《内科学》全册配套教学课件

《内科学》全册配套教学课件idiopathicthrombocytopeniapurpura

特发性血小板减少性紫癜概述1、定义：免疫介导—血小板过度破坏—出血性疾病。原发免疫性血小板减少症（primaryimmunethrombocytopenia)(immunethrombocytopeniaITP)发病：约占成人出血性疾病30%,儿童出血性疾病60%， 5～19/10万人，女:男1:1。诊断：排除性诊断，缺乏特异性。治疗：非特异，有效率60-70%。

Idiopathicthrombocytopenicpurpura

(ITP)HarringtonetalJLabClinMed38:1,1951Incidence:~3newcases/10106person-yrsPrevalence:~20cases/10106person-yrs121086420<1818–2425–3435–4445–5455–5959–6465–7475–8485–100TotalAge(yrs)Meanannualincidence

(per10106

person-yrs)FemalesMalesBrJHaematol2009;92:1165–1171.依年龄和性别的ITP年发病率（n=1145）发病机制由体液和细胞免疫介导：血小板破坏过多；抗血小板抗体。血小板生成不足：巨核细胞数量和质量异常。TPO水平相对不足巨核细胞成熟障碍和产板不良NEnglJMed,2002,346(13):995-1008临床表现临床上以不同程度和部位的出血为主要表现（一）起病1、隐匿2、多见于育龄妇女，起病缓慢，无明显诱因。临床表现（二）出血倾向1、皮肤粘膜出血2、内脏出血较少见，感染可加重出血。颅内出血是致死的主要原因。3、鼻衄、月经过多在部分慢性ITP患者可为唯一临床症状。关于ITP患者的出血ITP患者主要表现为皮肤粘膜出血（瘀点或紫癜），PLT>30109/L时很少有明显出血。严重内出血或致命性颅内出血十分罕见，有时发生于有合并症的老年患者。慢性ITP患者（PLT<30109/L）致命性出血的年发生率1.6~3.9%。这一危险性随年龄而异，<40岁者年发生率0.4%，而>60岁者年发生率可达13%。ArchinternMed2000;160(11):1630-8临床表现（三）乏力（四）一般无脾大，但部分病程超过半年的慢性型ITP患者可有轻度肿大。（五）血栓形成倾向（六）一般无贫血，若出血量多，可有贫血，且贫血与出血平行。实验室检查（一）血液检查1、血小板计数：减少2、血小板平均体积偏大3、出血时间延长4、血小板功能一般正常5、若出血严重，可有程度不等的贫血。实验室检查（二）骨髓检查

巨核细胞分化：

原巨核细胞→幼稚型巨核细胞→颗粒型巨核→产板型巨核细胞。正常以产板巨为主。

骨髓检查1、巨核细胞正常或增多，2、巨核细胞发育成熟障碍：

体积变小幼稚巨核细胞增多

产板型巨核细胞减少。2、粒系及红系正常，

若出血严重则红系增生，

铁染色可显示外铁消失，

铁粒幼细胞＜15%。诊断及鉴别诊断（一）ITP诊断是排除性诊断1、广泛出血累及皮肤、粘膜及内脏。2、至少2次检查BPC减少，血细胞形态无异常3、脾一般不增大4、骨髓检查：巨核细胞增多或正常，有成熟障碍。5、除外其他继发性血小板减少症诊断及鉴别诊断与继发性血小板减少症鉴别：1）再障2）白血病3）SLE4）脾功能亢进5）TTP6）药物性免疫性血小板减少。诊断ITP的特殊检查血小板抗体检测MAIPA法检测抗原特异性自身抗体，可以鉴别免疫性与非免疫性的血小板减少。血小板生成素水平（TPO）水平检测

鉴别血小板生成减少（TPO水平升高）和血小板破坏增加（TPO水平降低）分型1.

新诊断的ITP：ITP确诊3个月以内。2.

持续性ITP：确诊后3~12个月PLT持续减少，包括未自发缓解或停止治疗后不能维持完全缓解的患者。3.

慢性ITP：血小板减少持续>12个月。分型4.

重症ITP：血小板<10×109/L，存在需要治疗的出血症状或治疗过程中发生新的出血，需采用其它升高PLT的药物治疗或增加现有治疗药物的剂量。5.

