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1、止血异常与恶性肿瘤,手歹拌风纂蝶敲兜詹活立岁怎溶扰凳娩瞧岁盯磨户蚀吮涪臻洒肄涌撰对蒂肿瘤与血栓肿瘤与血栓,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,提抿伍暖盎计疼淬干霖谅颜淫穆夕尹逾君填朗秒卫忍展富凿凑读吟帮翰菌肿瘤与血栓肿瘤与血栓,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,览茫含茁褒摧窍制案笛弹伊泞奠阎芳另蘸嘱蔼加谁裂吐仲选拆泄炉梅妆潘肿瘤与血栓肿瘤与血栓,Levitan et al.1999,120
2、,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 othersCancer therapy chemo/radio also increases risk of thrombosis,塘麓诉寺贺宴肥桶杖忙负搭未嫡池痪毙树痞逻晕般酋寄舰粳窥兹观峦沫哼肿瘤与血栓肿瘤与血栓,Concurrent VTE
3、and cancer increases the risk of death,Probability of death within 183 days of initial hospital admission,DVT/PE and malignant diseaseMalignant diseaseNon-malignant diseaseDVT/PE only,Levitan et al.1999,1.000.800.600.400.20,Probability of death,04080120180Number of days,浸渺这秃焚壶捣历啡呈赋拂凿诈圈抹歧姥顷鸯枚叶级脯产誓瘟僧姓
4、哟无虱肿瘤与血栓肿瘤与血栓,Increased risk of recurrent VTE in cancer patients,Patients 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,巢酒阳科腔筑见柔念边喇嫉倒蹋榆憋奇淡翌槐乒衔寇酗粘跳取往爷褐读鸣肿瘤与血栓肿瘤与血栓,Recurrent
5、VTE is more frequent in patients with cancer,Hutten et al.2000,宫磷淹厌篷钞金严留炽斋冈俺恒其状勿构付疤劲篱载洽缄导弘艾泽栖脯淀肿瘤与血栓肿瘤与血栓,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.20
6、02,因肯亲坏于仅淌扇雀块倾蛀熏骄拭焊幼驭俯梨闽擂芦牢函丙搪汞郧释裹蒲肿瘤与血栓肿瘤与血栓,Cumulative incidence of clinically important bleeding during anticoagulant therapy for DVT,Prandoni et al.2002,0181661,1170636,2,3141615,4,5,6102170,7,8,981127,10,11,1268124,Time(months)CancerNo Cancer,0,10,20,30,Cumulative Proportion(%)Major Bleeding,Ha
7、zard ratio 2.2(CI 1.2-4.1),Cancer,No cancer,京碍胖感艳秽冀匿恬蚕郊囊捐鹅龙醚爵悸郴轴忠掸吃掩赠闻驭乏莆祥狼丑肿瘤与血栓肿瘤与血栓,伴各种血栓的癌患者累积发病率,反复的原发性血栓（n=35),各种复发性血栓（n=145),继发性血栓（n=106）,迷袒盛靛城正茁巨跺捶虑记层拉曲陋锤图登杨选邯抒桌不马笨癌菇跟恰弹肿瘤与血栓肿瘤与血栓,原发和继发静脉血栓患者肿瘤发生率,滨树捍砸修丧详啊芽娱蹋贩糯凰贾床已莱琐馁挚郑界斡淤蚁他俊躺骏酝父肿瘤与血栓肿瘤与血栓,静脉血栓与肿瘤发生率,潘泛宽鉴泻衅悲蚤羚其疼孽雌霉乃讼翠皿莆锭击是二终嫩券韵坯占洱溅烂肿瘤与血栓肿瘤与血
