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Chapter 3 BLOOD PHYSIOLOGY What will we discuss in this chapter? (Outline) Blood composing Outline I. II. Physical and chemical characteristics of blood III. Blood Cells 1. Hemopoietic process and hemopoietic stem cells 2. Hemopoietic microenvironment 3. Erythrocyte Physiology 4. Leukocyte Physiology 5. Platelet or Thrombocyte Physiology IV. Physiological Hemostasis 1. Endocrine functions of vessel endothelial cells 2. Physiological Characteristics of Platelet 3. Blood Coagulation 4. Fibrinolysis V. Blood Group 1. RBC Agglutination 2. ABO blood group system 3. Rh blood group system 4. Relation between blood volume and clinic 5. Principle of Transfusion and Cross-match test Blood and Internal Environmental Homeostasis Blood is that part of extracellular fluid within the cardiovascular system Blood forming During animals’ evolution, extracellular fluid was gradually shaped from the age-old time with ocean which was mainly salty solution. At last, extracellular fluid was differentiated into plasma and interstitial fluid and blood came from plasma and cells. The role of blood in internal environmental homeostasis Blood, the most active component in extracellular fluid, display functions as follows: (1) transportation; (2) pH value buffer; (3) temperature or thermal maintenance; (4) immunity and defence I. Blood composing Blood composing: plasma + blood cells Hematocrit: blood cells occupies the percentage of total blood volume. normal value male: 40-50% female: 37-48% newborn: 55% Blood component (summing-up) Terminology and normal value Chemical component of plasma Water: > 90% Small molecule: 2%, it is electrolytes, nutriment, metabolic products, hormone, enzyme,etc. Protein: 60-80 g/L, plasma protein include albumin (40-50 g/L), globulin (20-30 g/L,α1-, α2, β-, γ- ) and fibrinogen. Most of albumin and globulin made from liver. A/G and clinic. Function of plasma protein: (1) transportation, (2) nutrition, (3) forming colloid osmotic pressure, (4) coagulation and anticoagulation, (5) pH value buffer, (6) immunity (globulin) Chemical component of plasma H 2O 90 - 91% Plasma 血浆 Interstitial 组织液 fluid Intracellular 细胞内液 fluid Na+ 142 145 12 Cl- 104 117 4 Ca++ 2.5 2.4 <0.001 K+ 4.3 4.4 139 PO4- 2 2.3 29 Protein 蛋白质 14 0.4 54 (Unit:mmol/L) II. Physical and chemical characteristics of blood Specific gravity: total blood (1.050-1.060) more influenced by red blood cells; plasma (1.025-1.030) more influenced by plasma protein; RBC (1.090-1.092) more influenced by Hb. Viscosity: Blood relative viscosity (4~5) mainly depends on the numbers of red blood cells. Plasma relative viscosity (1.6~2.4) is mainly involved in plasma protein Plasma osmotic pressure is 300 mmol/L or 770kPa (1) Crystal osmotic pressure results from NaCl and modulates water distribution between inside and outside of cells. (2) Colloid osmotic pressure results from albumin and regulates water distribution between inside and outside of capillary. Plasma pH value is about 7.35~7.45, and usually buffer systems are NaHCO3/H2CO3 (20:1), protein salt/protein, Na2HPO4/ NaH2PO4, Hb salt/Hb, HbO salt/ HbO2, K2HPO4/ KH2PO4, KHCO3/H2CO3, etc [lungs and kidney mainly regulate Plasma pH value ]. Osmosis and Osmotic Pressure Osmosis is the movement of water down its concentration gradient. Osmosis is determined by the number of impermeable molecules. Osmotic pressure is the force drawing water down its concentration gradient. Osmosis and Osmotic Pressure A B Water [Water] > [Water] [Salt] < [Salt] Osmotic Pressure < Osmotic Pressure Osmosis is the movement of water from a high concentration to a low concentration. In this illustration, two compartments (A and B) are separated by a semipermeable membrane (broken vertical line). The water concentration in compartment A is greater than the concentration in compartment B because of the presence of salt (X) in B. Therefore, water will move down its concentration gradient from A to B. The force needed to prevent this water movement is called osmotic pressure. Tonicity The tonicity of a solution refers to the effect of the solution on cell volume. A hypertonic extracellular solution is one in which the water concentration is less outside the cell than inside; water leaves the