难治性ITP：同时满足以下3个条件：①脾切除后无效或复发；

②仍需要治疗以降低出血危险性；

③再次除外其它原因引起的血小板减少症，确诊为ITP。治疗（一）一般治疗，对症治疗。（二）观察无明显出血，血小板＞30X109/L，无手术、创伤

治疗指证不需治疗：若PLT>20~30109/L、无出血表现，勿需治疗，仅观察即可。需要治疗：PLT<20~30109/L，或<50109/L伴有粘膜出血（或出血危险如高血压、消化性溃疡等）。需要住院：PLT<20109/L伴粘膜出血，或有严重出血、危及生命出血。安全操作所需血小板数口腔科检查10×109/L拔牙、补牙

30×109/L小手术、正常阴道分娩

50×109/L大手术、剖腹产

80×109/LBrJHaematol,

2003;120:574-596.治疗

（三）首次诊断ITP的一线治疗1、首选糖皮质激素

（1）剂量与用法：Pred1mg/kg/d，BPC正常后，1个月快速减至最小维持量5-10mg。无效者4周停药。

（2）副作用：血压、血糖，预防感染治疗2、静脉输注丙种球蛋白（1）ITP急症的处理（2）不能耐受糖皮质激素或脾切前准备（3）有糖皮质激素使用禁忌症（4）400mg/kg/dX5天治疗（四）ITP的二线治疗脾切除1、适应证：（1）正规糖皮质激素治疗无效，迁延6月以上（2）强的松维持量＞30mg/d（3）有糖皮质激素使用禁忌症治疗2、禁忌证：（1）年龄＜2岁（2）妊娠期（3）因其他疾病不能耐受手术3、疗效：有效率70%～90%治疗2、药物治疗（1）抗CD20单克隆抗体（2）血小板生成药物（3）长春新碱（4）环孢素A（5）其他ManagementofITPAlternativetherapy(individualization):AgeofpatientSeverityofpresentationPlateletcountPrimaryrefractoryorrelapsedLengthoftimepriortorelapse规范治疗ITP治疗方案观察Plt>30109/L地塞米松40mgpo4d；或甲强1g/div3d。每2w一疗程、共三疗程新诊断ITPPlt<30109/L，伴出血CTX200-400mgiv.2/w6~8次（或CTX1giv.1/3w3次）VCR1mgiv.drip1/w3~4次CsA

3~6mg//kg/d，监测血药浓度有效者减量维持至少6月美罗华375(或100mg)/m2，1/w4次有效者可每3-6月375(或100)mg/m2，维持rhTPO300U/kg/d，S.C.14d或Plt>50109/L停用非常规治疗：移植无效时依情选其它方案可选任一方案，达那唑0.2，Bid~Tid，至少3月有效者减量维持治疗3月Plt<30109/LPlt<30109/L泼尼松1mg/kg/d21d泼尼松渐减量维持治疗3月Plt>30109/L持续性/慢性ITP脾切除（包括副脾）有效者CTX100mg、2~3次/w并渐减量维持，总剂量<10g有效者可每周给药1-2次维持重型ITP的抢救性治疗：若Plt<10109/L或严重出血，除激素外，可给予血小板输注、IVIg或rhTPO不接受或无效治疗

（六）急症处理（1）BPC＜20×109/L（2）出血广泛严重（3）疑有或已发生颅内出血者（4）近期将实施手术或分娩者治疗（1）血小板悬液输注（2）静注丙种球蛋白（3）大剂量甲泼尼龙简历

彭志刚，男，医学博士，教授，硕士研究生导师。广西医科大学第一附属医院大内科副主任、内科学教研室副主任、血液内科副主任，中华医学会血液学分会第七、八届全国青年委员，中华医学会血液学分会第七、八届“白血病和淋巴瘤学组”委员，现任广西医学会血液学分会主任委员。主要研究方向为血液肿瘤的临床及实验研究。

