IBHS 527 lecture 1

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IBHS 527 lecture 1
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2011-01-21 23:38:42
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blood: plasma and platelets. THE first lecture of spring semester ... get ready to rumble!
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  1. 3 components of the Cardiovascular system
    • 1. pump - heart
    • 2. conducting system - blood vessels
    • 3. fluid medium - blood (specialized fluid of connective tissue which contains cells suspended in a fluid matrix known as plasma)
  2. 4 functions of blood
    • 1. transport: dissolved gases, nutrients, hormones, and waste
    • -via RBCs and plasma
    • 2. defend: against toxins and pathogens
    • -via circulating WBCs and antibodies
    • 3. contain: minimizes fluid loss at injury site
    • -via platelets (clot) and vasoconstriction
    • 4. regulate:
    • a) body temperature by absorbing and redistributing heat
    • -via vasoconstriction and vasodilation
    • b) pH and ion composition
    • -blood absorbs acids generated by active tissues
    • -diffusion between ECF and blood eliminates ion gradients
  3. 4 physical characteristics of blood
    • 1. volume:
    • -average male: 5.5 liters
    • -average female: 4.5 liters
    • depends on body size differences, ~7% of body weight
    • 2. viscosity (viscosity is resistance of fluid to flow resulting from cohesion of its particles. Due to interactions of dissolved proteins formed elements and water molecules in plasma):
    • -5X more viscous than water: 5X more sticky
    • -5X more cohesive, resistant to flow
    • 3. temperature: 37-38 degrees celcius = slightly above normal body temp
    • 4. pH:
    • -avg - 7.40 (slightly alkaline)
    • -physiological range - 7.35-7.45
  4. whole blood is made of 2 parts
    • 1. plasma
    • 2. formed elements
  5. context: 2 parts of whole blood
    plasma
    fluid consisting of water, dissolved plasma proteins and other solutes
  6. context: 2 parts of whole blood
    formed elements
    bloods cells and cell fragments suspended in plasma
  7. context: 2 parts of whole blood
    3 types of formed elements
    • 1. red blood cells
    • 2. white blood cells
    • 3. platelets
  8. context: 3 types of formed elements
    red blood cells
    • erythrocyte/red corpuscle
    • more numerous, transport oxygen
  9. context: 3 types of formed elements
    white blood cells
    • leukocyte
    • less numerous, five classes, defense/immune
  10. context: 3 types of formed elements
    platelets
    small membrane bound cell fragments contain enzymes and substances important for clotting
  11. 3 layers of blood after centrifuge
    • 1. plasma (top): proteins-water-other solutes
    • 2. buffy coat: platelets-white blood cells
    • 3. erythrocytes (bottom) -significantly more (4.2-6.2 million)
  12. 5 types of WBCs (white blood cells)
    • 1. neutrophils (60-70%) most
    • 2. lymphocytes (20-25%)
    • 3. monocytes (3-8%)
    • 4. eosinophils (2-4%)
    • 5. basophils (0.5-1%) least
    • "Never Let Monkeys Eat Bananas"
  13. T/F
    red blood cells: biconcave discs, nucleated, contain hemoglobin; transport nitrogen and carbon dioxide
    FALSE. nucleated --> Anucleated (without nucleus); nitrogen --> oxygen (duh)
  14. 2 categories of white blood cells (leukocytes)
    • 1. granulocytes: cytoplasm contains large granules; have multi-lobed nuclei
    • 2. agranulocytes: cytoplasm contains small granules and nuclei that are not lobed
  15. context: granulocytes vs agranulocytes
    lymphocytes
    agranulocytes
  16. context: granulocytes vs agranulocytes
    eosinophils
    granulocytes
  17. context: granulocytes vs agranulocytes
    neutrophils
    granulocytes
  18. context: granulocytes vs agranulocytes
    monocytes
    agranulocytes
  19. context: granulocytes vs agranulocytes
    basophils
    granulocytes
  20. platelets in birds and reptiles (nonmammalian vertebrates)
    thrombocytes (nucleated cells)
  21. General composition of plasma
    • pale, yellow color
    • colloid: a liquid substance containing suspended substances that do not settle out of solution
  22. 3 parts of plasma
    • 1. water: 92%
    • 2. proteins: 7%
    • 3. other solutes: 1%
  23. T/F
    plasma proteins can cross the capillary wall
    • FALSE.
