血液的主要功能-夏强

1、Qiang XIA (夏强), MD & PhDDepartment of PhysiologyRoom C518, Block C, Research Building, School of MedicineTel: 88208252Email: Body Fluid = 60% of Body Weight (BW)Intracellular Fluid2/3, 40% of BWExtracellular Fluid1/3, 20% of BWPlasma 5% of BWInterstitial Fluid15% of BW70 kg Male, 42 LExtracellul

2、ar Fluid1/3, 20% of BWPlasma 5% of BWInterstitial Fluid15% of BWInternal EnvironmentExtracellular Fluid=Internal EnvironmentHomeostasisHomeostasis (from the Greek words for “same” and “steady”):maintenance of static or maintenance of static or constant conditions in constant conditions in the intern

3、al the internal environmentenvironmentWalter B. Cannon/wiki/Walter_Bradford_CannonComponents of Homeostasis:lConcentration of O2 and CO2 lpH of the internal environment lConcentration of nutrients and waste products lConcentration of salt and other electrolytes lVolume and pres

4、sure of extracellular fluid -RegulationBodys systems operate together to maintain homeostasis:Skin systemSkeletal and muscular systemCirculatory system Respiratory systemDigestive systemUrinary systemNervous systemEndocrine systemLymphatic systemReproductive systemPlasma（血浆）Blood Cells Red Blood Cel

5、ls (RBC) or Erythrocytes（红细胞） White Blood Cells (WBC) or Leucocytes（白血病） Platelets (PLT) or Thrombocytes（血小板）Plasma includes water, ions, proteins, nutrients, hormones, wastes, etc.The hematocrit is a rapid assessment of blood composition.It is the percent of the blood volume that is composed of RBC

6、s (red blood cells).the volume of red blood cells as a percentage of centrifuged whole bloodM: 4050%F: 3748% Hematocrit（packed cell volume, 血细胞比容）血细胞比容）International Council for Standardization in Haematology (ICSH) Recommendations for Surrogate Reference Method for the Packed Cell Volume1. Specific

7、 Gravity（比重）Depending on hematocrit & protein composition Whole blood：1.0501.060Plasma：1.0251.035Red blood cells：1.090relative viscosity of whole blood 45 depending on hematocritrelative viscosity of plasma 1.62.4 related to the protein composition of the plasmaThe osmotic pressure of a solution

8、 depends on the number of solute particles in the solution, NOT on their chemical composition and size Plasma osmotic pressure (300 mOsm/L） Crystalloid Osmotic Pressure（晶体渗透压） Pressure generated by all crystal substances, particularly electrolytes Important in maintaining fluid balance across cell m

9、embranes Colloid Osmotic Pressure（胶体渗透压） Osmotic pressure generated by plasma proteins, particularly albumin. Approximately 25 mmHg, but important in fluid transfer across capillariesNormal range: 7.357.45Buffer systems（缓冲系统）:NaHCO3/H2CO3, Pro-Na/Pro, Na2HPO4/NaH2PO4Hb-K/Hb, HbO2-K/HbO2, K2HPO4/KH2P

10、O4, KHCO3/H2CO3Transportation O2 and CO2 Nutrients (glucose, lipids, amino acids) Waste products (e.g., metabolites) Hormones Regulation pH Body temperatureProtection Blood coagulation ImmunityBody Fluid = 60% of Body Weight (BW)Intracellular Fluid2/3, 40% of BWExtracellular Fluid1/3, 20% of BWPlasm

11、a 5% of BWInterstitial Fluid15% of BW70 kg Male, 42 LWater (92% of plasma)serves as transport medium; carries heat Proteins (68% of plasma)Inorganic constituents (1% of plasma) e.g., Na+, Cl-, K+, Ca2+Nutrients glucose, amino acids, lipids & vitamins Waste products e.g., nitrogenous wastes like