LeukemiaPengZhigangDep.Hematology，

GuangxiMedicalUniversityConceptofleukemiaDefinitionLeukemiaisamalignantClonalheamotopoieticstemcells

disorderProliferationisoutofcontrolandapoptosisisinhibited.Leukemiacellisclonedandaccumulatedinagreatquantity,thenormalhemapoiesisisihibited.DifferentiationofHSCisblocked.LeukemiacellsarestoppedonadifferentiationstageofHSC&lackofthenormalfunction.ExtramedullaryinvolvementandmetastasisHematopoiesisPLURIPOTENTSTEMCELLCOMMITTEDPROGENITORCELLRECOGNIZABLEBONEMARROWPRECURSORCELLMATUREBLOODCELLmyeloblastmonoblastpronormoblastredcellneutrophilmonocytebasophilplateletCFU-BasoCFU-EosCFU-GMBFU-E/CFU-Eeosinophilpre-Tpre-BmyeloidprogenitorcelllymphoidprogenitorcelllymphoblastlymphoblastT-cellB-cell&plasmacellMIXEDPROGENITORCELLCFU-MegmegakaryocytepluripotentstemcellMyeloidmaturationmyeloblastpromyelocytemyelocytemetamyelocytebandneutrophilMATURATIONAdaptedandmodifiedfromUVawebsitemalignantblooddisorderspathophysiologyClinicalmanifestationHSCdifferentiationisblockedNormalbloodcellsaredecreasedThefunctionofBloodandimmunesystemareshortof.Anemia,fever,hemorrhageAbnormalmorphologypicturesofbloodandbonemarrow.

Proliferationisoutofcontrol,apoptosisisinhibited.Leukemiacellisaccumulatedinagreatquantity.LeukocytesandLeukostasis(白细胞淤滞)Liver,spleen,lymphnods,skin,CNSetc.areinfiltratedanddysfunctionalfrequently.Classificationofleukemias

Dependingonthedfferentiation

andthenaturalcourseofthedisease,Itcanbedividedintotwokinds:AcuteLeukemiaprogressesquicklycharacterizedbytheproliferationofundifferentiatedcellsinthebonemarrowLifespan<3-6msChronicLeukemiaslowerprogressionuncontrolledexpansionofmaturecellsLifespan>12msClassificationofleukemiasAcuteChronicMyeloidoriginLymphoidoriginAcuteMyelogenousLeukemia(AML)AcuteLymphoblasticLeukemia(ALL)ChronicMyelogenousLeukemia(CML)ChronicLymphoblasticLeukemia(CLL)AccordingtoKindofcellcanbedividedinto:

Epidemiology:incidenceIncidence:3-4/105

，increasewithyears?distributionoftype:acute>chronic,AML>ALLSpecialdistribution:

Sexman：female＝1.81：1AgeALL,adolescent80％<20y;AML,adultCML,20~50yearsold;CLL,50~70yearsoldAreaadultTlymphocyticleukemiaCML,easterncountriesCLL,westerncountries

Epidemiology:mortality2.51/105Areacity>thecountrysideChina<Singapore<Japan<USA<unitedKingdom<Sweden(7.5～9/105)Inorderofthemortalityofmalignanttumorsin1～14y，leukemiaismosthighin15～44y，leukemiaisthirdhigh(<stomachCa<liverCa)inallperson,leukemiaissixth(male)oreighthhigh(female)EtiologyMostcasesarisewithnoclearcausesomeacceptedriskfactorsforleukemogenesisEtiologyBiologicfactors:

virus:HTLV-1canresultinAcuteTlymphomaicleukemia.ImmunologydefectEtiologyPhysicalfactors

radiationexposure:ionicradiation,x-ray

1、atombomb2、highdoseXradiotherapy、

32PtherapyEtiologyChemicalfactorsChemicalexposure:benzenepetroleumPesticideOtherenvironmentalexposureshairdyessmokingPriorchemotherapy

alkylatingagents(cyclophosphamideandmelphalan)TopoisomeraseIIinhibitors,doxorubicinandmitoxantrone

EtiologyGeneticdisorders:

DownsyndromeBloomsyndromeFanconi’sanemiaataxia-telangiectasiaWiskott-AldrichsyndromeInidenticaltwins

fromotherblooddisordersMyeloproliferativeDisease(MPD)chronicmyeloidleukemia(CML)polycythemiavera(PV)primarythrombocythemia(PT)myelofibrosis(MF)myelodysplasticsyndrome(MDS)paroxysmalnocturnalhemoglobinuria(PNH)lymphomaormyelomaEtiologyPrinciplesofleukemogenesisamultistepprocessThemutationofgene(ras,myc)resultintheproliferationoftheleukemiccloneSomegeneticchangesresultindifferentiationblockedatanearlystageAcuteLeukemias

