RBC destruction

30. 18-30 Anemia anemia has three potential consequences: –tissue hypoxia and necrosis patient is lethargic shortness of breath upon exertion life threatening necrosis of brain, heart, or kidney –blood osmolarity is reduced producing tissue edema –blood viscosity is low heart races and pressure drops cardiac failure may ensue

31. Sickle-Cell Disease hereditary hemoglobin defects that occur mostly among people of African descent caused by a recessive allele that modifies the structure of the hemoglobin molecule (HbS) –differs only on the sixth amino acid of the beta chain –HbS does not bind oxygen well –RBCs become rigid, sticky, pointed at ends –clump together and block small blood vessels causing intense pain –can lead to kidney or heart failure, stroke, rheumatism or paralysis 18-31 Figure 18.10 7 µm Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. © Meckes/Ottawa/Photo Researchers, Inc.

32. 18-32 Blood Types blood types and transfusion compatibility are a matter of interactions between plasma proteins and erythrocytes Karl Landsteiner discovered blood types A, B and O in 1900 –won Nobel Prize blood types are based on interactions between antigens and antibodies

33. 18-33 Blood Antigens and Antibodies antigens –complex molecules on surface of cell membrane that are unique to the individual used to distinguish self from foreign foreign antigens generate an immune response agglutinogens – antigens on the surface of the RBC that is the basis for blood typing antibodies –proteins (gamma globulins) secreted by plasma cells part of immune response to foreign matter bind to antigens and mark them for destruction forms antigen-antibody complexes agglutinins – antibodies in the plasma that bring about transfusion mismatch agglutination –antibody molecule binding to antigens –causes clumping of red blood cells

34. 18-34 Blood Types RBC antigens called agglutinogens –called antigen A and B –determined by carbohydrate moieties found on RBC surface antibodies called agglutinins –found in plasma –anti-A and anti-B Figure 18.12 leaves Type OType B Type AType AB Galactose Fucose N-acetylgalactosamine Key Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display.

35. 18-35 ABO Group your ABO blood type is determined by presence or absence of antigens (agglutinogens) on RBCs –blood type A person has A antigens –blood type B person has B antigens –blood type AB has both A and B antigens –blood type O person has neither antigen most common - type O rarest - type AB

36. 18-36 ABO Blood Typing Figure 18.14 Type A Type B Type AB Type O Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. © Claude Revey/Phototake

37. 18-37 Plasma Antibodies antibodies (agglutinins); anti-A and anti-B appear 2-8 months after birth; at maximum concentration at 10 yr. –antibody-A and/or antibody-B (both or none) are found in plasma you do not form antibodies against your antigens agglutination –each antibody can attach to several foreign antigens on several different RBCs at the same time responsible for mismatched transfusion reaction –agglutinated RBCs block small blood vessels, hemolyze, and release their hemoglobin over the next few hours or days –Hb blocks kidney tubules and causes acute renal failure

38. 18-38 Agglutination of Erythrocytes Figure 18.13 Antibodies (agglutinins) Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display.

39. 18-39 Transfusion Reaction Figure 18.15 leaves Blood from type A donor Agglutinated RBCs block small vessels Donor RBCs agglutinated by recipient plasma Type B (anti-A) recipient Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display.

40. 18-40 Universal Donors and Recipients universal donor –Type O – most common blood type –lacks RBC antigens –donor’s plasma may have both antibodies against recipient’s RBCs (anti-A and anti-B) may give packed cells (minimal plasma) universal recipient –Type AB – rarest blood type –lacks plasma antibodies; no anti- A or B

41. 18-41 Rh Group Rh (C,D,E) agglutinogens discovered in rhesus monkey in 1940 –Rh D is the most reactive and a patient is considered blood type Rh + if they have D antigen (agglutinogens) on RBCs –Rh frequencies vary among ethnic groups Anti-D agglutinins not normally present –form in Rh - individuals exposed to Rh + blood Rh - woman with an Rh + fetus or transfusion of Rh + blood no problems with first transfusion or pregnancy

42. 18-42 Hemolytic Disease of Newborn occurs if Rh - mother has formed antibodies and is pregnant with second Rh + child –Anti-D antibodies can cross placenta prevention –RhoGAM given to pregnant Rh - women binds fetal agglutinogens in her blood so she will not form Anti-D antibodies

43. 18-43 Hemolytic Disease of Newborn Rh antibodies attack fetal blood causing severe anemia and toxic brain syndrome leaves Uterus Placenta Rh  mother (a) First pregnancy(b) Between pregnancies(c) Second pregnancy Rh antigen Rh + fetus Amniotic sac and chorion Anti-D antibody Second Rh + fetus Figure 18.16 Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display.

