癌症患者偶发性静脉血栓栓塞症的诊断与治疗ISTH SSC

Diagnosis and Treatment of Incidental Venous Thromboembolism in Cancer Patients: guidance from the SSC of the ISTH
癌症患者偶发性静脉血栓栓塞症的诊断与治疗：国际血栓与止血学会（ISTH）SSC指南山东省肿瘤医院呼吸肿瘤内科张品良

Scope and Methodology 范围和方法学

Modern computer tomography (CT) with its higher sensitivity and resolution has increased the detection of incidental venous thromboembolism (VTE) in the venous and pulmonary vasculature during routine imaging for cancer staging and response assessment. As a result, up to half of all VTEs diagnosed in oncology centers are incidental. Although widely accepted, the diagnosis of incidental VTE is made without using the standard imaging studies required for confirming the presence of symptomatic VTE (i.e. compression ultrasonography for deep vein thrombosis [DVT] and CT pulmonary angiography [CTPA] or ventilation/perfusion lung scan for pulmonary embolism [PE]). The accuracy and reliability of staging imaging in making a diagnosis of DVT or PE have not been established.
现代计算机体层摄影术（CT）具有更高的敏感性和图形分辨率，增加了在常规影像学癌症分期和疗效评估期间检出静脉和肺血管偶发性静脉血栓栓塞症（VTE）。因此，癌症中心多达一半的静脉血栓栓塞诊断是偶然的。尽管被广泛接受，但是偶发静脉血栓栓塞诊断不需要使用标准的影像学检查[即加压超声成像用于诊断深静脉血栓形成（DVT）和CT肺血管造影（CTPA）或肺通气/灌注扫描用于诊断肺栓塞（PE）]来确认症状性静脉血栓栓塞的存在。尚未确定分期影像学在诊断深静脉血栓或肺栓塞方面的准确性和可靠性。

In addition, the appropriate treatment of incidental VTE has been poorly studied. International clinical practice guidelines suggest or recommend standard anticoagulation as for symptomatic VTE. However, these recommendations are extrapolated from studies in symptomatic VTE and may not apply to all cases of incidental VTE because of the uncertainty of the age of the clots (which may vary from days to months), the clinical significance of isolated peripheral clots, such as isolated subsegmental PE (SSPE), and the risk-benefit of anticoagulation may differ for incidental versus symptomatic VTE.
此外，偶发静脉血栓栓塞合理治疗的研究缺乏。对于有症状的静脉血栓栓塞，国际临床实践指南建议或推荐标准抗凝治疗。然而，这些推荐是从有症状的静脉血栓栓塞研究中推断的，因此可能不适于所有偶然发现的静脉血栓栓塞形成病例，因为不确定血栓的时间（可能从数天到数月不等），孤立周围性血栓，如孤立性亚段肺栓塞（SSPE）的临床意义以及偶发与症状性静脉血栓栓塞抗凝的风险-受益可能不同。

This guidance statement will provide clinicians with practical advice on the diagnosis and management of incidental VTE in cancer patients. As previously defined, “recommend” indicates a strong guidance statement with good consensus among the panelists, whereby the clinician should consider adopting the practice in most cases, whereas “suggest” reflects a weak guidance statement with moderate consensus among the panel members, whereby the clinician may adopt the guidance statement or use an alternative approach to manage patients.
本指南将为临床医生提供癌症患者偶发静脉血栓栓塞的诊断与治疗实践建议。正如前面所定义的，“推荐”是一个强烈指引语句，小组成员具有良好的共识，因此，在大多数情况下临床医生应该考虑采纳这种做法，而“建议”反映出一个缺乏威严的指引语句，小组成员间中等共识，因此，临床医生可以采纳指引语句或使用替代方法来治疗患者。

Diagnosing Incidental VTE 偶发静脉血栓栓塞的诊断

Incidental versus Symptomatic VTE 偶发与症状性静脉血栓栓塞

Incidental VTE refers to DVT or PE that are clinically unsuspected at the time of the diagnosis. While incidental PE may be asymptomatic, as many as two-thirds of affected patients report having symptoms consistent with PE, such as fatigue or shortness of breath. However, these nonspecific symptoms are often attributed to the cancer or side effects of treatment. Consequently, clinicians should carefully review the clinical presentation to determine if a patient with an incidental VTE has had symptoms consistent with DVT or PE.
偶发静脉血栓栓塞是指在诊断时临床未怀疑深静脉血栓或肺栓塞。尽管偶发肺栓塞可能无症状，但是多达三分之二的患者有肺栓塞症状，如疲劳或气短。但是，这些非特异性症状往往被认为是癌症或治疗的副作用。因此，临床医生应该仔细评价临床表现以确定症状符合深静脉血栓形成或肺栓塞的患者是否有偶发性静脉血栓栓塞。