Classification(FABsystem)

AML（M1）

AML(M2)

APL（M3）

AML（M4）

AML（M4EO）

AML（M5）

AML（M6）

AML（M7）ALL:FABClassificationL1-Smallcells;subtyperepresents25-30%ofadultcasesL2-Largeandirregularnuclearshape,andnucleolusoftenlarge;subtyperepresents70%ofcases(mostcommon)L3–veryLarge;subtyperepresents1-2%ofadultcases

ALL（L1）

ALL（L2）

ALL（L3）Classification（二）WHOClassification

MICM分型

morphology:形态学FAB分型

immunology:免疫学用CD抗原单克隆抗体分型

cytogenetics:细胞遗传学染色体分型

molecularbiology:分子生物学基因分型ClinicalFeaturesdecreaseinnormalhematopoiesisaccumulationofblastcellsinothersites:infiltration

ClinicalFeaturesAnemia

(RBC↓)

•

pallor,weakness,fatigue,dyspnea,tachycardiaClinicalFeaturesbleedingPLT↓

•skin,purpura,mucosalbleeding,epistaxis,menorrhagia•life-threatening:brainbleeding•associatedwithDIC(promyelocyticleukemia)

ClinicalFeaturesInfections:

neutrophil↓

immune↓

•URI,gingivitis,pharyngitis,bronchitis

•pneumonitis,septicemia

•pathogens:gram-negative;fungusClinicalFeaturesdecreaseinnormalhematopoiesisaccumulationofblastcellsinothersites:infiltration

ClinicalFeaturesenlargementofliver,spleen,lymphnodes,

especiallyALLClinicalFeaturesbonepain,sternumtendernesschloroma/granulocyticsarcoma,Spinalcolumnororbit:exophthalmos,diplopia,blindnessClinicalFeaturesgumhypertrophySkin:rashes,palpable,hard,indigonodeClinicalFeaturesCNS-L:

oftenoccurredinALL,headache,dizziness,vomiting,neckrigidityClinicalFeaturestestisoftenoccurredinALL,TesticularpainlessenlargementanyorganLaboratorystudiesBlood：

WBCusuallyelevated,butcanbenormalorlow,WBC<1×109/L(hypoleukocytosis);>10×109/L(hyperleukocytosis)blastsarepresentanemia(normocytic),immatureRBCmaybepresentPLT↓thrombocytopeniaLaboratorystudiesBonemarrowaspirationnecessaryfordiagnosisusefulfordeterminingtypeusefulforprognosisLaboratorystudies

BonemarrowaspirationProliferative(mostcase);hypoplastic(10%)WHO:blasts>20%Auer‘srods(+)inAMLerythropoiesis↓megakaryocytopoiesis↓leukemiacells(showAuer’srods)

Laboratorystudies

Cytochemistry:

主要用于协助形态鉴别各类白血病常见AL的细胞化学鉴别急淋白血病(ALL) 急粒白血病 急性单核细胞白血病 过氧化物酶(POX)（－）分化差的原始细胞（－）～（＋）（－）～（＋）分化好的原始细胞（－）～（+++）

糖原PAS反应（＋）成块（－）或（＋），（－）或（＋）呈弥漫或颗粒状弥漫性淡红色 性淡红色或颗粒状

非特异性脂酶(NSE)（－）（－）～（＋）（＋）NaF抑制≥50%NaF抑制＜50%

LaboratorystudiescytochemicalstainsPeroxidasestain:AMLNonspecificesteraseandinhibitedbysodiumfluorid:M4,M5Periodicacid-Schiff(PAS)stain:ALLLaboratorystudiesImmunophenotypingCytogenetics表6-9-2白血病免疫学积分系统（EGILL，1998）分值B系T系髓系2

