肝素诱导的血小板减少症讲稿.ppt

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1、关于肝素关于肝素关于肝素关于肝素诱导诱导的血小板减少症的血小板减少症的血小板减少症的血小板减少症第一页，讲稿共四十五页哦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凝血与抗凝系统第二页，讲稿共四十五页哦EpidemiologyEpidemiologythe chance of significant exposure to heparin exceeds 50%in hospitalized patientsacute coronary syndrome (UA/MI)pul

2、monary embolismdeep venous thrombosis and prophylaxisatrial fibrillation/strokeheparinized pulmonary wedge cathetersPCIIABPSemi Thromb Hemost 1999;25 Suppl 1:57-60第三页，讲稿共四十五页哦U.S.Estimated Causes of Accidental DeathsU.S.Estimated Causes of Accidental Deaths 1000 100040,00040,00090,00090,000Deaths pe

3、r year第四页，讲稿共四十五页哦Medication Errors Hospital AuditMedication Errors Hospital Audit%REFERENCE第五页，讲稿共四十五页哦血小板减少症（血小板减少症（血小板减少症（血小板减少症（HIT/HITSHIT/HITSHIT/HITSHIT/HITS）美国每年有美国每年有1200万人因肢体或肺部血栓、心脏病或血管成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型术而接受肝素治疗36万人发生万人发生HIT12万人出现血栓并发症（静脉、动脉）万人出现血栓并发症（静脉、动脉）3.6万人死亡万人死亡 第六页，讲稿共四

4、十五页哦Heparin-induced ThrombocytopeniaHeparin-induced ThrombocytopeniaHeparin-induced thrombocytopenia(HIT),an antibody-mediated syndrome,is associated with significant morbidity and mortalityconsidered a rarity in the pastunrecognized by many cliniciansdiagnoses can be difficult to confirmuntil recen

5、tly there was no therapeutic options other than discontinuation of heparin第七页，讲稿共四十五页哦EpidemiologyEpidemiologythrombocytopenia is one of the most common laboratory abnormalities found among hospitalized patientsserologically proven HIT occurs in 1.5%to 3%of patients with heparin exposureN Engl J Med

6、 1995;332:1330-5第八页，讲稿共四十五页哦Cascade of events leading to formation of HIT antibodies Cascade of events leading to formation of HIT antibodies Cascade of events leading to formation of HIT antibodies and prothrombotic componentsand prothrombotic componentsand prothrombotic 第九页，讲稿共四十五页哦Bleeding and Cl

7、ottingBleeding 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第十页，讲稿共四十五页哦ThrombosisThrombosisthr

8、ombosis 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 amputationCirculation 1999;100:587-93Am J Med 1996;101:502-7Thr

9、omb Haemost 1993;70:554-61第十一页，讲稿共四十五页哦Other Clinical FeaturesOther Clinical FeaturesSkin lesions at heparin injection siteSkin necrosisAcute platelet activation Acute inflammatory reactions(fever,chills,etc.)第十二页，讲稿共四十五页哦Skin NecrosisSkin NecrosisUsed with permission from Warkentin TE.Br J Haematol

10、.1996;92:494497.第十三页，讲稿共四十五页哦Venous Limb GangreneVenous Limb Gangrene Used with permission from Warkentin TE,Elavathil LJ,Hayward CPM,Johnston MA,Russett JI,Kelton JG.Ann Intern Med.1997;127:804812.第十四页，讲稿共四十五页哦Morbidity and MortalityMorbidity and MortalityHIT-associated mortality is high(about 18%)

11、5%of affected patients require limb amputationOvert bleeding or bruising is rare even with severe thrombocytopeniaAppropriate management can limit morbidity and mortality第十五页，讲稿共四十五页哦HIT SyndromeHIT SyndromeType Inonimmunologic mechanisms(mild direct platelet activation by heparin)associated with an

12、 early(within 4 days)and usually mild decrease in platelet 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第十七页，讲稿共四十五页哦Risks for HITRisks

13、for HITType Iintravenous high-dose heparinType IIvaries with dose of heparinunfractionated heparin LMWHbovine porcinesurgical medical patients第十八页，讲稿共四十五页哦Diagnosis of HITDiagnosis of HITabsence of another clear cause for thrombocytopeniathe timing of thrombocytopeniathe degree of thrombocytopeniaad

14、verse clinical events(most often thrombocytpenia)positive laboratory tests for HIT antibodies第十九页，讲稿共四十五页哦Pathogenesis of Pathogenesis of Drug-induced thrombocytopeniaDrug-induced thrombocytopeniaCertain drugs(quinine,quinidine,sulfa antibiotics)link non-covalently to platelet membrane glycoproteins