12、urea Dissolved gases O2 & CO2 Hormones uCompositionPlasma proteinsAlbumins （白蛋白）(60-80% of plasma proteins) most important in maintenance of osmotic balance produced by liver Globulins （球蛋白）(1-, 2-, -, -)important for transport of materials through the blood (e.g., thyroid hormone & iron) cl

13、otting factors produced by liver except -globulins which are immunoglobulins (antibodies) produced by lymphocytes Fibrinogen（纤维蛋白原） important in clotting produced by liver BiconcaveNo nucleusFew organellesSmallHemoglobin moleculesuCountRBC countM: 4.05.51012/LF: 3.55.01012/LHemoglobin（血红蛋白）M: 120160

14、 g/LF: 110150 g/LuPhysiological properties Plastic deformability（可塑变形性）Erythrocyte Sedimentation Rate (ESR)（红细胞沉降率） The distance that red blood cells settle in a tube of blood in one hourNormal value Westergren method（魏氏法，国际血液学标准化委员会推荐魏氏法为标准法）:M: 015 mm/h，F: 020 mm/hAn indication of inflammation whi

15、ch increases in many diseases, such as tuberculosis & rheumatoid arthritis dSuspension stability（悬浮稳定性）International Council for Standardization in Haematology (ICSH) 红细胞叠连（rouleaux formation）Osmotic fragility （渗透脆性）the susceptibility of a red blood cell to break apart when exposed to saline sol

16、utions of a lower osmotic pressure than that of the human cellular fluidNotice that hemolysis begins in the 0.45% tube and is complete in the 0.35% tube.Only substances which act as impermeant molecules can be used to make isotonic solutions （等张溶液）. E.g. cells placed in an isosmotic solution （等渗溶液）

17、of urea (1.9%), a permeant molecule, will swell and bust. Solutions which have the same calculated osmotic pressure are said to be ISOSMOTIC but are not necessarily ISOTONIC（孙自珍，桂雅，邢孔庚。输液剂等渗等张渗透压的调整计算。数理医药学杂志，2007;20(5):703-704）uFunctions 1. Transport of O2 and CO22. BufferinguProduction of RBC (Ery

18、thropoiesis)Hemocytoblast stem cellStem cell becomes committedEarly erythroblasts have ribosomes Erythroblasts accumulate iron and hemoglobinNormoblasts eject organellesReleased as erythrocyte Nutritional Requirements for Erythropoiesis1. Many vitamins, minerals, and proteins are necessary for norma

19、l RBC production2. Clinically, folic acid（叶酸）, VitB12, and iron （铁） are the most important. Deficiencies of these factors lead to characteristic anemias（贫血）Diagram of iron kinetics from iron stores to developing red blood cell (RBC). Iron stores include the bone marrow, reticuloendothelial system (l

20、iver and spleen) and RBCs. Transferrin (total iron-binding capacity TIBC) transports iron (Fe) to developing erythrocytes. Iron is deposited in the RBC, and transferrin returns to storage sites to bind more Fe for transport. Lactoferrin is a competitor of transferrin; it takes Fe that is free and re

21、turns it to storage sites. Lactoferrin levels are elevated in anemia of chronic disease. Increases in interleukin-1 increase the sequestration of Fe in storage sites. (Hb=hemoglobin)uRegulation of Erythropoiesis1. Erythropoietin（促红细胞生成素）2. Hormones:Androgen（雄激素） OthersHypoxia-inducible factor-1, HIF

22、-1average lifespan = about 120 daysuDestruction of RBC Macrophages engulf old RBCsIron is salvagedHeme degrades into bilirubinAnemia is defined as a qualitative or quantitative deficiency of hemoglobin, a protein found inside red blood cells (RBCs)The three main classes of anemia： excessive blood lo

23、ss (acutely such as a hemorrhage or chronically through low-volume loss) excessive blood cell destruction (hemolysis) deficient red blood cell production (ineffective hematopoiesis)Iron deficiency anemiaIron deficiency anemia（缺铁性贫血）（缺铁性贫血）巨幼红细胞性贫血（megaloblastic anemia）HemolysisHemolysis（溶血）（溶血）Red b