CyCD79aCyCD22CyIgM

CD3TCRa/BTCRr/B

CyMPO1

CD19CD20CD10

CD2CD5CD8

CD117CD13CD33CD650.5

TdTCD24

TdTCD7CD1a

CD14CD15CD64IMMUNO-PHENOTYPING

mab M1 M2 M3 M4 M5 M6 M7CD13 + + + + + - -CD33 + + + + + - -CD14 - ± - + + - -CD41 - - - - - - +Ret - - - - - + -Lectoferrin- + - + - - - CD19 CD7 HLA-DR CD3 MPO T - + - + - B + - + - -ImmunophenotypingAccordingtoImmunophenotypeofleukemia,ALis

dividedintofourtypess:1acuteundifferentiatedleukemia

（AUL）2Acutemixedlineageleukemia

3(1)M+ALL;(2)L+AML4Asinglephenotype:(1)ALL;(2)AML表6-9-3AML常见的染色体和分子学异常的意义预后等级细胞遗传学（染色体）分子生物学异常良好t(15;17)（q22;q12）APL(PML/RARa)t(8;21)（q22;q22）AMLM2a(AML1/ETO)inv(16)（p13q22）/t(16;16)（p13;q22）

AMLM4Eo(CBFB/MYH11)正常核型伴有孤立的NPM1突变中等正常核型、孤立的+8、孤立的t(9;11)（p22；q23）、其他异常t(8;21)或inv(16)伴有c-kit突变不良复杂核型(≥3种)，-5、-7、5q-、7q-、11q23异常，除外t(9;11)、inv(3)、t(3;3)、t(6;9)、t(9;22)、正常核型伴有单独的FLT3-ITD表6-9-4ALL常见染色体和分子学异常的检出率染色体核型基因发生率（成人）发生率（儿童）超二倍体亚二倍体

--

7%2%

25%

1%t(9;22)（q22;q22）：Ph+t(12;21)（p13;q22）t(v;11q23)t(1;19)

BCR-ABL

TEL-AML1MLLE2A-PBX1

25%2%10%3%

3%22%8%5%t(5;14)（q31;q32）t(8;14)t(2;8)t(8;22)t(1;14)（p32;q11）t(10;14)（q24;q11）t(5;14)（q35;q32）

IL3-IGHc-myc

TAL1

HOX11HOX11L2

＜1%4%12%

8%1%

＜1%2%7%

1%3%

ChromosometranslocationFusiongeneM2t(8;21)AML1/ETOM3

t(15;17)PML/RARM4inv(16),t(16;16)CBF/MYH11M5t(4;11),11q23MLLabnormalitesALL(15%)L3t(9;22)t(8;14)BCR/ABLMYC,IgHrearrangementCommonCytogeneticAbnormalitiesinAMLandALLLaboratorystudiesChemistry:LDHand,UA↑DIC:APTT↑,PT↑,fibrinogen↓LaboratorystudiesChemistryCSFofGNS-L:

1,spinalfluidpressure↑（＞200mmH2O）2,WBC↑（＞0.01×109/L）3,Protein↑（＞450mg/L）4,blastspresentinthespinalfluid,

DiagnosisClinicalfeaturesBMaspiration:morphology,cytochemicalstaining,immunophenotyping,cytogenetics,molecularbiologyDifferentialDiagnosismyelodysplasticsyndromes(MDS)Infections:infectiousmononucleosisbonemarrowrecoveringfromacuteagranulocytosismegaloblasticanemiaTreatmentEliminateofhyperleukocytosis:

leukapheresishydroxyureahydratedchemotherapyLeukostasisaccumulationofblastsinmicrocirculationwithimpairedperfusionlungs: hypoxemia,dyspnea,pulmonaryinfiltratesCNS: stroke,dizziness,stupor,intracerebralhemorrhageonlyseenwithWBC>>50x109/LAvoidoftumorlysissyndromes:(Hyperkalemia;hyperphosphatemia;hyperuriemia;

hypocalcemia

combinationofhydration,allopurinol,andalkalinizationofurinewithsodiumbicarbonateTreatment

SupportivecareReplacementofbloodproducts:packedredbloodcells,platelets,freshfrozenplasma

Antibiotics

UseofgrowthfactorsMetabolicmanagementTreatment:Chemotherapy

aimsoftreatmenteliminateabnormalcloneallowrepopulationofmarrowwithnormalhemopoieticcellsTherapeuticprincipleofALearlycombinefullintervalrepeatChemotherapy

