课件：年会静脉血栓栓塞症.ppt

静脉血栓栓塞症： 警惕来自风湿病患者的风险,浙江大学医学院附属第二医院风湿科 张婷 吴华香 2013-4-21,APS，白塞病,血 栓,栓子脱落,栓 塞,近端DVT约50%并发PE,PE 中80-90%存在DVT,Pesavento R, et al. Minerva Cardioangiol 1997;45:369375 Girard P, et al. Chest 1999;116:903908,同一疾病，不同部位、不同阶段,静脉血栓栓塞症(VTE)包括深静脉血栓(DVT)和肺栓塞(PE),DVT和PE年发病率分别为1和0.5； 美国每年VTE新发病例超过60万，因此死亡病例数超过29万； 英国每年VTE致6万例患者死亡；PE占住院患者死因5-10%,20%,80%,80% 无症状,全球重大健康问题！,静脉血栓栓塞 (VTE),风湿性疾病,BD,APS,抗磷脂抗体综合征,白塞病,系统性红斑狼疮,类风湿关节炎,血管炎,ANCA相关性血管炎,其它血管炎,多发性肌炎、皮肌炎,风湿性疾病,治疗药物,非甾体类抗炎药,糖皮质激素,慢作用抗风湿药,生物制剂,其它,其它,APS:抗磷脂抗体综合症 BD:白塞病,Ramagopalan et al. BMC Medicine 2011, 9:1,APS是指抗磷脂抗体（aPL）介导的高凝状态，表现为反复静脉和动脉血栓栓塞事件(VTE、ATE)、血小板减少、病态妊娠等；占VTE的4%-14%； 以静脉受累最常见，约50%可出现下肢DVT，还可累及静脉窦、腹腔内静脉、视网膜静脉等少见部位；,抗磷脂抗体综合征(APS),Ortel TL. Thrombosis and the Antiphospholipid Syndrome. Hematology Am Soc Hematol Educ Program. 2005:462-468. Cervera R, Piette JC, Font J, et al. Antiphospholipid syndrome: clinical and immunologic manifestations and patterns of disease expression in a cohort of 1,000 patients. Arthritis Rheum. 2002;46:1019-1027. Prandoni P, Noventa F, Ghirarduzzi A, et al. The risk of recurrent venous thromboembolism after discontinuing anticoagulation in patients with acute proximal deep vein thrombosis or pulmonary embolism. A prospective cohort study in 1,626 patients. Haematologica. 2007;92:199-205,aPL与VTE风险增高相关 初次发作VTE后完成6月口服抗凝治疗者： 若aCL阳性，则再发血栓风险29%； 若无抗体，则为14%（P=0.0013）,Schulman S, Svenungsson E, Granqvist S, et al. Anticardiolipin antibodies predict early recurrence of thromboembolism and death among patients with venous thromboembolism following anticoagulant therapy. Am J Med. 1998;104:332-338.,系统性红斑狼疮(SLE),SLE是一种累及多系统、多器官并有多种自身抗体出现的自身免疫性疾病，其基本病例改变是免疫复合物介导的血管炎。,VTE&ATE风险均增高； 10%可出现VTE，可表现为腘静脉血栓（56%）、肺栓塞（22%）和累及深静脉、视网膜静脉、锁骨下静脉和硬脑膜静脉窦的血栓事件（分别为5.6%）； 诊断后5、10年出现VTE的累计风险2.8%、3.7%,Mok CC, Ho LY, Yu KL, et al. Venous thromboembolism in southern Chinese patients with systemic lupus erythematosus. Clin Rheumatol. 2010;29(6):599-604. Tektonidou MD, Laskari K, DB Panagiotakos, et al. Risk Factors for Thrombosis and Primary Thrombosis Prevention in Patients With Systemic Lupus Erythematosus With or Without Antiphospholipid Antibodies. Arthritis Rheum.2009;61(1):29-36.,aPL为确定危险因素：,Risk Factors for Thrombosis and Primary Thrombosis Prevention in Patients With Systemic Lupus Erythematosus With or Without Antiphospholipid Antibodies. Arthritis Rheum.2009;61(1):29-36.,SLE中ATE和VTE发生率因人种而异； 1996-2002年，香港，诊断SLE后60个月：,Mok CC, Tang SS, To CH, et al. Incidence and risk factors of thromboembolism in systemic lupus erythematosus: a comparison of three ethnic groups. Arthritis Rheum. 2005;52(9):2774-2782.,中国患者发生VTE较ATE少，但发生VTE比普通人高12倍,Arthritis Rheum. 