肝素相關(guān)性血小板減少的預(yù)防及對策

肝素相關(guān)性血小板減少

的預(yù)防及對策臨床實例73歲，男性2型糖尿病合并腎衰右頸內(nèi)靜脈置管透析普通肝素抗凝第六次導(dǎo)管不暢經(jīng)處理后無效更換導(dǎo)管繼續(xù)肝素抗凝/肝素水封管ELISAforHIT(+++)隨后兩次無肝素，生理鹽水沖洗，導(dǎo)管壓力上升第三次無肝素透析幾分鐘后突發(fā)血壓下降，紫紺，心跳驟停，復(fù)蘇無效

DavenportA.NephrolDialTransplant,2006;21:1721-24內(nèi)容概要認(rèn)識HIT的必要性和診斷思路HIT的預(yù)防措施HIT的治療對策血液凈化、PCI、CABG、骨科術(shù)后……肝素/低分子肝素的廣泛應(yīng)用預(yù)防性治療性肝素廣泛應(yīng)用基本概念肝素相關(guān)性血小板減少(Heparin-InducedThrombocytopenia,HIT)指患者使用肝素后不久或在肝素治療過程中出現(xiàn)的血小板減少

(＜150×109/L或比基礎(chǔ)值下降≥50%)可引起血栓形成，造成肢體及器官血栓栓塞，嚴(yán)重者危及生命HIT伴血栓形成綜合征(HITwiththrombosissyndrome,HITTS)藥物不良事件發(fā)生頻率的判斷“common”(or“frequent”):>1%“infrequent”(or“uncommon”):0.1~1%“rare”:0.1%CouncilforInternationalOrganizationofMedicalSciences(CIOMS).Benefit-riskbalanceformarketeddrugs:evaluatingsafetysignals.Switzerland,1998HIT發(fā)生率高-國外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血小板減少患者血栓事件發(fā)生率高WarkentinTE,etal.NEnglJMed,1995,332:1330-5Randomized,double-blindclinicaltrial,prophylaxisafterhipsurgeryHIT-臨床診斷的可能只是冰山一角AlexanderWahba,MMCTS,2010.004481HIT的發(fā)生增加住院時間和費用ToevaluatethefinancialimpactofHITAcase-controlstudy,22casepatientsand255controlsubjectsHITcasepatients:afinanciallossof$14,387perpatientanincreaseinlengthofstayof14.5daysSmytheMA,etal.Chest,2008;134:568-573說明書-法律依據(jù)肝素：

不良反應(yīng)中在用藥后8天左右有時可發(fā)生明顯血小板減少，與抗體產(chǎn)生免疫反應(yīng)相關(guān)，后期可合并臟器栓塞低分子肝素：不良反應(yīng)中也偶見血小板減少有肝素誘導(dǎo)的血小板減少癥史患者禁用有必要認(rèn)識和重視HIT!HIT分型CooneyNF.CriticalCarenurse,2006;26:30-36免疫型HIT發(fā)病機(jī)制JangIKandHurstingMJ.Circulation,2005;111:2671-83Virchow's三聯(lián)癥：血流淤滯、血管損傷和高凝狀態(tài)臨床表現(xiàn)-1接觸肝素或低分子肝素一般5～10天后血小板下降

(＜100×109/L或比基礎(chǔ)值下降≥50%)

(如近期曾用過肝素，發(fā)病時間提前)停用肝素后4～14天血小板恢復(fù)血栓形成ArepallyGMandOrtelTL.NEnglJMed,2006;355:809-17罕見出血臨床表現(xiàn)-2急性炎癥反應(yīng)

