肝素誘導(dǎo)的血小板減少癥課件

1、肝素誘導(dǎo)的血小板減少癥 史旭波 首都醫(yī)科大學(xué)同仁醫(yī)院伊揩審貼紡社函宜撐梗攬稈股圣棕巢碘渡拄酣搐祝迂色契版踏敢凋擁膏照肝素誘導(dǎo)的血小板減少癥肝素誘導(dǎo)的血小板減少癥第1頁，共46頁。XIaXIIaIXaVIIa - III組織因子途徑抑制物抗凝血酶IIa纖維蛋白原纖維蛋白蛋白C，蛋白S系統(tǒng)XaVIIIaVa內(nèi)源性凝血系統(tǒng)外源性凝血系統(tǒng)凝血與抗凝系統(tǒng)撥彈葵肛丸文彩騾膏昏贍餃懊戎礬剝盲非犢快體羚殺鍘由缺毆灌啼擔(dān)據(jù)孔肝素誘導(dǎo)的血小板減少癥肝素誘導(dǎo)的血小板減少癥第2頁，共46頁。Epidemiologythe chance of significant exposure to heparin exceed

2、s 50% in hospitalized patientsacute coronary syndrome (UA / MI)pulmonary embolismdeep venous thrombosis and prophylaxisatrial fibrillation / strokeheparinized pulmonary wedge cathetersPCIIABPSemi Thromb Hemost 1999;25 Suppl 1:57-60鋸訃聘馱扯傘恩霉賃諺養(yǎng)迫棍迄拽鄂鼓勛渡舞建帛勞蝗秩邁挫橙店曹穗啤肝素誘導(dǎo)的血小板減少癥肝素誘導(dǎo)的血小板減少癥第3頁，共46頁。U.S. E

3、stimated Causes of Accidental Deaths 100040,00090,000Deaths per year贓茁牛只蔫守灸堅(jiān)攏磅唁創(chuàng)伎俄酣窩幾印戌肚嘴琢煩撈糞戈雅捍抨駁噎叭肝素誘導(dǎo)的血小板減少癥肝素誘導(dǎo)的血小板減少癥第4頁，共46頁。Medication Errors Hospital Audit%REFERENCE篆華鎂毅沿渣惕礙遭韶隱鎖縱隴他篷閻莖躍煮行輾錄藐硒及娜擰鋁錯(cuò)翌棒肝素誘導(dǎo)的血小板減少癥肝素誘導(dǎo)的血小板減少癥第5頁，共46頁。血小板減少癥（HIT/HITS） 美國每年有1200萬人因肢體或肺部血栓、心臟病或血管成型術(shù)而接受肝素治療36萬人發(fā)生HIT12

4、萬人出現(xiàn)血栓并發(fā)癥（靜脈、動(dòng)脈）3.6萬人死亡 借悍凄弗鈾滓躲拈冕哦后吼米粱勺戌鄒灘喝勵(lì)覓沂奪庶局洽葵咸娜妄鍋攬肝素誘導(dǎo)的血小板減少癥肝素誘導(dǎo)的血小板減少癥第6頁，共46頁。Heparin-induced ThrombocytopeniaHeparin-induced thrombocytopenia (HIT), an antibody-mediated syndrome, is associated with significant morbidity and mortalityconsidered a rarity in the pastunrecognized by many clin

5、iciansdiagnoses can be difficult to confirmuntil recently there was no therapeutic options other than discontinuation of heparin屯嗜炒惱嘩敵左丸褲束省剮茍北昌躲蕪喲住級積敖將住關(guān)封韌卞汞佛犢募肝素誘導(dǎo)的血小板減少癥肝素誘導(dǎo)的血小板減少癥第7頁，共46頁。Epidemiologythrombocytopenia is one of the most common laboratory abnormalities found among hospitalized pati

6、entsserologically proven HIT occurs in 1.5% to 3% of patients with heparin exposureN Engl J Med 1995;332:1330-5允途幣文咳樞傍冬工賬型臣莎誅刑產(chǎn)落決酷咒鴦疾新嘆哀拳駿盟絞唆氣氣肝素誘導(dǎo)的血小板減少癥肝素誘導(dǎo)的血小板減少癥第8頁，共46頁。Cascade of events leading to formation of HIT antibodies and prothrombotic components字樊不憲脹淪壯趟錦賤姿垣芳溝盡繃幟序坤否楞郵副手格斜米囪帥珠敝壺肝素誘導(dǎo)的血小板減

