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1、止血异常与恶性肿瘤止血异常与恶性肿瘤 静脉血栓与恶性肿瘤静脉血栓与恶性肿瘤18651865年年TrousseauTrousseau即报道静脉血即报道静脉血栓出现于恶性肿瘤无症状时栓出现于恶性肿瘤无症状时恶性肿瘤静脉血栓的形成恶性肿瘤静脉血栓的形成1 1 游走性浅静脉炎：累及肢体、胸或腹游走性浅静脉炎：累及肢体、胸或腹2 2 DVT/PEDVT/PE:出现于病程任一时间，抗凝药出现于病程任一时间，抗凝药无效无效3 3 动脉血栓：常表现为卒中或急性周围动脉血栓：常表现为卒中或急性周围动脉阻塞动脉阻塞4 4 微血管血栓微血管血栓5 5 非菌性血栓性心内膜炎非菌性血栓性心内膜炎Levitan et a
2、l.1999OvaryBrainPancreasLymphomaLeukemiaColonLung12011711098817661020406080100120140Rate per 10,000 patientsRisk of thrombosis according to cancer typeTumors have procoagulant effect,some(ovary/brain)more than othersCancer therapy chemo/radio also increases risk of thrombosisConcurrent VTE and cance
3、r increases the Concurrent VTE and cancer increases the risk of deathrisk of deathProbability of death within 183 days of initial hospital admissionDVT/PE and malignant diseaseMalignant diseaseNon-malignant diseaseDVT/PE onlyLevitan et al.19991.000.800.600.400.20Probability of death04080120180Number
4、 of daysIncreased risk of recurrent VTE in cancer patientsPatients with cancer are at increased risk of recurrent VTE compared with patients without cancerPatients with cancer are also at increased risk of anticoagulant-associated bleedingRecurrent VTE is more frequent in patients with cancerRetrosp
5、ective study of thrombotic events during oralanticoagulation therapy for 3 monthsCancerNon cancerpRecurrent VTE(events per 100patient years)27.19.00.003Hutten et al.2000Cumulative proportion of recurrent VTE in patients treated with anticoagulant for initial DVT2024681012cancer%MonthsHazard ratio=3.
6、2(95%CI 1.9-5.4)18105no cancerPrandoni et al.2002Cumulative incidence of clinically important bleeding during anticoagulant therapy for DVTPrandoni et al.200201816611170636231416154561021707898112710111268124Time(months)CancerNo Cancer0102030Cumulative Proportion(%)Major BleedingHazard ratio 2.2(CI
7、1.2-4.1)CancerNo cancer伴各种血栓的癌患者累积发病率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原发和继发静脉血栓患者肿瘤发生率组别肿瘤发生率原发继发112/35（34%)2/48（4%)28/21（38%)1/83（1%)37/31（23%)5/82（6%)411/145（8%)2/105（2%)56/27（22%)3/51（6%)621/86（24%)8/207（4%)73/113（2.5%)0/83（0%)813/105（12%)10/569（2%)910/137（7%)
8、3/189（2%)1013/78（17%)5/154（3%)1118/279（6.5%)8/530（1.5%)1213/152（9%)8/112（7%)总计135/120955/2213（2.5%)静脉血栓与肿瘤发生率组别肿瘤发生率有VTE无VTE113/113(11.5%)0/115222/370(6%)24/1029(2%)39/113(8%)20/517(4%)4150/1383(11%)182/2412(7.5%)519/142(13.5%)23/844(3%)总计213/2121(10%)249/4917(5%)恶性肿瘤静脉血栓形成的原因恶性肿瘤静脉血栓形成的原因1.1.TFTF的高
9、表达的高表达2.2.粘蛋白和半胱氨酸蛋白酶直接激活粘蛋白和半胱氨酸蛋白酶直接激活FXFX3.3.细胞因子激活巨噬细胞或内皮细胞细胞因子激活巨噬细胞或内皮细胞4.4.AT-IIIAT-III、PCPC、PSPS下降下降5.5.化疗化疗癌瘤的血管内、外凝血的激活癌瘤的血管内、外凝血的激活乳腺癌中纤维蛋白的沉积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乳腺癌的血栓形成病期病期治疗方案治疗方案患者数患者数血栓数（血栓数（%）II a bCMFVP1431439(6.3)9(6.3)CMF1441445(3.5)5(3.5)CMFBCG1461468(5.4)8(5.4)IV