cell; cell volume decreases. An isotonic extracellular solution is one in which the water concentration is the same inside and outside the cell; no water movement; cell volume does not change. A hypotonic solution is one in which the water concentration is greater outside than inside the cell; water enters the cell; cell volume increases. An isosmotic solution may not be an isotonic solution if the particles are permeable to the cell membrane. III.Blood Cells Blood cells are erythrocyte (red blood cell, RBC), leukocyte (white blood cell, WBC) and thrombocyte (platelet, P). Blood Cells The forming processes of erythrocyte (red blood cell, RBC), leukocyte (white blood cell, WBC) and thrombocyte (platelet, P) originating from hematopoietic stem cells are hemopoiesis. Transfer of blood cells forming place: yolk sac hemopoiesis (early embryo period) → liver and spleen (second embryo month) → marrow↑and liver, spleen↓ (after fourth embryo month) → marrow (fetus birth time) and liver, spleen as complementary role. During adulthood (after 18), red marrow (flat bones, e.g. vertebra,ilium, sternum, rib, skull and long bone ending) rather than yellow marrow has hematopoietic functions. 1. Hemopoietic process and hemopoietic stem cells Hemopoietic process Stage one: Hemopoietic stem cells self renewal, steady numbers, active differentiation. Stage two: committed progenitors directional differentiation (CFU-GEMM, CFU-E, CFUGM, CFU-MK, CFU-TB). [CFU: colony- forming unit Stage three: precursors morphologic occurrence of various original blood cells. Hemopoietic stem cells Basic characteristics Self renewal in high degree, constant from young to old age. Multi- directional differentiation Large potential proliferation, Hemopoietic stem cells produce about 1×1011 blood cells releasing to blood for use. Surface sign According to CFU (colony forming unit), using fluorescence-activated cell sorting (FACS), its main surface sign is CD34+CD38-Lin-and CD34-CD38-Lin-. Note CD: cluster of differentiation of antigen on the white blood cells; Lin: systemic specific antigen on the hemopoietic cells. 2.Hemopoietic microenvironment Hemopoietic microenvironment: It includes stromal cell secreting extracellular matrix (ECM), multihemopoietic regulating factor, hemopoietic nerves and blood vessels. Stromal cells in the marrow come from fibrocyte, reticulocyte, endothelial cell, ectoblast cell, monocyte, engulfing cell, osteoblast and osteoclast. Stromal cells supply two material: one is soluble hemopoietic growth factor, another is membrane-combined adhesive molecule. Extracellular stroma synthesized and secreted by marrow stromal cell filling cellular interstice contains big molecules, such as collagen (typeI, II, III, IV), glycoprotein (fibronectin, laminin, hemopoieticnectin ) and protein amylose (sulfate cartilagetin, sulfate heparin, hyaluronic acid and sulfate dermatin, etc). Hemopoietic cells must adhere to stromal cell and is in the hemopoietic microenvironment for survival. 3.Erythrocyte Physiology Shape and number of red blood cells (RBC) Shape of RBC: like biconcave disc Its diameter is about 7~8 µm, peripheral thickness about 2.5 µm, central thickness about 1 µm and cubage about 90 µm3. Erythrocyte Physiology Number of RBC: It is most numbers in the blood. Normal value about RBC Male adult, 4.5~5.5×1012/L; average, 5.0×1012/L Female adult, 3.8~4.6× 1012/L; average, 4.2×1012/L Newborn, ≥ 6.0×1012/L Protein within RBC is hemoglobin (Hb). Hb in male adult, 120~160 g/L; Hb in female adult, 110~150 g/L; Hb in newborn (within 5 days), ≥ 200 g/L Pregnant female, numbers of RBC and Hb are relatively less (because of more plasma). Dweller lived in plateau, numbers of RBC and Hb are relatively more (because of compensation for anoxia). Physiological Characteristics and Functions of RBC ① ② Characteristics of RBC Permeability: semipermeable membrane, gas and urea freely passing through, negative ions easily in or out of RBC, and positive ions not. There are NaK ATPase as pump on the membrane of RBC and low-temperature-stored plasma easily has high kalium. Why? Plasticity and metamorphose: Plasticity and metamorphose depend on: 1) surface area-cubage ratio, 2) viscosity of Hb, 3) membrane elasticity and viscosity. Physiological Characteristics