Biology 221 Anatomy Physiology II TOPIC 1 Circulatory

Biology 221 Anatomy & Physiology II TOPIC 1 Circulatory System – Blood Chapter 17 pp. 644 -674 E. Lathrop-Davis / E. Gorski / S. Kabrhel

Major Components • Blood • Heart • Blood vessels Fig. 19. 2, p. 715 Good website: http: //www. fpnotebook. com/HEM. htm 2

Major Functions • Transport – carries nutrients, wastes, gases, hormones, etc. • Protection – against disease and toxins – against blood loss • Regulation – blood pressure – blood volume – body temperature 3

Physical Characteristics of Blood • Specific gravity = 1. 045 -1. 065 • Viscosity (relative to water) = 4. 5 -5. 5 • p. H = 7. 35 – 7. 45 – Acidemia – Alkalemia • Volume = 7 -9% of body weight – 5 -6 L in adult males – 4 -5 L in adult females • Temperature ~ 100. 4 o. F (38 o. C) 4

N Composition of Blood • Matrix (plasma) – ground substance (serum) – plasma proteins • Cells & cell fragments = “formed elements” • Think Spot: Classify blood as one of the 4 major tissue types 5

N Plasma: Definition and Composition • Plasma = whole blood minus formed elements • Serum = plasma minus clotting proteins • Constituents (Table 17. 1, p. 647) – 92% water – 7% plasma proteins, most made by liver – 1% non-protein solutes, including: • electrolytes – Example? • organic nutrients and wastes – Example? • respiratory gases – Example? 6

N Plasma Proteins • Albumins (~ 60% of plasma proteins) – exert osmotic force – buffer p. H • Globulins (~ 36%) – immunoglobulins (antibodies) protect against disease – transport proteins bind: • ions (e. g. , transferrin) and small molecules that would otherwise be lost • fatty acids, thyroid and steroid hormones 7

Plasma Proteins (con’t) • Fibrinogen and other clotting factors (~ 4% of all plasma proteins) • Other plasma proteins: – hormones (e. g. , insulin, glucagon; see A&P I Endocrine System) – enzymes (e. g. , renin; see Topic 10 Urinary System) – antibacterial proteins (e. g. , complement; see Topic 6) 8

N Formed Elements • Erythrocytes = RBCs transport respiratory gases • Leukocytes = WBCs protect against disease • Thrombocytes = platelets are involved in hemostasis 9

RBCs: Functions • Transport of respiratory gases (by hemoglobin) – transports about 98. 5% of O 2 (oxyhemoglobin) – transport about 23% of CO 2 (carbaminohemoglobin) • Aids conversion of CO 2 to bicarbonate (HCO 3 -; Topic 7 Respiratory System) 10

N RBCs: Characteristics • Life span up to 120 days • Small, biconcave disk • Anucleate, no ribosomes, no mitochondria – Think Spot: • Can RBCs replicate? • Can RBCs make new protein? • What type of ATP synthesis can RBCs do? http: //www. vh. org/adult/provider/pathology/CLIA/Hematology/14 Red. Cell. html 11

N RBCs: Oxygen Transport Capacity Ability to transport O 2 depends on: • RBC Size • RBC Abundance • Amount of hemoglobin 12

N RBCs: Size • Normal diameter = 7 -8 micrometers (μm) • Mean corpuscular volume (MCV) = average volume of individual RBCs in sample – microcytic – macrocytic Fig. 17. 3, p. 648 13

N RBCs: Abundance • Red blood cell count (part of complete blood cell count with differential white blood cell count, also called “CBC w/diff”) • Hematocrit = packed cell volume (PCV) 14

RBC Abundance: Red Blood Cell Count N • RBCs normally >95% of all formed elements • Normal values: – males: 4. 5 -6. 3 x 106 / mm 3 (microliter) – females: 4. 2 -5. 5 x 106 / mm 3 • Polycythemia: 8 -11 x 106 / mm 3 – Primary polycythemia (polycythemia vera) caused by cancer – Secondary polycythemia (erythrocytosis) caused by decreased oxygen to kidney • renal hypoxia • high altitude 15