10、a b CMFVP15915928(17.6)28(17.6)II a bCMFVP1021029(8.8)9(8.8)CMFVP+AT1031035(4.9)5(4.9)II bCMF+T35335334(9.6)34(9.6)T3523525(1.4)5(1.4)II a bEC50505(10)5(10)II bACT38338312(3.1)12(3.1)T3673676(1.6)6(1.6)II bCMFVP+T30330311(3.6)11(3.6)CMFVP3003004(1.3)4(1.3)T3953950 0I a bMFT77977933(4.2)33(4.2)CMFT76
11、976935(4.5)35(4.5)T7787789(1.2)9(1.2)人肿瘤促凝物质人肿瘤促凝物质TFPCA其它其它肺癌肺癌+？乳腺癌乳腺癌+？宫颈癌宫颈癌+？腺癌腺癌+？?肾癌肾癌+?神经母系胞癌神经母系胞癌？+?结肠癌结肠癌+?肝癌肝癌+黑色瘤黑色瘤+ANLL+?ALL+?淋巴瘤淋巴瘤+？+肿瘤中凝血试验的异常肿瘤中凝血试验的异常凝血酶原时间缩短或延长凝血酶原时间缩短或延长 伴有纤维蛋白原、伴有纤维蛋白原、FVFV 、VIII VIII、IXIX、XIXI和和XIIXIIAPTTAPTT时间缩短或延长时间缩短或延长 的升高或降低的升高或降低纤维蛋白原纤维蛋白原-纤维蛋白裂解产物（如纤维
12、蛋白裂解产物（如FPAFPA、D D二聚体、二聚体、B B 15-4215-42和单体）增加和单体）增加F1+2F1+2和和TATTAT增加增加AT-IIIAT-III、PCPC、PSPS下降下降APC-RAPC-R可能性可能性PAIPAI增加增加VWFVWF增加增加TFTF、FVIIaFVIIa或或TFPITFPI增加增加-TGTG增加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
13、毛膜癌2.2.不高表达的恶性瘤不高表达的恶性瘤 肾乳头状癌肾乳头状癌 乳腺小叶癌乳腺小叶癌 非星状细胞神经胶质瘤非星状细胞神经胶质瘤 前列腺腺癌前列腺腺癌 皮肤假性黑色瘤皮肤假性黑色瘤恶性肿瘤与血管内皮生长因子恶性肿瘤与血管内皮生长因子1.1.肿瘤细胞分泌肿瘤细胞分泌VEGFVEGF2.2.有两个受体，有两个受体，VEGF-R1(fle-1),VEGF-VEGF-R1(fle-1),VEGF-R2(flk-1/KDR)R2(flk-1/KDR)3.VEGF3.VEGF与肝素有亲和性与肝素有亲和性4.VEGF4.VEGF增加血管通透性增加血管通透性5.VEGF5.VEGF促促TFTF表达表达 血
14、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用肝素或LMWHLMWH治疗治疗DVTDVT药物药物患者数患者数复发复发DVTDVT数数（%）出血数（出血数（%）LMWH2136(2.8)1(0.5)UHiV21912（6.9）11（5.0）LMWH856（7.0）1（1.0）UHiV8512（14.0）3（4.0）LMWH671（1.5）0UHiV677（10.5）0LMWH1205（4.2）0UHiV1333（2.3）2（1.5）LMWH24713(5.3)5（2.0）UHiV25317(6.7)3（1.2）LMWH20214(6.9)1（0.4）UGiV19817(8.6)4（2.0
15、）LMWH51027(5.3)10（2.0）UHiV51125(4.9)8（1.6）CLOT trial bleedingLMWHOACP*n=338(%)n=335(%)Major bleed 19(5.6)12(3.6)0.27Any bleed 46(13.6)62(18.5)0.093*Fishers exact testThromboprophylaxis with dalteparin in cancer patients following abdominal surgery efficacyBergqvist et al.1995Dalteparin 2,500 IUDalte
16、parin 5,000 IU 0%5%10%15%20%8.8%15.1%Dalteparin 2,500 IU od(p=0.001)Dalteparin 5,000 IU odIncidence of VTE(n=1154)*Numbers represent those patients receiving correct prophylaxis.Prospective,randomized,double-blind,multicenter,dose-ranging trial of 2,070 patients assigned to either 2,500 IU or 5,000
17、IU dalteparin,once daily for 7 daysThromboprophylaxis with dalteparin in cancer patients following abdominal surgery-safetyBleeding complicationsDalteparin 2,500 IUDalteparin 5,000 IUpAll patients2.7%4.7%0.02Cancer patients3.6%4.6%NsNon-cancer patients0.9%5.0%0.01Bergqvist et al.1995Three major tria
18、ls with Fragmin in oncology Prolonged prophylaxis with Fragmin after major abdominal surgery(FAME)Randomized comparison of LMWH versus oral anticoagulant therapy for long-term anticoagulation in cancer patients with venous thromboembolism(CLOT)Fragmin advanced malignancy outcome study(FAMOUS)FAME:st