2005;52(9):2774-2782.,SLE妊娠与VTE风险,Second pregnancy outcomes for women with systemic lupus erythematosus, Ann Rheum Dis 2013;72:547551,VTE, Thrombophilia, Antithrombotic Therapy, and Pregnancy : Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 2012;141;e691S-e736S,类风湿关节炎(RA),2006:非心脏血管事件与全身炎症反应相关，ATE、脑血管事件和VTE 30年累计发生率分别为19.6%、21.6%和7.2%； 2009:美国国家医院出院调查统计（1975-2005） RA是住院患者发生VTE的危险因素,Liang KP, Liang KV, Matteson EL, et al. Incidence of noncardiac vascular disease in rheumatoid arthritis and relationship to extraarticular disease manifestations. Arthritis Rheum.2006;54(2):642-648. Matta F, Singala R, Yaekoub AY, et al. Risk of venous thromboembolism with rheumatoid arthritis. Thromb Haemost. 2009;101(1):134-138.,2012:Mayo1995-2007,813例RA,平均随访9.6年 vs 对照: 累计VTE发生率6.7% vs 2.8% (p=0.005),Bacani AK, Gabriel SE, Crowson CS, et al. Noncardiac vascular disease in rheumatoid arthritis: increase in venous thromboembolic events? Arthritis Rheum.2012;64(1):53-61.,血管炎,血管炎是指一大类以血管的炎症反应为主要病理改变的疾病，包括白塞病、韦格纳肉芽肿（WG）、显微镜下多动脉炎（MPA）、结节性多动脉炎等。 部分血管炎与抗中性粒细胞胞浆抗体（ANCA）相关，称之为ANCA相关性血管炎（AAV），包括WG、MPA以及病变局限于肾脏的血管炎等。,血管炎之白塞病(BD),BD患者高达40%可出现血管受累 大小动静脉均可累及，以静脉受累多见 最常见类型为双下肢DVT，占60-80% 此外，还可见下腔静脉栓塞、肺动脉血管瘤、布加综合征、周围动脉的动脉瘤、硬脑膜静脉窦血栓以及腹主动脉动脉瘤等 PE较少见,Seyahi E, Yurdakul S. Behets Syndrome and thrombosis. Mediterr J Hematol Infect Dis 2011, 3: e2011026 Tomasson G, Monach PA, Merkel PA. Thromboembolic disease in vasculitis. Curr Opin Rheumatol. 2009; 21(1): 4146.,VTE风险增高，且与活动度相关,血管炎之ANCA相关性血管炎(AAV),Merkel PA, Lo GH, Holbrook JT, et al. Brief communication: high incidence of venous thrombotic events among patients with Wegener granulomatosis: the Wegeners Clinical Occurrence of Thrombosis (WeCLOT) Study. Ann Intern Med. 2005; 42:620626. Weidner S, Hafezi-Rachti S, Rupprecht HD. Thromboembolic events as a complication of antineutrophil cytoplasmic antibody-associated vasculitis. Arthritis Rheum. 2006; 55:146149. Allenbach Y, Pagnoux C, Seror R, et al. Venous thromboembolic events in patients with different systemic necrotizing vasculitides: systematic study of on the French vasculitis study group (FVSG) patient cohort. Arthritis Rheum. 2007; 56:S767 Stassen PM, Derks RPH, Kallenberg CGM, et al. Venous thromboembolism in ANCA-associated vasculitisincidence and risk factors. Rheumatology 2008;47:530534.,四项病例对照研究,Stassen PM, Derks RPH, Kallenberg CGM, et al. Venous thromboembolism in ANCA-associated vasculitisincidence and risk factors. Rheumatology 2008;47:530534.,炎症性肌病,多发性肌炎(PM)和皮肌炎(DM)是一组病因不明、以横纹肌为主要病变的非化脓性炎症性肌病，其特点是四肢近端、肩周、颈周、髋周肌群进行性无力； 回顾性分析：123例PM和DM患者中，6例共6起新发血栓栓塞事件(6.3%)，均见于活动性DM患者，平均出现于诊断后4.3月；与应用静脉IVIG和高龄等显著相关（p均0.05）,Selva-OCallaghan A, Fernndez-Luque A, Martnez-Gmez X, et al. Venous thromboembolism in patients with dermatomyositis and polymyositis. Clin Exp Rheumatol. 