靜脈血栓栓塞癥和風(fēng)濕病患者的風(fēng)險(xiǎn)研究

1、靜脈血栓栓塞癥和風(fēng)濕病患者的風(fēng)險(xiǎn)研究APS，白塞病血 栓栓子脫落栓 塞近端DVT約50%并發(fā)PEPE 中80-90%存在DVTPesavento R, et al. Minerva Cardioangiol 1997;45:369375Girard P, et al. Chest 1999;116:903908同一疾病，不同部位、不同階段靜脈血栓栓塞癥(VTE)包括深靜脈血栓(DVT)和肺栓塞(PE) DVT和PE年發(fā)病率分別為1和；美國每年VTE新發(fā)病例超過60萬，因此死亡病例數(shù)超過29萬；英國每年VTE致6萬例患者死亡；PE占住院患者死因5-10%20%80%80% 無癥狀全球重大健康問題

2、！靜脈血栓栓塞(VTE)風(fēng)濕性疾病BDAPS抗磷脂抗體綜合征白塞病系統(tǒng)性紅斑狼瘡類風(fēng)濕關(guān)節(jié)炎血管炎ANCA相關(guān)性血管炎其它血管炎多發(fā)性肌炎、皮肌炎風(fēng)濕性疾病治療藥物非甾體類抗炎藥糖皮質(zhì)激素慢作用抗風(fēng)濕藥生物制劑其它其它APS:抗磷脂抗體綜合癥BD:白塞病Ramagopalan et al. BMC Medicine 2011, 9:1APSRosoveKhamashtaKrnic-Barrie隨診時(shí)間5年6年6.4年復(fù)發(fā)率52%69%51.8%非APS Prandoni et al隨診時(shí)間1年3年5年10年復(fù)發(fā)率10-12%20-25%30%40%APS是指抗磷脂抗體（aPL）介導(dǎo)的高凝狀態(tài)，

3、表現(xiàn)為反復(fù)靜脈和動(dòng)脈血栓栓塞事件(VTE、ATE)、血小板減少、病態(tài)妊娠等；占VTE的4%-14%； 以靜脈受累最常見，約50%可出現(xiàn)下肢DVT，還可累及靜脈竇、腹腔內(nèi)靜脈、視網(wǎng)膜靜脈等少見部位；抗磷脂抗體綜合征(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 imm

4、unologic 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 thrombo

5、sis or pulmonary embolism. A prospective cohort study in 1,626 patients. Haematologica. 2007;92:199-205aPL與VTE風(fēng)險(xiǎn)增高相關(guān)初次發(fā)作VTE后完成6月口服抗凝治療者： 若aCL陽性，則再發(fā)血栓風(fēng)險(xiǎn)29%； 若無抗體，則為14%（）Schulman S, Svenungsson E, Granqvist S, et al. Anticardiolipin antibodies predict early recurrence of thromboembolism and death amon

6、g patients with venous thromboembolism following anticoagulant therapy. Am J Med. 1998;104:332-338.系統(tǒng)性紅斑狼瘡(SLE) SLE是一種累及多系統(tǒng)、多器官并有多種自身抗體出現(xiàn)的自身免疫性疾病，其基本病例改變是免疫復(fù)合物介導(dǎo)的血管炎。VTE&ATE風(fēng)險(xiǎn)均增高；10%可出現(xiàn)VTE，可表現(xiàn)為腘靜脈血栓（56%）、肺栓塞（22%）和累及深靜脈、視網(wǎng)膜靜脈、鎖骨下靜脈和硬腦膜靜脈竇的血栓事件（分別為5.6%）； 診斷后5、10年出現(xiàn)VTE的累計(jì)風(fēng)險(xiǎn)2.8%、3.7%Mok CC, Ho LY, Yu KL

7、, 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 Wi

8、thout Antiphospholipid Antibodies. Arthritis Rheum.2009;61(1):29-36.SLEp=0.003aPL + -例數(shù)144例 144例血栓發(fā)生率20.1%7.6%aPL為確定危險(xiǎn)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)

9、:29-36.中國人非洲裔美國人白種人例數(shù)258140227ATE累計(jì)發(fā)生率8.5%8.1%5.1%VTE累計(jì)發(fā)生率3.7%6.6%10.3%SLE中ATE和VTE發(fā)生率因人種而異；1996-2002年，香港，診斷SLE后60個(gè)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

10、.中國患者發(fā)生VTE較ATE少，但發(fā)生VTE比普通人高12倍Arthritis Rheum. 2005;52(9):2774-2782.SLE妊娠與VTE風(fēng)險(xiǎn)Second pregnancy outcomes for women with systemic lupus erythematosus, Ann Rheum Dis 2013;72:547551VTE, Thrombophilia, Antithrombotic Therapy, and Pregnancy : Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: A