24、lood cells without (left and middle) and with (right) hemolysis. Note that the hemolyzed sample is transparent, because there are no cells to scatter light.White blood cells (Leucocytes)（白细胞）（白细胞）uTypes of WBC WBC Count (109/L) %GranulocytesGranulocytesNeutrophils2.07.05070Eosinophils0.020.50.55Baso

25、phils00.101MonocytesMonocytes0.120.838LymphocytesLymphocytes0.84.02040Total 410uWBC countTypeMicroscopic AppearanceDiagramApprox. %in adultsDiameter (m)Main targetsNucleusGranulesLifetimeNeutrophil54-62%10-12bacteria fungi multilobedfine, faintly pink6 hours-few days(days in spleen and other tissue)

26、Eosinophil1-6%10-12parasites in allergic reactions bi-lobedfull of pink-orange (when stained)8-12 days (circulate for 4-5 hours)Basophil1%12-15in allergic reactions bi- or tri-lobedlarge blue ?Overview tableTypeMicroscopic AppearanceDiagramApprox. %in adultsDiameter (m)Main targetsNucleusGranulesLif

27、etimeLymphocyte25-33%7-8B cells: various pathogens T cells: oCD4+ (helper): extracellular bacteria broken down into peptides presented by MHC class 2 molecule. oCD8+ cytotoxic T cells: virus-infected and tumor cells. o T cells: Natural killer cells: virus-infected and tumor cells. deeply staining, e

28、ccentricNK-cells and Cytotoxic (CD8+) T-cellsweeks to yearsMonocyte2-8%14-17Monocytes migrate from the bloodstream to other tissues and differentiate into tissue resident macrophages or dendritic cells.kidney shapednonehours-daysMacrophage21 (human) 13 (rat) Phagocytosis (engulfment and digestion) o

29、f cellular debris and pathogens, and stimulation of lymphocytes and other immune cells that respond to the pathogen.activated=days immature=months-yearsDendritic cellsMain function is as an antigen-presenting cell (APC) that activates T lymphocytes.similar to macrophagesMyeloblasts become all of the

30、 granular leukocytes Monoblasts become monocytes Lymphoblasts become lymphocytesPlatelets (Thrombocytes)uFormed in the bone marrow from cells called megakaryocytes uWithout nucleus, but can secrete a variety of substances unormal value: (100300) x 109/LuAverage lifespan=714 days uPlay an important r

31、ole in hemostasis1. AdhesionPlatelets adhere to the vessel wall at the site of injuryuPhysiological properties of plateletsvon Willebrand factor, vWFUnifying model of platelet adhesion to collagen at arterial shear. Two different pathways by which human and mouse platelets firmly adhere to collagen

32、at arterial shear are illustrated. In both, the majority of platelets are initially tethered to collagen via GP Ib/IX/V interacting with collagen-bound VWF (left), although a minority of platelets interact directly with collagen independently of VWF/GP Ib/IX/V. In the first pathway (upper), signalin

33、g from GP VI first leads to activation of integrins 21 (GP Ia/IIa) and IIb3 (GP IIb/IIIa). Activated integrins then firmly attach the platelet to collagen, either directly (21) or via collagen-bound VWF (IIb3) (right). In the second pathway (lower), platelets first adhere to collagen via integrin 21

34、, before GP VI engages collagen and induces activation. These two pathways are likely to reinforce each other and the events of thrombus formation. Release of secondary mediators (ADP and TxA2) would further potentiate these events (right). (Redrawn from Auger JM, Kuijpers MJ, Senis YA: Adhesion of

35、human and mouse platelets to collagen under shear: a unifying model. FASEB J 2005;19:825-827.)2. AggregationPlatelets adhere to one another Platelet Aggregation Pathway Platelet activation and coagulation normally do not occur within an intact blood vessel. After vessel wall injury, platelet-plug fo

