癌症患者内脏静脉血栓形成的治疗NCCN2016V1

Treatment of SPVT 内脏静脉血栓形成的治疗

The management of patients with SPVT encompasses the use of anticoagulation therapy with or without invasive procedures, such as CDT, (TIPS), surgical shunting, or surgical resection of bowel, as well as other medical management, such as the use of a β-blocker. Management depends on the extent and location of the thrombus, presence of acute symptoms of intestinal infarction, and signs of portal cavernoma or portal hypertension. In the absence of contraindications, anticoagulation with unfractionated heparin or LMWH (preferred) should be initiated, followed by oral anticoagulation for at least 6 months in the case of triggered thrombotic events, such as in a postsurgical setting. The benefit of anticoagulation as initial and long-term therapy in patients with SPVT has been reported in several studies. In a long-term follow-up study of patients with SPVT (n=95; median follow-up of 41 months) primarily treated with anticoagulation (LMWH 200 IU/kg per day for 7–10 days followed by oral anticoagulation for 6 months), 45% of patients with acute SPVT (n=21) had complete recanalization with anticoagulants. Patients requiring resection for intestinal infarction or having incomplete recanalization of thrombus or having inherited thrombophilia were given lifelong oral anticoagulation in this study. Recurrent VTE occurred in 18.5% of patients overall, and was significantly more frequent among patients with concurrent myeloproliferative disorders at presentation versus those without such disorders (70% vs. 13%; P < .0001). Moreover, recurrent VTE was only observed among patients who did not receive anticoagulation. Gastrointestinal (GI) bleeding occurred in 15% of patients and was significantly more frequent among patients with bleeding from esophageal varices at presentation compared with those without prior bleeding (57% vs. 5%; P < .0001). None of the patients receiving oral anticoagulation had bleeding events. In a recent prospective multicenter study in patients with acute portal vein thrombosis (n=95) treated with anticoagulation (initial therapy with heparin followed by oral anticoagulation targeting INR 2–3 for 6 months or long-term in patients with permanent prothrombotic disorders or obstruction of mesenteric vein), the 1-year recanalization rate in the portal vein was 38%. The 1-year recanalization rates in the mesenteric and splenic veins were 61% and 54%, respectively. GI bleeding occurred in 9% of patients, none of which were fatal events. Anticoagulation appears to lower the risk for recurrent thrombosis in patients with SPVT without increasing the risks for severe bleeding, including in patients with underlying prothrombotic states. However, a recent retrospective study in a large cohort of patients with SPVT (n=832) showed that the rate of recurrent VTE was not significantly improved with oral anticoagulation with warfarin (10- year recurrence-free survival rate was 89% vs. 77% in patients who did not receive anticoagulation; P = .38). Based on multivariate analysis, hormone therapy was the only independent predictor of recurrence. Major bleeding events were reported more frequently among patients receiving anticoagulation compared with those who did not (26% vs. 19%; P < .05). Moreover, based on multivariate analysis, presence of gastroesophageal varices and anticoagulation were independent predictors for bleeding events. In chronic SPVT, the presence of portal hypertension may increase the risk of bleeding from esophageal varices and splenomegaly may lead to decreased platelet counts, which can further increase the risks of bleeding events in patients treated with anticoagulation. Thus, in the absence of randomized controlled trials, the issue of long-term or lifelong anticoagulation remains somewhat controversial in patients with SPVT. An individual patient’s risk factor(s) for SPVT should be taken into consideration when weighing the risks and benefits of long-term anticoagulation. The panel currently recommends lifelong anticoagulation in patients with active cancer, underlying thrombophilia, and/or idiopathic thrombosis. 