Accuracy of Staging Imaging for Diagnosis of VTE 分期影像学诊断静脉血栓栓塞的准确性

The accuracy of contrast studies used for cancer staging in diagnosing PE or DVT has not been formally evaluated. Although CT of the chest has a high sensitivity for proximal PE that may approach CTPA, the main concern is the false positive rate when peripheral or subsegmental PE is incidentally detected. Performing confirmatory testing such as CTPA is often not practical or feasible because it exposes the patient to additional radiation and contrast and increases healthcare costs.
尚未正式评估用于癌症分期的对比研究在诊断肺栓塞或深静脉血栓形成方面的准确性。虽然胸部CT对于近端肺栓塞具有高灵敏度，可能接近CT肺血管造影（CTPA），但是，当偶然发现周围型或亚段肺栓塞时，主要担心的是假阳性率。进行确认检查如CT肺血管造影（CTPA）通常是不现实的或不可行的，因为这使病人增加辐射和对比剂暴露，并因此增加医疗费用。

More recently, the interobserver agreement for isolated SSPE in CTPA has been questioned. In a retrospective single center study, CTPA images of 70 cases (45% with cancer) diagnosed with symptomatic SSPE underwent a second review by an experienced chest radiologist. In only 51% of cases the reviewing radiologist agreed with the initial diagnosis, while 11% were judged to be false positives. Performing lower limb ultrasonography has been suggested in patients with incidental isolated SSPE since the presence of concomitant DVT would provide support that the incidental SSPE is likely clinically relevant.
最近，对于孤立性亚段肺栓塞（SSPE）CT肺动脉造影（CTPA）观察者间协议已经受到了质疑。在一项回顾性单中心研究中，诊断为症状性孤立亚段肺栓塞（SSPE）的70例（癌症45%）患者的CT肺动脉造影（CTPA）图像经有经验的胸部放射学家进行二次审核。只有51%的病例审核的放射学家同意最初的诊断，而11%被判定为假阳性。在偶然发现的孤立性亚段肺栓塞（SSPE）患者中，有人建议进行下肢超声，因为深静脉血栓的并存将支持可能有临床有意义的偶然发现的孤立性亚段肺栓塞（SSPE）。

Similarly, compression ultrasonography is advocated for confirming the presence of incidental iliofemoral DVT because filling defect artefacts may be caused by the low flow state of contrast in the pelvic region. Imaging the lower limbs may also detect silent DVT involving the femoral and popliteal veins. CT and magnetic resonance have better accuracy compared to ultrasonography and are the imaging of choice in the diagnosis of splanchnic DVT.
同样，提倡加压超声成像用于证实存在偶发性髂股深静脉血栓，因为充盈缺损伪影可能是由骨盆区域低流量状态反差所致。下肢成像还可以检测股静脉与腘静脉不活动的深静脉血栓。与超声相比，CT和MR有更好的准确性，因此是诊断内脏深静脉血栓的影像学选择。

Guidance Statement 指南说明

1. In cancer patients with a diagnosis of incidental VTE, we recommend a careful review of the history to exclude symptomatic VTE.
1. 在诊断为偶发静脉血栓栓塞的癌症患者中，我们推荐仔细审查病史以排除症状性静脉血栓栓塞。

2. In patients with incidental PE involving the main, lobar, segmental, or multiple subsegmental pulmonary arteries, we suggest no further testing is required to confirm the diagnosis.
2. 在累及肺主动脉、肺叶肺动脉、肺段肺动脉或多个亚段肺动脉的偶发性肺栓塞患者中，我们建议不需要进一步检查来确认诊断。

3. In patients with isolated SSPE, we recommend careful review of the images by radiologists and suggest performing compression ultrasonography of the lower limbs to detect concomitant incidental DVT.
3. 在孤立性亚段肺栓塞（SSPE）患者中，我们推荐由放射学家仔细复阅影像并建议进行下肢加压超声成像以发现并存的偶发深静脉血栓。

4. In patients with incidental iliofemoral DVT on CT of the abdomen and pelvis, we suggest confirming the diagnosis using Doppler ultrasonography of the pelvis and compression ultrasonography of the lower limbs.
4. 在腹盆腔CT偶然发现的髂股深静脉血栓患者中，我们建议使用盆腔多普勒超声和下肢加压超声成像确认诊断。