RBC Abundance: Hematocrit (PCV) • Ratio of formed elements to whole blood sample expressed as percentage – males: average 45% (range: 40 -54%) – females: average 42% (range 37 -47%) – minimum hematocrit to donate blood = 38% • Separates formed elements from plasma by centrifuging tiny sample of blood – >95% of formed elements are RBCs – “buffy coat” is WBCs and platelets Fig. 17. 1, p. 645 16

N RBC Abundance: Hematocrit • Blood doping – reinfusion of packed RBCs to increase hematocrit • Think Spot: – Why would blood doping be advantageous to athletes? – Which athletes would benefit most? 17

N RBCs: Hemoglobin (Hb) Structure • Globular protein with 4 protein chains: 2 alpha chains & 2 beta chains • Heme – non-protein molecule consisting of porphyrin ring with 1 iron (Fe) atom at center – 1 heme per protein chain – 1 iron binds 1 O 2 – Think Spot: • How many heme per Hb? • How many O 2 can each Hb bind? Fig. 17. 4, p. 649 18

N RBCs: Hemoglobin (Hb) Content • Accounts for > 95% of protein in RBC • Measured as g/dl using hemoglobinometer • Average values: – male: 14 -18 g/dl – female: 12 -16 g/dl – infants: 14 -20 g/dl 19

N RBCs: Hemoglobin (Hb) Content • Mean corpuscular Hb (MCH) = average mass of Hb in one RBC • Measured as hemoglobin concentration /number of RBCs – Think Spot: What measurements do you need to know? • Cells described based on color – normochromic – hyperchromic 20

RBCs: Hemoglobin-Related Disorders • Porphyria – lack of enzymes required to complete Hb synthesis leads to build up of intermediates – deposition in tissues causes: • skin lesions on exposure to sunlight leading to scarring • degeneration of nose and ear cartilage • Genetic anemias (linked to malaria survival) – Thalassemia – Sickle cell anemia 21

RBCs: Thalassemia • Genetic inability to produce adequate amounts of alpha or beta chains • Results in limited production of fragile, short-lived RBCs often with odd shapes • More common in people of Mediterranean descent http: //www. bloodline. net/s tories/story. Reader$2344 22

RBCs: Sickle-cell Anemia • Genetic mutation in which 7 th amino acid in beta chain is changed • Causes Hb. S molecules to stick when oxygen is not bound leading to characteristic sickle shape of RBCs • More common in people of African descent http: //www. sunyniagara. cc. ny. us/val/ sicklecellhigh. html 23

N RBCs: Erythropoiesis - Locations • 1 st 8 weeks of embryonic development, RBCs formed in yolk sac • 2 nd to 5 th months of fetal development, RBCs formed in liver (main supplier) and spleen • 5 th month on, RBCs formed in red bone marrow (myeloid tissue) • Post-natal development, formed in red bone marrow – portions of: vertebrae, ribs, scapula, skull, pelvis, proximal heads of femur and humerus 24

RBCs: Stages of Erythropoiesis Formed from hemocytoblasts Early stages differentiate and produce hemoglobin Normoblasts – lose nucleus, some mitochondria Fig. 17. 5, p. 650 25

Stages of Erythropoiesis (con’t) Reticulocytes – have ribosomes & mitochondria (no nucleus) – leaves bone marrow after ~ 2 days – reticulocyte count: normally ~ 0. 8% (0. 82. 0%) of circulating RBC population; indicator of RBC production levels Mature erythrocyte Fig. 17. 5, p. 650 26

N RBCs: Control of Erythropoiesis • Erythropoietin secreted by kidney under hypoxic conditions: – anemia – decreased blood flow to kidney – decreased oxygen availability • Erythropoietin stimulates: – increased division of stem cells and erythroblasts – increased maturation and production of Hb Fig. 17. 6, p. 651 27

Think-Pair-Share: Erythropoiesis Identify the parts of the feedback loop that controls erythropoiesis (is this negative or positive feedback? ) Stimulus Renal hypoxia Control Erythropoietin (secreted by kidney) Effect Increases development of cells and production of Hb Negative Type of feedback 28

