肿瘤与血栓课件

1、止血异常与恶性肿瘤 肿瘤与血栓止血异常与恶性肿瘤 肿瘤与血栓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肿瘤与血栓静脉血栓与恶性肿瘤1865年Trousseau即报道静脉血栓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2 DVT/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肿瘤与血栓恶性肿瘤静脉血栓的形成1 游走性浅静脉炎：累及肢体、胸或腹肿Levitan et al. 1999OvaryBrainPancreasLymphomaLeukemiaColonLung120

2、11711098817661020406080100120140Rate 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 thrombosis肿瘤与血栓Levitan et al. 1999OvaryBrainPConcurrent VTE and cancer increases th

3、e risk 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 of days肿瘤与血栓Concurrent VTE and cancer incrIncreased risk of recur

4、rent 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 bleeding肿瘤与血栓Increased risk of recurrent VTRecurrent VTE is more frequent in patients with cancerRet

5、rospective study of thrombotic events during oralanticoagulation therapy for 3 monthsCancerNon cancerpRecurrent VTE(events per 100patient years)27.19.00.003Hutten et al. 2000肿瘤与血栓Recurrent VTE is more frequentCumulative proportion of recurrent VTE in patients treated with anticoagulant for initial D

6、VT2024681012cancer%MonthsHazard ratio=3.2 (95%CI 1.9-5.4)18105no cancerPrandoni et al. 2002肿瘤与血栓Cumulative proportion of recurCumulative incidence of clinically important bleeding during anticoagulant therapy for DVTPrandoni et al. 200201816611170636231416154561021707898112710111268124Time (months)C

7、ancerNo Cancer0102030Cumulative Proportion (%)Major BleedingHazard ratio 2.2 (CI 1.2-4.1)CancerNo cancer肿瘤与血栓Cumulative incidence of clinic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）肿瘤与血栓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

8、 （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%)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%)肿瘤与血栓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静脉血栓与肿瘤发生率组别肿瘤发生率有VTE

9、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%)肿瘤与血栓静脉血栓与肿瘤发生率组别肿瘤发生率有VTE无VTE113/1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.化疗肿瘤与血栓恶性肿瘤静脉血栓形成的原因1.TF的高表达肿瘤与血栓癌瘤的

10、血管内、外凝血的激活肿瘤与血栓癌瘤的血管内、外凝血的激活肿瘤与血栓乳腺癌中纤维蛋白的沉积肿瘤与血栓乳腺癌中纤维蛋白的沉积肿瘤与血栓组织因子( TF)引起的血管增生肿瘤与血栓组织因子( TF)引起的血管增生肿瘤与血栓乳腺癌的血栓形成病期治疗方案患者数血栓数（%）II a bCMFVP1439(6.3)CMF1445(3.5)CMFBCG1468(5.4)IV a b CMFVP15928(17.6)II a bCMFVP1029(8.8)CMFVP+AT1035(4.9)II bCMF+T35334(9.6)T3525(1.4)II a bEC505(10)II bACT38312(3.1)T3

11、676(1.6)II bCMFVP+T30311(3.6)CMFVP3004(1.3)T3950I a bMFT77933(4.2)CMFT76935(4.5)T7789(1.2)肿瘤与血栓乳腺癌的血栓形成病期治疗方案患者数血栓数（%）II a bC人肿瘤促凝物质TFPCA其它肺癌+？乳腺癌+？宫颈癌+？腺癌+？?肾癌+?神经母系胞癌？+?结肠癌+?肝癌+黑色瘤+ANLL+?ALL+?淋巴瘤+？+肿瘤与血栓人肿瘤促凝物质TFPCA其它肺癌+？乳腺癌+？宫颈癌+？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

12、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增加肿瘤与血栓肿瘤中凝血试验的异常凝血酶原时间缩短或延长 伴有癌症患者血浆纤维蛋白原水平肿瘤与血栓癌症患者血浆纤维蛋白原水平肿瘤与血栓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 绒毛膜癌肿瘤与血栓血管内皮生长因子及其受体在人肿瘤的表达1.高表达的恶性瘤肿

