1. BLOOD 【血液】 Qiang XIA (夏强), PhD Department of Physiology School of Medicine Tel: 88206417, 88208252 Email: xiaqiang@zju.edu.cn

2. Body Fluid = 60% of Body Weight (BW) Intracellular Fluid 2/3, 40% of BW Extracellular Fluid 1/3, 20% of BW Plasma 5% of BW Interstitial Fluid 15% of BW 70 kg Male, 42 L Internal environment （内环境） Internal Environment

4. Homeostasis （稳态） Homeostasis (from the Greek words for “ same ” and “ steady ” ): maintenance of static or constant conditions in the internal environment Walter B. Cannon http://www.harvardsquarelib rary.org/unitarians/cannon_ walter.html

5. Components of Homeostasis: l Concentration of O 2 and CO 2 l pH of the internal environment l Concentration of nutrients and waste products l Concentration of salt and other electrolytes l Volume and pressure of extracellular fluid

6. Body's systems operate together to maintain homeostasis: Skin systemSkeletal and muscular system Circulatory systemRespiratory system Digestive systemUrinary system Nervous systemEndocrine system Lymphatic systemReproductive system How is homeostasis achieved?

7. Components of blood  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）

11. Normal Values for the Cellular Elements in Human Blood Cell Cells/ μ L (average) Approximate Normal Range Percentage of Total White Cells Total white blood cells90004000–11,000… Granulocytes Neutrophils54003000–600050–70 Eosinophils275150–3001–4 Basophils350–1000.4 Lymphocytes27501500–400020–40 Monocytes540300–6002–8 Erythrocytes Females4.8 × 10 6 …… Males5.4 × 10 6 …… Platelets300,000200,000–500,000…

12. Plasma includes water, ions, proteins, nutrients, hormones, wastes, etc. The hematocrit （血细胞比容） is a rapid assessment of blood composition. It is the percent of the blood volume that is composed of RBCs (red blood cells).

13. the volume of red blood cells as a percentage of centrifuged whole blood M: 40~50% F: 37~48% Hematocrit （ packed cell volume, 血细胞比容） International Council for Standardization in Haematology (ICSH) Recommendations for "Surrogate Reference" Method for the Packed Cell Volume

14. Physical & chemical properties of blood 1. Specific Gravity （比重） Depending on hematocrit & protein composition Whole blood ： 1.050~1.060 Plasma ： 1.025~1.035 Red blood cells ： 1.090

15. 2. Viscosity （粘度）  relative viscosity of whole blood 4~5 depending on hematocrit  relative viscosity of plasma 1.6~2.4 related to the protein composition of the plasma

16. 3. Osmotic Pressure （渗透压）  The osmotic pressure of a solution depends on the number of solute particles in the solution, NOT on their chemical composition and size

17.  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 membranes  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 capillaries

18. 4. Plasma pH  Normal range: 7.35~7.45  Buffer systems （缓冲系统） : NaHCO 3 /H 2 CO 3, Pro-Na/Pro, Na 2 HPO 4 /NaH 2 PO 4 Hb-K/Hb, HbO 2 -K/HbO 2, K 2 HPO 4 /KH 2 PO 4, KHCO 3 /H 2 CO 3

19. Functions of blood  Transportation  O 2 and CO 2  Nutrients (glucose, lipids, amino acids)  Waste products (e.g., metabolites)  Hormones  Regulation  pH  Body temperature  Protection  Blood coagulation  Immunity

20. Bone Marrow  In the adult, red blood cells, many white blood cells, and platelets are formed in the bone marrow  In the fetus, blood cells are also formed in the liver and spleen, and in adults such extramedullary hematopoiesis may occur in diseases in which the bone marrow becomes destroyed or fibrosed Changes in red bone marrow cellularity in various bones with age

