1、溶血性贫血,正常红细胞,结构组成：7.5um生理特点红细胞膜的通透性红细胞的可变形性渗透脆性悬浮稳定性代谢糖代谢:酵解酶、磷酸戊糖旁路功能氧运输,正常红细胞破坏,120天， 0.8%衰老RBC结构异常僵硬易被吞噬酶能力僵硬易被吞噬清除单位脾脏（识别衰老和缺陷RBC）肝骨髓/其他,红细胞成分,无线粒体和细胞核细胞膜血红蛋白珠蛋白血红素原卟啉IX亚铁原子,什么是溶血性贫血?,溶血体内红细胞过早破坏贫血红细胞破坏超过骨髓生成骨髓: 儿童 2-3倍 成人 6-8倍儿童更容易发生,资料,溶血时身体发生了什么改变?,Extravascular (liver and spleen),Intravascula
2、r血管内,Red cell,Macrophage巨噬细胞,Hb,globin,Fe,Protoporphyrin,Amino acid pool,Unconjugated bilirubin 未结合胆红素,Transferrin,Plasma Hb ,methemoglobin,Globin,Metheme,Hb dimer,Hepatocytes,Heme,Hemopexin血结素,Fe,Bilirubin,Conjugation,Fecal,Urobilinogen,Urine Urobilinogen尿胆元,Urine Hb血红蛋白尿,Urine Hemosiderin含铁血黄素,Hap
3、toglobin结合珠蛋白,Hb-haptoglobin complex,intestines,kidney,粪胆元,实验室指标,CBCAnemia Increased reticulocyte网织红细胞 count,Hemolytic markersIncreased bilirubinIncreased LDH/ GOT haptoglobin?Presence of hemalbumin游离血红蛋白?Hemosidenuria含铁血黄素尿?Hemoglobinuria血红蛋白尿?,最常见症状,苍白/皮肤颜色黄疸, 皮肤、眼、口腔尿色加深发热虚弱头晕昏睡体力不耐受,体征,皮肤或甲床苍白脉速
4、肝或脾肿大,诊断三步曲,第一步 确定溶血存在,1. 红细胞破坏血: 贫血或球形红细胞/红细胞碎片 尿便生化未结合胆红素 / 乳酸脱氢酶/ GOT红细胞寿命缩短,第一步 确定溶血存在,2. 骨髓代偿增生血片中红细胞的嗜多色性网织红细胞增多骨髓红细胞增多慢性长期溶血：骨骼改变：髓腔增大特殊面容：蒙古面容,血涂片,ABCDEFGHIJ,A-NormalB-Micro/hypoC-MacroD-TargetE-SpheroF-Heinz bodyG-SchistocyteH-nRBCI-PolychromJ-Teardrop,鉴别诊断,黄疸肝大压痛、消化道症状；直胆/间胆、ALT，AKP（+-）胆道梗
5、阻胆囊肿大，大便白: 直胆， ALT （+-）， AKP 先天性黄疸遗传性葡萄糖醛酸转换酶缺乏，间胆直胆, 缺乏溶血+贫血依据贫血出血营养性生成不良,第二步 确定溶血部位,Extravascular Hemolysis,Ingested by RE cell (spleen & liver),Heme,Globin,Iron,Protoporphyrin,Reutilized,bilirubin,Reutilized,鉴别诊断,血管外血管内脾脏 肿大 无肿大LDH bilirubin haptoglobin N to absent absenthemoglobinuria absent pre
6、sentfree Hb in plasma absent presenturine hemosiderin absent present,第三步 确定病因-1,外源性destroyed by becoming trapped in the spleeninfection, or destroyed from drugs 内源性 a defect within red blood cells themselves often inherited: sickle cell anemia 镰贫 and G6PD缺乏,第三步 确定病因-2,血管内外源性机械: prosthetic heart valv
7、e / march hemoglobinuria微血管病变: DIC, TTP, HUS免疫性acute hemolytic transfusion reaction, PNH 感染: malaria / Clostridium welchii sepsis内源性酶病：G6PD缺乏,第三步 确定病因-2,血管外内源性膜病球形红细胞增多, 椭圆形红细胞增多血红蛋白病 - Sickle cell, HbC etc.Thalassemia Syndromes地中海贫血 - , , 酶病外源型Immune and non-immune hemolytic anemia,直接（间接）抗人球蛋白试验,Pa
8、tients RBC,ABO Rh compatible plasma,+,incubate,patients plasma,Direct,+,ABO Rh compatible RBC,Indirect,渗透脆性试验 EOF,原理: 测定红细胞对不同浓度低滲氯化钠溶血的抵抗力-容积储备 - 渗透脆性-容积储备- 膜/容积 ：膜异常- 渗透脆性-容积储备 - 膜/容积：内容物减少,第三步 确定病因-3思路,1、寻找感染、机械损伤、微血管病变证据2、抗人球蛋白试验Coomb 实验+：免疫性溶血3、 Coomb 实验 先天性溶血4、红细胞脆性试验红细胞膜疾病：遗传性球型红细胞增多症正常红细胞酶疾病
