内脏静脉血栓的诊断与评估NCCN2016V1

Diagnosis and Evaluation of Splanchnic Vein Thrombosis (SPVT)  内脏静脉血栓(SPVT)的诊断与评估

SPVT refers to a relatively rare group of VTE within the splanchnic vasculature comprising the hepatic (characteristic of Budd-Chiari syndrome), portal, mesenteric, and splenic venous segments. Thrombotic events may occur in multiple segments (approximately 38%–50% of SPVT cases) or in isolated segments within the splanchnic vasculature, with isolated portal vein thrombosis (approximately 34%– 40% of SPVT cases) being the most common amongst the latter. Limited data are available to assess the relative prognosis of patients with SPVT according to the venous segment affected. In a large single- center retrospective analysis of patients with SPVT (n=832), the 10-year survival rate was significantly decreased among patients with thrombosis in multiple segments compared with those with thrombosis in a single/isolated segment (48% vs. 68%; P < .001); the 10-year survival rate for the entire cohort was 60%. Moreover, the 10-year survival rate was highest among patients with isolated hepatic vein thrombosis (82%), while the lowest survival rate (63%) was reported in those with isolated portal vein thrombosis (P = .045 for comparison of Kaplan-Meier survival estimates across subgroups of isolated SPVT). The investigators attributed the lower survival rate of patients with portal vein thrombosis to the relatively high incidence of malignancies present in this group; in this retrospective study, the presence of malignancy was significantly associated with decreased survival for patients with SPVT, both in univariate and multivariate analyses. In a separate retrospective study in patients with extrahepatic portal vein thrombosis (n=172), a concurrent diagnosis of mesenteric vein thrombosis was significantly predictive of decreased survival based on multivariate analysis; presence of cancer was also a significant independent predictor of mortality. Several smaller retrospective studies have also reported on adverse outcomes for patients with mesenteric vein thrombosis, with a 30-day mortality rate of 20%. Thromboses in the mesenteric vein can lead to intestinal infarction, which is frequently life- threatening. In one study, intestinal infarction was present in 45% of patients diagnosed with mesenteric vein thrombosis, of which 19% were fatal. 山东省肿瘤医院呼吸肿瘤内科张品良
内脏静脉血栓形成指的是在内脏血管包括肝脏(布加综合征的特征)、门静脉、肠系膜和脾静脉部分的内脏血管内发生的一个较罕见的静脉血栓栓塞类型。血栓事件可能发生在多部位(大约38%-50%的SPVT病例)或孤立发生在内脏血管部分，在后者中孤立的门静脉血栓形成(大约34%-40%的SPVT病例)最常见。根据静脉受累部分评估内脏静脉血栓形成患者相对预后的资料有限。在一项内脏静脉血栓形成患者(n=832)的大型单中心回顾性研究中，与单个/孤立部位血栓患者相比，多部位血栓患者10年生存率显著降低(68%对48%；P< .001)；全组10年生存率是60%。此外，报道的10年生存率在孤立肝静脉血栓形成患者当中最高(82%)，而孤立门静脉血栓形成者生存率最低(63%)(与孤立SPVT亚组比较，P =.045，卡普兰-迈耶交叉生存分析)。研究人员把门静脉血栓形成患者较低的生存率归因于在本组中存在相对高的恶性肿瘤发生率；在此回顾性研究中，单变量和多变量分析均显示，存在恶性肿瘤与SPVT患者生存期缩短显著相关。在一项肝外门静脉血栓形成患者(n=172)独立的回顾性研究中，多因素分析显示，并存肠系膜静脉血栓诊断显著预示生存期缩短；恶性肿瘤的存在也是一个有意义的独立的死亡预示因子。若干小型回顾性研究同样报道肠系膜静脉血栓患者结局不良，30日死亡率20%。肠系膜静脉血栓形成可以导致肠梗死，这往往是致命性的。在一项研究中，确诊为肠系膜静脉血栓的患者45%出现肠梗死，其中19%是致命的。

