1、基础血 液 学夏 立病理生理学教研室红细胞与贫血BLOODPlasma-Plasma-55%Formed elements-Formed elements-45%Buffy coat-Buffy coat-3%)are released into the blood prematurely.1.Erythropoiesis红细胞与贫血骨髓红系定向细胞增殖及其最重要受体的理论模型EPO：促红细胞生成素；GM-CSF：粒-巨核细胞集落刺激因子；IL3：白介素3；Transferrin:转铁蛋白；Fibronectin:纤连蛋白1.Erythropoiesis红细胞与贫血Too few RBCs l
2、eads to tissue hypoxiaRegulation of Erythropoiesis1.Erythropoiesis1.ErythropoiesisKidney(and liver toa smaller extent)releases ERYTHROPOIETIN.Erythropoietinstimulates redbone marrow.Enhancederythropoiesisincreases RBCcount.O2-carryingability of bloodincreases.Homeostasis:Normal blood oxygen levels S
3、timulus:Hypoxia(low bloodO2-carrying ability)due to Decreased RBC count Decreased amountof hemoglobin Decreased availability of O212345IMBALANCEIMBALANCE红细胞与贫血Hypoxia Inducible Factor(HIF)Regulation of ErythropoiesisRegulation of Erythropoiesis1.Erythropoiesis1.Erythropoiesis红细胞与贫血Erythropoietin(EPO
4、（促红细胞生成素）)34,000 Da,GlycoproteinReleased by the kidney in response to hypoxia(hemorrhage（出血）,hemolytic（溶血）,iron deficiency or high altitudes)Regulation of Erythropoiesis1.Erythropoiesis1.Erythropoiesis红细胞与贫血Regulation of ErythropoiesisRegulation of Erythropoiesis1.Erythropoiesis1.ErythropoiesisEryth
5、ropoietin(EPO)Direct stimulus for erythropoiesisMore rapid maturation of committed bone marrow cellsIncreased circulating reticulocyte count in 12 days 红细胞与贫血Regulation of ErythropoiesisRegulation of Erythropoiesis1.Erythropoiesis1.Erythropoiesis红细胞与贫血Balance between RBC production and destruction d
6、epends onHormonal controls(Erythropoietin,EPO)Adequate supplies of Folic Acid(folate（叶酸）)Vitamin B12,cyanocobalamin（氰钴胺）Amino Acids Iron Vitamin B6,pyridoxine（吡哆醇）Ascorbic Acid(Vitamin C)Regulation of ErythropoiesisRegulation of Erythropoiesis1.Erythropoiesis1.Erythropoiesis红细胞与贫血1.Erythropoiesis(Di
7、sease)1.Erythropoiesis(Disease)红细胞与贫血 Aplastic Anemia(AA,再生障碍贫血)1.Erythropoiesis(Disease)1.Erythropoiesis(Disease)The marrow biopsy section of a young adult with very severe aplastic anemiaA normal marrow biopsy section of a young adult.获得性再生障碍性贫血是一种血液中红细胞、中性粒细胞、单核细胞和血小板减少，而骨髓组织被脂肪组织代替、造血祖细胞几乎缺如的临床综
8、合征。红细胞与贫血病因：1、毒性物质：苯、有机磷2、病毒感染：EB、肝炎病毒、HIV3、药物：氯霉素、噻氯匹定4、自身免疫病：红斑狼疮5、妊娠共同发病途径：细胞毒T细胞自身反应An immune attack of Tc cells targets hematopoietic stem and progenitor cells(CD34+cells)apoptosis hematopoietic failureAplastic Anemia(AA,再生障碍贫血)1.Erythropoiesis(Disease)1.Erythropoiesis(Disease)红细胞与贫血Anemia of C