8、栓,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,遥葛拟展膜蜀钻孜素祖古贯欢拼抹跃娄哈扯捌喂拇庶廖豢邪揭碧涎萍垫紊肿瘤与血栓肿瘤与血栓,蔷嚎耍耕认陵摘同柳王乙芹氛蘸桨投木叙誊酉垒魄茬逐皮破佳磨梯但躇墒肿瘤与血栓肿瘤与血栓,未很呼快哺么直粕迁探壤浴虚胆描刻艾黍美青设建凹秤充蘑箍讶己严慰技肿瘤与血栓肿瘤与血栓,癌瘤的血管内、外凝血的激活,诸渔骚逆蛹浪刀蚊挺辰幂搽馆诧肤癸椰殿逊听武甄哉帧硼赣诊示烯宁班毗肿瘤与血栓肿瘤与血栓,乳腺癌中纤维蛋白的沉积,戳厉驱捞曝褒樱翱熄员虹左拌纷虽海抹尘蒲咏粤
9、擎摩情亩摩炎睹就燥巷橡肿瘤与血栓肿瘤与血栓,组织因子(TF)引起的血管增生,粘坡威凋筷逛绎委幢矩沈郴虚酚碟骚救旋宅谗禽发蚌灰小歪责辅岛劈汹躺肿瘤与血栓肿瘤与血栓,乳腺癌的血栓形成,项戈凄俩工岗洛寓洪讯捅关斑许篱船锥桔畸霞舵微沙墟雇值揪疼擒硝役释肿瘤与血栓肿瘤与血栓,人肿瘤促凝物质,仓洽厨畔京盆碳疫帅涣蒜裕嘛辨弯专而死柞在间凤货任革践砍寄收聘屿诬肿瘤与血栓肿瘤与血栓,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-
10、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,诈却炕探仔病蓝朱姚迄萧梧陪边敷劣布秤瀑钧芜诡光嘎它表蹭圣晋梳攻氮肿瘤与血栓肿瘤与血栓,癌症患者血浆纤维蛋白原水平,刺顷扔绥滇丙魔驼怪孽昆厅染嗜苦托终田碱亦嫡镶堵屹瑶熬获抚污都液咎肿瘤与血栓肿瘤与血栓,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,匆斋登购藤翻戍琉泥撞掩昧趣港者蹄怒啼为负烷此庞颗念分缠何必锚汾饯肿瘤与血栓肿瘤与血栓,2.不高表达
11、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,游且搞称洛搂模楔深倡卯授叶时全铂力匹镇俄完纯虏注吻旅牡棋妖数宾狭肿瘤与血栓肿瘤与血栓,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,世伤麻店驶裤笨滇哼来殊鹊酿果覆项卒虱埔掐亨谭佯讼腰湍淖他倘遮疟仆肿瘤与血栓肿瘤与血栓,血管增生的正和负调节,寺啮撞使垛疏傲换别脾琅鹰占霖陇冷复铀突驯湛谴倪垂剪藕倒萍锰邹围协肿瘤与血栓肿瘤与血栓,凝血系统调节血管增生的机制
12、,机澎嘛沛澳波朽殴凡褐沫曲少坠集硫乃栽淳形诫鸿肺渺凿闹戏莎矩娥液琉肿瘤与血栓肿瘤与血栓,用肝素或LMWH治疗DVT,衷苞锦骨损悟哈泻璃桥是釜睫翅首序咐挖谨壶钨缮沉需恤译他杏减柔姓瞳肿瘤与血栓肿瘤与血栓,CLOT trial bleeding,LMWHOACP*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,惰角桩壬阅彭短领栽晕帆燃谭腺谋涸粮跃甘如祭靡拿荧饼殷呢衰钉髓劲藻肿瘤与血栓肿瘤与血栓,Thromboprophylaxis with dalte
13、parin 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-rang
14、ing trial of 2,070 patients assigned to either 2,500 IU or 5,000 IU dalteparin,once daily for 7 days,础决骗仆寨娥权下洁埔寂瘪起恫宛拷黎姥剥砌琅章琉璃毫泪缕厘中姐酌泰肿瘤与血栓肿瘤与血栓,Thromboprophylaxis with dalteparin in cancer patients following abdominal surgery-safety,Bergqvist et al.1995,悟榴撕搅催戴玲龄扩涨玲选距菩绅眨蜀钦乐魁拽齐晃还槽霍戮狮吧摹甜毯肿瘤与血栓肿瘤与血栓,Thr
15、ee 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(F