内脏静脉血栓形成患者的治疗包括使用抗凝治疗±侵袭性操作，如经导管溶栓、(经颈静脉肝内门体分流术)、手术分流或肠切除以及其他内科治疗如应用β受体阻滞剂。处理取决于血栓的范围和部位、存在肠梗死的急性症状以及门脉海绵状（血管）瘤或门脉高压体征。在没有禁忌症的情况下，应该启动普通肝素或低分子肝素(首选)抗凝，然后口服抗凝，在引起血栓事件如术后状态的患者中至少6个月。在若干研究中已报道在内脏静脉血栓形成患者中抗凝作为最初与长期治疗获益。在一项长期随访研究中，内脏静脉血栓形成的患者(n=95；中位随访41个月)主要接受抗凝治疗(低分子肝素200IU/kg/d 7-10天然后口服抗凝6个月)，45%的急性内脏静脉血栓形成患者(n=21)用抗凝剂完全再通。在该研究中肠梗死需要切除或血栓不完全再通或遗传性易栓症患者终身口服抗凝。复发性静脉血栓栓塞发生于全部患者的18.5%，并且在发病时并存骨髓增生性疾患的患者当中比那些没有上述异常者显著更常见(70%对13%；P <.0001)。而且，复发性静脉血栓栓塞只在未接受抗凝的患者当中观察到。胃肠道(GI)出血发生于15%的患者并且与那些既往没有出血者相比在发病时食管静脉曲张出血患者当中显著更常见(57%对5%；P <.0001)。接受口服抗凝的患者当中没有一个有出血事件。在最近一项前瞻性、多中心研究中急性门静脉血栓形成患者(n=95)接受抗凝治疗(初始肝素治疗然后口服抗凝6个月目标INR2-3或对持久异常高凝或肠系膜静脉阻塞的患者长期抗凝)，门静脉1年再通率是38%。肠系膜静脉和脾静脉1年再通率分别是61%和54%。胃肠道出血发生于9%的患者，当中没有一个是致命性事件。抗凝似乎降低内脏静脉血栓形成患者的复发性血栓形成风险没有增加严重出血风险，包括具有高凝状态基础的患者。然而，最近在一个大规模内脏静脉血栓形成患者组(n=832)中的一项回顾性调查显示口服华法林抗凝未显著改善复发性静脉血栓栓塞发生率(10年无复发生存率是89%对未接受抗凝患者的77%；P =.38)。多因素分析显示，激素治疗是唯一独立的复发预测因子。与那些没有接受抗凝的患者相比接受抗凝的患者当中报道的严重出血事件更常见(26%对19%；P < .05)。而且，多因素分析显示，存在胃食管静脉曲张和抗凝是独立的出血事件预测因子。在慢性内脏静脉血栓形成方面，存在门脉高压可能增加食管静脉曲张出血的风险并且脾大可能导致血小板计数降低，在接受抗凝治疗的患者中其可进一步增加出血事件的风险。因而，在缺乏随机对照试验的情况下，在内脏静脉血栓形成患者中长期或终身抗凝的论点仍然有点争议。一个具体患者的内脏静脉血栓形成危险因素应该注意权衡长期抗凝的风险与收益。在癌症活跃、有易栓症基础和/或特发性血栓的患者中目前小组推荐终身抗凝。山东省肿瘤医院呼吸肿瘤内科张品良

In patients with acute SPVT with clinical deterioration or progression of thrombosis despite anticoagulation, more invasive approaches using CDT, TIPS, or surgical shunting may be required. Acute thrombosis involving the mesenteric veins is associated with high risks of intestinal infarction, which is life-threatening and requires immediate surgery to resect necrotic sections of the bowel. Catheter- directed thrombolytic therapy has been reported to have some success in acute SPVT in small retrospective studies. Thrombolytic therapy may be most suitable when administered locally for patients with recent thrombosis; however, this approach should be used with caution due to risks for major bleeding complications. The decision for administering thrombolytic therapy should be based on availability and expertise at the local institution, the location of the thrombus, and evaluation of risks of bleeding in individual patients. In addition, the selection of regimens should be based on institutional experience, with decisions made in conjunction with specialists in interventional radiology and vascular surgery. For patients with acute hepatic vein thrombosis with contraindications to anticoagulation or for patients with chronic hepatic vein thrombosis for whom medical management alone are unsuccessful, TIPS or surgical shunts may be considered. TIPS is an interventional radiologic procedure that creates a portocaval shunt between the hepatic and portal veins, and may be appropriate for patients with an occluded IVC or a portacaval pressure gradient<10 mm="" hg.="" tips="" may="" also="" be="" appropriate="" for="" patients="" with="" refractory="" ascites="" and="" progressive="" hepatic="" dysfunction="" despite="" medical="" management="" or="" interventions="" to="" achieve="" recanalization.="" this="" procedure="" is="" less="" invasive="" than="" surgical="" has="" been="" successful="" in="" reducing="" portal="" resolving="" improving="" function="" budd-chiari="" syndrome.="" although="" shunt="" stenosis="" common="" during="" associated="" promising="" long-term="" outcomes="" 5-year="" transplant-free="" survival="" rates="" of="" recent="" studies.="" portosystemic="" shunts="" without="" an="" occluded="" a="" portacaval="" pressure="" gradient="">10 mm Hg, and with preservation of hepatic function. The impact of surgical shunts versus other interventions on long-term outcomes is unknown; nevertheless, 5-year survival rates range from 75% to 87% in patients with Budd-Chiari syndrome undergoing successful surgical portosystemic shunts, and this procedure may improve survival outcomes in patients with intermediate-risk prognostic factors as defined by Darwish Murad et al. Of note, surgical shunts appear to have largely been replaced with TIPS in recent years.