9、hronic Renal Disease(慢性肾脏疾病的贫血)病变的肾脏产生EPO减少是贫血的主要原因 毒性代谢产物的累积导致红细胞寿命缩短、骨髓抑制 并发炎症或营养不良可加重贫血慢性肾脏疾病患者血细胞比容与内生肌酐清除率的关系。尿毒症患者的循环血EPO水平下降 正常个体和单纯贫血患者有肾的尿毒症患者无肾的尿毒症患者1.Erythropoiesis(Disease)1.Erythropoiesis(Disease)红细胞与贫血Anemia of Chronic Renal Disease(慢性肾脏疾病的贫血)A.外周血涂片慢性肾脏疾病没有特征性的红细胞改变。偶见红细胞碎片，靶形红细胞，棘形红细
10、胞等异常红细胞形态。B.外周血涂片溶血尿毒症综合征。大量的破碎红细胞是溶血尿毒症综合征的典型表现。红细胞大小不一和少量球形红细胞球形红细胞。1.Erythropoiesis(Disease)1.Erythropoiesis(Disease)红细胞与贫血2.Cell2.Cell MembraneMembraneFlexibility to change shapeThe red cell must be able to change shape and squeeze through small capillaries.红细胞与贫血Sphingomyelin(SM 鞘磷脂)Phosphatidy
11、lcholine(PC磷脂酰胆碱)Phosphatidylethanolamine(PE 磷脂酰乙醇胺)Phosphatidylserine(PS 磷脂酰丝氨酸)2.Cell2.Cell MembraneMembraneThe red cell membrane consists of a bipolar lipid layer supported by structural proteins.Protein,49%Lipid,42%Carbohydrate,8%Inorganic ion,1%Outermost layer:glycolipids,glycoproteins Central
12、layer:cholesterol,phospholipids Inner layer:cytoskeleton(骨架蛋白)Spectrin（血影蛋白）Ankyrin（锚蛋白）红细胞与贫血ProteinsIntegral proteins(I，内在蛋白)Band 3（区带3蛋白，阴离子交换蛋白）Glycophorin（血型糖蛋白）are important for the active transport of solutes across the membranePeripheral Proteins(P，周围蛋白)Spectrin（血影蛋白）Actin（肌动蛋白）Ankyrin（锚蛋白）B
13、and 4（区带4蛋白）membrane skeleton on the inner surfaceto maintain the biconcave shape of the red cellto strengthens the membrane against sheer force2.Cell2.Cell MembraneMembrane红细胞与贫血ProteinsIntegral proteins(I，内在蛋白)Band 3（区带3蛋白，阴离子交换蛋白）Glycophorin（血型糖蛋白）are important for the active transport of solutes
14、 across the membranePeripheral Proteins(P，周围蛋白)Spectrin（血影蛋白）Actin（肌动蛋白）Ankyrin（锚蛋白）Band 4（区带4蛋白）membrane skeleton on the inner surfaceto maintain the biconcave shape of the red cellto strengthens the membrane against sheer forceProteins in the red cell membrane can be solubilised by a detergent cal
15、led sodium dodecyl sulphate(SDS)and then be separated according to their size using polyacrylamide gel-electrophoresis(SDS-PAGE).2.Cell2.Cell MembraneMembrane红细胞与贫血Lipids60%phospholipid（磷脂）30%neutral lipids(mainly cholesterol（胆固醇）)10%glycolipids（糖脂）The phospho-and glyco-lipids are structural with po
16、lar groups(hydrophilic)on the external and internal surfaces of the cell.Non-polar groups(hydrophobic)form a barrier at the centre of the membrane.Asymmetry of membrane phospholipids膜磷脂的非对称分布2.Cell2.Cell MembraneMembraneSphingomyelin(SM 鞘磷脂)Phosphatidylcholine(PC磷脂酰胆碱)Phosphatidylethanolamine(PE 磷脂酰
17、乙醇胺)Phosphatidylserine(PS 磷脂酰丝氨酸)红细胞与贫血Carbohydratesare mostly found on the external surface of the red cell membrane.Monosaccharides（寡糖）are associated with specific blood group antigens,e.g.ABH and Lewis.A gene product(A transferase)GalGlcGalGlcNAcRed cell membraneType 2 precursorNote:14 linkageban
