肝素相关性血小板减少的预防及对策

肝素相关性血小板减少的预防及对策临床实例73岁，男性2型糖尿病合并肾衰右颈内静脉置管透析普通肝素抗凝第六次导管不畅经处理后无效更换导管继续肝素抗凝/肝素水封管ELISAforHIT(+++)随后两次无肝素，生理盐水冲洗，导管压力上升第三次无肝素透析几分钟后突发血压下降，紫绀，心跳骤停，复苏无效DavenportA.NephrolDialTransplant,2006;21:1721-24内容概要认识HIT的必要性和诊断思路HIT的预防措施HIT的治疗对策血液净化、PCI、CABG、骨科术后……肝素/低分子肝素的广泛应用预防性治疗性肝素广泛应用基本概念肝素相关性血小板减少(Heparin-InducedThrombocytopenia,HIT)指患者使用肝素后不久或在肝素治疗过程中出现的血小板减少(＜150×109/L或比基础值下降≥50%)可引起血栓形成，造成肢体及器官血栓栓塞，严重者危及生命HIT伴血栓形成综合征(HITwiththrombosissyndrome,HITTS)药物不良事件发生频率的判断“common”(or“frequent”):1%“infrequent”(or“uncommon”):0.1~1%“rare”:0.1%CouncilforInternationalOrganizationofMedicalSciences(CIOMS).Benefit-riskbalanceformarketeddrugs:evaluatingsafetysignals.Switzerland,1998HIT发生率高-国外TherapyClinicalPopulationatRiskIncidenceofPF4–HeparinAntibodies（％）IncidenceofHIT（％）Heparin[neworremote(100days)exposure]Patientsundergoingorthopedicsurgery143~5Adultsundergoingcardiacsurgery25~501~2Generalmedicalpatients8~200.8~3.0LMWH[neworremote(100days)exposure]MedicalpatientsPatientsundergoingsurgicalororthopedicprocedures2~80~0.9NEnglJMed,2006;355:809-17Heparin:unfractionatedheparin,UFH血小板减少患者血栓事件发生率高WarkentinTE,etal.NEnglJMed,1995,332:1330-5Randomized,double-blindclinicaltrial,prophylaxisafterhipsurgeryHIT-临床诊断的可能只是冰山一角AlexanderWahba,MMCTS,2010.004481HIT的发生增加住院时间和费用ToevaluatethefinancialimpactofHITAcase-controlstudy,22casepatientsand255controlsubjectsHITcasepatients:afinanciallossof$14,387perpatientanincreaseinlengthofstayof14.5daysSmytheMA,etal.Chest,2008;134:568-573说明书-法律依据肝素：不良反应中在用药后8天左右有时可发生明显血小板减少，与抗体产生免疫反应相关，后期可合并脏器栓塞低分子肝素：不良反应中也偶见血小板减少有肝素诱导的血小板减少症史患者禁用有必要认识和重视HIT!HIT分型CooneyNF.CriticalCarenurse,2006;26:30-36免疫型HIT发病机制JangIKandHurstingMJ.Circulation,2005;111:2671-83Virchow's三联症：血流淤滞、血管损伤和高凝状态临床表现-1接触肝素或低分子肝素一般5～10天后血小板下降(＜100×109/L或比基础值下降≥50%)(如近期曾用过肝素，发病时间提前)停用肝素后4～14天血小板恢复血栓形成ArepallyGMandOrtelTL.NEnglJMed,2006;355:809-17罕见出血临床表现-2急性炎症反应发热、寒战、皮肤潮红肝素导致的皮肤损害肾上腺出血性梗死(肾上腺静脉血栓形成)呼吸心跳骤停(HIT继用肝素)WarkentinTE，etal.Chest,2005;127:1857-61HIT诊断流程NEnglJMed,2006,355:809-17血小板监测WarkentinTEandGreinacherA.Chest,2004,126:311-337抗体检测CooneyNF.CriticalCarenurse,2006;26:30~36抗体检测DiagnosticAssaySensitivity,%Specificity,%EarlyPlateletFallLatePlateletFallPF4/heparinELISA97#9550~93PlateletSRA90~989580~97Heparin-inducedplateletaggregationassay90~989580~97CombinationofsensitiveplateletactivationandPF4-dependentantigenassay1009580~97WarkentinTEandGreinacherA.Chest,2004,126:311-337#:NEnglJMed,2006,355:809-17SRA:“goldstandard”Chest2009;135:1651-1664下肢B超检查ForpatientswithstronglysuspectedorconfirmedHIT,whetherornotthereisclinicalevidenceoflower-limbDVTRecommendroutineultrasonographyofthelower-limbveinsforinvestigationofDVT(Grade1C)Chest2008,133(suppl):340S-380S可疑HIT患者“4T”评分系统中国心血管病研究杂志,2006;4(5):389-390NephrolDialTransplant,2006;21:1721-1724CurrOpinPulmMed,2008;14(5):397-402Haematologica,2012;97(1):89-97“4T”可用于HIT的阴性排除血小板减少的原因假性血小板减少血液稀释血小板生成减少病毒感染累及骨髓、化放疗、骨髓增生不良血小板破环增加输血或移植后反应、传染性单核细胞增多症、球囊反搏、药物导致的血小板破环增加、抗心磷脂抗体综合征等利奈唑胺万古内容概要认识HIT的必要性和诊断思路HIT的预防措施HIT的治疗对策HIT预防策略提高认识和警惕性使用肝素抗凝者监测血小板提高认识和警惕性使用肝素抗凝者监测血小板关注HIT发生的危险因素OveralleffectofdifferenttypeCommonORforHIT95%CICommonORP-valueLowerUpperUFHvsLMHW5.292.849.860.0001SurgicalvsMedical3.251.985.350.0001FemalevsMale2.371.374.090.0015WarkentinTE,etal.Blood,2006,108:2937-2941牛UFH猪UFHAnnThoracSurg,2003,75:17-22HIT预防策略HIT预防策略高危患者使用低分子肝素替代普通肝素缩短普通肝素使用的时间(5~7天)高度怀疑HIT时停用肝素(包括肝素水冲洗)建立HIT档案(HITcard)HITcard内容概要认识HIT的必要性和诊断思路HIT的预防措施HIT的治疗对策基本治疗方案疾病状态治疗对策不需抗凝治疗停用肝素或LMWH需注射抗凝剂非肝素的抗凝剂需注射抗凝剂但无合适药物氯吡格雷+阿司匹林前列环素类大剂量丙球需口服抗凝剂维生素K拮抗剂大血管急性血栓栓塞血栓与栓子摘除术溶栓治疗其它治疗去纤酶(ancrod)血浆置换*糖皮质激素#*SeminHematol,1999,36:29-32#Hematology,2004,390-406Strategiesinheparin-inducedthrombocytopenia停用所有肝素静脉用非肝素类抗凝剂合适后续口服华发林避免预防性血小板输注AlexanderWahba,MMCTS,2011;2011:4481选择性非肝素抗凝剂Directthrombininhibitorslepirudin(重组水蛭素或来匹卢定)argatroban(阿加曲班)bivalirudin(比伐卢定)Anti-factorXaagentsdanaparoid*(达那肝素)Fondaparinux(磺达肝素)NEnglJMed,2006,355:809-17Chest2009,135:1651-64XaVaCa2+PL凝血酶原凝血酶纤维蛋白原纤维蛋白单体稳定的纤维蛋白*:美国FDA未批准国内上市：阿加曲班重组水蛭素vs阿加曲班CooneyNF.CriticalCarenurse,2006,26:30~36肾衰并发HIT患者抗凝选择Argatroban:idealalternativetoheparinnotexcretedbythekidneysnotrequiredoseadjustmentLepirudin:0.08mg/kg(dialysis)0.006~0.025mg/kg/h(CVVH)Danaparoid:2500Ubolus,200~600U/h(CVVH)Blood,2003,101(1):31-37合并HIT患者CPB时抗凝选择合并HIT患者介入治疗时抗凝选择JNeurointerventSurg,201058岁男性，慢性肾衰，肝功能不全，DVT，应用肝素3天后发生HITAnnPharmacother,2012;46:000肝素再应用ForpatientswithahistoryofHITwhoareHITantibodynegativeandrequirecardiacsurgery,werecommendtheuseofUFHoveranonheparinanticoagulant(Grade1B).Chest2008;133(suppl):340S-380S243pats,144patientsinitiallyhadpositivetestsforheparin-dependentantibodiesNEnglJMed,2001;344:1286-9250days(95%CI32~64)85days(95%CI64~124)华发林的使用HIT早期不要单独使用华发林诱发微血管血栓形成下肢坏疽（蛋白C、蛋白S水平下降）等血小板恢复(＞100～150×109/L)后使用与非肝素抗凝剂叠加使用至少4~5天维持INR2.0连续2天以上疗程取决于是否发生血栓(血小板恢复后2~4周/3~6月或更长)AmJHealth-SystPharm2008,65:1144-7Chest,2004,126:311-337NEnglJMed,2006,355:809-17血小板输注ForpatientswithstronglysuspectedorconfirmedHITwhodonothaveactivebleeding,wesuggestthatprophylacticplatelettr