21. Development of various formed elements of the blood from bone marrow cells

22. Plasma  The fluid portion of the blood, the plasma, is a remarkable solution containing an immense number of ions, inorganic molecules, and organic molecules that are in transit to various parts of the body or aid in the transport of other substances  Normal plasma volume is about 5% of body weight, or roughly 3500 mL in a 70-kg man  Plasma clots on standing, remaining fluid only if an anticoagulant is added  If whole blood is allowed to clot and the clot is removed, the remaining fluid is called serum  Serum has essentially the same composition as plasma, except that its fibrinogen and clotting factors II, V, and VIII have been removed and it has a higher serotonin content because of the breakdown of platelets during clotting

23. Water (92% of plasma) serves as transport medium; carries heat Proteins (6~8% of plasma) Inorganic constituents (1% of plasma) e.g., Na +, Cl -, K +, Ca 2+ … Nutrients glucose, amino acids, lipids & vitamins Waste products e.g., nitrogenous wastes like urea Dissolved gases O 2 & CO 2 Hormones u Composition

24. Albumins （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) clotting 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  Plasma proteins

25. Some of the Proteins Synthesized by the Liver: Physiologic Functions and Properties NamePrincipal FunctionBinding CharacteristicsSerum or Plasma Concentration AlbuminBinding and carrier protein; osmotic regulator Hormones, amino acids, steroids, vitamins, fatty acids 4500–5000 mg/dL OrosomucoidUncertain; may have a role in inflammationTrace; rises in inflammation α 1 - Antiprotease Trypsin and general protease inhibitor Proteases in serum and tissue secretions 1.3–1.4 mg/dL α- Fetoprotein Osmotic regulation; binding and carrier protein a Hormones, amino acidsFound normally in fetal blood α 2 - Macroglobulin Inhibitor of serum endoproteasesProteases150–420 mg/dL Antithrombin-III Protease inhibitor of intrinsic coagulation system 1:1 binding to proteases17–30 mg/dL CeruloplasminTransport of copperSix atoms copper/mol15–60 mg/dL C-reactive proteinUncertain; has role in tissue inflammationComplement C1q< 1 mg/dL; rises in inflammation FibrinogenPrecursor to fibrin in hemostasis200–450 mg/dL HaptoglobinBinding, transport of cell-free hemoglobinHemoglobin 1:1 binding40–180 mg/dL Hemopexin Binds to porphyrins, particularly heme for heme recycling 1:1 with heme50–100 mg/dL TransferrinTransport of ironTwo atoms iron/mol3.0–6.5 mg/dL Apolipoprotein BAssembly of lipoprotein particlesLipid carrier AngiotensinogenPrecursor to pressor peptide angiotensin II Proteins, coagulation factors II, VII, IX, XBlood clotting20 mg/dL Antithrombin C, protein CInhibition of blood clotting Insulinlike growth factor IMediator of anabolic effects of growth hormoneIGF-I receptor Steroid hormone-binding globulinCarrier protein for steroids in bloodstreamSteroid hormones3.3 mg/dL Thyroxine-binding globulin Carrier protein for thyroid hormone in bloodstream Thyroid hormones1.5 mg/dL Transthyretin (thyroid-binding prealbumin) Carrier protein for thyroid hormone in bloodstream Thyroid hormones25 mg/dL

26. Red blood cells (Erythrocytes) （红细胞）  The red blood cells (erythrocytes) carry hemoglobin in the circulation  They are biconcave disks that are manufactured in the bone marrow  In mammals, they lose their nuclei before entering the circulation  In humans, they survive in the circulation for an average of 120 days  The average normal red blood cell count is 5.4 million/ μ L in men and 4.8 million/ μ L in women  The number of red cells is also conveniently expressed as the hematocrit, or the percentage of the blood, by volume, that is occupied by erythrocytes.  Each human red blood cell is about 7.5 μ m in diameter and 2 μ m thick, and each contains approximately 29 pg of hemoglobin  There are thus about 3 × 10 13 red blood cells and about 900 g of hemoglobin in the circulating blood of an adult man