36、rmation is initiated by the adherence of platelets to subendothelial collagen. In high shear arterial blood, platelets are first slowed down from their blood flow velocity by interacting with the collagen-bound von Willebrand factor (VWF) and subsequently stopped by binding directly to collagen via

37、their glycoprotein receptor complex. The activation of these collagen receptors on platelets following their binding to collagen activates phospholipase C (PLC)-mediated cascades. This results in a mobilization of calcium from the dense tubula system. An increase in intracellular calcium is associat

38、ed with activation of several kinases necessary for morphological change, the presentation of the procoagulant surface, the secretion of platelet granular content, the activation of glycoproteins, and the activation of Phospholipase A2 (PLA2). Activation of PLA2 releases arachidonic acid (AA), which

39、 is a precursor for TBXA2 synthesis. PTGS1 catalyzes the first step in the formation of TBXA2 from AA. This reaction is irreversibly blocked by aspirin, which also leads to the blockage of platelet aggregation These processes result in the local accumulation of molecules like thrombin, TBXA2, and AD

40、P, which are important for the further recruitment of platelets as well as the amplification of activation signals as described above. The secreted agonists activate their respective G protein coupled receptors: thrombin receptor (F2R), thomboxane A2 receptor (TBXA2R), and ADP receptors (P2RY1 and P

41、2RY12). The P2RY12 receptor couples to Gi, and when activated by ADP, inhibits adenylate cyclase. This interaction counteracts the stimulation of cAMP formation by endothelial-derived prostaglandins, which alleviates the inhibitory effect of cAMP on IP3-mediated calcium release. Thienopyridines, a c

42、lass of oral antiplatelet agents, permanently inhibit P2RY12 signaling, which is sufficient to block platelet activation.F2R, TBXA2R and P2RY1 couple to the Gq-PLC-IP3-Ca2+ pathway, inducing shape change and platelet aggregation. In addition, receptor signaling through G12/13 (F2R; TBXA2R) contribut

43、es to morphological changes through activation of kinases.Platelet adhesion, cyotoskeletal reorganization, secretion, and amplification loops are all different steps towards the formation of a platelet-plug. These cascades result in the activation of the Fibrinogen Receptor expressed on platelet cel

44、ls. This activation develops binding sites for fibrinogen, which are not available in inactive platelets. The binding of fibrinogen results in the linkage of activated platelets through fibrinogen bridges, thereby mediating aggregation. Inhibition of this receptor through Glycoprotein IIb/IIIa inhib

45、itors blocks platelet aggregation induced by any agonist. Inducers of platelet aggregation ADP Low dose1st reversible phase High dose 2nd irreversible phase Thromboxane A2 (TXA2) Collagen ThrombinPhospholipidPhospholipidArachidonic AcidArachidonic AcidPhospholipase APhospholipase A2 2 TXATXA2 2Cyclo

46、-oxygenaseCyclo-oxygenasePGGPGG2 2 & PGH & PGH2 2PGIPGI2 2Prostacyclin synthaseProstacyclin synthase(Vascular endothelium)(Vascular endothelium)Thromboxane synthaseThromboxane synthase(Platelets)(Platelets)AggregationAggregation Anti-aggregation Anti-aggregationContractionContraction Relaxat

47、ion RelaxationPlatelet interactions with agonists and antagonists of platelet aggregation, the vessel wall, other platelets, and adhesive macromolecules. Agents in parentheses prevent the formation or inhibit the function of the adjacent agonists of platelet aggregation. ADP = adenosine diphosphate,

48、 VWF = von Willebrand factor, cAMP = cyclic adenosine monophosphate, GP = glycoprotein.3. Release or secretion: Platelets contain alpha and dense granules Dense granules: containing ADP or ATP, calcium, and serotonin -granules: containing platelet factor 4, PDGF, fibronectin, B-thromboglobulin, vWF,

49、 fibrinogen, and coagulation factors V and XIII Schematic drawing of the platelet (top figure), showing its alpha and dense granules and canalicular system. The bottom figure illustrates the platelets major functions, including secretion of stored products, as well as its attachment, via specific su