在尽管抗凝临床上血栓仍恶化或进展的急性内脏静脉血栓形成患者中，可能需要使用经导管溶栓、经颈静脉肝内门体分流术或手术分流更加侵袭性手段。急性血栓形成累及肠系膜静脉与肠梗死高危相关，其是致命性的且需要立即手术切除坏死的肠段。在小型回顾性研究中已报道经导管溶栓治疗急性内脏静脉血栓形成相当成功。对于新近血栓的患者局部给药溶栓治疗可能是最合适的；然而，由于严重的出血并发症风险该方法应该慎重使用。决定给予溶栓治疗应该根据当地机构的可用性与专业技巧、血栓部位以及特殊患者的出血风险评估。另外，方案的选择应该根据学会经验，和介入放射学及血管外科专家一起制定决策。对于具有抗凝禁忌症的急性肝静脉血栓形成患者或单纯内科治疗失败的慢性肝静脉血栓患者，可以考虑经颈静脉肝内门体分流术或手术旁路。经颈静脉肝内门体分流术是一种在肝脏与门静脉之间建立门腔静脉分流的介入性放射学操作，对于下腔静脉或门腔静脉阻塞压力梯度＜10mm Hg的患者可能是恰当的。经颈静脉肝内门体分流术可能同样适用于尽管内科治疗和/或干预获得再通的难治性腹水和进行性肝功能异常患者。该操作比外科手术侵袭性小，并且在布加综合征患者中降低门脉高压、解决腹水以及改善肝功能方面已获得成功。尽管在随访期间分流功能障碍或狭窄常见，但是在最近的研究中经颈静脉肝内门体分流术具有充满希望的远期疗效5年无移植生存率74%至78%。在没有下腔静脉阻塞、门腔静脉压力梯度>10mm Hg的患者中手术门体静脉分流可能是恰当的，具有保护肝脏的作用。分流术与其它干预比较对远期疗效的影响不明；虽然如此，在成功进行手术门体静脉分流的布加综合征患者中5年生存率75%-87%，并且在根据Darwish Murad等定义的预后因素中危患者中该措施可以改善生存结局。值得注意的是，近年来手术分流似乎已经基本上被经颈静脉肝内门体分流术所代替。

Patients with chronic portal or mesenteric vein thrombosis frequently present with cavernous transformation and/or signs of portal hypertension, the latter of which can lead to complications such as variceal bleeding. Gastroesophageal varices may be seen in 35% to 50% of patients with portal vein thrombosis at presentation, and remain a significant independent risk factor for major bleeding in patients with SPVT. Thus, an important goal in the management of patients with chronic portal or mesenteric thrombosis is risk reduction for and prevention of bleeding events. The use of β-blockers and endoscopic treatments has been evaluated in the primary and secondary prophylaxis for variceal bleeding in patients at high risk of bleeding events. In several prospective randomized studies comparing the use of variceal banding ligation versus propranolol for primary prophylaxis of variceal bleeding in cirrhotic patients presenting with high-risk gastroesophageal varices, the treatment methods were similarly effective in preventing variceal bleeding (which occurred in 12%–25% of patients with ligation versus 24%–29% receiving propranolol), with a similar overall mortality rate. In one of the studies, patients (n=75) treated with variceal banding ligation had a significantly decreased incidence of esophageal variceal bleeding compared with patients receiving propranolol (5% vs. 25%; P = .027), but at the expense of a higher incidence of subcardial variceal bleeding (8% vs. 0%; P = .027). In another prospective randomized trial comparing the effectiveness of primary prophylaxis using these methods in cirrhotic patients (n=60), ligation was reported to be more effective than propranolol in preventing variceal bleeding (which occurred in 7% vs. 30%; P = .043). A large randomized study comparing variceal banding