2011;29(5):846-849.,静脉血栓栓塞 (VTE),风湿性疾病,BD,APS,抗磷脂抗体综合征,白塞病,系统性红斑狼疮,类风湿关节炎,血管炎,ANCA相关性血管炎,其它血管炎,多发性肌炎、皮肌炎,风湿性疾病,治疗药物,非甾体类抗炎药,糖皮质激素,慢作用抗风湿药,生物制剂,其它,其它,APS:抗磷脂抗体综合症 BD:白塞病,非甾体类抗炎药(NSAIDs),Schmidt M, Christiansen CF, Horvth-Puh E, et al. Non-steroidal anti-inflammatory drug use and risk of venous thromboembolism. Thromb Haemost. 2011;9(7):1326-1333.,2011，丹麦北部（1999-2006）基于人群病例对照研究,2019/8/25,27,可编辑,英国：治疗9个月内，罗非昔布（15268例）、美洛昔康（19087例）、塞来昔布（17458例）治疗患者发生VTE者分别仅为6例（0.05%）、20例（0.1%）、17例（0.1%）,Layton D, Heeley E, Hughes K, et al. Comparison of the incidence rates of thromboembolic events reported for patients prescribed rofecoxib and meloxicam in general practice in England using prescription-event monitoring (PEM) data. Rheumatology 2003;42:13421353. Layton D, Hughes K, Harris S, et al. Comparison of the incidence rates of thromboembolic events reported for patients prescribed celecoxib and meloxicam in general practice in England using Prescription-Event Monitoring (PEM) data. Rheumatology 2003;42:13541364.,糖皮质激素(GCs),增加动脉粥样硬化风险 房扑、房颤风险增加 LUMINA研究:570例患者，51例在诊断SLE后至少1次VTE GCs日均用量是SLE发生VTE的危险因素？ VTE vs 无VTE患者日均用量分别为14.79.7mg vs 12.510.4mg，未见统计学差异,Christiansen CF, Christensen S, Mehnert F, et al. Glucocorticoid Use and Risk of Atrial Fibrillation or Flutter：A Population-Based, Case-Control Study. Arch Intern Med. 2009;169(18):1677-1683. Calvo-Aln J, Toloza SM, Fernndez M, et al; LUMINA Study Group. Systemic lupus erythematosus in a multiethnic US cohort (LUMINA). XXV. Smoking, older age, disease activity, lupus anticoagulant, and glucocorticoid dose as risk factors for the occurrence of venous thrombosis in lupus patients. Arthritis Rheum. 2005;52(7):2060-2068.,Calvo-Aln J, Toloza SM, Fernndez M, et al; LUMINA Study Group. Systemic lupus erythematosus in a multiethnic US cohort (LUMINA). XXV. Smoking, older age, disease activity, lupus anticoagulant, and glucocorticoid dose as risk factors for the occurrence of venous thrombosis in lupus patients. Arthritis Rheum. 2005;52(7):2060-2068.,Calvo-Aln J, Toloza SM, Fernndez M, et al; LUMINA Study Group. Systemic lupus erythematosus in a multiethnic US cohort (LUMINA). XXV. Smoking, older age, disease activity, lupus anticoagulant, and glucocorticoid dose as risk factors for the occurrence of venous thrombosis in lupus patients. Arthritis Rheum. 