    • large size and globular shape of most plasma proteins prevents them from crossing capillary wall and therefore they remain trapped in circulatory systems
  24. context: 3 parts of plasma
    4 types of plasma proteins
    • 1. albumin (most)
    • 2. globulin
    • 3. fibrinogen
    • 4. regulatory proteins (least)
  25. context: 4 types of plasma proteins
    albumin
    • 60% (of 7% that is proteins of plasma)
    • 2 functions:
    • 1. viscosity and osmotic pressure of blood (total molarity of that that pass across the wall):
    • -indirectly regulates ECF volume
    • 2. transport:
    • (a) fatty acids, (b) thyroid hormones, (c) steroid hormones, (d) drugs
  26. context: 4 types of plasma proteins
    globulins
    • 35% (of 7% that is proteins in plasma)
    • 2 functions:
    • 1. immunoglobulins: aka antibodies; defense
    • 2. transport globulins: bind small ions, hormones or compounds that might be lost in kidney or have low solubility
  27. context: 4 types of plasma proteins
    examples of transport globulins
    • 1. ions: ex. is metalloproteins (Fe2+ via transferrin)
    • 2. lipids: apolipoproteins carry triglycerides and lipids
    • 3. hormones: thyroxine via thyroid binding globulin
  28. context: 4 types of plasma proteins
    fibrinogin
    • 4% (of 7% that is proteins in plasma)
    • clotting protein
    • coagulation: soluble fibrinogen --> insoluble fibrin = clot formation
  29. context: 4 types of plasma proteins
    regulatory proteins
    • 1% (of 7% that is proteins in plasma)
    • ex: peptide hormones, luteinizing hormone (LH), thyroid stimulating hormone (TSH), prolactin (PRL), follicle stimulating hormone (FSH), insulin
    • info:
    • -levels may vary day to day or hour to hour
    • -without plasma proteins, substances would have low solubility or be excreted by kidneys
  30. 2 origins of plasma proteins
    • 1. liver: synthesize great than 90%
    • -all albumins
    • -all fibrinogens
    • -most globulin
    • 2. plasma cells (derived from lymphocytes):
    • -antibodies (of globulins)
    • *liver dysfunction can alter blood function
  31. context: 3 parts of plasma
    3 types of other solutes
    • 1. electrolytes/ions
    • 2. organic nutrients
    • 3. organic wastes
  32. context: 3 types of other solutes
    electrolytes/ions
    • ex: Na+, K+, Ca2+, Mg2+, Cl-, HCO3-, HPO4-, SO4-
    • 3 functions:
    • 1. Contribute to osmotic pressure
    • 2. Reservoir for cells' needs
    • 3. some buffer pH of blood (keep at narrow window)
  33. context: 3 types of other solutes
    organic nutrients
    • ex: lipids, carbohydrates, amino acids
    • 3 functions:
    • 1. energy
    • 2. maintenance
    • 3. growth
  34. context: 3 types of other solutes
    organic wastes
    • ex: Nitrogenous wastes (from proteins) like urea, uric acid, ammonium ion,
    • -Bilirubin (from hemoglobin of RBCs)
  35. context: formed elements
    origin of platelets
    cell fragments pinched or derived from megakaryocytes in red bone marrow
  36. context: formed elements
    characteristics of platelets
    • 1. have surface glycoproteins and receptors and proteins that allow adhesion to other molecules ex- collagen
    • 2. important in preventing blood loss (platelet plugs, promoting formation and contraction of clots)
    • 3. circulate for 9-12 days
    • 4. removed by phagocytes in the spleen
    • 5. 1/3 are reserved (in spleen) and mobilized for circulatory emergency like in cases of severe bleeding or hemorrhaging crisis
    • 6. ~150,000 - 500,000/µl of blood ~ avg. 350,000/µl