RBCs: Other Factors Influencing Erythropoiesis N • Androgens (testosterone) and growth hormone - stimulate erythropoiesis • Adequate diet – amino acids (for globin) – vitamins (B 12, folic acid) • Folate: leafy greens (especially spinach) • Vitamin B 12: eggs, meat, poultry, fish, dairy products, soy – iron (Fe) – red meats, raisins, leafy greens (especially spinach), kidney beans 29

RBCs: Diet Related Anemias • Pernicious anemia – lack of Vit. B 12 due to deficiency of intrinsic factor produced by gastric mucosa (see Topic 8) – Vit. B 12 important to DNA synthesis – RBCs enlarge but don’t divide, erythrocytes are macrocytic and normo- or hyperchromic • Iron-deficiency anemia – deficiency of iron in diet or inability to absorb iron; secondary to hemorrhagic anemia – RBCs are microcytic and hypochromic 30

N RBCs: Erythrocyte Recycling • 10% hemolyzed before degradation • 90% phagocytized by macrophages in spleen, liver, bone marrow • Amino acids released into blood • Heme broken into Fe and porphyrin ring See Fig. 17. 7, p. 652 31

N RBCs: Erythrocyte Recycling • Fe transported by transferrin to: – red bone marrow for reincorporation into Hb, or – liver or spleen for storage in ferritin or hemosiderin • Porphyrin ring of heme converted to bilirubin (or related substances) – excreted in bile and released in feces – excreted in urine 32

RBCs: Disorders of Erythrocyte Recycling N Jaundice • Yellowish color caused by deposition of bilirubin in skin due to hyperbilirubinemia • Caused by: – liver dysfunction (fails to process bilirubin properly) – blockage of bile ducts – excessive rupture of RBCs (e. g. , neonatal jaundice or transfusion reaction) 33

N RBCs: Blood Typing • Based on surface antigens (agglutinogens) • At least 50 kinds of proteins used; most common: – ABO blood group – Rh factor (D) • Testing relies on antigen-antibody reaction (agglutination) • For the ABO group, person makes antibodies (agglutinins) against antigens s/he doesn’t have 34

Think-Pair-Share: ABO Types Blood Type Agglutinogens Present Reacts with Agglutinins for Testing Person Makes Agglutinins A B AB[1] O[2] A B A&B neither Anti-A Anti-B neither Anti-B Anti-A neither Anti-A Anti-B O A, B, AB, O May Receive Blood From: A, O B, O A, B, AB, O May Give Blood To: A, AB B, AB AB [1] Universal Recipient [2] Universal Donor Table 17. 4, p. 668 35

ABO Blood Types Blood Type A B AB[1] O[2] Genotype IAIA or IAi IBIB or IBi IAIB ii Rh Factor Present or Absent (A+ or A-) Present or Absent (B+ or B-) Present or Absent (AB+ or AB-) Present or Absent (O+ or O-) http: //sln. fi. edu/biosci/blood/types. html http: //www. biology. arizona. edu/human_bio/problem_sets /blood_types/Intro. html [1] Universal Recipient [2] Universal Donor 36

Think-Pair-Share: Rh Blood Types Blood Type Agglutinogen D: Present or Absent Makes Agglutinins Against Agglutinogen: May Receive Blood From: May Give Blood To Without Reaction[2]: Genotype Rh+ Rh- Present Absent No Yes [1] Rh+ or Rh- [2] Rh+ or Rh‑ DD or Dd dd [1] Only makes antibodies (agglutinins) after exposure to Rh+ blood cells (via transfusion or during birth process) [2] Transfusion of Rh- individual with Rh+ blood results in production of anti-D agglutinins; sensitizes person to Rh factor and may result in anaphylaxis if exposed a second time. 37

N Blood Typing Disorders • Cross reactions – caused by giving blood type to which recipient has antibodies – cause agglutination (clumping) in vivo • Erythroblastosis fetalis – occurs when Rh - mother who has been exposed to Rh+ blood is carrying Rh+ fetus antibodies from mother cross placenta and attack fetal blood cells – Rho. GAM® agglutinates anti-Rh antibodies – Think Spot: What was the father’s Rh? 38