18、d 31234Fuc1234GalNAcDonor nucleotide(UDP-GalNAc)Acceptor sugar(Galactose)Specific 13linkageProducing blood group A antigen on the red cell of a group A individual.2.Cell2.Cell MembraneMembrane红细胞与贫血Membrane Function1.cellular deformability and membrane stability2.membrane permeability3.membrane anti
19、genicity and immunologic function4.receptors2.Cell2.Cell MembraneMembrane红细胞与贫血Membrane Function1.cellular deformability and membrane stability structural characteristics-Biconcave shape is the contribute to gas transport huge surface area relative to volume shorten the distance of gas exchange2.Cel
20、l2.Cell MembraneMembrane红细胞与贫血Membrane Function2.membrane permeability2.Cell2.Cell MembraneMembrane红细胞与贫血红细胞膜的通透性，人红细胞主要的离子转运途径AE1,band 3 anion exchanger;带3阴离子运转蛋白（高丰度跨膜糖蛋白，转运Cl-&HCO3-）AQP1,water channel aquaporin 1;水通道蛋白KCC1,氯化物-阳离子协同转运蛋白家族KCl协同转运系统 NKCC2,Na-K-Cl协同转运蛋白基底侧分子形式SK,small conductance po
21、tassium channel.小电导钾通道2.Cell2.Cell MembraneMembrane红细胞与贫血Membrane Function3.membrane antigenicity and immunologic function Blood group antigens are associated with the red cell membrane and are either integral to its structure or are adsorbed onto it from the plasma.They are made of proteins or carb
22、ohydrates.senescent cell antigen,SCA（老化抗原）2.Cell2.Cell MembraneMembrane红细胞与贫血ANTIGENS ON RBC MEMBRANEMembrane Function3.membrane antigenicity and immunologic function2.Cell2.Cell MembraneMembrane红细胞与贫血Membrane Function4.receptorshormone receptors：insulin，glucagonNeurotransmitter receptors：noradrenal
23、ineVirus receptors：flu.receptorothers：TfR，EPO receptor2.Cell2.Cell MembraneMembrane红细胞与贫血2.Cell2.Cell Membrane(disease)Membrane(disease)Hereditary Spherocytosis,Elliptocytosis（遗传性球形红细胞增多症，椭圆形红细胞增多症）abnormal spectrin gene reduced spectrin synthesis or dysfunctional spectrin spherocytes or elliptocyte
24、s遗传性球形红细胞增多症是一种以外周血涂片成熟红细胞呈球形、网织红细胞增多和脾脏肿大为特征的先天性溶血性贫血。红细胞在通过脾脏微循环时，由于细胞膜丢失和膜面积缩小而呈球形样改变并伴有变形可塑性降低。失去变形能力的红细胞在脾脏被破坏最终导致贫血。红细胞与贫血Hereditary Spherocytosis,Elliptocytosis（遗传性球形红细胞增多症，椭圆形红细胞增多症）遗传性球形红细胞增多症病理生理学。HS主要缺陷为细胞膜丢失，膜面积减少，表面积减少，导致细胞球形变，变形能力减弱。2.Cell2.Cell Membrane(disease)Membrane(disease)红细胞与贫血
25、the process of spherocytosis in hereditary spherocytosisHereditary Spherocytosis,Elliptocytosisreduced spectrin synthesisdysfunctional spectrinabnormal spectrin geneSpectrin malfunction within erythrocyte membraneErythrocytes are exposed to high sheer forces within the microcirculationCytoskeleton f