11、merican College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 2012;141;e691S-e736S 類風(fēng)濕關(guān)節(jié)炎(RA)PEDVTRA4818000例41000例(0.85%)79000例(1.64%)非RA8910550003366000(0.38%)7681000(0.86%)相對(duì)危險(xiǎn)度2.251.92006:非心臟血管事件與全身炎癥反應(yīng)相關(guān)，ATE、腦血管事件和VTE 30年累計(jì)發(fā)生率分別為19.6%、21.6%和7.2%；2009:美國國家醫(yī)院出院調(diào)查統(tǒng)計(jì)（1975-20

12、05） RA是住院患者發(fā)生VTE的危險(xiǎn)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 rheum

13、atoid arthritis. Thromb Haemost. 2009;101(1):134-138.2012:Mayo1995-2007,813例RA,平均隨訪年 vs 對(duì)照:累計(jì)VTE發(fā)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

14、大類以血管的炎癥反應(yīng)為主要病理改變的疾病，包括白塞病、韋格納肉芽腫（WG）、顯微鏡下多動(dòng)脈炎（MPA）、結(jié)節(jié)性多動(dòng)脈炎等。部分血管炎與抗中性粒細(xì)胞胞漿抗體（ANCA）相關(guān)，稱之為ANCA相關(guān)性血管炎（AAV），包括WG、MPA以及病變局限于腎臟的血管炎等。血管炎之白塞病(BD)BD患者高達(dá)40%可出現(xiàn)血管受累大小動(dòng)靜脈均可累及，以靜脈受累多見最常見類型為雙下肢DVT，占60-80%此外，還可見下腔靜脈栓塞、肺動(dòng)脈血管瘤、布加綜合征、周圍動(dòng)脈的動(dòng)脈瘤、硬腦膜靜脈竇血栓以及腹主動(dòng)脈動(dòng)脈瘤等PE較少見 Seyahi E, Yurdakul S. Behets Syndrome and thrombo

15、sis. Mediterr J Hematol Infect Dis 2011, 3: e2011026Tomasson G, Monach PA, Merkel PA. Thromboembolic disease in vasculitis. Curr Opin Rheumatol. 2009; 21(1): 4146.時(shí)間第一作者例數(shù)病種VTE發(fā)生率2005Merkel180WG7.0/100患者年2006Weidner105WG、MPA、腎血管炎4.3/100患者年2007Allenbach845CSS、WG、MPA7.6%2008Stassen198WG、MPA、腎血管炎1.8/10

16、0患者年，活動(dòng)期6.7/100患者年VTE風(fēng)險(xiǎn)增高，且與活動(dòng)度相關(guān)血管炎之ANCA相關(guān)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

17、 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:

18、 systematic study of on the French vasculitis study group (FVSG) patient cohort. Arthritis Rheum. 2007; 56:S767Stassen PM, Derks RPH, Kallenberg CGM, et al. Venous thromboembolism in ANCA-associated vasculitisincidence and risk factors. Rheumatology 2008;47:530534.四項(xiàng)病例對(duì)照研究Stassen PM, Derks RPH, Kall

19、enberg CGM, et al. Venous thromboembolism in ANCA-associated vasculitisincidence and risk factors. Rheumatology 2008;47:530534.炎癥性肌病多發(fā)性肌炎(PM)和皮肌炎(DM)是一組病因不明、以橫紋肌為主要病變的非化膿性炎癥性肌病，其特點(diǎn)是四肢近端、肩周、頸周、髖周肌群進(jìn)行性無力；回顧性分析：123例PM和DM患者中，6例共6起新發(fā)血栓栓塞事件(6.3%)，均見于活動(dòng)性DM患者，平均出現(xiàn)于診斷后月；與應(yīng)用靜脈IVIG和高齡等顯著相關(guān)（p均） Selva-OCallaghan

20、 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. 靜脈血栓栓塞(VTE)風(fēng)濕性疾病BDAPS抗磷脂抗體綜合征白塞病系統(tǒng)性紅斑狼瘡類風(fēng)濕關(guān)節(jié)炎血管炎ANCA相關(guān)性血管炎其它血管炎多發(fā)性肌炎、皮肌炎風(fēng)濕性疾病治療藥物非甾體類抗炎藥糖皮質(zhì)激素慢作用抗風(fēng)濕藥生物制劑其它其它APS:抗磷脂抗體綜合癥BD:白塞病非甾體類抗炎藥(NSAIDs)

21、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，丹麥北部（1999-2006）基于人群病例對(duì)照研究英國：治療9個(gè)月內(nèi)，羅非昔布（15268例）、美洛昔康（19087例）、塞來昔布（17458例）治療患者發(fā)生VTE者分別僅為6例（0.05%）、20例（0.1%）、17例（0.1%）Layton D, Heeley

22、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

23、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.糖皮質(zhì)激素(GCs)增加動(dòng)脈粥樣硬化風(fēng)險(xiǎn)房撲、房顫風(fēng)險(xiǎn)增加LUMINA研究:570例患者，51例在診斷SLE后至少1次VTEGCs日均用量是SLE發(fā)生VTE的危險(xiǎn)因素？ VTE vs 無