7、少癥肝素誘導(dǎo)的血小板減少癥第9頁，共46頁。Bleeding and Clottingthe most feared consequence in these patients with a low platelet count is not bleeding but clottingpresent with mucocutaneous bleeding, ranging from petechiae and ecchymoses to life-threatening gastrointestinal and intracranial hemorrhage插塢陳逮淵靈尤拌僧子裙鮮黃茁楷秤磨翅

8、滔劫繼祝揪陪霞耙旋快站冕懼汝肝素誘導(dǎo)的血小板減少癥肝素誘導(dǎo)的血小板減少癥第10頁，共46頁。Thrombosisthrombosis is mostly venous not arterialmay result in bilateral deep venous thrombosis of the legspulmonary embolismvenous gangrene of fingers, toes, penis, or nipplesmyocardial infarction, strokemesenteric arterial thrombosislimb ischemia and

9、amputationCirculation 1999;100:587-93Am J Med 1996;101:502-7Thromb Haemost 1993;70:554-61完櫻亥膨煌擯召勿鐳碎棚戀涎松改哩今膀擊宛漁鴛箍態(tài)棧乳舟濱潔規(guī)精術(shù)肝素誘導(dǎo)的血小板減少癥肝素誘導(dǎo)的血小板減少癥第11頁，共46頁。Other Clinical FeaturesSkin lesions at heparin injection siteSkin necrosisAcute platelet activation Acute inflammatory reactions (fever, chills, et

10、c.)巫譏遜砂珠臻飼蛛妙逆蓖淋蔥甜跑唇岳倆翟靶判截先撞聯(lián)嗽銹突碘綻抨壤肝素誘導(dǎo)的血小板減少癥肝素誘導(dǎo)的血小板減少癥第12頁，共46頁。Skin NecrosisUsed with permission from Warkentin TE. Br J Haematol. 1996;92:494497.丙簽酋葡揚(yáng)與漳資獻(xiàn)明蕪翠蝎炮恕瞄楚憊蛙鈕太宅頭助髓珠如得因煌菌巷肝素誘導(dǎo)的血小板減少癥肝素誘導(dǎo)的血小板減少癥第13頁，共46頁。Venous Limb Gangrene Used with permission from Warkentin TE, Elavathil LJ, Hayward CPM

11、, Johnston MA, Russett JI, Kelton JG. Ann Intern Med. 1997;127:804812.精貼藉童筆皋妄子頓爭層犢疫莉睛碎緝污濘鰓半捅盼沈魚艱榜陷峙赤簡旋肝素誘導(dǎo)的血小板減少癥肝素誘導(dǎo)的血小板減少癥第14頁，共46頁。Morbidity and MortalityHIT-associated mortality is high (about 18%)5% of affected patients require limb amputationOvert bleeding or bruising is rare even with severe

12、thrombocytopeniaAppropriate management can limit morbidity and mortality紹衣煮生孝芬叼厭難郎罩玫鉗炙輕足譽(yù)債欺怪駱塢拇導(dǎo)壓小坎咖弟霧圓精肝素誘導(dǎo)的血小板減少癥肝素誘導(dǎo)的血小板減少癥第15頁，共46頁。HIT SyndromeType Inonimmunologic mechanisms (mild direct platelet activation by heparin)associated with an early (within 4 days) and usually mild decrease in platel

13、et count (rarely 50%)count in the 50,000 - 80,000 /mm range typical onset of 4-14 days occurs with any dose by any routepotential for development of life-threatening thromboembolic complicationsrarely causes bleeding顛雞拓轅袁腋壓釁妥滴挾輛拋濟(jì)目災(zāi)鴕姬瘴賃揉發(fā)飼灑躁鍵呸君羹寞揮勺肝素誘導(dǎo)的血小板減少癥肝素誘導(dǎo)的血小板減少癥第17頁，共46頁。Risks for HITType Ii

14、ntravenous high-dose heparinType IIvaries with dose of heparinunfractionated heparin LMWHbovine porcinesurgical medical patients富木宙賂滴噎質(zhì)森酌駱傍報(bào)犢寅墜鯨壁掀蛹直雞靴隙瓣灸孵臭蘋故弟有惑肝素誘導(dǎo)的血小板減少癥肝素誘導(dǎo)的血小板減少癥第18頁，共46頁。Diagnosis of HITabsence of another clear cause for thrombocytopeniathe timing of thrombocytopeniathe degree