TwoorthreephasesRemissioninduction(inductionchemotherapy)ConsolidationtherapyMaintenancechemotherapyInductionchemotherapyaims–CRCompleteremission

:

nosignsorsymptomsofthediseasenormalperipheralbloodcellcountnormocellularmarrowwithlessthan5%blastsinthemarrowInaddition,therearenoextramedullaryinfiltration.ConsolidationtherapyConsolidationtherapy

istreatmenttoclearresidualleukemiawhenpatientsareinmorphologicremission.Molecularmarkersofresidualdiseasecanoftenbedetectedafterinductionchemotherapy,whichindicatestheneedforfurthertreatment.

MaintenancechemotherapyMaintenancechemotherapyisusedprimarilyinALLandAPL,sincelowdoseantileukemicagentsadministeredover18-24monthscanpreventrelapse.

TreatmentofALLRegimen

induced

remissionVP (classical)

VCR2mg+NS20ccVqw

Prednisone20~30mg/dp.oCR50%butrelapseeasily2.VDLPVCR1～2mg＋NS20ccVqw(1,8,15,21d)

DNR30～40mgVgttqd1～3d,15～17d

Pred40mg～60mgp.o1～14d

L-ASP10,000uVgtt19－28dCR80~90%VDLCP:TALL+CTX;Ph+ALL:+TKIConsolidationtherapyofALLTheconsolidationwithalternatingcyclesofhigh-doseAra-C(HDAC)andetoposidewithhigh-doseMTXHSCTCNS-LprophylaxisTheincidenceofCNSrelapseismuchhigherinpatientswithALLthaninthosewithAML;amongpediatricALL,therateofCNSrelapsewas20%inthefirstyear.CNS-LprophylaxisPatientswithALLrequirepreemptivetherapyforoccultCNSdiseasewitheither(1)intrathecalMTXandAra-Ccombinedwithcranialirradiation.(2)high-dosesystemicAra-CInductiontherapyofAML(noAPL)

regimensidarubicin+cytarabine(IA)daunorubicin+cytarabine(DA)CR50-80%HACR60-65%mitoxantrone+cytarabine(MA)TreatmentofAPLAPLismostcommonlyassociatedwithDICandfibrinolysis.95%ofcases,cytogeneticstestingrevealst(15;17)(q21;q11).MolecularstudiesrevealthePML/RARarearrangementATRAorArsenicTrioxideisthefirstchoiceretinoicacidsyndromeischaracterizedbyfever,weightgain,pleuralandpericardialeffusions,andrespiratorydistress.ConsolidationtherapyofAML(noAPL)good-riskAML,ie,t(8;21),16(inv16),

araCat3g/m2twiceadayondays1,3,and5ofeachcycle,repeatedmonthlyfor4consolidationcycles.Transplantationshouldbereservedforpatientswhorelapse.

ConsolidationtherapyofAML(noAPL)intermediate-riskcontroversial.Somereferpatientsinfirstremissionfortransplantationothersgiveconsolidationchemotherapywithhigh-dosearaCfor4coursesandreservetransplantationforpatientswhorelapse.ConsolidationtherapyofAML(noAPL)high-riskTheyarerarelycuredwithchemotherapyTheyshouldbeofferedallo-transplantationinfirstremission.

TreatmentofAPLconsolidationtherapy:usually2coursesofidarubicinandaraC.MaintenancetherapywithATRA,6-MP,andmethotrexateArsenicTrioxideTreatmentofrelapseandrefractoryAMLHSCTClinicaltrialTreatmentofAgedALReducedosechemotherapyChronicmyelogenousleukaemia

ChronicMyelogenousLeukemia(CML)CML -myeloproliferativedisoder-increasedproliferationofgranulocyticcellsstillhascapacitytodifferentiation

*peripheralbloodshowincreased granulocyticcellswiththeirimmature precursorsEpidemiologyofCML