Treatment of incidental VTE 偶发静脉血栓栓塞的治疗

Although largely based on observational and retrospective data, incidental VTE seems to carry a similarly poor prognosis in terms of recurrent VTE, bleeding, and mortality as symptomatic VTE. Furthermore, autopsy studies suggest that incidental PE represents a frequently unrecognized cause of death in cancer patients. Consequently, anticoagulant therapy is recommended for incidental VTE by major clinical practice guidelines. However, given the associated increased risk of bleeding, potential interference with antineoplastic treatments, impact on patient quality of life, and added cost, the decision to initiate anticoagulant therapy should be made with due consideration of these consequences and with informed consent of the patient.
尽管基本上是基于观察和回顾性数据，但是，在复发性静脉血栓栓塞、出血和症状性静脉血栓栓塞死亡方面，偶然发现的静脉血栓栓塞似乎带来同样的不良预后。此外，尸检研究提示，偶然发现的肺栓塞经常是癌症患者未被认识的死亡原因。因此，对于偶发静脉血栓栓塞，主要临床实践指南均推荐抗凝治疗。不过，考虑到相关出血风险增加、可能干扰抗肿瘤药治疗、影响患者的生活质量并增加成本，因此，决定开始抗凝治疗应适当考虑这些结果和患者的知情同意。

Anticoagulation of incidental distal thrombi or emboli such as isolated SSPE, although representing a small minority of incidental VTE, is particularly controversial. Case-control and observational studies in patients with incidental isolated SSPE have reported uneventful follow-up and similar survival as patients without PE in those who were not treated with anticoagulation, while major bleeding occurred in as many as 5% among those treated. These findings suggest that routine anticoagulation may unnecessarily expose some patients to the risk of anticoagulant-related bleeding without meaningful benefit. However, a recent meta-analysis demonstrated that the risk of recurrent symptomatic VTE in patients with SSPE is comparable to those with more proximal PE and suggested that untreated SSPE has a high risk of recurrence.
偶发远端血栓或栓子如孤立性亚段肺栓塞（SSPE）的抗凝，尽管代表偶发静脉血栓栓塞的少数派，却尤为有争议。偶发孤立亚段肺栓塞（SSPE）患者的病例对照与观察性研究报告，随访平安无事且生存期与未抗凝治疗的非肺栓塞患者相似，而接受治疗的患者中多达5%发生严重的出血。这些发现提示，常规抗凝可能让一些患者不必要地暴露于抗凝有关的出血风险，而无有意义的获益。然而，最近一项meta分析表明，在孤立性亚段肺栓塞（SSPE）患者中，复发性症状性静脉血栓栓塞的风险堪比那些更近端肺栓塞，因此认为，未治疗的孤立性亚段肺栓塞（SSPE）具有高复发风险。

There are no studies which specifically evaluated the management of incidental distal DVT. As for symptomatic cases, the approach could range from anticoagulation in all patients to serial ultrasonography to detect and treat those extending to the proximal veins.
没有研究专门评估偶发远端深静脉血栓的处理。至于有症状的病例，所有患者均抗凝并连续超声以检出并治疗那些延伸到近端静脉者。

Splanchnic DVT comprises a significant proportion of incidental VTE. However, very little is known about the natural history or need for anticoagulation of such thrombi. In cohort studies, approximately one-half are untreated by physicians. Some clinicians favor prompt start of anticoagulation in all these patients, while others consider treatment on a case-by-case basis targeting only those with acute symptoms or additional high risk features.
内脏深静脉血栓包括相当大一部分偶发的静脉血栓栓塞。然而，关于这种血栓的自然史或需要抗凝知之甚少。在队列研究中，大约有一半未经医生治疗。一些临床医生支持在所有这类患者中及时启动抗凝治疗，而其他人则考虑视情况而定只针对那些有急性症状或其他高危特征者治疗。

Based on currently available evidence, a suggested approach to managing cancer patients with incidental VTE is outlined in Figure.
根据现有的证据，在图中概述癌症患者偶发静脉血栓栓塞建议的一个处理方法。