27. Human red blood cells and fibrin fibrils

28. Structure  Biconcave  No nucleus  Few organelles  Small  Hemoglobin molecules Count RBC count M: 4.0~5.5×10 12 /L F: 3.5~5.0×10 12 /L Hemoglobin （血红蛋白） M: 120~160 g/L F: 110~150 g/L

29. Hemoglobin  The red, oxygen-carrying pigment in the red blood cells of vertebrates is hemoglobin, a protein with a molecular weight of 64,450

30. Reactions of Hemoglobin

31. Hemoglobin in the Fetus  The blood of the human fetus normally contains fetal hemoglobin (hemoglobin F)  Its structure is similar to that of hemoglobin A except that the β chains are replaced by γ chains; that is, hemoglobin F is α 2 γ 2  Fetal hemoglobin is normally replaced by adult hemoglobin soon after birth

32. u Physiological properties Plastic deformability a) Illustration showing structural modifications inside a sickle RBC. Modified, with permission, from (Barabino, Platt et al.,2010). (b-d) Typical morphologies of sickle RBCs measured by DPM; (b) echinocyte, (c) discocyte, and (d) crescent- shaped irreversibly sickled cell.

33. 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… Suspension stability （悬浮稳定性） International Council for Standardization in Haematology (ICSH)

34. 红细胞叠连（rouleaux formation）

35. Osmotic fragility （渗透脆性） the susceptibility of a red blood cell to break apart when exposed to saline solutions of a lower osmotic pressure than that of the human cellular fluid

36. Notice that hemolysis begins in the 0.45% tube and is complete in the 0.35% tube.

37. 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） 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

38. u Function of RBCs 1. Transport of O 2 and CO 2 2. Buffering

39. u Production of RBC (Erythropoiesis)

40.  Hemocytoblast stem cell  Stem cell becomes committed  Early erythroblasts have ribosomes  Erythroblasts accumulate iron and hemoglobin  Normoblasts eject organelles  Released as erythrocyte

41.  Nutritional Requirements for Erythropoiesis 1. Many vitamins, minerals, and proteins are necessary for normal RBC production 2. Clinically, folic acid （叶酸）, VitB 12, and iron （铁） are the most important. Deficiencies of these factors lead to characteristic anemias （贫血）

43.  Regulation of Erythropoiesis 1. Erythropoietin （促红细胞生成素） 2. Hormones: Androgen （雄激素） Others Hypoxia-inducible factor-1, HIF-1

44. Erythropoiesis is hormonally regulated: decreased oxygen delivery to the kidney causes the secretion of erythropoietin, which activates receptors in bone marrow, leading to an increase in the rate of erythropoiesis.

45. average lifespan = about 120 days u Destruction of RBC  Macrophages engulf old RBCs  Iron is salvaged  Heme degrades into bilirubin

46. Red cell formation and destruction

47. Role of the Spleen  The spleen is an important blood filter that removes aged or abnormal red cells  It also contains many platelets and plays a significant role in the immune system  Abnormal red cells are removed if they are not as flexible as normal red cells and consequently are unable to squeeze through the slits between the endothelial cells that line the splenic sinuses

48. Anemia （贫血）  Anemia 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 loss (acutely such as a hemorrhage or chronically through low-volume loss)  excessive blood cell destruction (hemolysis)  deficient red blood cell production (ineffective hematopoiesis)

49. Iron deficiency anemia （缺铁性贫血）

50. 巨幼红细胞性贫血（megaloblastic anemia）

52. 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.

53. White blood cells (Leucocytes) （白细胞） u Types of WBC

54. Leukopoiesis  Myeloblasts become all of the granular leukocytes  Monoblasts become monocytes  Lymphoblasts become lymphocytes

56. Platelets (Thrombocytes)  Platelets are small, granulated bodies that aggregate at sites of vascular injury  They lack nuclei and are 2–4 μ m in diameter  There are about 300,000/ μ L of circulating blood, and they normally have a half-life of about 4 days  The megakaryocytes, giant cells in the bone marrow, form platelets by pinching off bits of cytoplasm and extruding them into the circulation  Between 60 and 75% of the platelets that have been extruded from the bone marrow are in the circulating blood, and the remainder are mostly in the spleen  Splenectomy causes an increase in the platelet count (thrombocytosis)

57. 1. Adhesion Platelets adhere to the vessel wall at the site of injury u Physiological properties of platelets

58. 2. Aggregation Platelets adhere to one another

60. 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.