  37. cell fragments (platelets)
    membrane-bound pieces of cytoplasm 'shed' from megakaryocytes, have receptors, granules, actin, myosin
  38. megakaryocytes
    • enormous cells (up to 160µm in diameter)
    • process: shed cytoplasm in membrane packets during development and maturation in bone marrow --> membrane packets enter bloodstream as platelets (~4000 platelets made before nucleus of megakaryote gets phagocytosed)
  39. lifespan of platelets
    ~10 days before removal via phagocytosis in spleen
  40. thrombocytopoiesis
    stimulation of platelet production
  41. 3 (of many ways) to stimulate platelet production
    • 1. thrombopoietin (TPO)/ thrombocyte stimulating factor (produced in the kidneys):
    • - INC. megakaryocyte production
    • - INC. platelet formation by breaking down more of the megakaryocyte
    • 2. interleukin (IL-6):
    • -hormone INC. platelet formation
    • 3. multi-CSF (IL-13):
    • -stimulate platelets via promotion of megakaryocyte growth and formation
  42. 2 types of platelet production diseases
    • 1. thrombocytopenia
    • 2. thrombocytosis
  43. context: 2 types of platelet production diseases
    thrombocytopenia
    • -penia = deficient
    • abnormally low platelet count
    • - DEC. platelet production
    • - INC. platelet destruction
    • - less than 80,000/µl
    • - signs include bleeding digestive tract, skin, CNS
  44. context: 2 types of platelet production diseases
    thrombocytosis
    • accelerated platelet formation
    • in response to:
    • -cancer, inflammation, infection
    • greater than 1,000,000/µl
  45. 5 functions of platelets
    • 1. primary player in the clotting system
    • -including plasma proteins and vessels
    • 2. transport of chemicals important to clotting process
    • -release chemicals like enzymes and other factors at appropriate time and platelets help initiate and control clotting process
    • 3. formation of temporary patch in walls of damaged b.v.
    • 4. clump together at injury site, forming platelet plug - DEC. blood loss while clotting occurs
    • 5. active contraction after clot formation since it contains actin and myosin
    • -contract after clot is formed
  46. formation of blood clot
    • coagulation
    • -can occur anywhere like in blood vessels, test tube, floor, etc.
  47. cessation/end of blood loss
    • hemostasis (healthy process)
    • -initiated inside a leaking/damaged blood vessel
    • -formation of a clot at site of injury
    • -establishes the framework for tissue repair
  48. abnormal clotting of blood in an unbroken vessels
    • thrombosis
    • -obstruction of blood flow (vessel occlusion)
    • -clot (thrombus) formation inside a minimally damaged or non-leaking (but perhaps diseased) vessel
  49. 3 things regulate both hemostasis and thrombosis
    • 1. vessel wall
    • 2. coagulation
    • 3. platelets
  50. embolus
    a thrombus may grow large enough to obstruct a small vessel or piece may break loose and travel as an embolus
  51. embolism
    blockage of blood vessel by an embolus
  52. thromboembolism
    a thrombus that has moved from its site for formation (thromboembolus) and is now occluding a vessel (occurs mostly in veins which have lower pressure/force)
  53. 3 phases of hemostasis
    • 1. vascular: begins immediately
    • 2. platelet phase: occurs within 15 seconds
    • 3. coagulation: occurs after 30 seconds
  54. context: 3 phases of hemostasis
    vascular phase
    • 1. direct mechanical stimulation of perivascular nerves
    • 2. damage to endothelial cells of blood vessels (b.v.)