26、unction impaired;cell loses ability to deformSpherocyte:a small,more rigid,spherical erythrocyte resultsCells are either destroyed within the microcirculation or detected and removed by the reticuloendothelial system of the spleenHaemolysis;premature red cell death occurs causing anaemia2.Cell2.Cell
27、 Membrane(disease)Membrane(disease)红细胞与贫血The Congenital Dyserythropoietic Anemias（CDA）先天性红细胞生成异常性贫血先天性红细胞生成异常性贫血（CDA）是指一类罕见的，以红系无效造血，多核红细胞和组织内铁蓄积为特征的遗传性难治性贫血。可分为、型。先天性红细胞生成异常性贫血（CDA）型中带3蛋白-N-乙酰乳糖聚糖链合成不足，而鞘磷脂表现为过度糖基化。2.Cell2.Cell Membrane(disease)Membrane(disease)红细胞与贫血LipidsPS exposure磷脂酰丝氨酸外翻磷脂酰丝氨酸
28、外翻可启动凝血活化途径PS exposure to trigger thrombosis磷脂酰丝氨酸外翻可被巨噬细胞识别并吞噬PS exposure to be recognized and phagocytized by macrophage2.Cell2.Cell Membrane(disease)Membrane(disease)红细胞与贫血Alteration in lipid composition can produce target cells or acanthocytes.靶形红细胞棘形红细胞Lipids2.Cell2.Cell Membrane(disease)Membra
29、ne(disease)红细胞与贫血3.Cell3.Cell MetabolismMetabolism红细胞与贫血metabolic changes in erythropoiesis metabolic capabilitynormoblast reticulocyte mature erythrocyteMultiplication capacityDNA synthesizeRNA synthesizeRNA existenceProtein synthesizeHeme synthesizeLipoid synthesizeTricarboxylic acid cycleOxidativ
30、e phosphorylationTHE EMBDEN-MEYERHOF PATHWAY(EMP)Pentose-phosphate shunt pathway 3.Cell3.Cell MetabolismMetabolism红细胞与贫血3.Cell Metabolism3.Cell MetabolismHAEMOGLOBIN 血红蛋白 Haemoglobin,MW 68,000Da 96%of the red blood cells dry weight 65%of haemoglobin synthesis occurs during the nucleated stages of RB
31、C maturation and 35%occurs during the reticulocyte stage红细胞与贫血Hemegroup(a)Hemoglobin consists of globin珠蛋白(two alpha and two beta polypeptide chains)and four heme血红素 groups.(b)Iron-containing heme pigment(a protoporphyrin ring（原卟啉环）plus ferrous iron(Fe2+)a a Globin chainsb b Globin chainsHAEMOGLOBIN
32、 Structure3.Cell Metabolism3.Cell Metabolism红细胞与贫血HAEMOGLOBIN Function3.Cell Metabolism3.Cell MetabolismIron atom in each heme can bind to one O2 moleculeEach Hb molecule can transport four O2Hemoglobin binds reversibly with oxygenO2 loading in the lungs Produces oxyhemoglobin（氧合血红蛋白）(ruby red)O2 un
33、loading in the tissues Produces deoxyhemoglobin（脱氧血红蛋白）or reduced hemoglobin(dark red)CO2 loading in the tissues Produces carbaminohemoglobin（氨基甲酰血红蛋白）(carries 20%of CO2 in the blood)红细胞与贫血HAEMOGLOBIN Globin（珠蛋白）3.Cell Metabolism3.Cell MetabolismHemoglobin Genes and Gene Products、红细胞与贫血Mehta,A.B.,an