N RBCs: Other Anemias • Hemolytic anemia – RBCs break faster than they can be replaced – Causes include: transfusion reactions, sickle cell anemia, severe burns, reactions to certain toxins, some infections – Hemoglobinuria - Hb in urine due to increased release into blood • Hemorrhagic anemia – heavy bleeding (RBCs are normal in color and size but fewer than normal in number) 39

Think-Pair-Share: Anemia Identify the major types of anemia and their causes Type Cause Thalassemia Inability to produce alpha or beta chain Sickle cell Defect of beta chain Pernicious Low vit. B 12 due to lack of intrinsic factor Iron-deficiency Lack of iron in diet or inability to absorb Hemolytic Premature rupture of RBCs Hemolytic Bleeding 40

WBCs: Functions • Fight pathogens and provide both innate and adaptive immunity (see Topic 6) – pathogens = disease-causing agents • “microbes” include: bacteria, fungi (yeasts and molds), viruses, protozoa, algae • Clear debris from damaged areas (e. g. , during neuron regeneration; see A&P I: Spinal Nerves) • Fight cancer and virally-infected cells 41

WBCs: Types • Granulocytes contain stainable granules in cytoplasm – Neutrophils (10 -12 µm in diameter) – Eosinophils (10 -14 µm in diameter) – Basophils (8 -10 µm in diameter ) • Agranulocytes lack stainable granules – Lymphocytes (variable size; 5 -17 µm in diameter) – Monocytes (largest; 18 µm in diameter) 42

Granulocytes: Neutrophils • 50 -70% of WBCs (Marieb, 6 th Ed. ) • Phagocytic, especially against bacteria – Large number of lysosomes in cytoplasm • Highly mobile with short life spans (~ 10 hrs; less if highly active) • Neutrophilia – increase associated with acute bacterial infections http: //www. usc. edu/hsc/dental/ ghisto/bld/d_1. html 43

Granulocytes: Eosinophils • 2 -4% of WBCs (Marieb, 6 th Ed. ) • Phagocytize antibody-covered objects (especially worms); release cytotoxic enzymes onto target parasites • Lessens severity of allergic reactions by phagocytizing antibody-covered particles • Eosinophilia – increase associated with parasitic worm infections http: //www. funsci. com/fun 3_en/blood. htm#5 44

Granulocytes: Basophils • • < 1% (Marieb, 6 th Ed. ) Release histamine and heparin Associated with inflammation Basophilia – increase in number of basophils associated with allergic reactions and chronic inflammatory diseases http: //image. bloodline. net/ stories/story. Reader$1600 45

N Agranulocytes: Lymphocytes • 25 -45% (Marieb, 6 th Ed. ) • Most remain in lymphatic tissue (see Topics 5 and 6) • Increase associated with several types of infections, especially viral http: //www. usc. edu/hsc/dental /ghisto/bld/d_5. html 46

N Agranulocytes: Monocytes • 3 -8% (Marieb, 6 th Ed. ) • Some become fixed or wandering macrophages within tissues • Phagocytize viruses, debris, bacteria; enhance scar tissue formation • Associated with chronic infection http: //www. usc. edu/hsc /dental/ghisto/bld/d_6. html 47

Agranulocyte Disorders: Infectious Mononucleosis N • Highly contagious viral disease • Symptoms include large numbers of atypical agranulocytes, fatigue, soreness, chronic sore throat, low-grade fever http: //www. wadsworth. org/chemheme/microscope /atypicallymphocyte. htm http: //image. bloodline. net/stories/story. Reader$678 48

WBCs: Abundance • Normal = 4, 800 -10, 800 cells / mm 3 • Measured as part of a “CBC w/diff” – White blood cell count • number of WBCs in a sample – Differential WBC Count • relative abundance of different kinds of WBCs • count number of each different type in a total of 100 WBCs 49