Various risk factors have been identified in the development of SPVT, including inherited thrombophilic states (ie, antithrombin deficiency, protein C deficiency, protein S deficiency, Factor V Leiden mutation, prothrombin G20210A mutation) and acquired risk factors such as malignancies, myeloproliferative disorders (eg, polycythemia vera, essential thrombocythemia), JAK2V617F mutation with or without overt myeloproliferative disorders, paroxysmal nocturnal hemoglobinuria (PNH), abdominal surgery (eg, splenectomy), pancreatitis, and cirrhosis. In addition, the use of exogenous estrogen, such as oral contraceptives or hormone replacement therapy, has also been linked to SPVT. Patients with SPVT may have multiple risk factors, whether inherited and/or acquired. The presence of cancer itself, especially abdominal malignancies, is both a common risk factor for SPVT and a frequent cause of death in cancer patients with SPVT. Several retrospective studies have reported cancer to be a significant independent predictor of mortality in patients with SPVT. Moreover, among patients with cancer, the presence of SPVT has been associated with decreased survival. Portal vein thrombosis has been reported in about 20% to 30% of patients with hepatocellular carcinoma at the time of diagnosis. In a retrospective study of patients with hepatocellular carcinoma treated at a referral center in Germany (n=389), patients with portal vein thrombosis had significantly decreased median survival (6 months) compared with patients without portal vein thrombosis (16 months); based on multivariate analysis, presence of portal vein thrombosis was a significant independent predictor of 5-year survival in this population. The poor prognosis associated with SPVT in patients with hepatocellular carcinoma was demonstrated in another retrospective study (n=194), which also showed significantly decreased median survival in patients with portal vein thrombosis (2.3 months vs. 17.6 months in patients without; P = .004). In a recent meta-analysis of 30 randomized controlled trials in patients with previously untreated hepatocellular carcinoma receiving palliative treatments, the presence of portal vein thrombosis was identified as one of the independent predictors of decreased survival.
已经确定发生内脏静脉血栓形成的各种危险因素，包括遗传性易栓状态(即，抗凝血酶缺乏、蛋白质C缺乏、蛋白质S缺乏、莱登Ⅴ因子突变、凝血酶原G20210A突变)以及获得性危险因素如恶性肿瘤、骨髓增生性疾患(例如真性红细胞增多症、原发性血小板增多症)、JAK2V617F突变±明显的骨髓增生性疾患、阵发性睡眠性血红蛋白尿(PNH)、腹部手术(例如脾切除术)、胰腺炎和肝硬化。另外，使用外原性雌激素如口服避孕药或激素替代治疗，也与内脏静脉血栓形成有关。内脏静脉血栓形成患者可能有多重危险因素，遗传性和/或获得性。恶性肿瘤存在本身，尤其是腹部恶性肿瘤，两者都是常见的内脏静脉血栓形成危险因素并且是内脏静脉血栓形成癌症患者常见的死亡原因。一些回顾性研究已报道在内脏静脉血栓形成患者中恶性肿瘤是一个有意义的独立的死亡预示因子。此外，在癌症患者当中，出现内脏静脉血栓形成与生存期缩短相关。已报道大约20%-30%的肝细胞肝癌患者在诊断时有门静脉血栓形成。在对德国一家咨询中心治疗的肝细胞肝癌患者(n=389)的一项回顾性研究中,中位生存期与没有门静脉血栓形成患者(16个月)相比门静脉血栓形成患者显著缩短(6个月)；多因素分析显示，在这些人群中出现门静脉血栓是一个有意义的5年生存率独立预测因子。另一项回顾性研究表明在肝细胞肝癌患者(n=194)中内脏静脉血栓形成与不良预后有关，同样显示门静脉血栓形成患者中位生存期显著降低(2.3个月对无门静脉血栓形成患者17.6个月；P =.004)。在最近一项对30个接受姑息治疗的初治肝细胞癌患者随机对照试验的荟萃分析中，存在门静脉血栓形成被确定为生存期缩短的独立的预测因子之一。