Anticoagulant Options 抗凝方案

Extrapolating from symptomatic cancer-associated VTE, LMWH is preferred and can be given at full therapeutic doses for the first month tapering to 75% of full dose thereafter. Warfarin is an option if LMWH is not available or acceptable to patients, or in patients without active cancer. In the absence of cancer-specific studies, newer oral anticoagulants cannot be currently recommended. Filter insertion should be avoided, especially in patients who are asymptomatic and do not have any contraindications for anticoagulation.
从症状性癌症相关静脉血栓栓塞推断，低分子量肝素是首选的，第一个月可给予足量治疗量，之后逐渐减少到全量的75%。如果低分子量肝素不能获得或患者不接受，或在癌症不活跃的患者中，华法林是一个选择。在缺乏癌症特异性研究的情况下，新型口服抗凝剂目前不能推荐。过滤器插入应该避免，特别是在无症状和没有任何抗凝禁忌症的患者中。

Duration of Anticoagulation 抗凝持续时间

Optimal duration of therapy has not been studied in cancer patients with thrombosis. Published literature suggests that cancer patients with incidental VTE receive relatively short courses of anticoagulation for 3 to 6 months and that considerable variation exists for duration as well as dosing regimens. In particular, for cases of single segmental and SSPE, international surveys revealed that physicians often choose to not treat or use sub-therapeutic or prophylactic doses of LMWH for short periods. In cancer patients with incidental distal DVT or isolated SSPE without DVT, a shorter duration of anticoagulation – if the decision has been made to treat – to minimize exposure to anticoagulant therapy seems reasonable.
最佳治疗时间尚未在血栓形成的癌症患者中研究。已发表的文献表明，偶发静脉血栓栓塞的癌症患者接受相对较短的抗凝疗程3-6个月，而持续时间以及给药方案变化相当大。尤其是，对于单一段和亚段肺栓塞（SSPE）病例，国际调查显示，医生往往选择不治疗或短时间使用亚治疗性或预防剂量的低分子肝素。在偶发远端深静脉血栓形成或孤立性亚段肺栓塞（SSPE）而无深静脉血栓形成的癌症患者中，抗凝持续时间更短——如果已决定治疗——以减少抗凝治疗暴露似乎是合理的。

Guidance statement 指南说明

1. In cancer patients with incidental VTE, we recommend standard anticoagulation with LMWH in those with symptoms compatible with VTE.
1. 在偶发静脉血栓栓塞的癌症患者中，对于那些合并症状性静脉血栓栓塞者，我们建议用低分子肝素标准抗凝。

2. In patients with incidental proximal DVT, or PE of the main, lobar, segmental or multiple subsegmental pulmonary arteries, we recommend therapeutic anticoagulation for at least 6 months.
2. 在偶发近端深静脉血栓形成或肺主动脉、肺叶肺动脉、肺段肺动脉或多个亚段肺动脉肺栓塞的患者中，我们推荐治疗性抗凝至少6个月。

3. In patients with isolated SSPE with proximal DVT, we recommend therapeutic anticoagulation for at least 6 months.
3. 在孤立亚段肺栓塞（SSPE）合并近端深静脉血栓形成的患者中，我们推荐治疗性抗凝至少6个月。

4. In patients with isolated SSPE with distal DVT or without DVT, we suggest that the decision to provide anticoagulation is made on a case-by-case basis, considering the risk of bleeding, the presence of risk factors for recurrent thrombosis, performance status of the patient, and patient preference. If the decision is not to anticoagulate, we suggest clinical monitoring and serial bilateral compression ultrasonography after one week in those with distal DVT to detect thrombus extension.
4. 在孤立亚段肺栓塞（SSPE）有或没有远端深静脉血栓形成的患者中，我们建议视情况而定决定是否给予抗凝，考虑出血风险、存在的复发性血栓形成危险因素、患者的一般情况以及患者的意愿。如果决定不给予抗凝，在那些远端深静脉血栓形成患者中，我们建议临床监测和一周后连续双侧加压超声成像以发现血栓扩展。

5. In patients with incidental splanchnic vein thrombosis, we suggest anticoagulant therapy in patients with thrombosis that appears to be acute, shows progression or extension over time, and in those who are not actively bleeding nor have a very high risk of bleeding.
5. 在偶发内脏静脉血栓形成患者中，对于表现为随时间进展或扩展、似乎是急性血栓形成的患者，以及那些既无活动性出血也无高危出血风险的患者，我们建议抗凝治疗。

6. In cancer patients with evidence of disease or ongoing systemic or locoregional therapy, we suggest the periodic re-evaluation of the risks of bleeding and VTE recurrence as well as patient preferences to decide about extending LMWH beyond 6 months.
6. 在有疾病证据或正在进行全身或局部区域治疗的癌症患者中，我们建议定期重新评估出血和静脉血栓栓塞复发风险以及患者意愿以决定是否将低分子肝素延长到6个月以上。