and Functions of RBC Characteristics of RBC ③ Suspension stability: it cab be described by erythrocyte sedimentation rate (ESR) which is RBC descending distance per hour and suspension stability is inverse proportion to ESR. Normal value of ESR: male, 0~15 mm/h; female, 0~20 mm/h. ESR and clinic: some diseases bring about rouleaux formation (mainly involved in plasma component, e.g. globulin, fibrinogen, cholesterol) and speed up ESR. Physiological Characteristics and Functions of RBC ④ Characteristics of RBC Osmotic fragility: Changes in RBC put into lower osmotic salty solution. Osmotic fragility of aged RBC is large and easily results in rupture (hemolysis and ghost cell). Isosmotic solution, e.g. 0.85% NaCl, 1.4%NaHCO3, 5% glucose, etc. Isotonic solution, e.g. 0.85% NaCl Isosmotic solution does not equal to isotonic solution. Isosmotic solution, isotonic solution and clinic Physiological Characteristics and Functions of RBC Functions of RBC RBC can be used for transportation of O2 and CO2 in the blood. RBC can be served as pH buffer. Erythropoiesis Hemopoietic material for erythropoiesis: iron (Fe++) and protein, [reason for anemia] Influencing factors of RBC maturity: Vitamin B12 and folic acid (DNA metabolism), [clinic relation] Process of erythropoiesis: Hemopoietic stem cells→multi systemic hemopoietic progenitor cells→RBC-committed progenitor cells (BFU-E→CFUE)→original RBC→ earlier infantile RBC→medium-term infantile RBC→terminal infantile RBC→reticular RBC→mature RBC→blood for circulation. This process requires 6~7 days. [mitosis several times] [apoptosis] Place for Erythropoiesis Main place for Erythropoiesis is bone marrow. Aother place is liver. Regulation of Erythropoiesis 0.8% of total RBCs has self renewal, that is to say, 160×106 RBC production every minute. Burst forming unit-erythroid, BUF-E, important to earlier erythropoiesis, depends on stimulation of burst promoting activity, BPA outside body. BPA made by leucocyte is a glycoprotein whose molecular weight is about 25000~40000 Colony forming unit-erythroid, CFU-E, important to terminal erythropoiesis, depends on erythropoietin, EPO which is also a glycoprotein, molecular weight, 34000, plasma concentration 10 pmol/L, half life 5 hours, increasing release when anoxia. Life and breakage of RBC Life-span: 120 days, about 4 months, each RBC circulates 27 km averagely in vessels, short life-span for aged RBC Breakage: places are liver, spleen and lymphatic node, and after breakage, Hb released from RBC immediately combine with plasma α2-globulin (Hb touched protein) which is taken in by liver for iron reuse. Hb, very toxic if it get into blood, normally, it can be metabolized into bile pigment in liver. Clinic relation. 4.Leukocyte Physiology Classification and numbers of Leukocyte Number of Leukocyte (white blood cells, WBC): (4.0~10)×109/L Classification: It is granulocyte (neutrophil, eosinophil, basophil), monocyte and lymphocyte. Classification and numbers of Leukocyte TABLE. Classification and normal value of Leukocyte Absolute Value (×109/L) Total numbers of leukocytes Percentage (%) 4.0~10.0 Neutrophil (bacilliform nucleus) 0.04~0.5 1~5 Neutrophil (foliiform nucleus) 2.0~7.0 50~70 Eosinophil 0.02~0.5 0.5~5 Basophil 0.0~0.1 0~1 Monocyte 0.12~0.8 3~8 Lymphocyte 0.8~4.0 20~40 For Clinic Use Physiological Changes in Numbers of Leukocyte Newborn: Number is higher, 15×109/L, after birth 3 or 4 days to 3 months, being about 10×109/L, mainly, neutrophil, 70%; secondarily, lymphocyte. Circadian changes: Number of WBC is more in the afternoon than in the morning. Food taking, ache and mood excitation: Number of WBC is remarkably higher. Heavy exercise and laboring: Increasing numbers, about 35×109/L, return to original level after action stop. Terminal pregnancy of female: Numbers changes in 12~17×109/L, and during parturition, 34×109/L, and after parturition 2~5 days, number return to original level. Physiological Characteristics and Functions of WBC Terminology Diapedisis: Metamorphosed WBCs pass through vessel wall getting into interstitial fluid. Chemotaxis: It is a process that WBCs shift to some chemical material (metabolic production, antigenantibody complex, bacteria, toxin, etc). Phagocytosis: It is a process that WBCs enclose and