15%ofleukemiainadultsOccursmainlybetweentheageof30-70yrsCause;stillunknownIncreasedincidencewasreportedinradiationexposureareasuchasbenzene,andchemicals-Survivalforolderformtherapywas3-5yearsChronicphaseClinicalfeatures30percentofpatientareasymptomaticatthetimeofdiagnosisSymptomsaregradualinonset:easyfatigability,malaise,anorexia,abdominaldiscomfort,weightloss,excessivesweatingClinicalfeaturesLessfrequentsymptoms:Nightsweats,heatintolerance-mimickinghyperthyroidism,goutyarthitis,Physicalsigns:Pallor,splenomegaly,sternalpainClinicalfeaturessymptomsofleukostasistinnitus,stuporsplenicinfartion(leftupper-quadrantandleftshoulderpain),urticaria(resultofhistaminerelease)priapismLaboratoryfeaturesBloodTheWBC↑above22000/μl(oftenabove100000/μl),granulocytesatallstagesofdevelopmentThebasophilescountisincreased↑Neutrophilsalkalinephosphatase(NAP)activityisloworabsent(90%)LaboratoryfeaturesTheplateletcountisnormalorincreasedThehemoglobinconcentrationisdecreasedNucleatedredcellsinbloodfilmLaboratoryfeaturesBonemarrow:Themarrowishypercellular(granulocytichyperplasia)ChemistryprofileHyperuricemiaSerumvitaminB12-bindingproteineandserumvitaminB12levelsareincreasedLaboratoryfeaturesCytogenetictest-presenceofthePhchromosomeMoleculartest–presenceoftheBCR-ABLfusiongeneEtiologyofCMLPhiladelphiachromosome,Ph1(>95%)Non-Philadelphiachromosome(<5%)p190p210chimericproteinp239TyrosinekinaseactivityPathogenesis

AcceleratedphaseofCMLMostpatientseventuallybecameresistanttotherapyandthediseaseentersamoreagressivephaserefractorysplenomegalyorrefractoryleucocytosisSymptomsaregradualinonsetagainAcceleratedphaseofCMLCriteriaofacceleratedphaseBlastsinbloodorbonemarrow-10-19%Basophilia≥20%Thrombocytopenia<100G/lThrombocytaemia>1000G/lAdditionalchromosomalaberrationsReticulinfibrosisBlastphase(blastcrisis)ofCMLCriteriaofblastphaseBlasts≥20%Blasts+promylocte

inBonemarrow≥50%Blasts+promylocte

inperipheralblood≥

30%extramedullarytumors

Diagnosis

Clinicalfeatures:splenomegalytheperipheralbloodfilmshowsleucocyteswithmanyimmatureformsMarrowexaminationshowsincreasedcellularity.NAP(-)CytogeneticshowsthepresenceofthePhchromosomeandbcr/ablDifferentialdiagnosisDiseasesofsplenomegalyLeukemoidreactionMyelofibrosisTreatmentofCPEliminateofhyperleukocytosis:

leukapheresishydroxyureahydratedchemotherapyTreatmentofCPMoleculortargetingtreatmentImatinibmesylate(STI571)isthefirstchoiceItactsbyspecificallyinhibitingtheenhancedproteintyrosinekinaseactivityoftheBCR-ABLoncoproteinandthusreversingthepathologicallyperturbedsignaltransduction.Dose:400mg/dcurativeeffect:8yearsEFS81%、OS85%CCyR83%。ThesecondTKI:DasatinibCMLofT3151mutation:Allo-SCTTreatmentofCPHydroxyureaOftenusedinitiallyforwhitecellcountreductionDose:1-6g/dorally;Thedoseshouldbedecreasedto1-2g/dwhentheleukocytecountreaches20000/µlDrugshouldbestoppedifthewhitecountfallsto5000/µlItdoesnotalterlong-termprognosis

TreatmentofCP

(interferon-α，IFN-α)Interferonhasantiviralandanti-proliferativeactions.ItwasuntilrecentlythedrugofchoiceformanagingCMLinthechronicphase.Itrestoresspleensizeandbloodcountstonormalin70-80%ofpatients.Some10-20%ofpatientsachieveamajorcytogeneticremissionsideeffects:

Interferoninitiallycausesflu-likesymptomsOthersideeffectsincludeanorexia,weightloss,depression,alopecia,rashes,neuropathies,autoimmunedisorders,andthrombocytopenia.