44. 18-44 Leukocytes (WBCs) least abundant formed element –5,000 to 10,000 WBCs/  L protect against infectious microorganisms and other pathogens conspicuous nucleus spend only a few hours in the blood stream before migrating to connective tissue retain their organelles for protein synthesis granules –all WBCs have lysosomes called nonspecific (azurophilic) granules – inconspicuous so cytoplasm looks clear –granulocytes have specific granules that contain enzymes and other chemicals employed in defense against pathogens

45. 18-45 Types of Leukocytes granulocytes –neutrophils (60-70%)-polymorphonuclear leukocytes barely-visible granules in cytoplasm; 3 to 5 lobed nucleus –eosinophils (2-4%) large rosy-orange granules; bilobed nucleus –basophils (<1%) large, abundant, violet granules (obscure a large S-shaped nucleus) agranulocytes –lymphocytes (25-33%) variable amounts of bluish cytoplasm (scanty to abundant); ovoid/round, uniform dark violet nucleus –monocytes (3-8%) largest WBC; ovoid, kidney-, or horseshoe- shaped nucleus

46. 18-46 Granulocytes Figure TA 18.1Figure TA 18.2Figure TA 18.3 Neutrophils10 µmEosinophil10 µm Basophil 10 µm Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. all: © Ed Reschke

47. 18-47 Agranulocytes Figure TA 18.4Figure TA 18.5 Lymphocyte 10 µm Monocyte 10 µm Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. both: Michael Ross/Photo Researchers, Inc.

48. 18-48 Granulocyte Functions neutrophils - increased numbers in bacterial infections –phagocytosis of bacteria –release antimicrobial chemicals eosinophils - increased numbers in parasitic infections, collagen diseases, allergies, diseases of spleen and CNS –phagocytosis of antigen-antibody complexes, allergens, and inflammatory chemicals –release enzymes to destroy large parasites basophils - increased numbers in chicken pox, sinusitis, diabetes) –secrete histamine (vasodilator) – speeds flow of blood to an injured area –secrete heparin (anticoagulant) – promotes the mobility of other WBCs in the area

49. 18-49 Agranulocyte Functions lymphocytes - increased numbers in diverse infections and immune responses –destroy cells (cancer, foreign, and virally infected cells) –“present” antigens to activate other immune cells –coordinate actions of other immune cells –secrete antibodies and provide immune memory monocytes - increased numbers in viral infections and inflammation –leave bloodstream and transform into macrophages phagocytize pathogens and debris “present” antigens to activate other immune cells - antigen presenting cells (APCs)

50. 18-50 Complete Blood Count Hematocrit Hemoglobin concentration Total count for RBCs, reticulocytes, WBCs, and platelets Differential WBC count RBC size and hemoglobin concentration per RBC

51. 18-51 Leukocyte Life Cycle leukopoiesis – production of white blood cells –pluripotent stem cells – (PPSCs) myeloblasts – form neutrophils, eosinophils, basophils monoblasts - form monocytes lymphoblasts give rise to all forms of lymphocytes –T lymphocytes complete development in thymus red bone marrow stores and releases granulocytes and monocytes circulating WBCs do not stay in bloodstream –granulocytes leave in 8 hours and live 5 days longer –monocytes leave in 20 hours, transform into macrophages and live for several years –lymphocytes provide long-term immunity (decades) being continuously recycled from blood to tissue fluid to lymph and back to the blood

52. 18-52 Leukopoiesis Figure 18.18 leaves Lymphoblast B prolymphocyte B lymphocyte T lymphocyte NK cell T prolymphocyte NK prolymphocyte MonoblastPromonocyteMonocyte Basophil Eosinophil Neutrophil Pluripotent stem cell Colony-forming units (CFUs) Precursor cells Mature cells Eosinophilic myelocyte Eosinophilic promyelocyte Eosinophilic myeloblast Eosinophilic CFU Basophilic CFU Neutrophilic CFU Monocytic CFU Lymphocytic CFU Basophilic myeloblast Neutrophilic myeloblast Neutrophilic promyelocyte Basophilic promyelocyte Basophilic myelocyte Neutrophilic myelocyte Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display.