engulf exotic or extraneous material, and use intracellular enzyme digesting them. Physiological Characteristics and Functions of WBC ① Neutrophil Another name, polymorphonuclear, PMN, 6~8 h in the vessels, diapedisis, chemotaxis and phagocytosis (using its hydrolyzed enzyme) Function: It plays a very important role in nonspecific cellular immunity system which is against pathogenic microorganism, such as bacteria, virus, parasite, etc. Clinic relation: Number of neutrophil greatly increase occurring in acute inflammation and earlier time of chronic inflammation. number decrease of neutrophil will result in poor resistibility and easily suffering from infection. Physiological Characteristics and Functions of WBC ② Eosinophil Circadian changes: Its number is lower in the morning and higher at night. Function: 1. It limits and modulates the effects of basophil on fast allergic reaction. 2. It is involved in immune reaction against worm with opsonization. Clinic relation: Its number increase when person suffers from parasite infection or allergic reaction. Physiological Characteristics and Functions of WBC ③ Basophil Circulatory time: 12 hours Basogranules contain heparin, histamine, chemotactic factors and chronic reactive material for allergic reaction. Function: It is also involved in allergic reaction. 1. Heparin serves as lipase cobase and speeds up fatty decomposition. 2. Histamine and chronic reactive material increase permeability of capillary and contract bronchia smooth muscle, and result in allergic reaction such as measles, asthma. 3. Eosinophil chemotactic factor A released by basophil can attract eosinophil collection and modify eosinophil function. Physiological Characteristics and Functions of WBC ④ Monocyte Its body is large, diameter about 15~30 µm without granule Function: 1. It contains many nonspecific lipase and displays the powerful phagocytosis. 2. As soon as monocytes get into tissue from blood , it change name called macrophage activating monocyte- macrophage system to release many cytokins, such as colony stimulating factor (CSF), IL-1, IL-3, IL-6, TNFα, INF-α,β ,etc. 3. Cytokins induced by monocyte may modulate other cells growth. 4. Monocyte- macrophage system plays a very important role in specific immune responsive induction and regulation. Physiological Characteristics and Functions of WBC ⑤ Lymphocyte Classification: It can be separated into T- Lymphocyte and B- Lymphocyte. Function: 1. Lymphocytes serve as a nuclear role in immune responsive reaction. 2. T- Lymphocytes involved in cellular immunity. 3. B- Lymphocytes involved in humoral immunity. Clinic relation: Numbers increase of lymphocytes occur in Leukopoiesis, Regulation and Breakage Birth place: bone marrow, originating from hemopoietic stem cells, and leukopoiesis process is similar to RBC. Leukopoiesis, differentiation and growth are influenced by hemopoietic growth factor, HGF which are glycoprotein secreted by lymphocyte, monocytemacrophage, fibrous cell and endothelial cell. Colony stimulating factor, CSF, such as GM-CSF, G-CSF, M-CSF, Multi-CSF (IL-3) also influence Leukopoiesis. Life span: several hours to 3 or 4 days. Leukocyte breakage: site are liver, spleen and lymphatic node. Pus or purulence forming 5.Platelet or Thrombocyte Physiology Shape: Biconvex disk like, diameter about 2~4 µm, average cubage 8 µm3. Complicated structure: under the electronic microscope, there are α-granule, dense body, lysin peroxide enzyme, opening tubular system, dense tubular system, canaliculus,etc. Dense body: It contains ADP, ATP, 5-HT, Ca2+, epinephrine,etc. Source: Platelet comes from megakaryocyte fractionlet release in the marrow. Normal Value and Function of Platelet Normal value: 100×109 ~ 300×109, range from 6%~10% Normal changes: more number in the afternoon than in the morning, more in winter than in spring, more in the venous blood than capillary, after sport↑, pregnacy↑. *Functions: 1. It maintains capillary endothelial cells smooth and integrated (repairing endothelium and providing nutrition). 