患者发生栓塞的风险因患者入院病因和患者特点不同而存在差异。内科医师应评估所有入院患者发生静脉血栓栓塞的风险并考虑到出血风险和栓塞预防治疗的药物禁忌证。基础检查包括肾功能检查和全血细胞计数 (FBC),以及若疑似凝血异常还应检查凝血功能。
静脉血栓栓塞危险分层
通常的治疗指南强调根据患者的类型(药物或手术治疗)和手术类型采用不同的血栓预防方式。之后应根据患者其他静脉血栓栓塞的危险因素,采用有针对性的血栓预防治疗。[4]National Institute for Health and Care Excellence. Venous thromboembolism in over 16s: reducing the risk of hospital-acquired deep vein thrombosis or pulmonary embolism. Mar 2018 [internet publication].https://www.nice.org.uk/guidance/ng89
主要危险因素包括既往静脉血栓栓塞史(深静脉血栓形成 [DVT] 和/或肺栓塞 [PE])、易栓症、恶性肿瘤、处于术后状态、外伤、有中心静脉置管(上肢或下肢)、以及无法活动。其他危险因素包括慢性内科疾病、入院接受重症监护治疗、神经系统疾病伴肢体瘫痪、年龄增加、肥胖、含雌激素的避孕药和激素替代治疗 (HRT)、雄激素阻断治疗、静脉曲张、妊娠和产后 6 周内、一级亲属有 VTE 病史以及长时间旅行。然而,这些风险的证据存在一定争议。
出血风险的分层(与患者有关的因素、脊髓麻醉、神经外科手术操作)
由于药物治疗是栓塞预防治疗的主要基础,因此需要对出血的风险进行分层。如果患者有活动性出血、严重的血小板减少症以及凝血功能紊乱,禁忌药物治疗。[3]Gould MK, Garcia DA, Wren SM, et al. Prevention of VTE in nonorthopedic surgical patients: Antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest. 2012 Feb;141(2 Suppl):e227S-77S.https://journal.chestnet.org/article/S0012-3692(12)60125-1/fulltexthttp://www.ncbi.nlm.nih.gov/pubmed/22315263?tool=bestpractice.com 基线的全血细胞计数和凝血指标(如果怀疑凝血功能紊乱)有助于排除这些禁忌证。对于出血的高危患者,建议使用非药物治疗方式,包括分级加压弹力袜(GCS)和间歇性充气加压(IPC)设备。[3]Gould MK, Garcia DA, Wren SM, et al. Prevention of VTE in nonorthopedic surgical patients: Antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest. 2012 Feb;141(2 Suppl):e227S-77S.https://journal.chestnet.org/article/S0012-3692(12)60125-1/fulltexthttp://www.ncbi.nlm.nih.gov/pubmed/22315263?tool=bestpractice.com 临床评分可协助评估出血的风险并指导临床决策。 IMPROVE 出血风险评分已经过前瞻性验证,可辅助决定是否进行药物性血栓预防。[51]Hostler DC, Marx ES, Moores LK, et al. Validation of the International Medical Prevention Registry on Venous Thromboembolism bleeding risk score. Chest. 2016 Feb;149(2):372-9.http://www.ncbi.nlm.nih.gov/pubmed/26867833?tool=bestpractice.com[52]Rosenberg DJ, Press A, Fishbein J, et al. External validation of the IMPROVE bleeding risk assessment model in medical patients. Thromb Haemost. 2016 Aug 30;116(3):530-6.http://www.ncbi.nlm.nih.gov/pubmed/27307054?tool=bestpractice.com
对出血风险的评估还必须考虑是否有椎管内麻醉和止痛的操作。与治疗剂量不同,预防剂量的抗凝剂几乎不会引起脊髓血肿,[53]Horlocker, TT, Wedel, DJ, Rowlingson JC, et al. Regional anesthesia in the patient receiving antithrombotic or thrombolytic therapy: American Society of Regional Anesthesia and Pain Medicine Evidence-Based Guidelines (Third Edition). Reg Anesth Pain Med. 2010;35:64-101.http://www.ncbi.nlm.nih.gov/pubmed/20052816?tool=bestpractice.com 但尽管如此,仍应注意避免在导管的置入和移除前后给予抗凝药,以便减少抗凝药物的显著疗效对操作过程的影响。
其他药物治疗的禁忌证
既往有肝素诱导血小板减少症是使用普通肝素或低分子肝素的重要禁忌证。即使没有检测到抗血小板因子4(anti-PF4)抗体,也建议在有其他药物可选的情况下应避免使用上述两种肝素药物预防血栓。[54]Warkentin TE, Kelton JG. Temporal aspects of heparin-induced thrombocytopenia. N Engl J Med. 2001 Apr 26;344(17):1286-92.https://www.nejm.org/doi/full/10.1056/NEJM200104263441704http://www.ncbi.nlm.nih.gov/pubmed/11320387?tool=bestpractice.com