61.  Inducers of platelet aggregation  ADP  Low dose  1st reversible phase  High dose  2nd irreversible phase  Thromboxane A 2 (TXA 2 )  Collagen  Thrombin

62. Phospholipid Arachidonic Acid Phospholipase A 2 TXA 2 Cyclo-oxygenase PGG 2 & PGH 2 PGI 2 Prostacyclin synthase (Vascular endothelium) Thromboxane synthase (Platelets) Aggregation Anti-aggregation Contraction Relaxation

63. 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.

64.  3. 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

65. 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.

66. 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; IP 3 = inositol trisphosphate; MLC = myosin light chain; MLCK = myosin light chain kinase; P2Y 1, P2Y 12 = G-protein-coupled ADP receptors; PAF = platelet activating factor; PGG 2 /PGH 2 = prostaglandin arachidonic pathway intermediates; PIP 2 = phosphatidylinositol bisphosphate; PKC = protein kinase C; PLA 2 = phospholipase A 2 ; TK = tyrosine kinase; PLC = phospholipase C; TS = thromboxane synthase; TxA2 = thromboxane A 2 ; 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.)

67.  4. Contraction Clot retraction ( 血块回缩 )

68.  5. Adsorption Clotting factors: I, V, XI, XIII

69. Production of Platelets (Thrombocytes)  Formation  Large multinucleated cells that pushes against the wall of the capillary  Cytoplasmic extensions stick through and separate

70. Thrombopoietin 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 production of platelets by the bone marrow It stimulates the production and differentiation of megakaryocytes, the bone marrow cells that fragment into large numbers of platelets

73. Hemostasis （止血） Bleeding time (出血时间)：<9 min  Hemostasis is the process of forming clots in the walls of damaged blood vessels and preventing blood loss while maintaining blood in a fluid state within the vascular system  A collection of complex interrelated systemic mechanisms operates to maintain a balance between coagulation and anticoagulation

76. Summary of reactions involved in hemostasis

77. Role of platelets in hemostasis  Release of vasoconstricting substances  Formation of the "platelet plug"  Promotion of blood clotting  Clot retraction

78. System for Naming Blood-Clotting Factors FactorNames IFibrinogen IIProthrombin IIIThromboplastin IVCalcium VProaccelerin, labile factor, accelerator globulin VIIProconvertin, SPCA, stable factor VIII Antihemophilic factor (AHF), antihemophilic factor A, antihemophilic globulin (AHG) IX Plasma thromboplastic component (PTC), Christmas factor, antihemophilic factor B XStuart–Prower factor XIPlasma thromboplastin antecedent (PTA), antihemophilic factor C XIIHageman factor, glass factor XIIIFibrin-stabilizing factor, Laki–Lorand factor HMW-KHigh-molecular-weight kininogen, Fitzgerald factor Pre-KaPrekallikrein, Fletcher factor KaKallikrein PLPlatelet phospholipid

79. The liver plays a critical role in producing and modifying blood-borne proteins, including those used in the clotting pathway. Moreover, bile salts from the liver facilitate the absorption of lipids in the diet, including vitamin K, which is required for the synthesis of prothrombin.

80. Exploration of the details of the clotting pathway has yielded detailed information about the sequence, only a portion of which is represented here. Note thrombin’s influence in three different directions.

81. Knowledge that thrombin plays a central role in clotting has generated detailed studies of the possible pathways resulting in its formation: the extrinsic pathway is the more important of the two under most circumstances.