2. It is involved in physiological hemostasis. Platelet and clinic relation: decrease of platelet, abnormal immune reaction, will results in hemorrhage or bleeding, purpuric symptom. Platelet Forming and Regulation Platelet forming: Birth place is bone marrow, originating from hemopoietic stem cells, and differentiating into burst forming unitmegakaryocyte, BFU-MK, then continuously into CFU-MK, and into megakaryocyte, demarcation membrane system, DMS, into fractionlet release to the blood requiring 8~10 days. (one megakaryocyte can produce 200~7700 platelet). Regulation: Protein, Mpl, expressed by c-mpl (oncogene) exists in CD34+ located at hemopoietic stem cells/ committed progenitors, megakaryocyte and platelet, found by Methin in 1993, and its ligand named thrombopoietin, TPO was discovered in 1994 which promoted hemopoietic stem cells differentiating into megakaryocyte as hemopoietic stem cells positive regulating factor. Life- Span and Breakage of Platelet Life-span: Averagely, 7~14 days in the blood. It can be consumed when it displays physiological functions. Breakage: Aged platelet can be processed by phagocytosis in liver, spleen and lymphatic node. IV. Physiological Hemostasis *Definition: The process from vessel bleeding to automatic hemostasia. *Bleeding time: The time from vessel bleeding to automatic hemostasia. Normal time is 1~3 min and it is longer when platelet decrease. Process of hemostasis: 1. Blood vessel contraction or convulsion (induced by neuroreflex; 5-hydroxytryptamine,5-HT; thromboxane A2, TXA2; endothelin, ET ) 2. Platelet thrombosis forming (made by platelet adhesion, aggregation, release and contraction) 3. fibrin, clot forming and maintenance (made by blood coagulation activation) Physiological Hemostasis 1.Endocrine functions of vessel endothelial cells ① ② ③ ④ Material related to hemostasis are basal membrane, collagen (III, IV), microfibril, elastin, laminin, ectonectin, fibronectin, von Willebrand factor (vWF), protein enzyme, protein enzyme inhibitor, adhesive amylose, etc. Anticoagulative material: They are prostacyclin (PGI2), endothelium-derived relaxing factor (EDRF or nitric oxide, NO), tissue-type plasminogen activator (tPA), uPA, ADPase, ATIII, heparin sulfate, protein C, thrombomomodulin (TM), plasminogen activator (PA). Promoting coagulative material: Tissue factor, vWF, blood clotting factor V, plasminogen activator inhibitor (PAI-1, PAI-2, ATIII), TNFα, interleukin-1 (IL-1). Vessel constricting and relaxing modulators: endothelin1 (ET-1), EDRF (NO), PGI2, etc. Roles of Vessel Endothelial Cells in Physiological Hemostasis Roles are close related to its endocrine functions ① ② ③ Vessel endothelium serves as barrier between underendothelial structure (namely, collagen) and blood. As soon as collagen expose to blood, hemostasis of platelet is immediately activated to form thrombus blocking wounded vessels. Platelet activation can releases constrictive factors (TXA2, ET-1, 5-HT, etc) making vessel convulsion, lasting about 60 sec. Stimulated vessel endothelial cells release coagulative factors and Promoting coagulative material to realize, speed up blood coagulation. At the same time, cells also release anticoagulative factors and fibrinolysis material to modify blood coagulation. Inactive Platelet Under the electronic microscope Activated Platelet for Hemostasis Under the electronic microscope 2.Physiological Characteristics of Platelet Thrombocyte adhesion: its membrane glycoprotein (GP, GPIb/IX and GPIIa/IIIb), collagen (underendothelial structure), vWF (plasma component), fibrinogen are involved in adhesion. Mechanism: Exposed collagen+vWF →vWF changes →platelet membrane glycoprotein+changed vWF → Thrombocyte adhesion. Thrombocyte aggregation: induced by physiological factors such as ADP, thromboxane A2 (TXA2), epinephrine, 5-HT, histamine, collagen, thrombin, prostacyclin,etc and by pathological factors like bacteria, virus, immune complex, drugs, etc. The process can be separated into two phases: phase one is reversible aggregation and phase two irreversible aggregation. Two phases require Ca2+, fibrinogen and energy consumption. Mechanism : Various factors+corresponding receptors on the platelet →changes in the second messenger within platelet →cAMP↓, Ip3↑, Ca2+↑, cGMP↑→ platelet aggregation. Thrombocyte release: ADP, ATP, 5-HT, Ca2+ released from dense body, and β-platelet globin, PF4, vWF, fibrinogen, PFV, PDGF, thrombin sensitive protein from α-granule, and acid protein hydrolyzed