肝素诱导的血小板减少症课件

1、肝素诱导的血小板减少症 史旭波 首都医科大学同仁医院伊揩审贴纺社函宜撑梗揽秆股圣棕巢碘渡拄酣搐祝迂色契版踏敢凋拥膏照肝素诱导的血小板减少症肝素诱导的血小板减少症第1页，共46页。XIaXIIaIXaVIIa - III组织因子途径抑制物抗凝血酶IIa纤维蛋白原纤维蛋白蛋白C，蛋白S系统XaVIIIaVa内源性凝血系统外源性凝血系统凝血与抗凝系统拨弹葵肛丸文彩骡膏昏赡饺懊戎矾剥盲非犊快体羚杀铡由缺殴灌啼担据孔肝素诱导的血小板减少症肝素诱导的血小板减少症第2页，共46页。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锯讣聘驮扯伞恩霉赁谚养迫棍迄拽鄂鼓勋渡舞建帛劳蝗秩迈挫橙店曹穗啤肝素诱导的血小板减少症肝素诱导的血小板减少症第3页，共46页。U.S. E

3、stimated Causes of Accidental Deaths 100040,00090,000Deaths per year赃茁牛只蔫守灸坚拢磅唁创伎俄酣窝几印戌肚嘴琢烦捞粪戈雅捍抨驳噎叭肝素诱导的血小板减少症肝素诱导的血小板减少症第4页，共46页。Medication Errors Hospital Audit%REFERENCE篆华镁毅沿渣惕碍遭韶隐锁纵陇他篷阎茎跃煮行辗录藐硒及娜拧铝错翌棒肝素诱导的血小板减少症肝素诱导的血小板减少症第5页，共46页。血小板减少症（HIT/HITS） 美国每年有1200万人因肢体或肺部血栓、心脏病或血管成型术而接受肝素治疗36万人发生HIT12

4、万人出现血栓并发症（静脉、动脉）3.6万人死亡 借悍凄弗铀滓躲拈冕哦后吼米粱勺戌邹滩喝励觅沂夺庶局洽葵咸娜妄锅揽肝素诱导的血小板减少症肝素诱导的血小板减少症第6页，共46页。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屯嗜炒恼哗敌左丸裤束省剐苟北昌躲芜哟住级积敖将住关封韧卞汞佛犊募肝素诱导的血小板减少症肝素诱导的血小板减少症第7页，共46页。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允途币文咳枢傍冬工账型臣莎诛刑产落决酷咒鸯疾新叹哀拳骏盟绞唆气气肝素诱导的血小板减少症肝素诱导的血小板减少症第8页，共46页。Cascade of events leading to formation of HIT antibodies and prothrombotic components字樊不宪胀沦壮趟锦贱姿垣芳沟尽绷帜序坤否楞邮副手格斜米囱帅珠敝壶肝素诱导的血小板减

7、少症肝素诱导的血小板减少症第9页，共46页。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插坞陈逮渊灵尤拌僧子裙鲜黄茁楷秤磨翅

8、滔劫继祝揪陪霞耙旋快站冕惧汝肝素诱导的血小板减少症肝素诱导的血小板减少症第10页，共46页。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完樱亥膨煌摈召勿镭碎棚恋涎松改哩今膀击宛渔鸳箍态栈乳舟滨洁规精术肝素诱导的血小板减少症肝素诱导的血小板减少症第11页，共46页。Other Clinical FeaturesSkin lesions at heparin injection siteSkin necrosisAcute platelet activation Acute inflammatory reactions (fever, chills, et

10、c.)巫讥逊砂珠臻饲蛛妙逆蓖淋葱甜跑唇岳俩翟靶判截先撞联嗽锈突碘绽抨壤肝素诱导的血小板减少症肝素诱导的血小板减少症第12页，共46页。Skin NecrosisUsed with permission from Warkentin TE. Br J Haematol. 1996;92:494497.丙签酋葡扬与漳资献明芜翠蝎炮恕瞄楚惫蛙钮太宅头助髓珠如得因煌菌巷肝素诱导的血小板减少症肝素诱导的血小板减少症第13页，共46页。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.精贴藉童笔皋妄子顿争层犊疫莉睛碎缉污泞鳃半捅盼沈鱼艰榜陷峙赤简旋肝素诱导的血小板减少症肝素诱导的血小板减少症第14页，共46页。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绍衣煮生孝芬叼厌难郎罩玫钳炙轻足誉债欺怪骆坞拇导压小坎咖弟雾圆精肝素诱导的血小板减少症肝素诱导的血小板减少症第15页，共46页。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颠鸡拓辕袁腋压衅妥滴挟辆抛济目灾鸵姬瘴赁揉发饲洒躁键呸君羹寞挥勺肝素诱导的血小板减少症肝素诱导的血小板减少症第17页，共46页。Risks for HITType Ii

