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 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,Levitan et al. 1999,120,117,110,98,81,76,61,0,20,40,60,80,100,120,140,Rate per 10,000 patients,Risk of thrombosis according to cancer type,Tumors have procoagulant effect, some (ovary/brain) more than others Cancer therapy chemo/radio also increases risk of thrombosis,Concurrent VTE and cancer increases the risk of death,Probability of death within 183 days of initial hospital admission,DVT/PE and malignant disease Malignant disease Non-malignant disease DVT/PE only,Levitan et al. 1999,1.00 0.80 0.60 0.40 0.20,Probability of death,0 40 80 120 180 Number of days,Increased risk of recurrent VTE in cancer patients,Patients with cancer are at increased risk of recurrent VTE compared with patients without cancer Patients with cancer are also at increased risk of anticoagulant-associated bleeding,Recurrent VTE is more frequent in patients with cancer,Hutten et al. 2000,Cumulative proportion of recurrent VTE in patients treated with anticoagulant for initial DVT,20,2,4,6,8,10,12,cancer,%,Months,Hazard ratio=3.2 (95%CI 1.9-5.4),18,10,5,no cancer,Prandoni et al. 2002,Cumulative incidence of clinically important bleeding during anticoagulant therapy for DVT,Prandoni et al. 2002,0 181 661,1 170 636,2,3 141 615,4,5,6 102 170,7,8,9 81 127,10,11,12 68 124,Time (months) Cancer No Cancer,0,10,20,30,Cumulative Proportion (%) Major Bleeding,Hazard ratio 2.2 (CI 1.2-4.1),Cancer,No cancer,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FX 3.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XII APTT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VEGF 2.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,CLOT trial bleeding,LMWH OAC P* n=338 (%) n=335 (%) Major bleed 19 (5.6) 12 (3.6) 0.27 Any bleed 46 (13.6) 62 (18.5) 0.093,*Fishers exact test,Thromboprophylaxis with dalteparin in cancer patients following abdominal surgery efficacy,Bergqvist et al. 1995,Dalteparin 2,500 IU,Dalteparin 5,000 IU,0%,5%,10%,15%,20%,8.8%,15.1%,Incidence 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 IU dalteparin, once daily for 7 days,Thromboprophylaxis with dalteparin in cancer patients following abdominal surgery - safety,Bergqvist et al. 1995,Three 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 thromboembolism (CLOT) Fragmin advanced malignancy outcome study (FAMOUS),FAME: study design,Major abdominal surgery with and without malignancy,Bilateral venography (assessor-blinded),7 Days,21 Days,TP with dalteparin (5,000 IU sc od) + TED,Prolonged TP dalteparin (5,000 IU sc od),No TP,R,All VTE,n=165,n=178,Incidence of all VTE 28 days after major abdominal surgery,RRR: 55% (95% CI: 15% 76%),Unpublished data, presented at ISTH 2003,Proximal DVT,Incidence of proximal DVT 28 days after major abdominal surgery,RRR: 77% (95% CI: 22% 93%),Unpublished data, presented at ISTH 2003,All DVT,7.3%,14.9%,0,2,4,6,8,10,12,14,16,18,n=165,n=175,Incidence of all DVT (%),Prolonged (28-day) TP with,dalteparin,Short-term (7-day) TP with,dalteparin,P= 0.027,Incidence of all DVT 28 days after major abdominal surgery,RRR: 51% (95% CI: 6% 74%),NNT: 14 (8 100),Unpublished data, presented at ISTH 2003,CLOT trial design,Cancer patients with acute DVT and/or PE,R,n=677,5-7 days,6 months,INR 2.0-3.0,Month 1: 200 IU/kg sc od Month 26: 7580% of full-dose,200 IU/kg sc,200 IU/kg sc,CLOT endpoints,Primary endpoint symptomatic recurrent VTE Secondary endpoints bleeding central vein thrombosis of upper limb, neck and chest mortality,CLOT trial recurrent VTE,Days post-randomization,CLOT 12-month survival,CLOT 12-month survival,Treatment for 1 year or until death,R,Advanced solid tumor malignancy,N/Saline placebo,Dalteparin 5000 IU od,FAMOUS: trial design,FAMOUS endpoints,Primary endpoint mortality at 1 year Secondary endpoints VTE safety feasibility,FAMOUS: survival curves for all ITT patients in dalteparin