Clinical manifestations of acute SPVT typically include abdominal pain, ascites, hepatomegaly, nausea, vomiting, anorexia, and diarrhea. SPVT may also be an incidental finding. Among patients with acute thrombosis in the mesenteric vein, intestinal infarction has been reported in 30% to 45% of patients at the time of diagnosis. Abdominal pain associated with mesenteric vein thrombosis has been described as a mid-abdominal, colicky pain. Fever, guarding, and rebound tenderness may also be present, which may be indicative of progression to bowel infarction. Chronic SPVT may often be asymptomatic due to formation of collateral veins, although abdominal pain, nausea, vomiting, anorexia, lower-extremity edema, and splenomegaly have been reported with chronic presentations. Weight loss, abdominal distension, and postprandial abdominal pain may also be associated with chronic mesenteric vein thrombosis. Presence of splenomegaly and/or esophageal varices is a sign of portal hypertension associated with chronic SPVT, and complications may arise due to bleeding from varices.
急性内脏静脉血栓形成的临床表现一般包括腹痛、腹水、肝大、恶心、呕吐、厌食和腹泻。内脏静脉血栓形成也可能是一个偶然发现。在肠系膜静脉急性血栓形成患者当中，在诊断时30%-45%有肠梗死。与肠系膜静脉血栓有关的腹痛描述为腹部正中绞痛。发热、腹壁紧张和反跳痛也可能存在，可能指示发展为肠梗死。慢性内脏静脉血栓形成由于侧支静脉的形成经常可以无症状，虽然已报道有腹痛、恶心、呕吐、厌食、下肢水肿和脾大慢性表现。体重减轻、腹胀和餐后腹痛也可能与慢性肠系膜静脉血栓有关。出现脾大和/或食管静脉曲张是一种与慢性内脏静脉血栓形成有关的门脉高压征，且由于静脉曲张可能并发出血。

The diagnostic evaluation includes both imaging and laboratory testing. Diagnosis is confirmed by the absence of blood flow or presence of a thrombus in the splanchnic veins based on noninvasive imaging by duplex ultrasonography, CT angiography (CTA) and/or MR venography (MRV) of the abdomen. Acute SPVT is associated with presenting signs or symptoms of ≤8 weeks duration, with no portal cavernoma (cavernous transformation showing a network of collaterals around the portal vein) and no signs of portal hypertension. The presence of portal cavernoma on imaging is indicative of chronic thrombosis.
诊断评估包括影像与实验室检查。确诊根据腹部无创性影像学双功超声检查、CT血管造影(CTA)和/或MR静脉造影(MRV)显示内脏静脉中没有血流或存在血栓。急性内脏静脉血栓形成相关表现是症状或体征持续≤8周、没有门脉海绵状（血管）瘤(海绵状转化说明门静脉周围侧枝网)并且没有门静脉高血征象。影像存在门脉海绵状（血管）瘤是慢性血栓的表现。

For suspected cases of SPVT involving the hepatic and/or portal veins, duplex ultrasonography is considered the initial choice of imaging. CTA or MRV may be useful in evaluating vascular structure, venous patency, presence of ascites, potential impairment of the bowel and other adjacent organs, and for identifying complications such as bowel ischemia. For cases of SPVT involving the mesenteric veins, use of duplex ultrasonography frequently may be limited by overlying bowel gas; for suspected mesenteric vein thrombosis, CTA is the preferred method of diagnostic imaging. Once a diagnosis of SPVT has been established, considerations may be given to evaluate the patient for thrombophilia or to test for PNH or the JAK2 gene mutation. PNH is a rare acquired hematopoietic disorder resulting in chronic hemolysis, and has been associated with a high propensity for venous thrombosis particularly in the splanchnic vasculature. PNH is an important acquired risk factor for SPVT; in a recent post hoc analysis (n=77) from a study of patients with Budd-Chiari syndrome, patients who had underlying PNH more frequently presented with additional SPVT (ie, portal, mesenteric, or splenic vein thrombosis) at baseline compared with patients without PNH (47% vs. 10%; P = .002). The JAK2V617F mutation is detected in a high proportion of patients with polycythemia vera, essential thrombocythemia, and primary myelofibrosis, and now constitutes a part of both diagnostic and prognostic assessment of these myeloproliferative disorders. The presence of myeloproliferative disorders or having JAK2V617F mutation, with or without myeloproliferative disorders, is the most common acquired risk factor for SPVT. In the absence of overt myeloproliferative disorders, JAK2V617F has been detected in approximately 20% to 40% of patients with SPVT. Mutations in exon 12 of JAK2 may also be associated with SPVT in patients without JAK2V617F.
对于可疑内脏静脉血栓形成累及肝和/或门静脉病例，初始的影像选择考虑双功超声检查。CT血管造影(CTA)或MR静脉造影(MRV)可能有助于评估血管结构、静脉开放、腹水的存在、肠及其他邻近器官的潜在损害以及发现并发症如肠缺血。对于内脏静脉血栓累及肠系膜静脉的病例，双功超声检查经常可能受到上面覆盖的肠道气体限制；对于怀疑肠系膜静脉血栓形成者，CT血管造影(CTA)是首选的诊断方法。一旦确诊内脏静脉血栓形成，可考虑评估患者易栓症或PNH或JAK2基因突变检测。阵发性睡眠性血红蛋白尿症是一种罕见的导致慢性溶血的获得性造血功能障碍，并且有高度静脉血栓特别是内脏血管血栓形成倾向。阵发性睡眠性血红蛋白尿症是内脏静脉血栓形成一个重要的获得性危险因素；在最近一项来自布加综合征患者一项研究的事后分析中，与基线时无阵发性睡眠性血红蛋白尿症的患者相比，有潜在阵发性睡眠性血红蛋白尿症的患者更常出现其他部位的内脏静脉血栓形成(即，门脉、肠系膜或脾静脉血栓)(10%对47%；P= .002)。真性红细胞增多症、原发性血小板增多症以及原发性骨髓纤维化患者检出JAK2V617F突变比例高，且目前是这些骨髓增生性疾患诊断与预后评估的一部分。存在骨髓增生性疾患或有JAK2V617F突变±骨髓增生性疾患，是最常见的内脏静脉血栓形成获得性危险因素。在没有明显的骨髓增生性疾患的情况下，大约20%-40%的内脏静脉血栓形成患者检出JAK2V617F。在无JAK2V617F患者中JAK2外显子12突变也可能与内脏静脉血栓形成有关。