enzyme, tissue hydrolyzed enzyme from lysosome. Thrombocyte contraction: Loose platelet thrombus could turn into compact platelet thrombus by Ca2+ release and cytoskeleton movement (filament/canaliculus) within platelet. Roles of Platelet in Hemostasis Activation of platelet: Stimulus brings about thrombocyte adhesion, aggregation, release and contraction. Loose platelet thrombus forming: First phase of hemostasis. Blood coagulation activation by platelet: Fibrin net forming, second phase of hemostasis. *Roles of platelet in hemostasis: 1. Activated platelets supply lecithoid (phospholipid) surface for blood clotting factor and involve in activating factor X and prothrombin. 2. Surface of platelet membrane combine with many blood clotting factor, such as fibrinogen, FV, FXI, FXIII to speed up coagulation. 3. Activated platelets release α-granule which contains fibrinogen to intensify fibrin forming and blood coagulation. 4. Activated platelets contract clot with its contractive protein to solidify blood coagulation. 3.Blood Coagulation Blood Clotting Factor Definition: The process of blood flow from flowing liquid to gel or gelatin. Serum: Light yellow fluid after blood coagulation. Difference between serum and plasma mainly consists in no fibrinogen in serum. Blood coagulation is a series of complicated biochemical reactions with various enzymes. Blood clotting factor: Material which are directly involved in blood coagulation. There are 12 factors named Roman numerals, except Ca2+, phospholipid,other factors being protein, and except FIII (TF), others are in fresh plasma synthesized by liver with VitK . Blood clotting enzymes have two type: inactive and activated type [FII, FVII, FIX, Fx, FXI, FXII, FXIII]. Blood Clotting Factor Factor Name Plasma Concentration I Fibrinogen 3000 II Prothrombin 100 III Tissue factor IV Ca2+ 100 V Proaccelerin 10 Ⅶ Proconvertin 0.5 Ⅷ Antihemophilic factor,AHF 0.1 Ⅸ Plasma thromboplastic 5 component,PTC(Christmas factor) Ⅹ Stuart-Prower Factor 10 Ⅺ Plasma thromoboplastin 5 antecedent,PTA Ⅻ Contact factor or Hageman factor 40 XIII Fibrin-stabilizing factor 10 - High-molecular weight 80 kininogen,HMW-K - Prekallikrein,Pre-K or Fletcher factor 35 Synthesizing Half life Chromsome site Liver Liver (with Vit K) Endothelial cell Endothelial cell, platelet Liver (with Vit K) Liver Liver (with Vit K) site 4~5 d 3d 12~15 h 4~7 h 8~10 h 24 h 4 11 1 13 Ⅹ Ⅹ Liver (with Vit K) Liver 2d 2~3 d 13 4 Liver Liver, platelet Liver 24 h 8d - 5 6,1 3 Liver - 4 Blood Coagulation Intrinsic pathway of blood coagulation: All blood clotting factors involved in blood coagulation come from blood. Eyewinker surface with negative charges (collagenin) on the endothelium of blood vessel activates blood FXII as beginning of coagulation named surface activation. Extrinsic pathway of blood coagulation: Stimulus activates tissue factor (FIII) as beginning of coagulation. Extrinsic pathway of blood coagulation is faster than intrinsic pathway of blood coagulation because its steps are more simple. *Basic steps of blood coagulation [typical positive feedback]: Prothrombin activator forming [FXa-Va-Ca2+-phospholipid] Step 1 Prothrombin thrombin Step 2 Fibrinogen fibrin (clot) Step 3 Hemophilia A, B, C in the clinic results from deficiency of FVIII, FIX, FXI in the blood, respectively. Process of Blood Coagulation Extrinsic pathway Intrinsic pathway (Tissue Factor,TF) ( Eyewinker surface ) Ⅻ TF+Ⅶ Ⅺ Ca2+ Ⅶ-TF Ⅹa Ⅶa-TF Ⅸ Ca2+ ,PL Ca2+ PL S: Ⅺa Ca2+ Ⅷa PL PL: phospholipid HK: high molecular weight kininogen Ⅻa Ⅱ Ⅹa Ca2+ Ⅴa PL ⅩⅢ Ⅱa Subendothelium PK: prekallikrein K: kallikrein PK Ⅸa Ⅹ CL: cross linking fibrin Ca2+ S K HK Ⅰ Ⅰa ⅩⅢa Ca2+ CLⅠa Anticoagulative system in blood Cellular anticoagulative system: Liver cell and reticular endothelial cell could engulf blood clotting factor, tissue factor, prothrombin complex and soluble fibrin monomer. Humoral anticoagulative system: 1. Amino acid protease inhibitors in blood include antithrombin III, Clinhibitor, α1 antitrypsin, α2 antiplasmin, α2 huge globin, heparin coenzyme II, protease nexin-1 (PN-1) to combine with FIXa, FXa, FXIa, FXIIa and thrombin and then inactivate them for anticoagulation. Heparin can intensify functions of antithrombin III. 2. Protein C system are protein