超敏反应是禁忌证,建议使用替代药物治疗。
基础化验
在开始血栓预防治疗之前,所有患者都需要进行下述化验检查。
肾功能:由于低分子肝素和磺达肝癸钠是通过肾脏排泄的,因此对于有慢性肾脏疾病的患者应小心使用。[55]Cestac P, Bagheri H, Lapeyre-Mestre M, et al. Utilisation and safety of low molecular weight heparins: prospective observational study in medical inpatients. Drug Saf. 2003;26(3):197-207.http://www.ncbi.nlm.nih.gov/pubmed/12580648?tool=bestpractice.com[56]Lim W, Dentali F, Eikelboom JW, et al. Meta-analysis: low-molecular-weight heparin and bleeding in patients with severe renal insufficiency. Ann Intern Med. 2006 May 2;144(9):673-84.http://www.ncbi.nlm.nih.gov/pubmed/16670137?tool=bestpractice.com 在开始血栓预防治疗之前,应检测肌酐水平并计算肌酐清除率。
全血细胞计数:可以排除急性血红蛋白减少或严重血小板减少症,这些疾病是药物抗血栓治疗的禁忌证。
抗凝情况:如果怀疑凝血紊乱必须检测凝血情况。
血清抗血小板因子4抗体:如果临床上怀疑使用普通肝素或普通肝素后发生肝素诱导血小板减少症(血小板计数减少50%以上,在使用肝素时同时发生动脉或静脉血栓),应进行此项检查。
内科患者
一般来说,静脉血栓栓塞的预防包括采用药物或非药物措施来降低深静脉血栓和肺栓塞的风险。当出现以下情况时,可使用药物预防血栓:如果患者因肺功能或心血管功能不全入院、或伴有急性感染、风湿病、炎症或因内科疾病导致无法活动以及其他一种或多种静脉血栓栓塞危险因素。[50]Kahn SR, Lim W, Dunn AS, et al. Prevention of VTE in nonsurgical patients: Antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest. 2012 Feb;141(2 Suppl):e195S-226S.https://journal.chestnet.org/article/S0012-3692(12)60124-X/fulltexthttp://www.ncbi.nlm.nih.gov/pubmed/22315261?tool=bestpractice.com[57]Samama MM, Cohen AT, Darmon JY, et al; Prophylaxis in Medical Patients with Enoxaparin Study Group. A comparison of enoxaparin with placebo for the prevention of venous thromboembolism in acutely ill medical patients. N Engl J Med. 1999 Sep 9;341(11):793-800.https://www.nejm.org/doi/full/10.1056/NEJM199909093411103http://www.ncbi.nlm.nih.gov/pubmed/10477777?tool=bestpractice.com
对特殊内科患者的治疗建议(ICU、肿瘤和置管患者)
几乎所有危重患者均需要接受血栓预防治疗。[50]Kahn SR, Lim W, Dunn AS, et al. Prevention of VTE in nonsurgical patients: Antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest. 2012 Feb;141(2 Suppl):e195S-226S.https://journal.chestnet.org/article/S0012-3692(12)60124-X/fulltexthttp://www.ncbi.nlm.nih.gov/pubmed/22315261?tool=bestpractice.com 对于接受化疗药物治疗的非卧床患者,通常不建议予以血栓预防治疗。[50]Kahn SR, Lim W, Dunn AS, et al. Prevention of VTE in nonsurgical patients: Antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest. 2012 Feb;141(2 Suppl):e195S-226S.https://journal.chestnet.org/article/S0012-3692(12)60124-X/fulltexthttp://www.ncbi.nlm.nih.gov/pubmed/22315261?tool=bestpractice.com 这是因为尽管低分子肝素临床试验的结果很乐观,安全问题以及患者所关注的问题仍旧存在。[58]Di Nisio M, Porreca E, Candeloro M, et al. Primary prophylaxis for venous thromboembolism in ambulatory cancer patients receiving chemotherapy. Cochrane Database Syst Rev. 2016 Dec 1;(12):CD008500.http://cochranelibrary-wiley.com/doi/10.1002/14651858.CD008500.pub4/fullhttp://www.ncbi.nlm.nih.gov/pubmed/27906452?tool=bestpractice.com 但是,对于有 VTE 高风险的门诊化疗肿瘤患者,例如胰腺癌患者,血栓预防可能起到一定作用。临床试验显示低分子肝素能够安全地降低各种肿瘤高危患者静脉血栓栓塞的发生率。