Diagnosis and Evaluation of PE 肺栓塞的诊断与评估

Diagnosis of PE in adults with cancer should include an increased level of clinical suspicion on presentation of any clinically overt signs or symptoms that could represent acute PE. Classic clinical signs and/or symptoms, including unexplained shortness of breath, chest pain- particularly pleuritic chest pain—tachycardia, apprehension, tachypnea, syncope, and hypoxia, are not present in all cases of acute PE. The clinical presentation of PE can range from stable hemodynamics to cardiogenic shock. In the prospective multicenter MASTER registry, the most common presenting symptoms of PE were dyspnea, pain, and tachypnea, which were present in 85%, 40%, and 29% of patients with PE, respectively.
在成人恶性肿瘤患者中肺栓塞的诊断应该包括临床上出现可能提示急性肺栓塞的任何一种明显的症状或体征临床怀疑程度增加。典型的临床症状和/或体征包括无法解释的呼吸短促、胸痛—特别是胸膜炎性胸痛—心动过速、忧虑、呼吸急促、晕厥和缺氧，不是所有的急性肺栓塞病例都存在。肺栓塞的临床表现可从血液动力学稳定到心源性休克各异。在前瞻性、多中心MASTER注册研究中，肺栓塞最常见的主诉是呼吸困难、疼痛和呼吸急促，分别出现于85%、40%和29%的肺栓塞患者。

Radiographic evidence of DVT is found in up to 50% to 70% of patients presenting with symptomatic PE and vice versa. Asymptomatic patients with incidental radiographic findings of PE should be treated similarly to patients with symptomatic PE, as many have subtle clinical symptoms of active disease on further evaluation. They should undergo additional workup to evaluate for PE; however, repeat imaging is not routinely needed for these patients. As mentioned previously, in patients with a high clinical suspicion of PE and without contraindications to anticoagulation, early initiation of anticoagulation should be considered while awaiting results from imaging studies.
高达50%-70%有症状的肺栓塞患者中发现深静脉血栓的放射影像学证据，反之亦然。放射影像偶然发现的无症状肺栓塞患者应该与有症状的肺栓塞患者同样处理，在进一步评价时与疾病活跃患者具有一样多的微妙的临床症状。他们应接受其他评估肺栓塞的检查；但是，对于这些患者不常规要求重复影像学检查。如上所述，在临床高度怀疑肺栓塞并且没有抗凝禁忌症的患者中，在等待影像检查结果的时候应该考虑早期启动抗凝。