C (PC), thrombomodulin (TM), protein S and Protein C inhibitors. Main functions of PC consist in ①It inactivates FVa, FVIIIa with phospholipid and Ca2+; ②It blocks FXa combining with platelet phospholipid membrane to reduce prothrombin activation; ③It stimulates plasminogen activators release to trigger fibrinolysis; ④ Protein S is a coenzyme of PC and greatly intensify functions of PC. 3. Tissue factor pathway inhibitor (TFPI) mainly coming from vessel endothelial cells inhibits FXa and inactivates FVIIa-TF complex to block extrinsic pathway of coagulation with negative feed back. 4. Heparin used in the clinic widely is due to ①It combines with antithrombin III to increase functions of antithrombin III; ②It stimulates vessel endothelial cell greatlu releasing TFPI and other anticoagulative material; ③It intensifies PC activation and stimulates vessel endothelial cell releasing plasminogen activators to increase fibrinolysis. [lower molecular weight heparin is less hemorrhage] 4.Fibrinolysis Fibrinolytic system is involved in fibrinolysis, tissue repair and vessel rebirth. Two fibrinolytic systems: cellular one and plasma one. The former is leucocyte, macrophage, endothelial cell, mesothelial cell and platelet to engulf and digest fibrin. The latter is plasminogen activators (PA) and its inhibitors (PAI), plasminogen, plasmin. Basic steps: Endothelial cells (Extrinsic pathway ) (Urokinase, uPA) Kallikrein (Intrinsic pathway) uPA tPA Plasminogen PAI-1 α2-antiplasmin α2-huge globin Fibrin or fibrinogen Cl-inhibitors uPAG Plasmin Fibrin dissolution Blood Coagulation and Fibrinolysis Antifibrinolysis: Fibrinolytic Inhibitors and Its Functions Main fibrinolytic inhibitors: They are plasminogen activator inhibitor type-1 (PAI-1, in platelet), α2antiplasmin (in liver), α2-huge globin, α1-antitrypsin, antithrombin III, alexin C1 inhibitor. PAI-1 synthesis and release: PAI-1 made by endothelial cell, smooth muscular cell, mesothelial cell, megakaryocyte is stored in platelet with inactive form. Some factors such as thrombin, IL-1, TNFα, etc stimulate its release from platelet. PAI-1 function: It inhibits tPA (tissue-type plasminogen activator) limiting local fibrinolysis of thrombus. α2-antiplasmin characteristics: (1) Quick effect, (2) Inhibit plasminogen adhering to fibrin; (3) Combine with fibrin αchain and block fibrinolysis Clinic relation: Innate deficiency of α2-antiplasmin often brings about serious hemorrhage. V. Blood Group History: ABO blood group system was firstly found by Landsteiner in 1901. Definition for blood group*: Types of specific antigens on the blood cell. Agglutination: Combination of the same antigen (or named agglutinogen, glycoprotein/glycolipid on the membrane of blood cell) and antibody (or named agglutinin, r-globin in serum) results in harmful immune reactions showing hemolysis. Human leukocyte antigen, HLA have widespread distribution in the body and involves in immune repulsive reaction of organ transplant. Platelet antigens such as PI, Zw, Ko, etc may bring about fever heat when transfusion occur. 1. RBC Agglutination Antigen-Antibody Harmful immune Reaction Blood Coagulation RBC Agglutination Antigen of Blood Group Antigen: Its genes are located at allele on euchromosome, namely, expressed gene. Genotpye is genetic gene in blood group system and phenotype is antigen produced by corresponding genetic gene and amorph is noneffective allele. Genes in the blood system decide differential specific antigen on the membrane with control of enzymatic activity. Antibody of Blood Group Crude antibody: It is the unexposed antibody to correlative RBC, e.g., IgM in ABO blood group system which can not pass through placenta for the sake of big molecule. Immune antibody: Various extraordinary RBC antigens (transfusion or parturition) sensitize lymphatic cells producing antibody such as Rh, Kell, Duffy, kidd, which belong to IgG (small molecule) and IgM (big molecule). Blood Group of RBC Number: 23 types, 193 antigens, more important blood groups are ABO, Rh, MNSs, Lutheran, kell, Lewis, duff, kidd, etc and all of them could result in hemolysis during transfusion. ABO blood group system: Blood group Antigen on the RBC Antibody in the serum A A Anti-B B B Anti-A AB O A+B Anti-A+Anti-B 2. ABO blood group