19、udy designMajor abdominal surgery with and without malignancyBilateral venography(assessor-blinded)7 Days21 DaysTP with dalteparin(5,000 IU sc od)+TED Prolonged TPdalteparin(5,000 IU sc od)No TPRAll VTEn=165n=178Incidence of all VTE 28 days after major abdominal surgeryRRR:55%(95%CI:15%76%)7.3%16.2%
20、024681012141618Incidence of all VTE(%)Prolonged(28-day)TP withdalteparinShort-term(7-day)TP withdalteparinP=0.01NNT:12(7 44)Unpublished data,presented at ISTH 2003Proximal DVTIncidence of proximal DVT 28 days after major abdominal surgeryRRR:77%(95%CI:22%93%)1.8%8.0%0246810n=165n=175Incidence of pro
21、ximal DVT(%)Prolonged(28-day)TP withdalteparinShort-term(7-day)TP withdalteparinP=0.009NNT:17(10 59)Unpublished data,presented at ISTH 2003All DVT7.3%14.9%024681012141618n=165n=175Incidence of all DVT(%)Prolonged(28-day)TP withdalteparinShort-term(7-day)TP withdalteparinP=0.027Incidence of all DVT 2
22、8 days after major abdominal surgeryRRR:51%(95%CI:6%74%)NNT:14(8 100)Unpublished data,presented at ISTH 2003CLOT trial designCancer patients with acute DVT and/or PERDalteparinOral anticoagulantDalteparinn=677 Dalteparin5-7 days6 monthsMonth 1:200 IU/kg sc od Month 26:7580%of full-dose200 IU/kg sc20
23、0 IU/kg scCLOT endpointsPrimary endpointsymptomatic recurrent VTESecondary endpointsbleeding central vein thrombosis of upper limb,neck and chestmortalityCLOT trial recurrent VTE 05 10 15 20 25Days post-randomization0306090120150180210Probability of recurrent VTE(%)Risk reduction=52%P=0.0017Daltepar
24、inOACDays post-randomizationOACDalteparinPatients without metastasesn=150 P=0.03Probability of survival(%)01020304050607080901000306090120150180210240270300330360390CLOT 12-month survivalProbability of survival(%)Days post-randomization01020304050607080901000306090120 150 180 210 240 270 300 330 360
25、 390DalteparinOACPatients with metastasesn=452 P=0.55CLOT 12-month survival Treatment for 1 year or until deathRAdvanced solid tumor malignancyN/Saline placeboDalteparin 5000 IU odFAMOUS:trial designFAMOUS endpointsPrimary endpointmortality at 1 yearSecondary endpointsVTEsafetyfeasibilityFAMOUS:surv
26、ival curves for all ITT patients in dalteparin and placebo groupsKaplanMeier survival distribution function estimateNo.at risk:DalteparinPlacebo1908530221254Dalteparin18472159852Placebo0122436486072841.00.90.80.70.60.50.40.30.20.10.0Time from randomization(months)Median survival(months)and 95%CIDalt
27、eparin:10.8(9.27,13.5)Placebo:9.14(7.33,11.5)P=0.19(Wilcoxon)FAMOUS:survival analysis-patients surviving 17 monthsKaplanMeier survival distribution estimate17 23 29 35 41 47 53 59 6571 77 831.00.90.80.70.60.50.40.30.20.04717 10 9 9 8 8 5 3 2 0 Placebo55 31 26 22 20 13 8 5 5 53 DalteparinTime from randomization(months)No.at risk:DalteparinPlaceboMedian survival(months)and 95%CIDalteparin:43.5(33,52.3)Placebo:24.3(22.4,41.5)P=0.03(Wilcoxon)