血液的主要功能Function of Blood

夏 强， MD & PhD浙江大学医学院生理学系医学院科研楼 C 座 518 室

电话： 88208252Email ： xiaqiang@zju.edu.cn

• Plasma （血浆）

• Blood Cells

– Red Blood Cells (RBC) or Erythrocytes （红细胞）

– White Blood Cells (WBC) or Leucocytes （白细胞）

– Platelets (PLT) or Thrombocytes （血小板）

血液的成分

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 RBCs (red blood cells).

Hematocrit （ packed cell volume, 血细胞比容）

血量• 是指全身血液的总量• 占体重的 7-8%

休克种类的图示。没有休克 ( 左 ), 血管扩张，分布性休克 ( 中 ), 低血容量休克，失血引起 ( 右 )

血液的功能• 运输

– O2 and CO2 – Nutrients (glucose, lipids, amino acids) – Waste products (e.g., metabolites) – Hormones

• 调节– pH– Body temperature

• 保护– Blood coagulation– Immunity

红细胞Red blood cells (Erythrocytes)

• RBC count– M: 4.0~5.5×1012/L– F: 3.5~5.0×1012/L

• Hemoglobin （血红蛋白）– M: 120~160 g/L– F: 110~150 g/L

• 功能：– 运输 O2 和 CO2

– 缓冲

Erythrocyte Sedimentation Rate (ESR) （红细胞沉降率）– The distance that red blood cells settle in a tube of blood in

one hour

• Normal 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: 0~15 mm/h ， F: 0~20 mm/h

• An indication of inflammation which increases in many diseases,

such as tuberculosis & rheumatoid arthritis…

d

International Council for Standardization in Haematology (ICSH)

Iron deficiency anemia（缺铁性贫血）

巨幼红细胞性贫血（ megaloblastic anemia ）

Hemolysis（溶血）Red blood cells without (left and middle) and with (right) hemolysis.

Note that the hemolyzed sample is transparent, because there are no cells to scatter light.

白细胞White blood cells (Leucocytes)

WBC Count (109/L) %Granulocytes粒细胞

Neutrophils 中性粒细胞 2.0~7.0 50~70Eosinophils 嗜酸性粒细胞 0.02~0.5 0.5~5Basophils 嗜碱性粒细胞 0~0.1 0~1

Monocytes单核细胞 0.12~0.8 3~8Lymphocytes淋巴细胞 0.8~4.0 20~40

Total 4~10

WBC count

Type Microscopic Appearance

Diagram Approx. %in adults

Diameter (μm)

Main targets Nucleus Granules Lifetime

Neutrophil 54-62% 10-12 bacteria fungi

multilobed fine, faintly pink

6 hours-few days(days in spleen and other tissue)

Eosinophil 1-6% 10-12 parasites in allergic reactions

bi-lobed full of pink-orange (when stained)

8-12 days (circulate for 4-5 hours)

Basophil <1% 12-15 in allergic reactions

bi- or tri-lobed large blue  ?

Overview table

Type Microscopic Appearance

Diagram Approx. %in adults

Diameter (μm)

Main targets Nucleus Granules Lifetime

Lymphocyte 25-33% 7-8 B 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, eccentric

NK-cells and Cytotoxic (CD8+) T-cells

weeks to years

Monocyte 2-8% 14-17 Monocytes migrate from the bloodstream to other tissues and differentiate into tissue resident macrophages or dendritic cells.

kidney shaped

none hours-days

Macrophage 21 (human) 13 (rat)

Phagocytosis (engulfment and digestion) of cellular debris and pathogens, and stimulation of lymphocytes and other immune cells that respond to the pathogen.

activated=days immature=months-years

Dendritic cells Main function is as an antigen-presenting cell (APC) that activates T lymphocytes.

similar to macrophages

血小板Platelets (Thrombocytes)

• 正常值：– (100~300) x 109/L

• 主要参与止血

1. 黏附 Adhesion

Platelets adhere to the vessel wall at the site of injury

血小板的生理特性

von Willebrand factor, vWF

Unifying model of platelet adhesion to collagen at arterial shear. Two different pathways by which human and mouse platelets firmly adhere to collagen 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), signaling from GP VI first leads to activation of integrins α2β1 (GP Ia/IIa) and αIIbβ3 (GP IIb/IIIa). Activated integrins then firmly attach the platelet to collagen, either directly (α2β1) or via collagen-bound VWF (αIIbβ3) (right). In the second pathway (lower), platelets first adhere to collagen via integrin α2β1, 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 human and mouse platelets to collagen under shear: a unifying model. FASEB J 2005;19:825-827.)

2. 聚集 Aggregation

Platelets 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 formation 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 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 associated 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 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 ADP, 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 P2RY12). 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 class 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) contributes 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 cells. 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 inhibitors 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

– Thrombin

Phospholipid

Arachidonic Acid

Phospholipase A2

TXA2

Cyclo-oxygenase

PGG2 & PGH2

PGI2

Prostacyclin synthase(Vascular endothelium)

Thromboxane synthase(Platelets)

Aggregation Anti-aggregationContraction Relaxation

Platelet 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, VWF = von Willebrand factor, cAMP = cyclic adenosine monophosphate, GP = glycoprotein.