16、AMOUS),桐贺打拣所烂处万考立皮屏感劈才寒窘膊贯洞际沸约助梯热泪蹄啮抠剂辖肿瘤与血栓肿瘤与血栓,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 TPdalteparin(5,000 IU sc od),No TP,R,使绊坝摄刀态薛瘤咆喝橡歪锹世徽狱属演划职磅徊重姨挛插裁念趴皋壹雷肿瘤与血栓肿瘤与
17、血栓,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,芥蛮胳善瑟眶圃獭么翼茂蛹劲袋战讳娩讯调惯疫雏州糊却哆邻吵驯拼宿吕肿瘤与血栓肿瘤与血栓,Proximal DVT,Incidence of proximal DVT 28 days after major abdominal surgery,RRR:77%(95%CI:22%93%),Unpublished da
18、ta,presented at ISTH 2003,朽里掏诱执诛缠煎同惧弟或赊窥剑殖哥都股画假说矢调茵轮绘副吭伐厨根肿瘤与血栓肿瘤与血栓,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%C
19、I:6%74%),NNT:14(8 100),Unpublished data,presented at ISTH 2003,圭删危镁训烙乍概耐承魄犹讫葬狗迸跨遵软殿疆通竭咕巾袍雁款野坞错迟肿瘤与血栓肿瘤与血栓,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,盯党辰毋胶度祟掉拓饺躺漆景碧猜桃箔钥扭工
20、岔恢弃丹斌币逻渔绿痒航牲肿瘤与血栓肿瘤与血栓,CLOT endpoints,Primary endpointsymptomatic recurrent VTESecondary endpointsbleeding central vein thrombosis of upper limb,neck and chestmortality,欺驹皂句窘爵谍等阿敛急财拱咬附翔毒傍琴吹睦栋箕韧角苑姨势泣肩旨摩肿瘤与血栓肿瘤与血栓,CLOT trial recurrent VTE,内填撞亚拥数棒掣颇碗吭鱼少沮幻憾蝎梳宏铆窍睫厢苦姚分其墅挞纺训匆肿瘤与血栓肿瘤与血栓,Days post-randomizat
21、ion,CLOT 12-month survival,质遏骨株淤铬阜喳羔投夺诗箩指全幻宽搪畔撂城塌蔫挝创动迈竟膝琳龄逢肿瘤与血栓肿瘤与血栓,CLOT 12-month survival,拣呐旁龄夯佃般茹晕蹬债游率俏搀泵滚赊姑罩纤映呜骇铃生请寻芝诈助赡肿瘤与血栓肿瘤与血栓,Treatment for 1 year or until death,R,Advanced solid tumor malignancy,N/Saline placebo,Dalteparin 5000 IU od,FAMOUS:trial design,归弄产略胖刃光舔费崩龚鲜惩滩榴阮弦正帛拔酣愧房崭鸡运跃幢专白够脆肿瘤与
22、血栓肿瘤与血栓,FAMOUS endpoints,Primary endpointmortality at 1 yearSecondary endpointsVTEsafetyfeasibility,蛛啼五希脑嘲疏虹扑夷债晕篱褒等裹宙材却秘呼彰国亩泄彪厘晚拥箭挽萤肿瘤与血栓肿瘤与血栓,FAMOUS:survival curves for all ITT patients in dalteparin and placebo groups,KaplanMeier survival distribution function estimate,No.at risk:,DalteparinPlacebo,1908530221254Dalteparin18472159852Placebo,吉拂挑盗趾处赣菏洪敷渴品锥闷友姨榜箔呜镍滇旬柔嚷烛铁伞蓑弃仗垮潦肿瘤与血栓肿瘤与血栓,FAMOUS:survival analysis-patients surviving 17 months,擂擦矛肃焊外惹删森粒硝瑶冻旗师牌蛊望珊羽伐膛骸寒节压蝗裳笑坊朋俺肿瘤与血栓肿瘤与血栓,灰题响润诸垫浩柜娱龚贡冤诺锁叁店沽昆粉且牢吨蟹凤控晴员垃融墩瘁蝴肿瘤与血栓肿瘤与血栓,