發(fā)熱、寒戰(zhàn)、皮膚潮紅肝素導(dǎo)致的皮膚損害腎上腺出血性梗死(腎上腺靜脈血栓形成)呼吸心跳驟停(HIT繼用肝素)WarkentinTE，etal.Chest,2005;127:1857-61HIT診斷流程NEnglJMed,2006,355:809-17血小板監(jiān)測WarkentinTEandGreinacherA.Chest,2004,126:311-337抗體檢測CooneyNF.CriticalCarenurse,2006;26:30~36抗體檢測DiagnosticAssaySensitivity,%Specificity,%EarlyPlateletFallLatePlateletFallPF4/heparinELISA>97#>9550~93PlateletSRA90~98>9580~97Heparin-inducedplateletaggregationassay90~98>9580~97CombinationofsensitiveplateletactivationandPF4-dependentantigenassay1009580~97WarkentinTEandGreinacherA.Chest,2004,126:311-337#:NEnglJMed,2006,355:809-17SRA:“goldstandard”Chest2009;135:1651-1664下肢B超檢查ForpatientswithstronglysuspectedorconfirmedHIT,whetherornotthereisclinicalevidenceoflower-limbDVTRecommendroutineultrasonographyofthelower-limbveinsforinvestigationofDVT(Grade1C)Chest2008,133(suppl):340S-380S可疑HIT患者“4T”評分系統(tǒng)中國心血管病研究雜志,2006;4(5):389-390NephrolDialTransplant,2006;21:1721-1724CurrOpinPulmMed,2008;14(5):397-402Haematologica,2012;97(1):89-97“4T”可用于HIT的陰性排除血小板減少的原因假性血小板減少血液稀釋血小板生成減少病毒感染累及骨髓、化放療、骨髓增生不良血小板破環(huán)增加輸血或移植后反應(yīng)、傳染性單核細(xì)胞增多癥、球囊反搏、藥物導(dǎo)致的血小板破環(huán)增加、抗心磷脂抗體綜合征等利奈唑胺萬古內(nèi)容概要認(rèn)識HIT的必要性和診斷思路HIT的預(yù)防措施HIT的治療對策HIT預(yù)防策略提高認(rèn)識和警惕性使用肝素抗凝者監(jiān)測血小板提高認(rèn)識和警惕性使用肝素抗凝者監(jiān)測血小板關(guān)注HIT發(fā)生的危險因素OveralleffectofdifferenttypeCommonORforHIT95%CICommonORP-valueLowerUpperUFHvsLMHW5.292.849.86<0.0001SurgicalvsMedical3.251.985.35<0.0001FemalevsMale2.371.374.090.0015WarkentinTE,etal.Blood,2006,108:2937-2941牛UFH>豬UFHAnnThoracSurg,2003,75:17-22HIT預(yù)防策略HIT預(yù)防策略高?；颊呤褂玫头肿痈嗡靥娲胀ǜ嗡乜s短普通肝素使用的時間(<5~7天)高度懷疑HIT時停用肝素(包括肝素水沖洗)建立HIT檔案(HITcard)HITcard內(nèi)容概要認(rèn)識HIT的必要性和診斷思路HIT的預(yù)防措施HIT的治療對策基本治療方案疾病狀態(tài)治療對策不需抗凝治療停用肝素或LMWH需注射抗凝劑非肝素的抗凝劑需注射抗凝劑但無合適藥物氯吡格雷+阿司匹林前列環(huán)素類大劑量丙球需口服抗凝劑維生素K拮抗劑大血管急性血栓栓塞血栓與栓子摘除術(shù)溶栓治療其它治療去纖酶(ancrod)血漿置換*糖皮質(zhì)激素#

*SeminHematol,1999,36:29-32#Hematology,2004,390-406Strategiesinheparin-inducedthrombocytopenia停用所有肝素靜脈用非肝素類抗凝劑合適后續(xù)口服華發(fā)林避免預(yù)防性血小板輸注AlexanderWahba,MMCTS,2011;2011:4481選擇性非肝素抗凝劑Directthrombininhibitors

lepirudin(重組水蛭素或來匹盧定)

argatroban(阿加曲班)

bivalirudin(比伐盧定)Anti-factorXaagents

danaparoid*

(達(dá)那肝素)Fondaparinux(磺達(dá)肝素)NEnglJMed,2006,355:809-17Chest2009,135:1651-64

Xa

VaCa2+PL凝血酶原

凝血酶

纖維蛋白原纖維蛋白單體穩(wěn)定的纖維蛋白*:美國FDA未批準(zhǔn)國內(nèi)上市：阿加曲班重組水蛭素vs阿加曲班CooneyNF.CriticalCarenurse,2006,26:30~36腎衰并發(fā)HIT患者抗凝選擇Argatroban:idealalternativetoheparinnotexcretedbythekidneysnotrequiredoseadjustmentLepirudin: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時抗凝選擇合并HIT患者介入治療時抗凝選擇JNeurointerventSurg,201058歲男性，慢性腎衰，肝功能不全，DVT，應(yīng)用肝素3天后發(fā)生HITAnnPharmacother,2012;46:000肝素再應(yīng)用ForpatientswithahistoryofHITwhoareHITantibodynegativeandrequirecardiacsurgery,werecommendtheuseofUFHoveranonheparinanticoagulant(Grade1B).

Chest2008;133(suppl):340S-380S243pats,144patientsinitiallyhadpositivetestsforheparin-dependentantibodiesNEnglJMed,2001;344:1286-9250days(95%CI32~64)85days(95%CI64~124)華發(fā)林的使用HIT早期不要單獨使用華發(fā)林

誘發(fā)微血管血栓形成下肢壞疽（蛋白C、蛋白S水平下降）

等血小板恢復(fù)(＞100～150×109/L)后使用

與非肝素抗凝劑疊加使用至少4~5天維持INR>2.0連續(xù)2天以上療程取決于是否發(fā)生血栓(血小板恢復(fù)后2~4周/3~6月或更長)AmJHealth-SystPharm2008,65:1144-7Chest,2004,126:311-337NEnglJMed,2006,355:809-17血小板輸注ForpatientswithstronglysuspectedorconfirmedHITwhodonothaveactivebleeding,wesuggestthatprophylacticplatelettransfusionsshouldnotbegiven(Grade2C)Chest2008;133