34、d A.V.Hoffbrand.2000.Haematology at a glance,Blackwell Science,Malden,Mass.HbF:2 and 2HbA1:2 and 2HbA2:2 and 2HbE:2 and 2Yolk sacLiverSpleenBone marrow3.Cell Metabolism3.Cell MetabolismHemoglobin Genes and Gene ProductsHAEMOGLOBIN Globin（珠蛋白）红细胞与贫血Embryonic haemoglobins include Gower 1,Gower 2 and H
35、b Portland.HbF is the predominant haemoglobin of fetal life(65-95%).Adults have only trace amounts of HbF(95%)and HbA2(2.5-3.5%)are the main adult haemoglobins.3.Cell Metabolism3.Cell MetabolismSix Hb variants are normally formed.HAEMOGLOBIN Globin（珠蛋白）红细胞与贫血3.Cell Metabolism3.Cell MetabolismHemin c
36、an accelerate the synthesis珠蛋白的合成受血红素调节HRI，Heme-regulated eIF2 kinase；eIF，eukaryote Initiation factor；eIF-2B，eIF-2B GDP-GTP exchange factorHAEMOGLOBIN Globin（珠蛋白）红细胞与贫血(卟啉)（吡咯环）（次甲基）HAEMOGLOBIN HEME（血红素）3.Cell Metabolism3.Cell Metabolism红细胞与贫血HAEMOGLOBIN HEME（血红素）3.Cell Metabolism3.Cell MetabolismHE
37、ME consists of four pyrrole rings（吡咯环）with a central iron atom linked to the four nitrogen atoms.The iron atom has two further binding sites,one of which is bound to a globin histidine residue and the other binds reversibly to oxygen.红细胞与贫血3.Cell Metabolism3.Cell MetabolismHAEMOGLOBIN HEME（血红素）血红素合成
38、的限速酶：ALA synthase，aminolevulinic acid合酶(-氨基-酮基戊酸合酶)辅酶：磷酸吡哆醛（Vit B6）红细胞与贫血3.Cell Metabolism3.Cell MetabolismRegulation of ALA Synthase（ALA合酶的调节）Level of enzyme synthesis（ALA合酶的表达水平）Enzyme synthesis,as well as its transport to the mitochondria,is inhibited by elevated levels of heme and hemin(the Fe3+
39、oxidation product of heme)（过量的血红素高铁血红素抑制酶合成）Enzyme synthesis is upregulated by a large number of drugs including barbiturates,steroids(e.g.testosterone)and some oral contraceptives.（巴比妥类药物，类固醇，睾丸素，口服避孕药）Level of enzyme activity（ALA合酶的酶活性）Heme（血红素）and hemin（高铁血红素）inhibit ALA synthase activityRequires
40、 pyridoxal phosphate(Vitamin B6，磷酸吡哆醛)as a coenzymeHAEMOGLOBIN HEME（血红素）红细胞与贫血3.Cell Metabolism 3.Cell Metabolism(disease)(disease)PORPHYRIAS卟啉症卟啉病是由于血红素生物合成途径中酶缺陷导致反应过程中间代谢产物过量生成与蓄积，并引发神经系统症状和（或）关照性皮肤症状等疾患血红素生物合成途径中各种酶与中间代谢产物，以及与酶缺乏相对应的卟啉病类型。红细胞与贫血IronProtoporphyrinGlobinHaemHaemoglobinThalassaemia
41、Iron deficiencyChronic inflammationMalignancyChronic infections and inflammatory disorders cause chronic anaemia as a result of;1.slightly shortened red blood cell life span 2.sequestration of iron in inflammatory cells called macrophagesBoth procedures result in a decrease in the amount of iron ava
42、ilable to make red blood cells.3.Cell Metabolism 3.Cell Metabolism(disease)(disease)红细胞与贫血HEMOGLOBINOPATHY 血红蛋白病血红蛋白病是全球最常见的遗传性红细胞疾病。是指珠蛋白生成障碍贫血（珠蛋白合成不足）和异常血红蛋白病（珠蛋白一级结构中氨基酸突变），以地中海贫血和镰状细胞综合征为主。可导致中度到重度贫血。3.Cell Metabolism 3.Cell Metabolism(disease)(disease)红细胞与贫血地中海贫血以一条或多条珠蛋白链合成缺陷的遗传性疾病。包括和-地中海贫血。
43、由于珠蛋白链合成的不平衡，导致无效红细胞生成，溶血和不同程度的贫血。HEMOGLOBINOPATHY-Thalassemias（地中海贫血）3.Cell Metabolism 3.Cell Metabolism(disease)(disease)红细胞与贫血HEMOGLOBINOPATHY-Thalassemias（地中海贫血）地中海贫血，过多的 链形成 4分子（HBH）（可溶）-地中海贫血，过多的链（不可溶）致红细胞损伤，造成重度贫血。3.Cell Metabolism 3.Cell Metabolism(disease)(disease)红细胞与贫血HEMOGLOBINOPATHY-Tha
44、lassemias（地中海贫血）3.Cell Metabolism 3.Cell Metabolism(disease)(disease)红细胞与贫血HEMOGLOBINOPATHY-Sickle cell anemia(镰状细胞贫血)3.Cell Metabolism 3.Cell Metabolism(disease)(disease)红细胞与贫血镰状细胞综合征是-珠蛋白链第6位氨基酸谷氨酸被缬氨酸所替代，导致血红蛋白分子脱氧时变得不可溶，形成HBS多聚体，改变了红细胞的正常结构，使红细胞呈僵硬，并由双凹圆盘状变为镰刀形。这类红细胞变形能力差，易破损溶血，导致血管阻塞、组织缺氧、损伤、坏死
45、。Genetics of Sickle Cell AnemiaHEMOGLOBINOPATHY-Sickle cell anemia(镰状细胞贫血)3.Cell Metabolism 3.Cell Metabolism(disease)(disease)红细胞与贫血Hemoglobin ElectrophoresisHomozygous HbSNormal neonateNormal adultHbSCHeterozygous HbSRelative protein chargeStart(samples applied here)Anode(+)Cathode(-)HEMOGLOBINOPA
46、THY-Sickle cell anemia3.Cell Metabolism 3.Cell Metabolism(disease)(disease)红细胞与贫血HEMOGLOBINOPATHY-Sickle cell anemia3.Cell Metabolism 3.Cell Metabolism(disease)(disease)红细胞与贫血Schema summarizing the pathophysiology of sickle cell anemia.K+,potassium;NO,nitric oxide;PS,phosphatidylserine;RBC,red blood
47、 cell;ROS,reactive oxygen species;TF,tissue factor;WBC,white blood cell;XO,xanthine oxidase.HEMOGLOBINOPATHY-Sickle cell anemia3.Cell Metabolism 3.Cell Metabolism(disease)(disease)红细胞与贫血metabolic changes in erythropoiesis metabolic capabilitynormoblast reticulocyte mature erythrocyteMultiplication c
48、apacityDNA synthesizeRNA synthesizeRNA existenceProtein synthesizeHeme synthesizeLipoid synthesizeTricarboxylic acid cycleOxidative phosphorylationTHE EMBDEN-MEYERHOF PATHWAY(EMP)Pentose-phosphate shunt pathway 3.Cell3.Cell MetabolismMetabolism红细胞与贫血3.Cell Metabolism3.Cell MetabolismGlycometabolismM
49、ature red cells no mitochondrial apparatus for oxidative metabolism-Red cells deliver oxygen,not consume itLimited Glucose as a source of energyGlycolysis generates ATP and 2,3-bisphosphoglycerate （2,3-二膦酸甘油酸，2,3-DPG）The pentose phosphate pathway produces NADPH Glutathione synthesis(谷胱甘肽合成)the antio
50、xidant defense system红细胞与贫血Energy required for:Maintenance of cation pumpsMaintenance of RBC integrity and deformabilityReduce oxidants in the systemMaintenance of HB in reduced stateMaintenance of reduced sulfhydryl groups in HB and other proteins3.Cell Metabolism3.Cell MetabolismGlycometabolism红细胞