15、very rarely,IgG antibodies are produced that recognize these drug-glycoprotein complexesmacrophages remove the complexes causing severe thrombocytopenia第二十页，讲稿共四十五页哦Comparison of HIT and other Comparison of HIT and other Drug-Induced ThrombocytopeniaDrug-Induced Thrombocytopenia HIT Quinine/SulfaFre

16、quency1/1001/10,000Onset5-8 days 7 daysPlatelet count20-150 x109/L 50%that begins after 5 days of heparin therapy,but with the platelet count 150 x 109/L,should also raise the suspicion of HIT 第二十三页，讲稿共四十五页哦Common Laboratory Tests for HITCommon Laboratory Tests for HITTestAdvantagesDisadvantagesPAAR

17、apid and simpleLow sensitivity-not suitable fortesting multiple samplesSRASensitivity 90%Washed platelet(technicallydemanding),needs radiolabeledmaterial 14CHIPARapid,sensitivity 90%Washed plateletsELISAHigh sensitivity,High cost,lower specificity for clinically significant HITThromb Haemost 1998;79

18、:1-7platelet aggregation assay(PAA)serotonin release assay(SRA)heparin induced platelet activation(HIPA)第二十四页，讲稿共四十五页哦Functional AssayFunctional AssayPlatelet aggregation assay(PAA)performed by many laboratoriesincubate platelet-rich plasma from normal donors with patient plasma and heparinlimited b

19、y poor sensitivity and specificity because heparin can activate platelets under these conditions,even in the absence of HIT antibodies第二十五页，讲稿共四十五页哦Antigen AssayAntigen AssayAntibodies against heparin/PF4 complexes(the major antigen of HIT)are measured by colorimetric absorbanceTwo ELISA have been d

20、evelopedStagoGTIlimited by high cost第二十六页，讲稿共四十五页哦Management of HITManagement of HITrisk for thrombosis is high in HIT,prevention of thrombosis is the goal of interventionheparin is contraindicated in patients with HITdiscontinuation of heparin-all sources of heparin must be eliminatedmost patients

21、will require treatment with an alternate anticoagulant forinitial clinical problemHIT induced thrombosis第二十七页，讲稿共四十五页哦HIT HIT HIT HIT 处理措施处理措施处理措施处理措施药物药物 可用可用 禁用禁用 评价评价华法令华法令 xwarfarin in the absence of an anticoagulantcan precipitate venous limb gangrene补充血小板补充血小板 xinfusing platelets merely“adds f

22、uel to the fire”静脉滤器静脉滤器 xoften results in devastating caval,pelvic,andlower leg venous thrombosis低分子肝素低分子肝素 xlow molecular weight heparin usually cross-react with unfractionated heparin after HIT or HITTS(HIT thrombosis syndrome)has occurred水蛭素水蛭素/阿加曲班阿加曲班 xBeware renal insufficiency,antibody forma

23、tion血浆置换血浆置换 xremoves micro-particles formed from plateletactivation;not a standard indication 阿司匹林阿司匹林 x can inhibit platelet activation by HIT 氯吡格雷氯吡格雷 x antibodies Gp2b/3a受体受体 x 阻滞剂阻滞剂第二十八页，讲稿共四十五页哦Steps to Prevent HITSteps to Prevent HITporcine heparin preferred over bovine heparinLMWH preferred

24、 over unfractionated heapirnoral anticoagulation should be started as early as possible to reduce the duration of heparin exposureintravenous adapters should not be flush with heparinmonitoring serial plate counts for developing thrombocytopenia第二十九页，讲稿共四十五页哦第七次第七次第七次第七次ACCPACCP抗栓和溶栓会议抗栓和溶栓会议抗栓和溶栓会议

25、抗栓和溶栓会议肝素诱导的血小板减少症防治指南肝素诱导的血小板减少症防治指南肝素诱导的血小板减少症防治指南肝素诱导的血小板减少症防治指南第三十页，讲稿共四十五页哦HITHITHITHIT监测监测监测监测血小板计数血小板计数血小板计数血小板计数接接受受治治疗疗剂剂量量UFHUFH患患者者，建建议议隔隔日日血血小小板板计计数数，直直到到第第1414天或直至停用天或直至停用UFHUFH(2C(2C级级)100100天天内内接接受受过过UFHUFH治治疗疗的的患患者者或或既既往往是是否否使使用用过过UFHUFH的的病病史史不不详详者者，再再次次开开始始使使用用UFHUFH或或LMWHLMWH时时，建建议