82. The Clotting Mechanism

83. Tissue factor pathway (extrinsic) Following damage to the blood vessel, endothelium Tissue Factor (TF) is released, forming a complex with FVII and in so doing, activating it (TF-FVIIa). TF-FVIIa activates FIX and FX. FVII is itself activated by thrombin, FXIa, plasmin, FXII and FXa. The activation of FXa by TF-FVIIa is almost immediately inhibited by tissue factor pathway inhibitor (TFPI). FXa and its co-factor FVa form the prothrombinase complex, which activates prothrombin to thrombin. Thrombin then activates other components of the coagulation cascade, including FV and FVIII (which activates FXI, which, in turn, activates FIX), and activates and releases FVIII from being bound to vWF. FVIIIa is the co-factor of FIXa, and together they form the "tenase" complex, which activates FX; and so the cycle continues. ("Tenase" is a contraction of "ten" and the suffix "-ase" used for enzymes.)

84. Contact activation pathway (intrinsic)  The contact activation pathway begins with formation of the primary complex on collagen by high-molecular-weight kininogen (HMWK), prekallikrein, and FXII (Hageman factor). Prekallikrein is converted to kallikrein and FXII becomes FXIIa.  FXIIa converts FXI into FXIa.  Factor XIa activates FIX, which with its co-factor FVIIIa form the tenase complex, which activates FX to FXa.  The minor role that the contact activation pathway has in initiating clot formation can be illustrated by the fact that patients with severe deficiencies of FXII, HMWK, and prekallikrein do not have a bleeding disorder.

85. Final common pathway  Thrombin has a large array of functions  Its primary role is the conversion of fibrinogen to fibrin, the building block of a hemostatic plug.  In addition, it activates Factors VIII and V and their inhibitor protein C (in the presence of thrombomodulin), and it activates Factor XIII, which forms covalent bonds that crosslink the fibrin polymers that form from activated monomers.  Following activation by the contact factor or tissue factor pathways, the coagulation cascade is maintained in a prothrombotic state by the continued activation of FVIII and FIX to form the tenase complex, until it is down-regulated by the anticoagulant pathways.

87. Fibrin Polymerization Structure of Fibrinogen

88. 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.

89. Anticlotting Mechanisms  The tendency of blood to clot is balanced in vivo by reactions that prevent clotting inside the blood vessels, break down any clots that do form, or both  These reactions include the interaction between the platelet-aggregating effect of thromboxane A2 and the antiaggregating effect of prostacyclin, which causes clots to form at the site when a blood vessel is injured but keeps the vessel lumen free of clot

90. Examples of Diseases Due to Deficiency of Clotting Factors Deficiency of Factor:Clinical SyndromeCause I Afibrinogenemia 无纤维蛋白原血 症 Depletion during pregnancy with premature separation of placenta; also congenital (rare) II Hypoprothrombinemia (hemorrhagic tendency in liver disease) 低凝血酶原血症 Decreased hepatic synthesis, usually secondary to vitamin K deficiency V Parahemophilia 副血友病 Congenital VIIHypoconvertinemiaCongenital VIII Hemophilia A (classic hemophilia) 甲型血友病 Congenital defect due to various abnormalities of the gene on X chromosome that codes for factor VIII; disease is therefore inherited as a sex- linked characteristic IXHemophilia B (Christmas disease)Congenital XStuart–Prower factor deficiencyCongenital XIPTA deficiencyCongenital XIIHageman traitCongenital

91. Anticlotting Mechanisms  Antithrombin III is a circulating protease inhibitor that binds to serine proteases in the coagulation system, blocking their activity as clotting factors. This binding is facilitated by heparin, a naturally occurring anticoagulant that is a mixture of sulfated polysaccharides. The clotting factors that are inhibited are the active forms of factors IX, X, XI, and XII  The endothelium of the blood vessels also plays an active role in preventing the extension of clots. All endothelial cells except those in the cerebral microcirculation produce thrombomodulin, a thrombin-binding protein, on their surfaces. In circulating blood, thrombin is a procoagulant that activates factors V and VIII, but when it binds to thrombomodulin, it becomes an anticoagulant in that the thrombomodulin–thrombin complex activates protein C. Activated protein C (APC), along with its cofactor protein S, inactivates factors V and VIII and inactivates an inhibitor of tissue plasminogen activator, increasing the formation of plasmin  Plasmin (fibrinolysin) is the active component of the plasminogen (fibrinolytic) system