Neither a chest radiograph nor an electrocardiogram (EKG) in a patient with suspected PE is sensitive or specific enough to diagnose PE. However, a chest radiograph facilitates the diagnosis of comorbidities and conditions with clinically similar presentations and is useful in the interpretation of a ventilation-perfusion (VQ) lung scan. The EKG provides information about existing cardiac disease and PE-related changes. Furthermore, EKG patterns characteristic of right ventricular (RV) strain have been associated with PE, and inverted T waves in precordial leads may be evident in cases of massive PE.
在一例可疑肺栓塞的患者中胸片或心电图(EKG)对于诊断肺栓塞两个都不是敏感或足够特异的。但是，胸片有助于诊断并存疾病和临床表现相似的情况以及在判读肺扫描通气灌注(VQ)方面是有用的。EKG提供有关存在心脏病和肺栓塞相关变化的信息。此外，右心室(RV)劳损的心电图图像特征与肺栓塞有关，并且在巨大肺栓塞的病例中胸导联T波反转可能是明显的。

The NCCN Panel recommends CTA, which allows for indirect evaluation of pulmonary vessels, as the preferred imaging technique for the initial diagnosis of PE in most patients. Advantages of this method include accurate imaging of mediastinal and parenchymal structures; accurate visualization of emboli in many regions of the pulmonary vasculature; the capability to be performed in conjunction with indirect CT venography, which can detect DVT (since the most common cause of PE is DVT in lower extremities or pelvis); and the ability to detect signs of RV enlargement, which can be used in assessing the patient’s risk for adverse clinical outcomes. Disadvantages of CTA include the associated radiation exposure and the need for large amounts of IV contrast, particularly when CTA is followed by indirect CT venography.
NCCN小组推荐CT血管造影，提供肺血管的间接评估，对于大多数初次诊断肺栓塞的患者作为首选的影像手段。这种方法的优点包括纵隔和薄壁组织结构精确成像；在肺血管的许多区域，栓子准确显像；能够与间接CT静脉造影同时进行，可以检出DVT（因为PE最常见的原因是下肢或盆腔DVT）；并且能够发现右室扩大的迹象，可用于评估患者不良临床结局的风险。CT血管造影的缺点包括相关的辐射暴露以及需要静脉注射大量的对比剂，尤其是当CT血管造影再加上间接CT静脉造影的时候。

Alternative imaging modalities used for the diagnosis for PE include: 1) VQ lung scan; and 2) conventional pulmonary angiography. A VQ scan is associated with less fetal radiation exposure than CTA, so it is useful for pregnant patients and patients with renal insufficiency or untreatable contrast allergies in whom IV contrast is not feasible. It is also less invasive than conventional pulmonary angiography. A normal VQ scan result essentially excludes PE. In a recent non-inferiority study, 1417 patients determined to have a high risk for PE according to the Wells criteria were randomized to undergo CTA or VQ scanning. CTA identified significantly more PE than VQ scans (19.2% vs. 14.2%; 95% CI, 1.1%–8.9%). Elderly patients are more likely than younger patients to be diagnosed with an intermediate probability VQ scan result. Both intermediate and low-probability VQ scan results lack diagnostic utility and should be considered indeterminate. Further diagnostic testing should be performed if clinically indicated. In a patient clinically suspected to have a PE, a high-probability VQ scan is diagnostic. Conventional pulmonary angiography (direct pulmonary angiography), often considered to be the gold standard for PE diagnosis, is infrequently used today because of its invasive nature. Rarely, this method is combined with catheter-directed thrombectomy or thrombolysis. These measures should be planned before and executed simultaneously with conventional pulmonary angiography.
可供选择用于肺栓塞诊断的显像方式包括：1)肺通气灌注扫描；和2)传统的肺血管造影。通气灌注扫描比CT血管造影胎儿辐射暴露更少，因此被用于妊娠以及肾功能不全患者或无法医治的对比剂过敏静脉注射对比剂不可行者。其侵袭性也比传统的肺血管造影少。通气灌注扫描结果正常基本上排除肺栓塞。在最近一项非劣效性研究，1417例根据Wells标准确定具有高危肺栓塞的患者被随机分入接受CT血管造影或通气灌注扫描。CT血管造影比通气灌注扫描确定显著更多的肺栓塞(19.2%对14.2%；95% CI，1.1%-8.9%)。老年患者比年轻患者更可能被诊断为中等概率通气灌注扫描结果。中与低标度通气灌注扫描结果两者都缺乏诊断效用并且应该考虑是不确定的。如果临床需要应该进行进一步的诊断检查。在一例临床怀疑肺栓塞患者中，高标度通气灌注扫描是诊断性的。传统的肺血管造影(直接肺血管造影)，常常认为是肺栓塞诊断的金标准，由于其侵袭性现在很少使用。罕见该方法联合导管引导的血栓切除术或溶栓。这些措施应该在同时的传统肺血管造影之前安排并施行。