26、议先先进进行行血血小小板板计计数数，随随后后在在肝肝素素治治疗疗后后的的2424小小时时以以内内再再次次血小板计数血小板计数(2(2C C级级)第三十一页，讲稿共四十五页哦HITHITHITHIT监测监测监测监测血小板计数血小板计数血小板计数血小板计数 静静脉脉UFHUFH注注射射后后3030minmin内内出出现现发发热热、寒寒战战、呼呼吸吸困困难难、或或其其他他不不常常见见的的症症状状体体征征，建建议议立立即即进进行行血血小小板板计数，并与先前的计数值进行比较计数，并与先前的计数值进行比较(1(1C C级级)第三十二页，讲稿共四十五页哦HITHITHITHIT监测监测监测监测血小板计数血小

27、板计数血小板计数血小板计数 HITHIT发生率不高患者（发生率不高患者（0.1-1%0.1-1%）下下列列患患者者建建议议术术后后4-144-14天天，至至少少隔隔2-32-3天天进进行行血血小小板板计数（或直到停用计数（或直到停用UFHUFH）(2C(2C级级)内科内科/产科患者预防性使用产科患者预防性使用UFHUFH 术后患者预防性使用术后患者预防性使用LMWHLMWH UFH UFH冲洗穿刺导管冲洗穿刺导管 或内科或内科/产科患者使用过产科患者使用过UFHUFH后接受后接受LMWHLMWH治疗治疗第三十三页，讲稿共四十五页哦HITHITHITHIT监测监测监测监测血小板计数血小板计数血小

28、板计数血小板计数 HITHIT发生率很低患者（发生率很低患者（0.1%0.1%）仅仅接接受受LMWHLMWH治治疗疗的的内内科科/产产科科患患者者或或仅仅在在血血管管内内介介入入治治疗疗中中使使用用UFHUFH的的患患者者（HITHIT危危险险0.1%0.1%），建建议临床医师不常规使用血小板监测议临床医师不常规使用血小板监测(2(2C C级级)第三十四页，讲稿共四十五页哦HITHITHITHIT监测监测监测监测血小板计数血小板计数血小板计数血小板计数 HITHIT抗体筛查抗体筛查使使用用肝肝素素的的患患者者，如如果果无无血血小小板板减减少少症症、血血栓栓形形成成、肝肝素素诱诱发发的的皮皮肤肤

29、改改变变或或其其他他HITHIT相相关关的的情情况况，不不建议常规监测建议常规监测HITHIT抗体抗体(1(1C C级级)第三十五页，讲稿共四十五页哦HITHITHITHIT治疗治疗治疗治疗 非肝素类抗凝药物治疗非肝素类抗凝药物治疗HITHIT高高度度怀怀疑疑（或或确确诊诊）HITHIT，无无论论是是否否合合并并血血栓栓栓栓塞塞，建建议议选选用用另另外外一一种种非非肝肝素素抗抗凝凝剂剂，如如来来匹匹卢卢定定（1 1C C级级），阿阿加加曲曲班班（1 1C C级级），比比伐伐卢卢定定（2 2C C级级），或或达达那那肝肝素素（1 1B B级级）,而而不不是是继继续续使使用用UFHUFH或或LMW

30、HLMWH，也不建议不使用抗凝剂（有或无下腔静脉滤器）。也不建议不使用抗凝剂（有或无下腔静脉滤器）。第三十六页，讲稿共四十五页哦HITHITHITHIT治疗治疗治疗治疗 非肝素类抗凝药物治疗非肝素类抗凝药物治疗HITHIT高度怀疑（或确诊）高度怀疑（或确诊）HITHIT，无论是否有下肢无论是否有下肢DVTDVT的临的临床证据，建议常规下肢静脉超声以明确是否存在床证据，建议常规下肢静脉超声以明确是否存在DVTDVT（ICIC级）级）第三十七页，讲稿共四十五页哦HITHITHITHIT治疗治疗治疗治疗 VKAsVKAs 高度怀疑或确诊高度怀疑或确诊HITHIT的患者的患者建建议议不不使使用用维维生

31、生素素K K拮拮抗抗剂剂（香香豆豆素素），直直至至血血小小板板计计数明显恢复（如至少数明显恢复（如至少10010100109 9/L L，最好最好15010150109 9/L L）VKAVKA仅仅用用于于替替换换抗抗凝凝剂剂时时的的重重叠叠期期（最最少少重重叠叠5 5天天），起起始始剂剂量量小小，替替换换使使用用的的抗抗凝凝剂剂直直到到血血小小板板计计数数恢恢复复至至稳稳定定状状态态时时，或或至至少少最最近近2 2天天的的INRINR达达到到靶靶治治疗疗目目标标范范围围内才能停用（内才能停用（ICIC级）级）第三十八页，讲稿共四十五页哦HITHITHITHIT治疗治疗治疗治疗 VKAs VK