Think-Pair-Share: Differential WBC Count List the types of WBCs in order of abundance and indicate whether each is a granulocyte or an agranulocyte Fig. 17. 9, p. 655 Type of WBC Most: Neutrophil Granulocyte/Agranulocyte Granulocyte Lymphocyte Agranulocyte Monocyte Agranulocyte Eosinophil Granulocyte Least: Basophil Granulocyte 50

WBCs: Abundance Disorders • Leukopenia < 4, 800 cells / mm 3 – Response to some drugs and some autoimmune disorders • Leukocytosis > 11, 000 cells / mm 3 – normal with disease – > 100, 000 WBCs / mm 3 not uncommon with leukemia 51

Leukopoiesis • Formation of WBCs • All arise from hemocytoblasts • Controlled by: – cytokines – thymic hormones (thymosin) – presence of antigens 52

Control of Leukopoiesis • Cytokines – Colony stimulating factors (CSFs) • stimulate production and development • named according to WBC type stimulated • multi-CSF stimulates production of all types plus platelets – Interleukins • released by WBCs; affect activity of other WBCs • most important to lymphocyte production 53

Control of Leukopoiesis • Thymic hormones (thymosin) promote differentiation and maintenance of T cell lymphocytes • Presence of antigens stimulates lymphocyte production (see Topic 6) 54

Leukopoiesis: Lymphocytes Hemocytoblasts lymphoid stem cells lymphoblasts intermediate stages lymphocytes Fig. 17. 11, p. 659 55

Leukopoiesis: Monocytes & Granulocytes Hemocytoblasts myeloid stem cells monoblasts monocytes or myeloblast differentiated myelocytes various band cells various granulocytes Fig. 17. 11, p. 659 56

N Leukopoiesis Disorders: Leukemia • Cancer of WBC producing cells • Named according to cell type involved – e. g. , myelocytic leukemia • Acute leukemia – comes from “-blast” cells – occurs more often in children • Chronic leukemia – comes from later stages – more common in elderly 57

Platelet Functions • Platelet plug formation • Enhance clotting • Clot retraction 58

Platelet: Description & Abundance • Small (2 -4 µm in diameter), anucleate cell fragments • Short-lived (5 -10 days) • Normal abundance: 150, 000 – 400, 000 platelets / mm 3 of plasma 59

Platelets: Abundance Disorders • Thrombocytopenia < 80, 000/mm 3 – caused by excess platelet destruction or inadequate production – symptoms include bleeding in digestive tract, skin, CNS • Thrombocytosis > 500, 000 / mm 3 – caused by infection, inflammation, cancer 60

Platelet Formation and Control • Formation: – hemocytoblasts megakaryocyte platelet • Regulation: – thrombopoietin (TPO or thrombocytestimulating factor) from kidneys – multi-CSF Fig. 17. 12, p. 660 61

Hemostasis • Stoppage of bleeding • 3 Phases (each with its own major mechanisms): – Vascular phase (vascular spasm) – Platelet phase (platelet plug formation) – Coagulation (clotting ) 62

Vascular Phase • Very rapid response • Vascular spasm – contraction of vessel smooth muscle • Endothelial cells – contract to pull vessel walls closer together – release chemicals that stimulate vascular spasm & division of endothelial cells, smooth muscle cells and fibroblasts – in capillaries, endothelial cells on opposite sides become sticky and adhere to each other to close vessel 63

Platelet Phase – Stages of Platelet Plug Formation 1. Platelet adhesion – platelets stick to collagen fibers exposed by break in vessel – Aided by von Willebrand factor (VWF) from endothelial cells 2. Platelet aggregation – activated platelets change shape & develop processes to reach out to other platelets 64

Platelet Plug Formation • Encounter between platelet and fiber causes release of platelet chemicals • Chemicals attract more platelets to affected area and induce changes in them resulting in adherence and aggregation of more platelets • Think Spot: What type of feedback is this? Fig. 1. 6, p. 12 65

Chemicals That Stimulate Platelet Plug Formation N Activated platelets release chemicals that enhance hemostasis: • protein clotting factors • calcium ions (clotting factor IV) • ADP • thromboxane A 2 • serotonin • platelet-derived growth factor 66