53. 18-53 Leukocyte Disorders leukopenia - low WBC count below 5000/  L –causes: radiation, poisons, infectious disease –effects: elevated risk of infection leukocytosis - high WBC count above 10,000/  L –causes: infection, allergy and disease –differential WBC count – identifies what percentage of the total WBC count consist of each type of leukocyte leukemia - cancer of hemopoietic tissue that usually produces an extraordinary high number of circulating leukocytes and their precursors –myeloid leukemia – uncontrolled granulocyte production –lymphoid leukemia - uncontrolled lymphocyte or monocyte production –acute leukemia – appears suddenly, progresses rapidly, death within months –chronic leukemia –undetected for months, survival time three years –effects - normal cell percentages disrupted; impaired clotting; opportunistic infections

54. 18-54 Normal and Leukemic Blood Figure 18.19 a-b Platelets Neutrophils Lymphocyte Erythrocytes (a) Monocyte (b) 75 µm Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. © Ed Reschke

55. 18-55 Hemostasis hemostasis – the cessation of bleeding –stopping potentially fatal leaks –hemorrhage – excessive bleeding three hemostatic mechanisms –vascular spasm –platelet plug formation –blood clotting (coagulation) platelets play an important role in all three

56. 18-56 Platelets platelets - small fragments of megakaryocyte cells –2-4  m diameter; contain “granules” –complex internal structure and open canalicular system –amoeboid movement and phagocytosis normal platelet count - 130,000 to 400,000 platelets/  L functions –secrete vasoconstrictors that help reduce blood loss –stick together to form platelet plugs to seal small breaks –secrete procoagulants or clotting factors promote clotting –initiate formation of clot-dissolving enzyme –chemically attract neutrophils and monocytes to sites of inflammation –phagocytize and destroy bacteria –secrete growth factors that stimulate mitosis to repair blood vessels

57. 18-57 Platelets Figure 18.20 a-b Platelets WBC RBC Megakaryocyte Pseudopod Granules Mitochondria (a) (b) Bloodflow Proplatelets Endothelium 2 µm Open canalicular system Sinusoid of bone marrow Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. a: NIBSC/Science Photo Library/Photo Researchers, Inc.

58. 18-58 Platelet Production -Thrombopoiesis stem cells (that develop receptors for thrombopoietin) become megakaryoblasts megakaryoblasts –repeatedly replicate DNA without dividing –forms gigantic cell called megakaryocyte with a multilobed nucleus 100  m in diameter, remains in bone marrow megakaryocytes – live in bone marrow adjacent to blood sinusoids –long tendrils of cytoplasm (proplatelets) protrude into the blood sinusoids – blood flow splits off fragments called platelets –circulate freely for 10 days –40% are stored in spleen

59. 18-59 Hemostasis all 3 pathways involve platelets Figure 18.21 a-c Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. (b) Platelet plug formation(c) Coagulation Vasoconstriction Platelet Endothelial cells Vessel injury Platelet plug Collagen fibers (a) Vascular spasm Blood clot

60. 18-60 Hemostasis - Vascular Spasm vascular spasm - prompt constriction of a broken vessel –most immediate protection against blood loss causes: –pain receptors some directly innervate blood vessels to constrict –smooth muscle injury –platelets release serotonin (vasoconstrictor) effects: –prompt constriction of a broken vessel pain receptors - short duration (minutes) smooth muscle injury - longer duration –provides time for other two clotting pathways

61. 18-61 Hemostasis -Platelet Plug Formation endothelium smooth, coated with prostacyclin – a platelet repellant platelet plug formation –broken vessel exposes collagen –platelet pseudopods stick to damaged vessel and other platelets - pseudopods contract and draw walls of vessel together forming a platelet plug –platelets degranulate releasing a variety of substances serotonin is a vasoconstrictor ADP attracts and degranulates more platelets thromboxane A 2, an eicosanoid, promotes platelet aggregation, degranulation and vasoconstriction –positive feedback cycle is active until break in small vessel is sealed

62. 18-62 Hemostasis - Coagulation coagulation (clotting) – last and most effective defense against bleeding –conversion of plasma protein fibrinogen into insoluble fibrin threads to form framework of clot procoagulants (clotting factors), usually produced by the liver, are present in plasma –activate one factor and it will activate the next to form a reaction cascade extrinsic pathway –factors released by damaged tissues begin cascade intrinsic pathway –factors found in blood begin cascade (platelet degranulation)

63. 18-63 SEM of Blood Clot Figure 18.22 Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. © P. Motta/SPL/Photo Researchers, Inc.