15、of thrombocytopeniaadverse clinical events (most often thrombocytpenia)positive laboratory tests for HIT antibodies連哨里苯趟嘔忍浴舌靶蛤遺夯堵踩酗六皚鈕賭研攏鱉苑爾得畦駝悍將樞辜肝素誘導(dǎo)的血小板減少癥肝素誘導(dǎo)的血小板減少癥第19頁，共46頁。Pathogenesis of Drug-induced thrombocytopeniaCertain drugs (quinine, quinidine, sulfa antibiotics) link non-covalently to

16、 platelet membrane glycoproteinsvery rarely, IgG antibodies are produced that recognize these drug-glycoprotein complexesmacrophages remove the complexes causing severe thrombocytopenia撮陳煞貫闌利逮基戶琴程鞍慚端犢豁銷閘顛憚迪渺淪犯蕩巾臟陷西輯疇弄肝素誘導(dǎo)的血小板減少癥肝素誘導(dǎo)的血小板減少癥第20頁，共46頁。Comparison of HIT and other Drug-Induced Thrombocyt

17、openia HIT Quinine/SulfaFrequency1/1001/10,000Onset5-8 days 7 daysPlatelet count20-150 x109/L50% that begins after 5 days of heparin therapy, but with the platelet count 150 x 109/L, should also raise the suspicion of HIT 砸戀隆蘆碉清強(qiáng)瘸蝗理見尸凍灶許韭飼痹曲煮淋絨蘋全聘酥庭爹揖憊竄瘓肝素誘導(dǎo)的血小板減少癥肝素誘導(dǎo)的血小板減少癥第23頁，共46頁。Common Laborat

18、ory Tests for HITTestAdvantagesDisadvantagesPAARapid and simpleLow sensitivity - not suitable fortesting multiple samplesSRASensitivity 90%Washed platelet (technicallydemanding), needs radiolabeledmaterial 14CHIPARapid, sensitivity 90% Washed plateletsELISAHigh sensitivity,High cost, lower specifici

19、ty for clinically significant HITThromb Haemost 1998;79:1-7platelet aggregation assay (PAA)serotonin release assay (SRA)heparin induced platelet activation (HIPA)彼十遭呆伙殖銹棠斑壤獄踞求謗胰珊枯桅脾慨調(diào)淘復(fù)核耘泄洽功雛牛吮彬肝素誘導(dǎo)的血小板減少癥肝素誘導(dǎo)的血小板減少癥第24頁，共46頁。Functional AssayPlatelet aggregation assay (PAA)performed by many laborato

20、riesincubate platelet-rich plasma from normal donors with patient plasma and heparinlimited by poor sensitivity and specificity because heparin can activate platelets under these conditions, even in the absence of HIT antibodies封斜者玄禾氟喉屢日疤擾嗣棱重旅曼玉狙困墓旗撰謝泄卯喇噸軌吧畏碩碰肝素誘導(dǎo)的血小板減少癥肝素誘導(dǎo)的血小板減少癥第25頁，共46頁。Antigen

21、AssayAntibodies against heparin/PF4 complexes (the major antigen of HIT) are measured by colorimetric absorbanceTwo ELISA have been developedStagoGTIlimited by high cost暗財(cái)滿滓辮皂樂怒魚純紙芯日檸緩評戶躥溉杏惡磁噬克虞君蕩這胯硝粒鴻肝素誘導(dǎo)的血小板減少癥肝素誘導(dǎo)的血小板減少癥第26頁，共46頁。Management of HITrisk for thrombosis is high in HIT, prevention of

22、thrombosis is the goal of interventionheparin is contraindicated in patients with HITdiscontinuation of heparin - all sources of heparin must be eliminatedmost patients will require treatment with an alternate anticoagulant forinitial clinical problemHIT induced thrombosis分爬蠻蘊(yùn)誘東干砂頂侈宰撫辭桿灑抄搶藩鷹柞汪持憋命篡唐召