• 3. 释放或分泌 Release or secretion:

Platelets contain alpha and dense granules– Dense granules: containing ADP or ATP, calcium,

and serotonin – α-granules: containing platelet factor 4, PDGF,

fibronectin, B-thromboglobulin, vWF, 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 platelet's major functions, including secretion of stored products, as well as its attachment, via specific surface 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 representation of selected platelet responses to activation and the congenital disorders of platelet function. AC = adenylyl cyclase; BSS = Bernard–Soulier syndrome; CO = cyclooxygenase; DG = diacylglycerol; G = GTP-binding protein; IP3 = inositol trisphosphate; MLC = myosin light chain; MLCK = myosin light chain 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 = thromboxane 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 signal transduction and secretion. Am J Med Sci 1998; 316:69-76.)

• 4. 收缩 ContractionClot retraction ( 血块回缩 )

• 5. 吸附 Adsorption Clotting factors: I, V, XI, XIII

止血Hemostasis

• 正常情况下，小血管受损后引起的出血，在几分钟内就会自行停止

• 三个机制：– Vascular spasm （血管收缩）– Formation of a platelet plug （血小板血栓形成）– Blood coagulation (clotting) （血液凝固）

血液凝固Blood coagulation

Clotting factor SynonymsI fibrinogen 纤维蛋白原II prothrombin 凝血酶原III tissue thromboplastin 组织因子IV Ca2+

V proaccelerin 前加速素易变因子VII proconvertin 前转变素稳定因子VIII antihemophilic factor 抗血友病因子IX plasma thromboplastin component 血浆凝血活酶X Stuart-Prower factorXI plasma thromboplastin antecedent 血浆凝血活酶前质XII contact factor 接触因子XIII fibrin-stabilizing factor 纤维蛋白稳定因子

Clotting factors

Number and/or name FunctionI (fibrinogen) Forms clot (fibrin)II (prothrombin) Its active form (IIa) activates I, V, VII, VIII, XI, XIII, protein C, platelets

Tissue factor Co-factor of VIIa (formerly known as factor III)Calcium Required for coagulation factors to bind to phospholipid (formerly known as

factor IV)V (proaccelerin, labile factor) Co-factor of X with which it forms the prothrombinase complex

VI Unassigned – old name of Factor VaVII (stable factor) Activates IX, XVIII (antihemophilic factor) Co-factor of IX with which it forms the tenase complexIX (Christmas factor) Activates X: forms tenase complex with factor VIIIX (Stuart-Prower factor) Activates II: forms prothrombinase complex with factor VXI (plasma thromboplastin antecedent) Activates IXXII (Hageman factor) Activates factor XI and prekallikreinXIII (fibrin-stabilizing factor) Crosslinks fibrinvon Willebrand factor Binds to VIII, mediates platelet adhesionprekallikrein Activates XII and prekallikrein; cleaves HMWKhigh-molecular-weight kininogen (HMWK) Supports reciprocal activation of XII, XI, and prekallikreinfibronectin Mediates cell adhesionantithrombin III Inhibits IIa, Xa, and other proteases;heparin cofactor II Inhibits IIa, cofactor for heparin and dermatan sulfate ("minor

antithrombin")protein C Inactivates Va and VIIIaprotein S Cofactor for activated protein C (APC, inactive when bound to C4b-binding

protein)protein Z Mediates thrombin adhesion to phospholipids and stimulates degradation

of factor X by ZPIProtein Z-related protease inhibitor (ZPI) Degrades factors X (in presence of protein Z) and XI (independently)

plasminogen Converts to plasmin, lyses fibrin and other proteinsalpha 2-antiplasmin Inhibits plasmintissue plasminogen activator (tPA) Activates plasminogenurokinase Activates plasminogenplasminogen activator inhibitor-1 (PAI1) Inactivates tPA & urokinase (endothelial PAI)plasminogen activator inhibitor-2 (PAI2) Inactivates tPA & urokinase (placental PAI)cancer procoagulant Pathological factor X activator linked to thrombosis in cancer

Coagulation factors and related substances

Coagulation cascade

3 processes

2 pathways

Fibrin Polymerization

Structure of Fibrinogen

A deficiency of a clotting factor can lead to

uncontrolled bleeding.

Vitamin K is a cofactor needed for the synthesis of

factors II, VII, IX, & X in the liver. So a deficiency of

Vitamin K predisposes to bleeding.

内源性抗凝物质 Anticoagulants

• 丝氨酸蛋白酶抑制物 Serine Protease Inhibitors ：主要有抗凝血酶、肝素辅因子 II 、 C1 抑制物等

• 蛋白质 C 系统 Protein C system• 组织因子途径抑制物 Tissue factor pathway

inhibitor (TFPI)• 肝素 Heparin

纤维蛋白溶解Fibrinolysis

小结• 血管内皮• 凝血系统• 抗凝物质• 纤溶系统• 单核 - 巨噬细胞的吞噬• 血流的稀释• 纤维蛋白的吸附