13、瘤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 皮肤假性黑色瘤肿瘤与血栓2.不高表达的恶性瘤肿瘤与血栓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表达肿瘤与血栓恶性肿瘤与血管内皮生长因子1.肿瘤细胞分泌VEGF肿瘤与血栓 血管增生的正和负调节肿瘤与血栓 血管增生的正和负调节肿瘤与血栓凝血系统调节血管增生的机制肿瘤与血栓凝血系统调节血管增生的机制肿瘤与血栓用肝素或LMWH治疗DVT药物患者数复发DVT数（%

14、）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）LMWH51027(5.3)10（2.0）UHiV51125(4.9)8（1.6）肿瘤与血栓用肝素或LMWH治疗DVT药物患者数复发DVT数（%）出血

15、数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 test肿瘤与血栓CLOT trial bleedingLMWHOACThromboprophylaxis with dalteparin in cancer patients following abdominal surgery efficacyBergqvist et al. 1995Dalteparin 2,500 IUDaltep

16、arin 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 5,0

17、00 IU dalteparin, once daily for 7 days肿瘤与血栓Thromboprophylaxis with daltepThromboprophylaxis 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

18、%0.01Bergqvist et al. 1995肿瘤与血栓Thromboprophylaxis with daltepThree major trials 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

19、 thromboembolism (CLOT)Fragmin advanced malignancy outcome study (FAMOUS) 肿瘤与血栓Three major trials with FragmiFAME: study 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

20、IU sc od) No TPR肿瘤与血栓FAME: study designMajor abdomAll VTEn=165n=178Incidence of all VTE 28 days after major abdominal surgeryRRR: 55% (95% CI: 15% 76%)7.3%16.2%024681012141618Incidence of all VTE (%)Prolonged (28-day) TP withdalteparinShort-term (7-day) TP withdalteparinP= 0.01NNT: 12 (7 44)Unpublis

21、hed data, presented at ISTH 2003肿瘤与血栓All VTEn=165n=178Incidence of Proximal DVTIncidence of proximal DVT 28 days after major abdominal surgeryRRR: 77% (95% CI: 22% 93%)1.8%8.0%0246810n=165n=175Incidence of proximal DVT (%)Prolonged (28-day) TP withdalteparinShort-term (7-day) TP withdalteparinP = 0.

22、009NNT: 17 (10 59)Unpublished data, presented at ISTH 2003肿瘤与血栓Proximal DVTIncidence of proxiAll 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 28 days after major abdominal surgeryRRR:

23、 51% (95% CI: 6% 74%)NNT: 14 (8 100)Unpublished data, presented at ISTH 2003肿瘤与血栓All DVT7.3%14.9%02468101214161CLOT trial designCancer patients with acute DVT and/or PERDalteparinOral anticoagulantDalteparinn=677 Dalteparin5-7 days6 monthsINR 2.0-3.0Month 1: 200 IU/kg sc od Month 26: 7580% of full-d

24、ose200 IU/kg sc200 IU/kg sc肿瘤与血栓CLOT trial designCancer patienCLOT endpointsPrimary endpointsymptomatic recurrent VTESecondary endpointsbleeding central vein thrombosis of upper limb, neck and chestmortality肿瘤与血栓CLOT endpointsPrimary endpointCLOT trial recurrent VTE 05 10 15 20 25Days post-randomiza

25、tion0306090120150180210Probability of recurrent VTE (%)Risk reduction=52%P=0.0017DalteparinOAC肿瘤与血栓CLOT trial recurrent VTE Days post-randomizationOACDalteparinPatients without metastasesn=150 P=0.03Probability of survival (%)01020304050607080901000306090120150180210240270300330360390CLOT 12-month s

26、urvival肿瘤与血栓Days post-randomizationOACDaltProbability of survival (%)Days post-randomization01020304050607080901000306090120150180210240270300330360390DalteparinOACPatients with metastasesn=452 P=0.55CLOT 12-month survival 肿瘤与血栓Probability of survival (%)DayTreatment for 1 year or until deathRAdvanced solid tumor malignancyN/Saline placeboDalteparin 5000 IU odFAMOUS: trial design肿瘤与血栓Treatment for 1 year or until FAMOUS endpointsPrimary endpointmortality at 1 yearSecondary endpointsVTEsafetyfeasibility肿瘤与血栓F