32、As使用使用VKAsVKAs的患者在诊断为的患者在诊断为HITHIT后，建议使用维生素后，建议使用维生素K K逆转逆转VKAVKA抗凝疗效抗凝疗效（2C2C级）级）第三十九页，讲稿共四十五页哦HITHITHITHIT治疗治疗治疗治疗 LMWHLMWH治疗治疗HITHIT高高度度怀怀疑疑HITHIT的的患患者者，无无论论是是否否合合并并血血栓栓形形成成，建建议议不使用不使用LMWHLMWH（IC+IC+级）级）高度怀疑或确诊高度怀疑或确诊HITHIT的患者，如无活动性出血，不建的患者，如无活动性出血，不建议预防性输注血小板议预防性输注血小板（2 2C C级）级）第四十页，讲稿共四十五页哦HITH

33、ITHITHIT治疗治疗治疗治疗 特殊患者群特殊患者群有有HITHIT病病史史，HITHIT抗抗体体阴阴性性，需需要要接接受受心心脏脏手手术术的的患患者者，建建议议使使用用UFHUFH，而而不不使使用用非非肝肝素素类类抗抗凝凝剂剂（1 1C C级）级）注：术前和术后抗凝治疗应使用非肝素抗凝剂注：术前和术后抗凝治疗应使用非肝素抗凝剂第四十一页，讲稿共四十五页哦HITHITHITHIT治疗治疗治疗治疗 特殊患者群特殊患者群 急性急性HITHIT 急性急性HITHIT（血小板减少，血小板减少，HITHIT抗体阳性），需要接受抗体阳性），需要接受心脏手术的患者，建议采用下列措施（优选药物以降序心脏手术

34、的患者，建议采用下列措施（优选药物以降序排列）排列）：推迟手术（如果可能），直到推迟手术（如果可能），直到HITHIT抗体转为阴性抗体转为阴性1 1C C级级体外循环下体外循环下CABGCABG中抗凝使用比伐卢定中抗凝使用比伐卢定1 1C C级级或无需体外循环下的或无需体外循环下的CABGCABG中抗凝使用比伐卢定中抗凝使用比伐卢定1 1C C级级第四十二页，讲稿共四十五页哦HITHITHITHIT治疗治疗治疗治疗 特殊患者群特殊患者群 急性急性HITHIT使用来匹卢定术中抗凝（患者的肾功能正常）使用来匹卢定术中抗凝（患者的肾功能正常）1 1C C级；级；使用使用UFHUFH加抗血小板药物，使

35、用依前列醇（如果无加抗血小板药物，使用依前列醇（如果无ECTECT监测条件或患者监测条件或患者肾功能不全）肾功能不全）2 2C C级；级；使用使用UFHUFH加抗血小板药物，替罗非班（加抗血小板药物，替罗非班（2 2C C级）；级）；或术中使用达那肝素抗凝（如果可监测抗或术中使用达那肝素抗凝（如果可监测抗XaXa因子）因子）2 2C C级）级）第四十三页，讲稿共四十五页哦HITHITHITHIT治疗治疗治疗治疗 特殊患者群特殊患者群 亚急性亚急性HITHIT亚亚急急性性HITHIT（血血小小板板计计数数恢恢复复，HITHIT抗抗体体阳阳性性）建建议议推推迟迟手手术术（如如果果可可能能）直直到到HITHIT抗抗体体转转为为阴阴性性，然然后后使使用用肝素肝素1 1C C级级。或者建议使用非肝素类抗凝剂。或者建议使用非肝素类抗凝剂2 2C C级级急性或既往有急性或既往有HITHIT病史，需要接受心脏导管治疗或病史，需要接受心脏导管治疗或PCIPCI的患者，建议选用其他抗凝剂，如的患者，建议选用其他抗凝剂，如阿加曲班阿加曲班（1 1C C级）级），比伐卢定比伐卢定（1 1C C级）级），来匹卢定，来匹卢定（1 1C C级）级），或达那肝素，或达那肝素（2 2C C级），而不使用肝素级），而不使用肝素第四十四页，讲稿共四十五页哦感感谢谢大大家家观观看看第四十五页，讲稿共四十五页哦