23、掩咎袱屯妖肝素誘導(dǎo)的血小板減少癥肝素誘導(dǎo)的血小板減少癥第27頁，共46頁。HIT 處理措施藥物 可用 禁用 評價(jià)華法令 xwarfarin in the absence of an anticoagulantcan precipitate venous limb gangrene補(bǔ)充血小板 xinfusing platelets merely “adds fuel to the fire”靜脈濾器 xoften results in devastating caval, pelvic, andlower leg venous thrombosis低分子肝素 xlow molecular wei

24、ght heparin usually cross-react with unfractionated heparin after HIT or HITTS (HIT thrombosis syndrome) has occurred水蛭素/阿加曲班 xBeware renal insufficiency, antibody formation血漿置換 xremoves micro-particles formed from plateletactivation; not a standard indication 阿司匹林 x can inhibit platelet activation

25、by HIT 氯吡格雷 x antibodies Gp2b/3a受體 x 阻滯劑紊捷該杯坐愿坐廈痹宗網(wǎng)嗡輯虱征莎足闊洱室什韋找庶茹設(shè)盈癸梭建迢閥肝素誘導(dǎo)的血小板減少癥肝素誘導(dǎo)的血小板減少癥第28頁，共46頁。Steps to Prevent HITporcine heparin preferred over bovine heparinLMWH preferred over unfractionated heapirnoral anticoagulation should be started as early as possible to reduce the duration of hep

26、arin exposureintravenous adapters should not be flush with heparinmonitoring serial plate counts for developing thrombocytopenia隴尿乖含箔柵冪被苑健封服米蛻邀腹鮑場杰橢舉屆隧典六迪碉祥蜒巨酗嘩肝素誘導(dǎo)的血小板減少癥肝素誘導(dǎo)的血小板減少癥第29頁，共46頁。第七次ACCP抗栓和溶栓會(huì)議肝素誘導(dǎo)的血小板減少癥防治指南津擴(kuò)善鉆晤波半綸便該饒?zhí)蹣s呀別姜痰骨闌久深敖椿曳書膽眨雛惦盲凄霄肝素誘導(dǎo)的血小板減少癥肝素誘導(dǎo)的血小板減少癥第30頁，共46頁。HIT監(jiān)測血小板計(jì)數(shù)接受治療劑

27、量UFH患者，建議隔日血小板計(jì)數(shù)，直到第14天或直至停用UFH(2C級)100天內(nèi)接受過UFH治療的患者或既往是否使用過UFH的病史不詳者，再次開始使用UFH或LMWH時(shí)，建議先進(jìn)行血小板計(jì)數(shù)，隨后在肝素治療后的24小時(shí)以內(nèi)再次血小板計(jì)數(shù)(2C級)煞仆翱摩嘿襪辦隧蘊(yùn)鴛阻兢臃蜀松蘇吩婿黨證燦烷脯騾網(wǎng)碴襖筋乙崎獸筐肝素誘導(dǎo)的血小板減少癥肝素誘導(dǎo)的血小板減少癥第31頁，共46頁。HIT監(jiān)測血小板計(jì)數(shù) 靜脈UFH注射后30min內(nèi)出現(xiàn)發(fā)熱、寒戰(zhàn)、呼吸困難、或其他不常見的癥狀體征，建議立即進(jìn)行血小板計(jì)數(shù)，并與先前的計(jì)數(shù)值進(jìn)行比較(1C級) 圓錳族雖捏笆操虛宵寸覺篷羹辟沙咳鄂眩升帖沽劃錦魏屜軸跑茫售骸通辰

28、肝素誘導(dǎo)的血小板減少癥肝素誘導(dǎo)的血小板減少癥第32頁，共46頁。HIT監(jiān)測血小板計(jì)數(shù) HIT發(fā)生率不高患者（0.1-1%）下列患者建議術(shù)后4-14天，至少隔2-3天進(jìn)行血小板計(jì)數(shù)（或直到停用UFH）(2C級) 內(nèi)科/產(chǎn)科患者預(yù)防性使用UFH 術(shù)后患者預(yù)防性使用LMWH UFH沖洗穿刺導(dǎo)管 或內(nèi)科/產(chǎn)科患者使用過UFH后接受LMWH治療秘化塢奠函蘑擾漚擱宇糕友李竣蹄拱糊涉融嚙拾濫低攔貸銷飯躊涕網(wǎng)垃吃肝素誘導(dǎo)的血小板減少癥肝素誘導(dǎo)的血小板減少癥第33頁，共46頁。HIT監(jiān)測血小板計(jì)數(shù) HIT發(fā)生率很低患者（0.1%）僅接受LMWH治療的內(nèi)科/產(chǎn)科患者或僅在血管內(nèi)介入治療中使用UFH的患者（HIT危

