肿瘤与血栓.ppt

止血异常与恶性肿瘤,静脉血栓与恶性肿瘤,1865年Trousseau即报道静脉血栓出现于恶性肿瘤无症状时,恶性肿瘤静脉血栓的形成,1游走性浅静脉炎：累及肢体、胸或腹2DVT/PE:出现于病程任一时间，抗凝药无效3动脉血栓：常表现为卒中或急性周围动脉阻塞4微血管血栓5非菌性血栓性心内膜炎,Levitanetal.1999,120,117,110,98,81,76,61,0,20,40,60,80,100,120,140,Rateper10,000patients,Riskofthrombosisaccordingtocancertype,Tumorshaveprocoagulanteffect,some(ovary/brain)morethanothersCancertherapychemo/radioalsoincreasesriskofthrombosis,ConcurrentVTEandcancerincreasestheriskofdeath,Probabilityofdeathwithin183daysofinitialhospitaladmission,DVT/PEandmalignantdiseaseMalignantdiseaseNon-malignantdiseaseDVT/PEonly,Levitanetal.1999,1.000.800.600.400.20,Probabilityofdeath,04080120180Numberofdays,IncreasedriskofrecurrentVTEincancerpatients,PatientswithcancerareatincreasedriskofrecurrentVTEcomparedwithpatientswithoutcancerPatientswithcancerarealsoatincreasedriskofanticoagulant-associatedbleeding,RecurrentVTEismorefrequentinpatientswithcancer,Huttenetal.2000,CumulativeproportionofrecurrentVTEinpatientstreatedwithanticoagulantforinitialDVT,20,2,4,6,8,10,12,cancer,%,Months,Hazardratio=3.2(95%CI1.9-5.4),18,10,5,nocancer,Prandonietal.2002,CumulativeincidenceofclinicallyimportantbleedingduringanticoagulanttherapyforDVT,Prandonietal.2002,0181661,1170636,2,3141615,4,5,6102170,7,8,981127,10,11,1268124,Time(months)CancerNoCancer,0,10,20,30,CumulativeProportion(%)MajorBleeding,Hazardratio2.2(CI1.2-4.1),Cancer,Nocancer,伴各种血栓的癌患者累积发病率,反复的原发性血栓（n=35),各种复发性血栓（n=145),继发性血栓（n=106）,原发和继发静脉血栓患者肿瘤发生率,静脉血栓与肿瘤发生率,恶性肿瘤静脉血栓形成的原因,1.TF的高表达2.粘蛋白和半胱氨酸蛋白酶直接激活FX3.细胞因子激活巨噬细胞或内皮细胞4.AT-III、PC、PS下降5.化疗,癌瘤的血管内、外凝血的激活,乳腺癌中纤维蛋白的沉积,组织因子(TF)引起的血管增生,乳腺癌的血栓形成,人肿瘤促凝物质,肿瘤中凝血试验的异常,凝血酶原时间缩短或延长伴有纤维蛋白原、FV、VIII、IX、XI和XIIAPTT时间缩短或延长的升高或降低纤维蛋白原-纤维蛋白裂解产物（如FPA、D二聚体、B15-42和单体）增加F1+2和TAT增加AT-III、PC、PS下降APC-R可能性PAI增加VWF增加TF、FVIIa或TFPI增加-TG增加,癌症患者血浆纤维蛋白原水平,血管内皮生长因子及其受体在人肿瘤的表达,1.高表达的恶性瘤胃肠系统腺癌（胃、十二指肠、胰、结肠）乳腺癌宫颈癌膀胱癌肾细胞癌卵巢癌血管母细胞瘤星细胞瘤（包括神经胶母细胞瘤）脑膜瘤绒毛膜癌,2.不高表达的恶性瘤肾乳头状癌乳腺小叶癌非星状细胞神经胶质瘤前列腺腺癌皮肤假性黑色瘤,恶性肿瘤与血管内皮生长因子,1.肿瘤细胞分泌VEGF2.有两个受体，VEGF-R1(fle-1),VEGF-R2(flk-1/KDR)3.VEGF与肝素有亲和性4.VEGF增加血管通透性5.VEGF促TF表达,血管增生的正和负调节,凝血系统调节血管增生的机制,用肝素或LMWH治疗DVT,CLOTtrialbleeding,LMWHOACP*n=338(%)n=335(%)Majorbleed19(5.6)12(3.6)0.27Anybleed46(13.6)62(18.5)0.093,*Fishersexacttest,Thromboprophylaxiswithdalteparinincancerpatientsfollowingabdominalsurgeryefficacy,Bergqvistetal.1995,Dalteparin2,500IU,Dalteparin5,000IU,0%,5%,10%,15%,20%,8.8%,15.1%,IncidenceofVTE(n=1154)*,*Numbersrepresentthosepatientsreceivingcorrectprophylaxis.,Prospective,randomized,double-blind,multicenter,dose-rangingtrialof2,070patientsassignedtoeither2,500IUor5,000IUdalteparin,oncedailyfor7days,Thromboprophylaxiswithdalteparinincancerpatientsfollowingabdominalsurgery-safety,Bergqvistetal.1995,ThreemajortrialswithFragmininoncology,ProlongedprophylaxiswithFragminaftermajorabdominalsurgery(FAME)RandomizedcomparisonofLMWHversusoralanticoagulanttherapyforlong-termanticoagulationincancerpatientswithvenousthromboembolism(CLOT)Fragminadvancedmalignancyoutcomestudy(FAMOUS),FAME:studydesign,Majorabdominalsurgerywithandwithoutmalignancy,Bilateralvenography(assessor-blinded),7Days,21Days,TPwithdalteparin(5,000IUscod)+TED,ProlongedTPdalteparin(5,000IUscod),NoTP,R,AllVTE,n=165,n=178,IncidenceofallVTE28daysaftermajorabdominalsurgery,RRR:55%(95%CI:15%76%),Unpublisheddata,presentedatISTH2003,ProximalDVT,IncidenceofproximalDVT28daysaftermajorabdominalsurgery,RRR:77%(95%CI:22%93%),Unpublisheddata,presentedatISTH2003,AllDVT,7.3%,14.9%,0,2,4,6,8,10,12,14,16,18,n=165,n=175,IncidenceofallDVT(%),Prolonged(28-day)TPwith,dalteparin,Short-term(7-day)TPwith,dalteparin,P=0.027,IncidenceofallDVT28daysaftermajorabdominalsurgery,RRR:51%(95%CI:6%74%),NNT:14(8100),Unpublisheddata,presentedatISTH2003,CLOTtrialdesign,CancerpatientswithacuteDVTand/orPE,R,n=677,5-7days,6months,INR2.0-3.0,Month1:200IU/kgscodMonth26:7580%offull-dose,200IU/kgsc,200IU/kgsc,CLOTendpoints,PrimaryendpointsymptomaticrecurrentVTESecondaryendpointsbleedingcentralveinthrombosisofupperlimb,neckandchestmortality,CLOTtrialrecurrentVTE,Dayspost-randomization,CLOT12-monthsurvival,CLOT12-monthsurvival,Treatmentfor1yearoruntildeath,R,Advancedsolidtumormalignancy,N/Salineplacebo,Dalteparin5000IUod,FAMOUS:trialdesign,FAMOUSendpoints,Primaryendpointmortalityat1yearSecondaryendpointsVTEsafetyfeasibility,FAMOUS:surviva