92. In an uninjured vessel, thrombin bound to thrombomodulin activates protein C, which blocks the clotting response.

93. Anticoagulants  Heparin is a naturally occurring anticoagulant that facilitates the action of antithrombin III. Low-molecular-weight fragments have been produced from unfractionated heparin, and these are seeing increased clinical use because they have a longer half-life and produce a more predictable anticoagulant response than unfractionated heparin. The highly basic protein protamine forms an irreversible complex with heparin and is used clinically to neutralize heparin  In vivo, a plasma Ca2+ level low enough to interfere with blood clotting is incompatible with life, but clotting can be prevented in vitro if Ca2+ is removed from the blood by the addition of substances such as oxalates, which form insoluble salts with Ca2+, or chelating agents, which bind Ca2+  Coumarin derivatives ( 香豆素类 ) such as dicumarol and warfarin are also effective anticoagulants. They inhibit the action of vitamin K, which is a necessary cofactor for the enzyme that catalyzes the conversion of glutamic acid residues to γ -carboxyglutamic acid residues. Six of the proteins involved in clotting require conversion of a number of glutamic acid residues to γ -carboxyglutamic acid residues before being released into the circulation, and hence all six are vitamin K-dependent. These proteins are factors II (prothrombin), VII, IX, and X, protein C, and protein S

94. Fibrinolysis （纤维蛋白溶解） o 2 processes o Activation of plasminogen o Degradation of fibrin o 4 components of plasma fibrinolysis system o Plasminogen （纤维蛋白溶解酶原） o Plasmin （纤维蛋白溶解酶） o Plasminogen activator o Plasminogen inhibitor

95. Following tissue repair, fibrin clots are dissolved in a process mediated by plasmin; synthetic plasminogen activators can be used immediately after a stroke or heart attack to help dissolve clots and restore blood flow.

96. o 2 pathways of plasminogen activation Fibrin Degradation Products (FDP)

97. The fibrinolytic system and its regulation by protein C

99. Blood Types  The membranes of human red cells contain a variety of blood group antigens, which are also called agglutinogens ( 凝集原 )  The most important and best known of these are the A and B antigens, but there are many more

100. Antigens of the ABO system on the surface of red blood cells

101. Summary of ABO System Blood Type Agglutinins in Plasma Frequency in United States % Plasma Agglutinates Red Cells of Type: OAnti-A, anti-B45A, B, AB AAnti-B41B, AB BAnti-A10A, AB ABNone4

102. The Rh Group  Aside from the antigens of the ABO system, those of the Rh system are of the greatest clinical importance  The Rh factor, named for the rhesus monkey because it was first studied using the blood of this animal, is a system composed primarily of the C, D, and E antigens, although it actually contains many more  Unlike the ABO antigens, the system has not been detected in tissues other than red cells  D is by far the most antigenic component, and the term Rh-positive as it is generally used means that the individual has agglutinogen D  The D protein is not glycosylated, and its function is unknown  The Rh-negative individual has no D antigen and forms the anti-D agglutinin when injected with D-positive cells  The Rh typing serum used in routine blood typing is anti-D serum  Eighty-five per cent of Caucasians are D-positive and 15% are D-negative; over 99% of Asians are D-positive  Unlike the antibodies of the ABO system, anti-D antibodies do not develop without exposure of a D-negative individual to D-positive red cells by transfusion or entrance of fetal blood into the maternal circulation  D-negative individuals who have received a transfusion of D-positive blood (even years previously) can have appreciable anti-D titers and thus may develop transfusion reactions when transfused again with D-positive blood

103.  Hemolytic Disease of the Newborn

104. Thank you for your attention!