ligation with or without propranolol for primary prophylaxis of variceal bleeding in patients with high-risk varices (n=144) showed that the combined modality did not significantly reduce the risks of bleeding (actuarial probability, 7% vs. 11%; P = .72) or death (actuarial probability, 8% vs. 15%; P = .37) at 20 months compared with ligation alone. The use of variceal banding ligation and propranolol has also been evaluated in the secondary prophylaxis setting in patients with noncirrhotic portal hypertension at risk of recurrent variceal bleeding. In a recent study (n=101), the incidence of recurrent variceal bleeding was found to be similar between patients receiving ligation versus propranolol (24% vs. 18%; P = .625) for prevention of recurrent bleeding. However, a recent meta-analysis of randomized studies demonstrated that variceal banding ligation or sclerotherapy combined with β-blockers was significantly more effective than endoscopic treatment alone in preventing overall recurrent bleeding (OR, 2.20; 95% CI, 1.69–2.85; P < .0001) and in decreasing overall mortality (OR, 1.43; 95% CI, 1.03–1.98; P = .03), suggesting that combined modality may be preferred as secondary prophylaxis for esophageal variceal bleeding. The panel recommends initiation of β- blockers in patients with chronic portal or mesenteric thrombosis presenting with gastroesophageal varices with or without signs of portal hypertension. In patients who had prior variceal bleeding, it may be appropriate to consider variceal banding ligation or sclerotherapy in conjunction with β-blockers.
慢性门静脉或肠系膜静脉血栓患者常常表现为海绵状转化和/或门静脉高血征象，后者可导致诸如静脉曲张出血并发症。发病时门静脉血栓形成患者中35%-50%可见胃食管静脉曲张，而且在内脏静脉血栓形成患者中仍然是严重出血的一个显著的独立危险因素。因此，在慢性门静脉或肠系膜血管血栓形成患者的治疗中一个重要的目标是降低并预防出血事件的风险。在出血事件高危患者中已评估了应用β受体阻滞剂和内窥镜治疗用于初级和二级静脉曲张出血预防。在若干前瞻性随机研究中比较使用静脉曲张结扎对比普萘洛尔用于高危胃食管静脉曲张的肝硬变患者静脉曲张出血的初级预防，这些治疗方法在预防静脉曲张出血方面是同样有效的(结扎患者发生率12%-25%对普萘洛尔患者24%-29%)，总死亡率相似。在其中的一项研究中，接受静脉曲张结扎治疗的患者(n=75)与接受普萘洛尔患者相比显著降低了食管静脉曲张出血的发生率(5%对25%；P=.027)，但是贲门下静脉曲张出血发生率更高(8%对0%；P=.027)。在另外一项前瞻性随机试验中在肝硬变患者(n=60)中比较使用这些方法初级预防的效果，据报道在预防静脉曲张出血方面结扎比普萘洛尔更有效(发生率7%对30%；P=.043)。一项大型随机研究比较静脉曲张结扎±普萘洛尔用于高危静脉曲张患者(n=144)静脉曲张出血的初级预防显示，与单独结扎相比，联合模式未显著降低20个月时的出血风险(精算概率，7%对11%；P=.72)或死亡(精算概率，8%对15%；P=.37)。也在非硬化性门静脉高压患者中评估了使用静脉曲张结扎和普萘洛尔二级预防静脉曲张出血复发风险。在最近一项研究中(n=101)，发现在接受结扎与普萘洛尔对预防患者反复出血之间复发性静脉曲张出血的发生率是相似的(24%对18%；P=.625)。然而，最近一项随机研究荟萃分析显示静脉曲张结扎或硬化疗法联合β受体阻滞剂显著比单独内窥镜治疗在预防各种反复出血方面(OR，2.20；95% CI，1.69-2.85；P<.0001)以及降低总死亡率方面(OR，1.43；95% CI，1.03–1.98；P=.03)更有效，提示作为食管静脉曲张出血二级预防措施联合模式可能是首选的。专家组推荐在具有慢性门静脉或肠系膜血管血栓形成有胃食管静脉曲张±门静脉高血征象表现的患者中启动β-阻滞剂。在既往有静脉曲张出血的患者中，可适当考虑静脉曲张结扎或硬化疗法联合β受体阻滞剂。