50、rface glycoproteins (GP), to denuded epithelium (bottom) and other platelets (left).VWF: von Willebrand factor; TSP: thrombospondin; PF4: platelet factor 4; PDGF: platelet derived growth factor; -TG: beta thromboglobulin; ADP: adenosine diphosphate; ATP: adenosine triphosphate. A schematic represent

51、ation of selected platelet responses to activation and the congenital disorders of platelet function. AC = adenylyl cyclase; BSS = BernardSoulier syndrome; CO = cyclooxygenase; DG = diacylglycerol; G = GTP-binding protein; IP3 = inositol trisphosphate; MLC = myosin light chain; MLCK = myosin light c

52、hain kinase; P2Y1, P2Y12 = G-protein-coupled ADP receptors; PAF = platelet activating factor; PGG2/PGH2 = prostaglandin arachidonic pathway intermediates; PIP2 = phosphatidylinositol bisphosphate; PKC = protein kinase C; PLA2 = phospholipase A2; TK = tyrosine kinase; PLC = phospholipase C; TS = thro

53、mboxane synthase; TxA2 = thromboxane A2; vWD = von Willebrand disease; vWF = von Willebrand factor. The Roman numerals in the circles represent coagulation factors and yellow Ps indicate phosphorylation. (Modified with permission from Rao AK: Congenital disorders of platelet function: disorders of s

54、ignal transduction and secretion. Am J Med Sci 1998; 316:69-76.)4. ContractionClot retraction (血块回缩)5. Adsorption Clotting factors: I, V, XI, XIIIFormationFormation Large multinucleated cells that pushes against the Large multinucleated cells that pushes against the wall of the capillarywall of the

55、capillary Cytoplasmic extensions stick through and separate Cytoplasmic extensions stick through and separate Thrombopoietin (leukemia virus oncogene ligand, megakaryocyte growth and development factor), is a glycoprotein hormone produced mainly by the liver and the kidney that regulates the product

56、ion of platelets by the bone marrowIt stimulates the production and differentiation of megakaryocytes, the bone marrow cells that fragment into large numbers of platelets The arrest of bleeding following injury and the result of 3 interacting, overlapping mechanisms:Vascular spasm（血管收缩）（血管收缩）Formati

57、on of a platelet plug（血小板血栓形成）（血小板血栓形成）Blood coagulation (clotting)（血液凝固）（血液凝固）Bleeding time (出血时间)：9 minoVasoconstriction: reduced blood flow facilitates contact activation of platelets and coagulation factors oExposure of sub-endothelial basement membrane and collagen oRelease of tissue thrombopla

58、stins (组织因子组织因子) oSynthesis of basement membrane components, tissue factor (组织因子组织因子), vWF, plasminogen activator (纤溶酶原激活物纤溶酶原激活物), antithrombin III (抗凝血酶抗凝血酶III), thrombomodulin (血栓调节蛋白血栓调节蛋白)Release of vasoconstricting substances Formation of the platelet plug Promotion of blood clotting Clot retr

59、action Clotting factorSynonymsIfibrinogen纤维蛋白原II prothrombin凝血酶原III tissue thromboplastin组织因子IV Ca2+Vproaccelerin前加速素易变因子VII proconvertin前转变素稳定因子VIIIantihemophilic factor抗血友病因子IXplasma thromboplastin component血浆凝血活酶XStuart-Prower factorXI plasma thromboplastin antecedent血浆凝血活酶前质XIIcontact factor接触因子

60、XIII fibrin-stabilizing factor纤维蛋白稳定因子uBlood coagulationNumber and/or nameFunctionI (fibrinogen)Forms clot (fibrin)II (prothrombin)Its active form (IIa) activates I, V, VII, VIII, XI, XIII, protein C, plateletsTissue factorCo-factor of VIIa (formerly known as factor III)CalciumRequired for coagulation factors to bind to phospholipid (