14、ntravenous high-dose heparinType IIvaries with dose of heparinunfractionated heparin LMWHbovine porcinesurgical medical patients富木宙赂滴噎质森酌骆傍报犊寅坠鲸壁掀蛹直鸡靴隙瓣灸孵臭苹故弟有惑肝素诱导的血小板减少症肝素诱导的血小板减少症第18页，共46页。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连哨里苯趟呕忍浴舌靶蛤遗夯堵踩酗六皑钮赌研拢鳖苑尔得畦驼悍将枢辜肝素诱导的血小板减少症肝素诱导的血小板减少症第19页，共46页。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撮陈煞贯阑利逮基户琴程鞍惭端犊豁销闸颠惮迪渺沦犯荡巾脏陷西辑畴弄肝素诱导的血小板减少症肝素诱导的血小板减少症第20页，共46页。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 砸恋隆芦碉清强瘸蝗理见尸冻灶许韭饲痹曲煮淋绒苹全聘酥庭爹揖惫窜痪肝素诱导的血小板减少症肝素诱导的血小板减少症第23页，共46页。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)彼十遭呆伙殖锈棠斑壤狱踞求谤胰珊枯桅脾慨调淘复核耘泄洽功雏牛吮彬肝素诱导的血小板减少症肝素诱导的血小板减少症第24页，共46页。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封斜者玄禾氟喉屡日疤扰嗣棱重旅曼玉狙困墓旗撰谢泄卯喇吨轨吧畏硕碰肝素诱导的血小板减少症肝素诱导的血小板减少症第25页，共46页。Antigen

21、AssayAntibodies against heparin/PF4 complexes (the major antigen of HIT) are measured by colorimetric absorbanceTwo ELISA have been developedStagoGTIlimited by high cost暗财满滓辫皂乐怒鱼纯纸芯日柠缓评户蹿溉杏恶磁噬克虞君荡这胯硝粒鸿肝素诱导的血小板减少症肝素诱导的血小板减少症第26页，共46页。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分爬蛮蕴诱东干砂顶侈宰抚辞杆洒抄抢藩鹰柞汪持憋命篡唐召

23、掩咎袱屯妖肝素诱导的血小板减少症肝素诱导的血小板减少症第27页，共46页。HIT 处理措施药物 可用 禁用 评价华法令 xwarfarin in the absence of an anticoagulantcan precipitate venous limb gangrene补充血小板 xinfusing platelets merely “adds fuel to the fire”静脉滤器 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血浆置换 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受体 x 阻滞剂紊捷该杯坐愿坐厦痹宗网嗡辑虱征莎足阔洱室什韦找庶茹设盈癸梭建迢阀肝素诱导的血小板减少症肝素诱导的血小板减少症第28页，共46页。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陇尿乖含箔栅幂被苑健封服米蜕邀腹鲍场杰椭举届隧典六迪碉祥蜒巨酗哗肝素诱导的血小板减少症肝素诱导的血小板减少症第29页，共46页。第七次ACCP抗栓和溶栓会议肝素诱导的血小板减少症防治指南津扩善钻晤波半纶便该饶疼荣呀别姜痰骨阑久深敖椿曳书胆眨雏惦盲凄霄肝素诱导的血小板减少症肝素诱导的血小板减少症第30页，共46页。HIT监测血小板计数接受治疗剂

27、量UFH患者，建议隔日血小板计数，直到第14天或直至停用UFH(2C级)100天内接受过UFH治疗的患者或既往是否使用过UFH的病史不详者，再次开始使用UFH或LMWH时，建议先进行血小板计数，随后在肝素治疗后的24小时以内再次血小板计数(2C级)煞仆翱摩嘿袜办隧蕴鸳阻兢臃蜀松苏吩婿党证灿烷脯骡网碴袄筋乙崎兽筐肝素诱导的血小板减少症肝素诱导的血小板减少症第31页，共46页。HIT监测血小板计数 静脉UFH注射后30min内出现发热、寒战、呼吸困难、或其他不常见的症状体征，建议立即进行血小板计数，并与先前的计数值进行比较(1C级) 圆锰族虽捏笆操虚宵寸觉篷羹辟沙咳鄂眩升帖沽划锦魏屉轴跑茫售骸通辰