9、血红蛋白病：地中海贫血,遗传性球形红细胞增多症,病因,最常见的红细胞膜病1/5000 in northern European populations遗传方式常染色体显性遗传常染色体隐性遗传25% no previous family history-new mutations + recessive inheritanceencode RBC membrane cytoskeleton proteins genes mutations,RED CELL CYTOSKELETON,Membrane defects,Model of RBC membrane,资料,loss of membran
10、e = loss of SA = loss of deformability = increased splenic clearance,Normal,Hereditary spherocytosis,membrane,cytoskeleton,病因,结构缺陷血影蛋白 / 锚蛋白 / band 3Deficiency surface area deficiency leading to spherocytosislipid bilayer skeleton uncoupling membrane loss in the form of microvesicles脾窦破坏脾切除,临床表现,新生儿
11、the cause and require phototherapy or exchange transfusions在儿童严重程度不一无症状三联症：贫血 + 黄疸 + 脾大胆色素结石: 可早在4-5岁发生危象溶血危象再障危象：微小病毒巨幼贫危象,实验室,Evidence for hemolysisReticulocytosis 6-20% (10%) + anemia 6-10g/L -indirect bilirubin MCV n/+ MCHC (36-36g/ml RBCs)reticulocytes and sperocytes: Spherocytes: microcytic小细胞
12、 + hyperchromic高色素 + less central pallor 15-20%BM: erythroid hyperplasiagallstone,资料,诊断,Blood filmSpherocytes and reticulocytesSpherocytes can confirmed: 渗透脆性试验家族史脾肿大osmotic fragility testnegative DATRBC membrane protein analysis (80%)鉴别：自免溶贫,治疗,脾切除Not recommend hb10g/dl + Ret 5-6yrLaporoscopeic spl
13、enectomyBefore: vaccines for encapsulated organismsAfter: oral prolphylactic penicillinPostsolenectomy thrombocytosisFolic acid 1mg/24hrTransfusion,G6PD 酶缺乏,Glycolytic Pathway,Glucose,Glucose-6-phosphate,ATP,ADP,Fructose-6-phosphate,hexokinase,Glucosephosphate isomerasec,Fructose-1,6-bisphosphate,AT
14、P,ADP,Glyceraldehyde-3-phosphate,Dihydroxy-acetone Phosphate,phosphofructokinase,aldolase,Triosephophate isomerase,.,Anaerobic Glycolysis,Hexose Monophosphate Shunt,Glucose-6-dehydrogenase6-phosphogluconate dehydrogense,NADP,NADPH,Glutathione reductase,Reduced glutathione(anti-oxidant),Oxodozed Glut
15、athione,Glutathione peroxidase,H2O2,H2O,Glutathione synthetase,Glycine,cysteine Glutamic Acid,Glutamylcysteine synthetase,Role of G6PD,Glucose,Glucose-6-phosphate,6-Phosphogluconate,Ribose-5-phosphate,Fructose-6-phosphate,Glyceraldehyde-3-phosphate,+,Glyceraldehyde-3-phosphate,Pentose Shunt,ATP,ADP,
16、G6PDehydrogenase,NADPH,NADP+,GSSG,GSH,GSH reductase,NADPH,NADP+,H2O,H2O2,O2,Catalase,Maintaining adequate levels of NADPHNADPH back to NADP+ reduction of oxidized glutathione (GSSG) to glutathione (GSH).detoxify the harmful oxidant H2O2.prevent oxidative damage to hemoglobin,NADPH 还原型辅酶GSH 还原型谷光甘肽,G