24、VTE患者日均用量分別為 vs ，未見統(tǒng)計(jì)學(xué)差異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 erythe

25、matosus 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 Stud

26、y 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,

27、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

28、-2068.僅選取入組后發(fā)生VTE患者進(jìn)行分析（）（）（ 1.88-2.17 ）（ 1.10-1.26 ）（0.90-0.99 ）IRR （95%CI）免疫抑制劑環(huán)孢素：TTP、HUS個(gè)案報(bào)道：腎移植，上矢狀竇、橫竇血栓沙利度胺：2006年，說明書添加黑框警告，即多發(fā)性骨髓瘤患者接受沙利度胺和地塞米松治療時(shí)，患者可因預(yù)防性抗血栓治療獲益?zhèn)€案：麻風(fēng)結(jié)節(jié)紅斑，與GCs聯(lián)用，增加VTE風(fēng)險(xiǎn)Ahamed R, Bandula W, Chamara R. An unexpected case of venous and pulmonary thrombo-embolism in a patient tr

29、eated with thalidomide for refractory erythema nodosum leprosum: a case report. Thrombosis J 2011, 9:2272例應(yīng)用Adalimumab的RA患者76例測(cè)得抗抗體(28%)8例出現(xiàn)血栓栓塞事件4例抗抗體陽性患者年4例抗抗體陰性患者年，；存在抗抗體患者VTE發(fā)生率高于未產(chǎn)生抗體者應(yīng)用依那西普、英夫利昔單抗和阿達(dá)木單抗后，少量個(gè)案報(bào)道VTE生物制劑Korswagen LA, Bartelds GM, Krieckaert CL, Turkstra F， et al. Venous and arter

30、ial 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 Rheu

31、m. 2011;63(4):877-883. 英國風(fēng)濕病協(xié)會(huì)生物制劑注冊(cè)研究：11881例應(yīng)用抗TNF以及3673例應(yīng)用傳統(tǒng)DMARDs治療者，初發(fā)VTE者：抗TNF組151例（0.13%）以及DMARDs組45例（0.12%）；該結(jié)果表明，抗TNF治療并未進(jìn)一步增加RA患者VTE風(fēng)險(xiǎn)，依那西普、英夫利昔單抗和阿達(dá)木單抗之間在導(dǎo)致VTE方面并無顯著差異Davies R, Galloway JB, Watson KD, et al; BSRBR Control Centre Consortium, British Society for Rheumatology Biologics Regist

32、er. 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靜脈免疫球蛋白(IVIG)增加血栓事件風(fēng)險(xiǎn)，每個(gè)療程發(fā)生率為0.15-1.2%：ATE：發(fā)生率是VTE的4倍，多發(fā)生于輸注早期（49%4小時(shí)，77%24小時(shí)），與靜脈血

33、流瘀滯因素包括肥胖和制動(dòng)相關(guān)；46例自身免疫性疾病患者輸注IVIG，6例（13%）出現(xiàn)血栓栓塞事件，其中50%發(fā)生于輸注過程中，其余見于輸注后1-8日；VTE 3例，心肌梗死和腦卒中各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

34、. Intravenous immunoglobulin-associated arterial and venous thrombosis; report of a series and review of the literature. Br J Dermatol.2006;155(4):714-721.靜脈血栓栓塞(VTE)風(fēng)濕性疾病BDAPS抗磷脂抗體綜合征白塞病系統(tǒng)性紅斑狼瘡類風(fēng)濕關(guān)節(jié)炎血管炎ANCA相關(guān)性血管炎其它血管炎多發(fā)性肌炎、皮肌炎風(fēng)濕性疾病治療藥物非甾體類抗炎藥糖皮質(zhì)激素慢作用抗風(fēng)濕藥生物制劑其它其它APS:抗磷脂抗體綜合癥BD:白塞病治療、預(yù)防？20余篇系列文獻(xiàn)冠心病、瓣

35、膜病、房顫骨科手術(shù)非骨科手術(shù)周圍動(dòng)脈疾病內(nèi)科疾病抗凝治療對(duì)于急性VTE患者，推薦腸外抗凝劑（1B）或利伐沙班作為初始抗凝治療；建議低分子肝素（LMWH）或磺達(dá)肝癸鈉治療，優(yōu)于靜脈（2C）或皮下注射（2B）普通肝素治療（LMWH vs UFH，死亡率降低、VTE復(fù)發(fā)率下降、大出血事件減少）對(duì)于伴有低血壓的肺栓塞患者，建議溶栓治療（2C）急性VTE患者應(yīng)用LMWH，在每日劑量相同情況下，建議每日1次應(yīng)用，優(yōu)于每日2次 (2C) ；急性VTE患者，推薦早期應(yīng)用VKA（例如，與靜脈治療同一天開始）優(yōu)于晚用；靜脈抗凝至少5日直至INR2達(dá)24小時(shí)（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 , Mill