system Antigen (agglutinogen) and antibody (agglutinin) in ABO blood subgroup system Blood group A A1 A2 B A+ A1 A B AB A1B A2B O Antigen on the RBC Antibody in the serum Anti-B Anti-B+ Anti-A1 Anti-A A+ A1 +B A+B Anti-A1 Anti-A+Anti-B Inheritance of ABO blood group Inheritance: The A, B, H agglutinogen in ABO blood group system controlled by gene which is located at allele on No.9 chromosome (9q34.1-q34.2). Genotype and Phenotype: Genotype and Phenotype in ABO blood group system Genotype phenotype OO O AA, AO A BB, BO B AB AB Inheritance of ABO blood group Genetic relationship of ABO blood group Parents’ blood group Offspring possible blood group Offspring impossible blood group O×O O A, B, AB A×A O, A B, AB A×O O, A B, AB B×B O, B A, AB B×O O, B A, AB B×A O, A, B, AB ____ AB×O A,B O, AB AB×A A , B, AB O AB×B A , B, AB O AB×AB A , B, AB O Distribution of ABO blood group Mid Europe: Type A 40%, Type O 40%, Type B 10%, Type AB 6%. America aborigines: Type O 90%. China Han nationality: Type A 31.31%, Type B 28.06%, Type AB 9.77%, Type O 30.86%. Other chinese minority is different. Bloog group can be used in research on anthropology 3. Rh blood group system Rh antigen (Rh factor) is about 40 kinds and Rh factors related to clinic are D, E, C, c, e and most important is D antigen. Membrane of RBC has D antigen meaning Rh Positive, otherwise, Rh negative. Most of people (99%) are Rh Positive and less than 1% persons are Rh negative. Rh blood group characteristics: Immune antobody and incomplete antibody, IgG; while ABO blood group, crude antibody and complete antibody,IgM. Rh blood group system and clinic work Transfusion and pregnacy [Clinic meaning] Quantification of Blood Volume Blood volume is an important determinant of systemic arterial pressure. Circulatory system is essentially a closed container including a volume of blood equal to approximately 5 liters or 70-80mL/Kg of the body weight (in kilograms). 4. Relation between blood volume and clinic When you donate 10 % of total blood volume, your body compensates so that blood pressure does not change, and the volume is replaced through the normal ingestion of fluids. Volume loss up to 30-40 % of total blood volume can be tolerated if the loss is corrected within 30 min (e.g. artery contraction increases peripheral resistance but artery blood pressure can not maintain the normal levels which occur in symptoms such as light-headed, dazzled, force-lacked, etc) Blood loss more than 40 % of total blood volume will threaten the life, results in shock and the measures in the hospital should be immediately taken for life survival [Transfusion]. 5. Principle of Transfusion Transfusion is widely used in clinic treatment. Principle of transfusion*: 1. Identification of blood group must be taken before transfusion. 2. Cross-match test must be done before transfusion. 3. The same tpyes of blood group for transfusion should be firstly considered. 4. The different tpyes of blood group for transfusion should be very careful, small amount and slow import and if condition is better, changes in the same tpyes of blood group for transfusion. Cross-match test for transfusion RBC 红细胞 RBC 红细胞 Donator Receiver 受 血 者 供 血 者 Serum Serum 血清 血清 Main side of 主侧凝集反应 agglutination Subordinary side 次侧凝集反应 of agglutination - - + +, - - + Decision Perfect match, transfusion 相合,可以输血 × No match, transfusion 不合,不能输血 Transfusion under emergency 应急情况下输血 +: Agglutination; -: No agglutination Types of Transfusion According to source of transfusion, allogenetic transfusion (more use), autologous transfusion. According to component of transfusion, whole blood transfusion, transfusion of blood components Autologous transfusion has some advantages: It decreases infection. It blocks syndrome (fever, hemolysis) induced by allogenetic transfusion. ③ It stimulates bone marrow hemopoiesis towards RBC. ① ② Transfusion of blood components is good. Summarization PLEASE TAKE DOWN Consideration after class 1. Please describe classification and main effects of leucocyte. 2. What is the elementary process of blood coagulation and main factors which have participated in blood coagulation? 3. Please describe the principle of classification and blood transfusion of ABO blood group system. Thank You for Your Attention