[59]Wharin C, Tagalakis V. Management of venous thromboembolism in cancer patients and the role of the new oral anticoagulants. Blood Rev. 2014 Jan;28(1):1-8.http://www.ncbi.nlm.nih.gov/pubmed/24360911?tool=bestpractice.com 应注意的是化疗时同时接受沙利度胺或来那度胺治疗,或接受地塞米松治疗的患者存在静脉血栓的高危因素。美国临床肿瘤协会、欧洲内科肿瘤协会和国际骨髓瘤工作组织建议对这些患者进行血栓预防治疗。[25]Palumbo A, Rajkumar SV, Dimopoulos MA, et al. Prevention of thalidomide- and lenalidomide-associated thrombosis in myeloma. Leukemia. 2008 Feb;22(2):414-23.http://www.ncbi.nlm.nih.gov/pubmed/18094721?tool=bestpractice.com[60]Mandalà M, Falanga A, Roila F; ESMO Guidelines Working Group. Management of venous thromboembolism (VTE) in cancer patients: ESMO Clinical Practice Guidelines. Ann Oncol. 2011 Sep;22 Suppl 6:vi85-92.http://www.ncbi.nlm.nih.gov/pubmed/21908511?tool=bestpractice.com[61]Lyman GH, Bohlke K, Khorana AA, et al. Venous thromboembolism prophylaxis and treatment in patients with cancer: American Society of Clinical Oncology clinical practice guideline update 2014. J Clin Oncol. 2015 Feb 20;33(6):654-6.http://ascopubs.org/doi/full/10.1200/JCO.2014.59.7351http://www.ncbi.nlm.nih.gov/pubmed/25605844?tool=bestpractice.com
不建议用药预防导管引起的血栓栓塞。[50]Kahn SR, Lim W, Dunn AS, et al. Prevention of VTE in nonsurgical patients: Antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest. 2012 Feb;141(2 Suppl):e195S-226S.https://journal.chestnet.org/article/S0012-3692(12)60124-X/fulltexthttp://www.ncbi.nlm.nih.gov/pubmed/22315261?tool=bestpractice.com[62]Nicolaides AN, Fareed J, Kakkar AK, et al. Prevention and treatment of venous thromboembolism - international consensus statement. Int Angiol. 2013 Apr;32(2):111-260.https://europeanvenousforum.org/wp-content/uploads/2015/02/IUA_Guidelines_2013.pdfhttp://www.ncbi.nlm.nih.gov/pubmed/24402349?tool=bestpractice.com
手术
在血管外科手术中,仅建议针对存在静脉血栓栓塞风险或大手术(例如主动脉瘤修复术、主动脉股动脉旁路手术)的患者进行血栓预防治疗。[3]Gould MK, Garcia DA, Wren SM, et al. Prevention of VTE in nonorthopedic surgical patients: Antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest. 2012 Feb;141(2 Suppl):e227S-77S.https://journal.chestnet.org/article/S0012-3692(12)60125-1/fulltexthttp://www.ncbi.nlm.nih.gov/pubmed/22315263?tool=bestpractice.com[4]National Institute for Health and Care Excellence. Venous thromboembolism in over 16s: reducing the risk of hospital-acquired deep vein thrombosis or pulmonary embolism. Mar 2018 [internet publication].https://www.nice.org.uk/guidance/ng89