2005;52(7):2060-2068.,仅选取入组后发生VTE患者进行分析,2005.1.12011.12.31,2.31（2.18-2.45）,3.06（2.77-3.38）,2.02（ 1.88-2.17 ）,1.18（ 1.10-1.26 ）,0.94（0.90-0.99 ）,IRR （95%CI）,免疫抑制剂,环孢素： TTP、HUS 个案报道：肾移植，上矢状窦、横窦血栓 沙利度胺： 2006年，说明书添加黑框警告，即多发性骨髓瘤患者接受沙利度胺和地塞米松治疗时，患者可因预防性抗血栓治疗获益 个案：麻风结节红斑，与GCs联用，增加VTE风险,Rajapakse S, Gnanajothy R, Lokunarangoda N, et al. A kidney transplant patient on cyclosporine therapy presenting with dural venous sinus thrombosis: a case report. Cases J 2009, 2:9139 doi:10.1186/1757-1626-2-9139. Ahamed R, Bandula W, Chamara R. An unexpected case of venous and pulmonary thrombo-embolism in a patient treated with thalidomide for refractory erythema nodosum leprosum: a case report. Thrombosis J 2011, 9:2,272例应用Adalimumab的RA患者,76例测得抗抗体(28%),8例出现血栓栓塞事件,4例抗抗体阳性: 26.9/1000患者年,4例抗抗体阴性: 8.4/1000患者年,RR 7.6，p=0.025；存在抗抗体患者VTE发生率高于未产生抗体者,应用依那西普、英夫利昔单抗和阿达木单抗后，少量个案报道VTE,生物制剂,Korswagen LA, Bartelds GM, Krieckaert CL, Turkstra F， et al. Venous and arterial thromboembolic events in adalimumab-treated patients with antiadalimumab antibodies: a case series and cohort study. Arthritis Rheum. 2011;63(4):877-883. Makol A, Grover M, Guggenheim C, et al. Etanercept and venous thromboembolism: a case series. J Medical Case Reports 2010, 4:12.,Arthritis Rheum. 2011;63(4):877-883.,英国风湿病协会生物制剂注册研究：11881例应用抗TNF以及3673例应用传统DMARDs治疗者，初发VTE者：抗TNF组151例（0.13%）以及DMARDs组45例（0.12%）； 该结果表明，抗TNF治疗并未进一步增加RA患者VTE风险，依那西普、英夫利昔单抗和阿达木单抗之间在导致VTE方面并无显著差异,Davies R, Galloway JB, Watson KD, et al; BSRBR Control Centre Consortium, British Society for Rheumatology Biologics Register. Venous thrombotic events are not increased in patients with rheumatoid arthritis treated with anti-TNF therapy: results from the British Society for Rheumatology Biologics Register. Ann Rheum Dis 2011;70:18311834,静脉免疫球蛋白(IVIG),增加血栓事件风险，每个疗程发生率为0.15-1.2%： ATE：发生率是VTE的4倍，多发生于输注早期（49%24小时），与静脉血流瘀滞因素包括肥胖和制动相关； 46例自身免疫性疾病患者输注IVIG，6例（13%）出现血栓栓塞事件，其中50%发生于输注过程中，其余见于输注后1-8日；VTE 3例，心肌梗死和脑卒中各1例,Paran D, Herishanu Y, Elkayam O, et al. Venous and arterial thrombosis following administration of intravenous immunoglobulins. Blood Coagul Fibrinolysis.2005;16(5): 313-318. Marie I, Maurey G, Herv F, et al. Intravenous immunoglobulin-associated arterial and venous thrombosis; report of a series and review of the literature. Br J Dermatol.2006;155(4):714-721.,静脉血栓栓塞 (VTE),风湿性疾病,BD,APS,抗磷脂抗体综合征,白塞病,系统性红斑狼疮,类风湿关节炎,血管炎,ANCA相关性血管炎,其它血管炎,多发性肌炎、皮肌炎,风湿性疾病,治疗药物,非甾体类抗炎药,糖皮质激素,慢作用抗风湿药,生物制剂,其它,其它,APS:抗磷脂抗体综合症 BD:白塞病,治疗、预防？,20余篇系列文献 冠心病、瓣膜病、房颤 骨科手术 非骨科手术 周围动脉疾病 内科疾病 ,抗凝治疗,对于急性VTE患者，推荐肠外抗凝剂（1B）或利伐沙班作为初始抗凝治疗； 建议低分子肝素（LMWH）或磺达肝癸钠治疗，优于静脉（2C）或皮下注射（2B）普通肝素治疗（LMWH vs UFH，死亡率降低、VTE复发率下降、大出血事件减少） 对于伴有低血压的肺栓塞患者，建议溶栓治疗（2C）,急性VTE患者应用LMWH，在每日剂量相同情况下，建议每日1次应用，优于每日2次 (2C) ； 急性VTE患者，推荐早期应用VKA（例如，与静脉治疗同一天开始）优于晚用；静脉抗凝至少5日直至INR2达24小时（1B）,Hull RD , Raskob GE , Rosenbloom D , et al . Heparin for 5 days as compared with 10 days in the initial treatment of proximal venous thrombosis . N Engl J Med . 1990 ; 322 ( 18 ): 1260 - 1264 . Gallus AS , Jackaman J , Tillett J , Mills W , Wycherley A . Sa