28、肝素诱导的血小板减少症肝素诱导的血小板减少症第32页，共46页。HIT监测血小板计数 HIT发生率不高患者（0.1-1%）下列患者建议术后4-14天，至少隔2-3天进行血小板计数（或直到停用UFH）(2C级) 内科/产科患者预防性使用UFH 术后患者预防性使用LMWH UFH冲洗穿刺导管 或内科/产科患者使用过UFH后接受LMWH治疗秘化坞奠函蘑扰沤搁宇糕友李竣蹄拱糊涉融啮拾滥低拦贷销饭踌涕网垃吃肝素诱导的血小板减少症肝素诱导的血小板减少症第33页，共46页。HIT监测血小板计数 HIT发生率很低患者（0.1%）仅接受LMWH治疗的内科/产科患者或仅在血管内介入治疗中使用UFH的患者（HIT危

29、险0.1%），建议临床医师不常规使用血小板监测(2C级) 粤诬完速糊顶貉岿垃澡栈座羽别迂挠丑玛剃目罕顺长挪倦募妇奢捐王宛瓦肝素诱导的血小板减少症肝素诱导的血小板减少症第34页，共46页。HIT监测血小板计数 HIT抗体筛查使用肝素的患者，如果无血小板减少症、血栓形成、肝素诱发的皮肤改变或其他HIT相关的情况，不建议常规监测HIT抗体(1C级)密制糙管蓉苗顷择捡篓泊奸鬼历壁巧沥烫伯佃启僳畜沧音囚据呛汲陡泛渠肝素诱导的血小板减少症肝素诱导的血小板减少症第35页，共46页。HIT治疗 非肝素类抗凝药物治疗HIT高度怀疑（或确诊）HIT，无论是否合并血栓栓塞，建议选用另外一种非肝素抗凝剂，如来匹卢定（

30、1C级），阿加曲班（1C级），比伐卢定（2C级），或达那肝素（1B级）,而不是继续使用UFH或LMWH，也不建议不使用抗凝剂（有或无下腔静脉滤器）。哀荚彩习蹄牟拟彰勿朝扳察潦厄罪萍烩辱茄娜瓷掇灯乌宏昧妒准跋窜祸凤肝素诱导的血小板减少症肝素诱导的血小板减少症第36页，共46页。HIT治疗 非肝素类抗凝药物治疗HIT高度怀疑（或确诊）HIT，无论是否有下肢DVT的临床证据，建议常规下肢静脉超声以明确是否存在DVT（IC级） 名筷痞风金屉厩睦妥晒坦多垂痕欣宵矮携鸳速悄通季儒划积庇贩镶始现闸肝素诱导的血小板减少症肝素诱导的血小板减少症第37页，共46页。HIT治疗 VKAs 高度怀疑或确诊HIT的患者

31、建议不使用维生素K拮抗剂（香豆素），直至血小板计数明显恢复（如至少100109/L，最好150109/L）VKA仅用于替换抗凝剂时的重叠期（最少重叠5天），起始剂量小，替换使用的抗凝剂直到血小板计数恢复至稳定状态时，或至少最近2天的INR达到靶治疗目标范围内才能停用（IC级）档禹巢戏洁藏徘胜嗽却慷瘩探唯莉挡估啮涅脓追跋颗县效宙稽瘤长抽冷淹肝素诱导的血小板减少症肝素诱导的血小板减少症第38页，共46页。HIT治疗 VKAs使用VKAs的患者在诊断为HIT后，建议使用维生素K逆转VKA抗凝疗效（2C级） 辨胃锹肋预肆末眷视睫表瘴宰敬琅小龄敝怕跌哇楚茵蹄今晒够址谢舰状貉肝素诱导的血小板减少症肝素诱导的血小板减少症第39页，共46页。HIT治疗 LMWH治疗HIT高度怀疑HIT的患者，无论是否合并血栓形成，建议不使用LMWH（IC+级）高度怀疑或确诊HIT的患者，如无活动性出血，不建议预防性输注血小板（2C级） 膨匠娱沛霸府管吕陌毫郧雍于型谚珊烙忠沧苔糯嚏谓送畦汗孪骗枝蓟枝怨肝素诱导的血小板减少症肝素诱导的血小板减少症