Natural Limits to Platelet Plug Formation • Prostacyclin (PGI 2; local prostaglandin) that inhibits platelet aggregation • Inhibiting compounds secreted by WBCs • Clotting (isolates platelet plug from circulation) • Antithrombin (inhibits action of thrombin) 67

Coagulation (Clotting) Phase • Series of reactions resulting in formation of insoluble fibrin fibers • Reactions occur as cascades resulting in large amount of fibrin formed from small amount of initial reactants • Positive feedback loop in which thrombin, produced by common pathway, stimulates formation of tissue factor and release of PF-3 from platelets used in early stages 68

Pathways of Coagulation • Two initial pathways share a common pathway at the end; differ in starting point and stimulus • Intrinsic pathway – many steps; slower – starts with activation of proenzymes in blood – may occur within an unbroken vessel • Extrinsic pathway – fewer steps; faster – starts with tissue factor (factor III) 69

N Pathways of Coagulation • Common pathway – from formation of prothrombin activator* to formation of fibrin from fibrinogen Fig. 17. 13 a and b, p. 663 70

N Coagulation Requirements • Clotting factors (procoagulants) – protein enzymes – synthesized by liver (synthesis of 4 factors by liver requires vitamin K) • Ca 2+ ions • Fibrinogen (also made by liver) 71

N Measuring Coagulation • Partial thromboplastin time (PTT) – Tests intrinsic and common pathways – Used to monitor patients on heparin • Prothrombin Time – Tests extrinsic and common pathways – Used to monitor patients on warfarin (Coumadin) 72

N Measuring Coagulation • Bleeding time – Time for small puncture wound to stop bleeding (in vivo) – Used to detect platelet defects 73

Clot Retraction • Platelets that adhere to fibrin fibers • Contraction of platelets pulls torn edges of vessel together • Reduces size of damaged area 74

Fibrinolysis • Breakdown of fibrin fibers by plasmin • Plasmin is formed from inactive precursor called plasminogen • Plasminogen is activated by: – thrombin and activated factor XII produced by common pathway of clotting – tissue plasminogen activator (TPA) produced by damaged tissues 75

Natural Control of Clotting • Dilution of procoagulants • Plasma anticoagulants – e. g. , antithrombin III produced by platelets – inactivate thrombin • Heparin – released by basophils and mast cells – accelerates activity of antithrombin III 76

Clinical Control of Clotting • Heparin interferes with conversion of prothrombin to thrombin; enhances action of antithrombin III • Aspirin interferes with platelet aggregation • Warfarin (Coumadin) interferes with production of clotting factors that require vit. K for synthesis • Think Spot: Which would be fastest? 77

N Bleeding Disorders • Hemophilia – include recessive, X-linked genetic (more common) and autosomal diseases – adequate amounts of functional clotting factors are not made • von Willebrand disease – common genetic bleeding disorder (autosomal dominant) – failure to make adequate amounts of von Willebrand’s factor, which stabilizes factor VIII and stimulates platelet adhesion 78

Thromboembolytic Disorders: Thrombus • Clot in intact vessel wall • Thrombosis – obstruction caused by thrombus • Deep vein thrombosis (DVT) – obstruction in vein (most often in leg or pelvis) – Major causes of DVT: • Trauma http: //hcd 2. bupa. co. uk/fact_sheets • Inactivity /mosby_factsheets/Deep_Vein_Thr ombosis. html • Surgery 79

Thromboembolitic Disorders: Embolus N • Abnormal mass in blood, especially a clot • May result in embolism (blockage of vessel) and cause ischemia (decrease in blood supply) and infarct (tissue necrosis) – pulmonary embolism (emboli) – stroke – myocardial infarct 80

N Thromboembolitic Disorders: DIC • Disseminated Intravascular Coagulation – reaction to sepsis, massive trauma, transfusion reactions, abruptio placentae, certain toxins (e. g. , some snake venoms), ebola virus infection – initially, clotting is widespread resulting in overuse of platelets and procoagulants – leads to tissue damage due to blockage of small vessels by fibrin deposition – leads to abnormal bleeding due to decrease in available procoagulants 81