64. 18-64 Coagulation Pathways extrinsic pathway –initiated by release of tissue thromboplastin (factor III) from damaged tissue –cascade to factor VII, V and X (fewer steps) intrinsic pathway –initiated by platelets releasing Hageman factor (factor XII ) –cascade to factor XI to IX to VIII to X calcium required for either pathway Figure 18.23 Inactive Extrinsic mechanismIntrinsic mechanism Factor V Factor XIIPlatelets Fibrin Thrombin Factor VII Inactive Ca 2+ Damaged perivascular tissues Thromboplastin (factor III) Factor VIII (active) Ca 2+, PF 3 Factor IX (active) Factor XI (active) Factor X (active) Factor III Factor V Ca 2+ PF 3 Prothrombin activator Prothrombin (factor II) Fibrinogen (factor I) Fibrin polymer Factor XIII Ca 2+ Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display.

65. 18-65 Enzyme Amplification in Clotting rapid clotting - each activated cofactor activates many more molecules in next step of sequence Fibrin Thrombin Reaction cascade (time) Prothrombin activator Factor XII Factor XI Factor IX Factor VIII Factor X Figure 18.24 Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display.

66. 18-66 Completion of Coagulation activation of factor X –leads to production of prothrombin activator prothrombin activator –converts prothrombin to thrombin thrombin –converts fibrinogen into fibrin positive feedback - thrombin speeds up formation of prothrombin activator

67. 18-67 Fate of Blood Clots clot retraction occurs within 30 minutes platelet-derived growth factor secreted by platelets and endothelial cells –mitotic stimulant for fibroblasts and smooth muscle to multiply and repair damaged vessel fibrinolysis - dissolution of a clot –factor XII speeds up formation of kallikrein enzyme –kallikrein converts plasminogen into plasmin, a fibrin-dissolving enzyme that breaks up the clot

68. 18-68 Blood Clot Dissolution positive feedback occurs plasmin promotes formation of fibrin PlasminPlasminogen Clot dissolution Kallikrein Prekallikrein Factor XII Positive feedback loop Fibrin polymer Fibrin degradation products Figure 18.25 Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display.

69. 18-69 Prevention of Inappropriate Clotting platelet repulsion –platelets do not adhere to prostacyclin-coating thrombin dilution –by rapidly flowing blood heart slowing in shock can result in clot formation natural anticoagulants –heparin (from basophils and mast cells) interferes with formation of prothrombin activator –antithrombin (from liver) deactivates thrombin before it can act on fibrinogen

70. 18-70 Clotting Disorders - Hemophilia deficiency of any clotting factor can shut down the coagulation cascade hemophilia – family of hereditary diseases characterized by deficiencies of one factor or another sex-linked recessive (on X chromosome) –hemophilia A missing factor VIII (83% of cases) –hemophilia B missing factor IX (15% of cases) note: hemophilia C missing factor XI (autosomal) physical exertion causes bleeding and excruciating pain –transfusion of plasma or purified clotting factors –factor VIII produced by transgenic bacteria hematomas – masses of clotted blood in the tissues

71. 18-71 Coagulation Disorders thrombosis - abnormal clotting in unbroken vessel –thrombus - clot most likely to occur in leg veins of inactive people –pulmonary embolism - clot may break free, travel from veins to lungs embolus – anything that can travel in the blood and block blood vessels infarction (tissue death) may occur if clot blocks blood supply to an organ (MI or stroke) –650,000 Americans die annually of thromboembolism – traveling blood clots

72. 18-72 Clinical Management of Clotting goal - prevent formation of clots or dissolve existing clots preventing clots –Vitamin K is required for formation of clotting factors coumarin (Coumadin) is a vitamin K antagonist –aspirin suppresses thromboxane A 2 –other anticoagulants discovered in animal research medicinal leeches used since 1884 (hirudin) snake venom from vipers (Arvin)

73. 18-73 goal - prevent formation of clots or dissolve existing clots dissolving clots that have already formed –streptokinase – enzyme make by streptococci bacteria used to dissolve clots in coronary vessels digests almost any protein –tissue plasminogen activator (TPA) – works faster, is more specific, and now made by transgenic bacteria –hementin – produced by giant Amazon leech Clinical Management of Clotting