  55. context: vascular phase
    process of direct mechanical stimulation of perivascular nerves
    • damage to b.v. triggers contraction of vascular smooth muscle cells (SMC) in vessel wall
    • -reflex neurogenic mechanism --> vasoconstriction for ~30 mins --> local, transient vascular spasm --> decreases blood flow
  56. context: vascular phase
    process of damage to endothelial cells of blood vessels
    damaged endothelial cells contract: expose basal lamina and collagen (INC. thrombogenic) and allows platelets to become "activated" --> damaged endothelial cells become sticky: promotes 'sealing' the edges of damaged blood vessels together and favors attachment of platelets to site of injury
  57. context: vascular phase
    damaged endothelial cells release 3 things
    • 1. endothelins
    • 2. ADP
    • 3. tissue factor
  58. context: 3 things released from damaged endothelial cells
    endothelins
    quickly stimulate SMC contraction --> spasm --> augments neurogenic vasoconstriction --> eventually stimulate division of endothelial cells, SMC and fibroblasts --> repair
  59. context: 3 things released from damaged endothelial cells
    ADP
    initiates platelet phase
  60. context: 3 things released from damaged endothelial cells
    tissue factor
    • aka factor III or thromboplastin
    • initiate coagulation phase
  61. context: 3 phases of hemostasis
    platelet phase
    platelets at site of injury encounter collagen (or test tube, or kicked around by eddy flow, etc.) and sticky endothelium and become "activated"
  62. platelet activation
    platelets undergo shape change, change in membrane receptors and release secretory granules (2 types)
  63. 3 characteristics of activated platelets
    • 1. adhesion and shape change
    • 2. secretion
    • 3. aggregation
  64. context: 3 characteristics of activated platelets
    platelet adhesion and conformational change
    • platelets attach to sticky endothelial cells, the exposed basal lamina and/or the exposed collagen --> develop cytoplasmic processes that "reach" toward other platelets --> express receptors favoring adhesion and aggregation
    • Players:
    • 1. glycoprotein Ib (GpIb):
    • binds vWF (von willebrand factor - "paste") in ECM
    • 2. GpIIb-IIIa:
    • binds fibrinogen (aggregation)
    • 3. ADP (aggregation)
  65. context: 3 characteristics of activated platelets
    secretion
    • release granules
    • 5 chemicals secreted (positive feedback loop):
    • 1. more ADP --> more aggregation and more ADP release
    • 2. thromboxane A2 (cox enzyme used) --> aggregation and vasoconstriction
    • 3. 5-HT --> vasoconstriction
    • 4. Ca2+ --> aggregation, coagulation
    • 5. coagulation factors (V and VIII) --> coagulation
    • *looks like a SAC (serotonin, ADP, calcium)
  66. context: 3 characteristics of activated platelets
    platelet aggregation
    • more platelets arrive at site and adhere to each other
    • -platelet aggregation results in plugging the leak (platelet plug) --> may seal slightly damaged blood vessel
  67. context: 3 phases of hemostasis
    coagulation
    • blood clotting
    • process: involves a complex sequence of steps leading to conversion of circulating fibrinogen into insoluble protein fibrin
  68. context: 3 phases of hemostasis
    coagulation factors
    proteins found in plasma that circulate in inactive state until tissues are injured and damaged tissues and platelets produce chemicals that begin activation of the factors
  69. context: 3 phases of hemostasis
    3 pathways of coagulation
    • 1. extrinsic
    • 2. intrinsic
    • 3. common pathway
    • *results in blood clot. A network of threadlike fibrinfibers, trapped blood cells, platelets and fluid, effectively seals off the damaged portion of the blood vessel
  70. context: 3 pathways of coagulation
    extrinsic pathway
    • initiated via release of tissue factor III/thromboplastin from damaged endothelium. shorter, faster
    • -begins in the vessel wall, outside bloodstream
    • -damaged cells release tissue factor (TF)
    • TF + other compounds = enzyme complex that activates factor X
  71. context: 3 pathways of coagulation
    intrinsic pathway
    • initiated by exposure of blood to negatively charged surface (collagen, glass tube) --> activation of pro-enzymes (ex - factor XII) aided by platelet factors (PF-3)
    • -begins with circulating proenzymes within bloodstream
    • activation of enzymes by collagen --> platelets release factors (ex- PF-3) --> series of reactions activates factor X
  72. context: 3 pathways of coagulation
    common pathway
    • activation of factor X by the extrinsic and/or intrinsic pathways
    • -intrinsic and extrinsic pathways converge
    • forms enzyme prothrombinase (factor Xa with calcium and potassium + other compounds) --> converts prothrombin to thrombin --> thrombin converts soluble fibrinogen to insoluble fibrin (KEY step in clotting)
  73. context: 3 phases of hemostasis
    both pathways of coagulation
    • both extrinsic and intrinsic pathways:
    • 1. are activated during vessel damage
    • 2. results in activation of factor X
    • 3. require Ca2+ (brings together the negative factors due to gamma carboxylation)
    • 4. contain factors that are synthesized in the liver and platelets and require vitamin K (important in post-translational modification with glutamic acid and negative charge)
  74. context: coagulation phase
    reaction nutshell
    • activated coagulation factors (enzyme) + proenzyme of coagulation factor (substrate) + cofactors (speed)
    • *13 clotting factors total, not activated in numerical order
  75. What happens after fibrin is finally created?
    • fibrinogen --> fibrin -- (activated factor XIII) --> x-linked fibrin net
    • -fibrin net: traps RBCs and plasma (controls snowball effect) --> platelets contract (actin and myosin) via thrombin --> pull fibrin net and ultimately edges of blood vessels closer together --> clot retraction (30-60 mins to DEC. bleeding and INC. healing) --> bleeding stops in 1-4 mins.