Fatality due to PE primarily occurs through RV heart failure and cardiogenic shock. Since the 3-month mortality rate of patients with PE has been reported to be 15%, outpatient management should be limited to individuals at low-risk for adverse outcomes. The panel recommends that patients with PE be risk-stratified. CTA or echocardiography can be used to assess PE patients for RV enlargement/dysfunction, which is associated with an increased risk for adverse clinical outcomes. Elevated serum troponin levels, which are released due to endomyocardial damage, have also been associated with adverse clinical outcomes as has the presence of residual DVT on lower-extremity duplex imaging. A recent study demonstrated that combining the results from at least 2 of the above tests (ie, serum troponin measurement, echocardiography for detecting RV dysfunction, lower-extremity ultrasonography for detecting DVT) improved the specificity and positive predictive value compared with the use of individual tests alone in identifying patients at high risk for PE-related mortality.
肺栓塞死亡主要是由于出现右心室心力衰竭和心源性休克。因为已报道的肺栓塞患者3个月死亡率是15%，门诊处理应局限于不良结局低危的个体。专家组推荐肺栓塞患者风险分层。CT血管造影或超声心动图可用于评估肺栓塞患者右心室增大/功能障碍，其与临床不良结局的风险增加相关。血清肌钙蛋白水平升高是由于心内膜心肌损害释放造成的，在下肢二重成像存在残余的深静脉血栓时，也与临床不良结局有关。最近一项研究显示在识别高危肺栓塞相关死亡的患者方面与仅仅使用单一检查相比，联合至少2项上述检测结果(即，血清肌钙蛋白测定、超声心动图检测右心室功能障碍，下肢超声检查用于检测深静脉血栓)提高了特异性和阳性预测值。

A clinical risk assessment tool–the Pulmonary Embolism Severity Index (PESI)–has also been used to assess the advisability of outpatient management and intensity of initial follow-up and treatment. The PESI score is a validated patient assessment rule that includes age, sex, a history of heart or lung disease, a history of cancer, and physiologic signs associated with PE that can be used to determine a patient’s risk for an adverse outcome associated with PE. Another stratification tool, known as the RIETE (Computerized Registry of Patients with Venous Thromboembolism) Cancer Score, has been developed to identify individuals at low-risk of mortality from PE and validated in the cancer population. The NCCN Panel recommends that upon diagnosis, all cancer patients with PE be considered for risk stratification with a combination of imaging modalities (CTA or transthoracic echocardiogram to assess RV enlargement or dysfunction) plus serum troponin measurement. The PESI or RIETE score can be included as an adjunctive risk assessment tool, but should not be substituted for the above risk-stratification procedures until validation studies are conducted in patients with cancer.
一个临床风险评估工具-肺栓塞严重指数(PESI)-也已用来评估门诊患者的合理处理与初期随访与治疗的强度。PESI得分是一个证实了的患者评估规则包括年龄、性别、心或肺疾病病史、恶性肿瘤病史以及与肺栓塞相关的生理体征，可用于确定一例患者肺栓塞不良预后风险。另一个分层工具，即RIETE(计算机登记的静脉血栓栓塞患者)癌症评分，已开发用于识别肺栓塞低危死亡个体并且已在恶性肿瘤人群中证实。NCCN小组推荐刚一诊断时，所有合并肺栓塞的肿瘤患者就应考虑用联合影像手段(CT血管造影或经胸超声心动图以评价右心室增大或功能障碍)加血清肌钙蛋白测定进行危险分层。肺栓塞严重指数或RIETE评分可算作为一种辅助风险评估工具，但是不应取代上述风险分层措施直到研究验证才能在癌症患者中实施。