17、6PD酶缺乏是发生了什么?,Glucose,Glucose-6-phosphate,6-Phosphogluconate,Ribose-5-phosphate,Fructose-6-phosphate,Glyceraldehyde-3-phosphate,+,Pentose Shunt,G6PDehydrogenase,NADPH,NADP+,GSSG,GSH,GSH reductase,NADPH,NADP+,H2O,H2O2,O2,Catalase,NAD+,NADH,Fe2+ (oxyHb),Fe3+(metHb),Drugs,Glyceraldehyde-3-phosphate,2 O
18、H,Hemolysis,SuperoxideDesmutase(SOD),(Fe2+),GSH Peroxidase,NADPH,(O2 ),G6PD酶缺乏,Occurs in males, frequent in southern ChinaX-linked, 男性发病女性是否发病：G6PD缺乏数量5种临床表现酶活性严重缺乏伴代偿性慢性溶血：活性0酶活性严重缺乏：95% 22 = HbA2 (3%),病因,珠蛋白基因的缺失或点突变所致组成珠蛋白的肽链4种:、链分别由其相应的基因编码基因的缺失或点突变造成各种肽链合成障碍致使血红蛋白的组分改变其中以和地中海贫血较为常见,地贫,珠蛋白基因缺陷珠蛋
19、白肽链一种或几种合成减少/-Hb组分改变: 小细胞低色素贫血临床症状不一: 多为慢性进行性溶贫 分布地区地中海沿岸国家和东南亚各国我国长江以南各省均有报道，以广东、广西、海南、四川、重庆发病率较高，北方较少遗传咨询及产前诊断非常重要鉴别诊断: IDA,Beta 地贫,Beta 地贫,Beta globin: two gene, chromosome 11p15.5主要基因的点突变，少数基因缺失链生成完全受抑制: 0地贫链生成部分受抑制：地贫,重型Cooley贫血,0或的纯合子/0与+双重杂合子链生成完全或几乎完全受抑制HbA22HbF 22 HbF氧亲合力组织缺氧过剩的链沉积RBC链包涵体附着
20、RBC膜变僵硬破坏 “无效造血”临床慢性溶血性贫血贫血/缺氧EPO骨髓造血 骨骼改变贫血肠道对铁的吸收 + 反复输血铁在组织中大量贮存含铁血黄素沉着症:血色病,重型Cooley贫血,慢性进行性贫血出生时无症状312个月发病面色苍白，肝脾大，发育不良，常轻度黄疽症状随年龄增长明显骨骼变大、髓腔增宽先发生于掌骨，以后为长骨和肋骨1岁后特殊面容：颅骨改变：头颅变大、额部隆起、颧高、鼻梁塌陷，两眼距增宽并发气管炎或肺炎并发含铁血黄素沉着症：过多的铁沉着于心肌+其它脏器（肝、胰腺、脑垂体等）该脏器损害的相应症状最严重：心力衰竭（贫血和铁沉着造成心肌损害）患儿死亡如不治疗，多于5岁前死亡,重型Cooley
21、贫血,实验室检查外周血: 小细胞低色素，RBC大小不等，中央浅染区扩大异形、靶形、碎片/有核、点彩、嗜多染红细胞、豪-周氏小体等；网织红细胞正常或增高骨髓：RBC增生明显活跃，中、晚幼红细胞多EOF HbF0.40重要依据: 0.1颅骨X线片颅骨内外板变薄，板障增宽，在骨皮质间出现垂直短发样骨刺,资料,轻型,0或+地贫的杂合子状态/链合成轻度减少 无症状或轻度贫血，脾不大或轻度大病程经过良好，能存活至老年易被忽略，多在重型患者家族调查时被发现实验室检查成熟红细胞有轻度形态改变，红细胞渗透脆胜正常或减低，血红蛋白电泳显示HbA2含量增高（0.0350.060): 本型特点HbF含量正常,中间型,
22、+地贫双重杂合子+某些变异型纯合子+两种不同变异型双重杂合子状态介于重型和轻型间临床表现：多于幼童期出现，介于轻型和重型间中度贫血脾脏轻或中度大黄疽可有可无骨骼改变较轻 实验室检查外周血象和骨髓象的改变如重型： : 12yMany months or yearsInvolving other blood elementsResponse to glucocorticoids: variable and inconsistentMortality 10%Underlying systemic disease,实验室,Anemia: 50% reticulocytes (early low Ret
23、) + uncleated RBCsWBC + Plt normal: exclude Evanssyndromehigh LDH, high indirect bilirubinCoombs test +,Laboratory vs Clinical,Hemolysis,Mild,Moderate,Severe,Labs,No hemolysis,+/- Anemia+Reticulocytes,+ Anemia+ Reticulocytes,Coombs,+,+,+Indirect +,Fulminant爆发性,Hgb in plasma & urine -Shock,+Indirect +,治疗,Steroids静脉用丙种球蛋白脾切除免疫抑制剂CyclophosphamideCSARituxmabFolic acid supplementation血浆置换输血?,