  76. Fibrinolysis
    • removal of fibrin clots after vessel has healed and is tightly regulated
    • once damaged vessel has een repaired, fibrin clot must be dissolved to restore normal flow
  77. process of fibrinolysis
    endothelial cells during reduced blood flow release tissue plasminogen activator (tPA) --> plasminogen --> plasmin (enzyme) --> hydrolyze fibrin --> clot dissolved
  78. fibrinolytic drugs
    • use: for patients with: heart attack or stroke
    • 1. tPA
    • 2. recombinant forms- ex: alteplase, reteplase, tenecteplase)
    • 3. stretokinase (bacterial enzyme)
    • 4. urokinase
    • *"cool" treatment: vampire bat venom saliva
  79. regulation of coagulation
    blood clotting restricted by substances that deactivate or remove clotting factors
  80. anticoagulants
    function to prevent coagulation factors from initiating clot formation and coagulation occurs when coagulation factor concentration exceeds a given threshold. at site of injury, threshold is exceeded
  81. 5 anticoagulants
    • 1. antithrombin III
    • 2. Heparin
    • 3. prostacyclins
    • 4. thrombomodulin
    • 5. protein C
  82. context: 5 anticoagulants
    antithrombin III
    • produced by the liver
    • inactivates thrombin and other factors
  83. context: 5 anticoagulants
    Heparin
    • produced by basophils (wbc) and endothelial cells
    • a cofactor that accelerates activity of antithrombin III
  84. context: 5 anticoagulants
    prostacyclins
    • prostaglandin derived from endothelial cells
    • causes vasodilation and inhibits release of coagulating factors from platelets
  85. context: 5 anticoagulants
    thrombomodulin
    • released by damaged endothelial cells
    • converts thrombin to an enzyme that activate protein C
  86. context: 5 anticoagulants
    protein C
    a plasma protein that inactivates several clotting factors and stimulates plasmin (breaks fibrin strands)
  87. context: regulation of coagulation
    process of anticoagulants
    (1) thrombomodulin activates protein C --> (2) tissue-plasminogen activator [T-PA] converts plasminogen to plasmin [released by damaged tissue] --> plasma proteins: (a) plasmin breaks down fibrin strands through process of fibrinolysis which is normal healing process, (b) protein C activates plasmin --> Heparin activates antithrombin --> (c) antithrombin inhibits thrombin
  88. context: regulation of coagulation
    normal period
    • un-damaged (healthy) endothelial cells release prostacyclin which is an anti-aggregation factor
    • WBC entering damaged area release platelet inhibitory factors
    • plasma enzyme and high levels of 5-HT inhibit ADP
    • clot development isolates pro-aggregation factors from circulation
  89. context: clinical interest
    two types of drugs for anti-coagulants
    • 1. anti-clotting drugs
    • 2. anti-platelet drugs
  90. context: clinical interest: 2 types of drug for anti-coagulants
    2 anti-clotting drugs
    • 1. Warfarin: inhibits coagulation factors VII, IX, X (inhibits vitamin-K dependent Gamma- carboxylation reactions)
    • 2. Heparin: binds to and activates anti-thrombin III (enhances anti-thrombin III which inhibits thrombin and inhibits fibrin net formation)
  91. context: clinical interest: 2 types of drug for anti-coagulants
    4 anti-platelet drugs
    • 1. Aspirin (acetylsalicyclic acid or ASA): inhibits cyclooxygenase reduces production of or DEC. thromboxane A2 and ultimately DEC. platelet activation
    • 2. Plavix (Clopidogrel): DEC. platelet aggregation via block ADP receptor on platelets
    • 3. Aggrastat (Tirofiban): block glycoprotein IIb/IIIa ex- blocks fibrinogen induced platelet aggregation to DEC. aggregation
    • 4. Integrilin: "cool" drug that is a synthetic hexapeptide from venom in rattlesnake

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