对于妇科、泌尿科或普外科的小手术(如经尿道操作)以及没有额外静脉血栓栓塞危险因素的患者,不要求使用血栓预防治疗。[3]Gould MK, Garcia DA, Wren SM, et al. Prevention of VTE in nonorthopedic surgical patients: Antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest. 2012 Feb;141(2 Suppl):e227S-77S.https://journal.chestnet.org/article/S0012-3692(12)60125-1/fulltexthttp://www.ncbi.nlm.nih.gov/pubmed/22315263?tool=bestpractice.com 国际共识指南推荐对这些低风险患者使用循序加压弹力袜 (GCS)。[62]Nicolaides AN, Fareed J, Kakkar AK, et al. Prevention and treatment of venous thromboembolism - international consensus statement. Int Angiol. 2013 Apr;32(2):111-260.https://europeanvenousforum.org/wp-content/uploads/2015/02/IUA_Guidelines_2013.pdfhttp://www.ncbi.nlm.nih.gov/pubmed/24402349?tool=bestpractice.com 大手术或存在静脉血栓栓塞危险因素的患者建议予以预防治疗。[3]Gould MK, Garcia DA, Wren SM, et al. Prevention of VTE in nonorthopedic surgical patients: Antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest. 2012 Feb;141(2 Suppl):e227S-77S.https://journal.chestnet.org/article/S0012-3692(12)60125-1/fulltexthttp://www.ncbi.nlm.nih.gov/pubmed/22315263?tool=bestpractice.com
对于胸外科手术或冠状动脉旁路移植术 (CABG) 的患者应常规采用血栓预防治疗。[3]Gould MK, Garcia DA, Wren SM, et al. Prevention of VTE in nonorthopedic surgical patients: Antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest. 2012 Feb;141(2 Suppl):e227S-77S.https://journal.chestnet.org/article/S0012-3692(12)60125-1/fulltexthttp://www.ncbi.nlm.nih.gov/pubmed/22315263?tool=bestpractice.com
接受神经外科手术的患者(如脑膜瘤切除)是一类特殊人群,因为存在出血以及潜在出血后遗症的风险。对于出血风险低的高危患者,推荐采用常规的机械性血栓预防(GCS 和间歇充气加压 [IPC] 装置),并加用一种药物。[3]Gould MK, Garcia DA, Wren SM, et al. Prevention of VTE in nonorthopedic surgical patients: Antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest. 2012 Feb;141(2 Suppl):e227S-77S.https://journal.chestnet.org/article/S0012-3692(12)60125-1/fulltexthttp://www.ncbi.nlm.nih.gov/pubmed/22315263?tool=bestpractice.com[4]National Institute for Health and Care Excellence. Venous thromboembolism in over 16s: reducing the risk of hospital-acquired deep vein thrombosis or pulmonary embolism. Mar 2018 [internet publication].https://www.nice.org.uk/guidance/ng89[62]Nicolaides AN, Fareed J, Kakkar AK, et al. Prevention and treatment of venous thromboembolism - international consensus statement. Int Angiol. 2013 Apr;32(2):111-260.https://europeanvenousforum.org/wp-content/uploads/2015/02/IUA_Guidelines_2013.pdfhttp://www.ncbi.nlm.nih.gov/pubmed/24402349?tool=bestpractice.com
外伤、骨科手术患者以及急性脊髓损伤的患者都属于高危人群。严重创伤患者除非存在禁忌证,否则应给予药物预防治疗。对高风险患者可加用机械性预防治疗。[3]Gould MK, Garcia DA, Wren SM, et al. Prevention of VTE in nonorthopedic surgical patients: Antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest. 2012 Feb;141(2 Suppl):e227S-77S.https://journal.chestnet.org/article/S0012-3692(12)60125-1/fulltexthttp://www.ncbi.nlm.nih.gov/pubmed/22315263?tool=bestpractice.com[62]Nicolaides AN, Fareed J, Kakkar AK, et al. Prevention and treatment of venous thromboembolism - international consensus statement. Int Angiol. 2013 Apr;32(2):111-260.https://europeanvenousforum.org/wp-content/uploads/2015/02/IUA_Guidelines_2013.pdfhttp://www.ncbi.nlm.nih.gov/pubmed/24402349?tool=bestpractice.com 对于接受脊柱手术的高风险患者,如果没有禁忌症,可联合使用药物预防治疗与机械性预防治疗。