TreatmentofCP

(Allo–HSCT)

Allo-HSCTistheonlywaytocureCML5yearsosisabout80%forCMLinchronicphase.Indication:AnewdiagnosisofchildrenandadolescentsThemosthighriskpredictionofdiseaseprogressionpossibilityTKItreatmentfailureorintolerancetothepatients.TreatmentofAdvancedphasedisease

TreatmentofAP:ThefirstorsecondTKIAllo-HSCTTreatmentofBP/BC:TKI+chemotherapyAllo-HSCT程鹏血液内科副主任主任医师无党派人士，医学硕士；硕士研究生导师广西医学会血液病学会秘书广西医师协会血液病学分会总干事《血栓与止血》杂志专业期刊编委。研究方向：1、出凝血疾病的诊断和治疗2、地中海贫血的血栓前状态3、妊娠相关血小板减少

Hemorrhagicdisease

出血性疾病概述

GuangXiMedicalUniversitychengpeng2015.03.19定义

因止血功能缺陷而引起的以自发性出血或血管损伤后止血不止为特征的疾病。HemostasisandThrombosisVascular

，Platelets

，Coagulation血管（Vascular）的止血作用内膜（intima)外膜(advertitia)中膜(media)血管的结构程鹏血液内科学主任医师

无党派人士，医学硕士；

硕士研究生导师。广西医学会血液病学会秘书《血栓与止血》杂志专业期刊编委。研究方向1、血液病出凝血机制研究2、地中海贫血的血栓前状态3、出血性疾病ITP血栓前状态CoagulationCoagulationFactors：

FactorsⅠ～ⅤFactorsⅦ～ⅩⅢPK激肽释放酶原HMWK高分子量激肽原vWF血管性血友病因子凝血因子共14个，按罗马字命名的有12个，尚有高分子量激肽原(HMWK)，激肽释放酶原(PK)大多数由肝脏产生正常情况下，所有因子都处于无活性状态依赖维生素K的凝血因子因子II（凝血酶原）因子VII（稳定因子）因子IX（血浆凝血活酶成分）因子X（Stuare-Prower因子)

凝血过程

两个途径（内源性、外源性）三个阶段：一、凝血活酶生成二、凝血酶生成三、纤维蛋白生成内源性凝血途径外源性凝血途径

负电荷物质ⅫⅫaⅪⅪaⅢⅨⅨaⅦaⅦCa2+ⅢⅧCa2+PF3

ⅩⅩaⅤ凝血活酶Ca2+

磷脂

凝血酶原（Ⅱ）凝血酶（Ⅱa）

ⅠⅠa←ⅩⅢa←－ⅩⅢⅠbCa2+注：PF3血小板第3因子，Ⅰa：不稳定纤维蛋白Ⅰb：稳定纤维蛋白凝血酶诱导血小板不可逆聚集，加速其活化激活Ⅻ因子，启动内源性凝血系统激活ⅩⅢ因子，加速稳定纤维蛋白的形成加速凝血酶原激活纤溶酶原纤溶酶纤维蛋白溶解+抗凝与纤维蛋白溶解机制（一）抗凝系统的组成及作用1、抗凝血酶（ATantithrombin）

主要功能：灭活FⅩa及凝血酶

其他丝氨酸蛋白酶：FⅨa、FⅪa、FⅫa

抗凝与纤维蛋白溶解机制2、蛋白C系统(proteinC、proteinS、TM)

凝血酶+TM—裂解PC—形成活化PC（APC）—灭活FⅤa、FⅧa抗凝与纤维蛋白溶解机制3、组织因子途径抑制物

(tissuefactorpathwayinhibitorTFPI)4、肝素(heparin)抗凝系统的组成和作用FⅫaPC-S（一）AT-Ⅲ

FⅪaFⅨaⅧaFⅩaFⅤaPF3Ca++TFPI+Hyvecinthrombinprothrombin（一）（一）（一）（一）（一）（一）（一）（二）纤维蛋白溶解系统组成与激活1、组成：（1）纤溶酶原（plasminogenPLG）（2）组织型纤溶酶原活化剂（t-PAtissueplasminogenactivator）(3)尿激酶型纤溶酶原活化剂（u-PAurokinaseplasminogenactivator）。