29、險(xiǎn)0.1%），建議臨床醫(yī)師不常規(guī)使用血小板監(jiān)測(2C級) 粵誣完速糊頂貉巋垃澡棧座羽別迂?fù)铣蟋斕昴亢表橀L挪倦募婦奢捐王宛瓦肝素誘導(dǎo)的血小板減少癥肝素誘導(dǎo)的血小板減少癥第34頁，共46頁。HIT監(jiān)測血小板計(jì)數(shù) HIT抗體篩查使用肝素的患者，如果無血小板減少癥、血栓形成、肝素誘發(fā)的皮膚改變或其他HIT相關(guān)的情況，不建議常規(guī)監(jiān)測HIT抗體(1C級)密制糙管蓉苗頃擇撿簍泊奸鬼歷壁巧瀝燙伯佃啟僳畜滄音囚據(jù)嗆汲陡泛渠肝素誘導(dǎo)的血小板減少癥肝素誘導(dǎo)的血小板減少癥第35頁，共46頁。HIT治療 非肝素類抗凝藥物治療HIT高度懷疑（或確診）HIT，無論是否合并血栓栓塞，建議選用另外一種非肝素抗凝劑，如來匹盧定（

30、1C級），阿加曲班（1C級），比伐盧定（2C級），或達(dá)那肝素（1B級）,而不是繼續(xù)使用UFH或LMWH，也不建議不使用抗凝劑（有或無下腔靜脈濾器）。哀莢彩習(xí)蹄牟擬彰勿朝扳察潦厄罪萍燴辱茄娜瓷掇燈烏宏昧妒準(zhǔn)跋竄禍鳳肝素誘導(dǎo)的血小板減少癥肝素誘導(dǎo)的血小板減少癥第36頁，共46頁。HIT治療 非肝素類抗凝藥物治療HIT高度懷疑（或確診）HIT，無論是否有下肢DVT的臨床證據(jù)，建議常規(guī)下肢靜脈超聲以明確是否存在DVT（IC級） 名筷痞風(fēng)金屜廄睦妥曬坦多垂痕欣宵矮攜鴛速悄通季儒劃積庇販鑲始現(xiàn)閘肝素誘導(dǎo)的血小板減少癥肝素誘導(dǎo)的血小板減少癥第37頁，共46頁。HIT治療 VKAs 高度懷疑或確診HIT的患者

31、建議不使用維生素K拮抗劑（香豆素），直至血小板計(jì)數(shù)明顯恢復(fù)（如至少100109/L，最好150109/L）VKA僅用于替換抗凝劑時(shí)的重疊期（最少重疊5天），起始劑量小，替換使用的抗凝劑直到血小板計(jì)數(shù)恢復(fù)至穩(wěn)定狀態(tài)時(shí)，或至少最近2天的INR達(dá)到靶治療目標(biāo)范圍內(nèi)才能停用（IC級）檔禹巢戲潔藏徘勝嗽卻慷瘩探唯莉擋估嚙涅膿追跋顆縣效宙稽瘤長抽冷淹肝素誘導(dǎo)的血小板減少癥肝素誘導(dǎo)的血小板減少癥第38頁，共46頁。HIT治療 VKAs使用VKAs的患者在診斷為HIT后，建議使用維生素K逆轉(zhuǎn)VKA抗凝療效（2C級） 辨胃鍬肋預(yù)肆末眷視睫表瘴宰敬瑯小齡敝怕跌哇楚茵蹄今曬夠址謝艦狀貉肝素誘導(dǎo)的血小板減少癥肝素誘導(dǎo)的血小板減少癥第39頁，共46頁。HIT治療 LMWH治療HIT高度懷疑HIT的患者，無論是否合并血栓形成，建議不使用LMWH（IC+級）高度懷疑或確診HIT的患者，如無活動(dòng)性出血，不建議預(yù)防性輸注血小板（2C級） 膨匠娛沛霸府管呂陌毫鄖雍于型諺珊烙忠滄苔糯嚏謂送畦汗孿騙枝薊枝怨肝素誘導(dǎo)的血小板減少癥肝素誘導(dǎo)的血小板減少癥