骨科手术的患者是极高危的人群。[63]Dahl OE, Caprini JA, Colwell CW Jr, et al. Fatal vascular outcomes following major orthopedic surgery. Thromb Haemost. 2005 May;93(5):860-6.http://www.ncbi.nlm.nih.gov/pubmed/15886800?tool=bestpractice.com[64]Cordell-Smith JA, Williams SC, Harper WM, et al. Lower limb arthroplasty complicated by deep venous thrombosis: prevalence and subjective outcome. J Bone Joint Surg Br. 2004 Jan;86(1):99-101.http://www.ncbi.nlm.nih.gov/pubmed/14765874?tool=bestpractice.com 髋关节或膝关节置换后如果没有予以预防治疗则发生深静脉血栓栓塞的概率为40%~60%。[3]Gould MK, Garcia DA, Wren SM, et al. Prevention of VTE in nonorthopedic surgical patients: Antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest. 2012 Feb;141(2 Suppl):e227S-77S.https://journal.chestnet.org/article/S0012-3692(12)60125-1/fulltexthttp://www.ncbi.nlm.nih.gov/pubmed/22315263?tool=bestpractice.com 髋关节骨折,全髋置换和全膝关节置换应保证常规预防血栓治疗。如果髋关节骨折后手术延迟,应在手术前给予抗栓治疗。[48]Falck-Ytter Y, Francis CW, Johanson NA, et al. Prevention of VTE in orthopedic surgery patients: Antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest. 2012 Feb;141(2 Suppl):e278S-325S.https://journal.chestnet.org/article/S0012-3692(12)60126-3/fulltexthttp://www.ncbi.nlm.nih.gov/pubmed/22315265?tool=bestpractice.com[62]Nicolaides AN, Fareed J, Kakkar AK, et al. Prevention and treatment of venous thromboembolism - international consensus statement. Int Angiol. 2013 Apr;32(2):111-260.https://europeanvenousforum.org/wp-content/uploads/2015/02/IUA_Guidelines_2013.pdfhttp://www.ncbi.nlm.nih.gov/pubmed/24402349?tool=bestpractice.com 小腿胫腓骨或踝关节骨折通常不建议进行血栓预防治疗,除非存在静脉血栓栓塞额外危险因素。[48]Falck-Ytter Y, Francis CW, Johanson NA, et al. Prevention of VTE in orthopedic surgery patients: Antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest. 2012 Feb;141(2 Suppl):e278S-325S.https://journal.chestnet.org/article/S0012-3692(12)60126-3/fulltexthttp://www.ncbi.nlm.nih.gov/pubmed/22315265?tool=bestpractice.com[62]Nicolaides AN, Fareed J, Kakkar AK, et al. Prevention and treatment of venous thromboembolism - international consensus statement. Int Angiol. 2013 Apr;32(2):111-260.https://europeanvenousforum.org/wp-content/uploads/2015/02/IUA_Guidelines_2013.pdfhttp://www.ncbi.nlm.nih.gov/pubmed/24402349?tool=bestpractice.com
不论是否预防血栓治疗,关节镜手术后近端发生深静脉血栓的概率非常低。关节镜手术后目前不建议给予血栓预防性治疗。[65]Sun Y, Chen D, Xu Z, et al. Deep venous thrombosis after knee arthroscopy: a systematic review and meta-analysis. Arthroscopy. 2014 Mar;30(3):406-12.http://www.ncbi.nlm.nih.gov/pubmed/24581264?tool=bestpractice.com
肥胖手术的患者可能也是高危人群,尽管目前尚无足够证据支持。建议根据体重调整剂量后,常规进行血栓药物预防性治疗。[3]Gould MK, Garcia DA, Wren SM, et al. Prevention of VTE in nonorthopedic surgical patients: Antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest. 2012 Feb;141(2 Suppl):e227S-77S.https://journal.chestnet.org/article/S0012-3692(12)60125-1/fulltexthttp://www.ncbi.nlm.nih.gov/pubmed/22315263?tool=bestpractice.com