肝素诱导的血小板减少症.ppt

肝素诱导的血小板减少症 史旭波 首都医科大学同仁医院,XIa,XIIa,IXa,VIIa - 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,Xa,VIIIa,Va,内源性凝血系统,外源性凝血系统,凝血与抗凝系统,Epidemiology,the chance of significant exposure to heparin exceeds 50% in hospitalized patients acute coronary syndrome (UA / MI) pulmonary embolism deep venous thrombosis and prophylaxis atrial fibrillation / stroke heparinized pulmonary wedge catheters PCI IABP,Semi Thromb Hemost 1999;25 Suppl 1:57-60,U.S. Estimated Causes of Accidental Deaths, 1000,40,000,90,000,Deaths per year,Medication Errors Hospital Audit,%,REFERENCE,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HIT 12万人出现血栓并发症（静脉、动脉） 3.6万人死亡,Heparin-induced Thrombocytopenia,Heparin-induced thrombocytopenia (HIT), an antibody-mediated syndrome, is associated with significant morbidity and mortality considered a rarity in the past unrecognized by many clinicians diagnoses can be difficult to confirm until recently there was no therapeutic options other than discontinuation of heparin,Epidemiology,thrombocytopenia is one of the most common laboratory abnormalities found among hospitalized patients serologically proven HIT occurs in 1.5% to 3% of patients with heparin exposure,N Engl J Med 1995;332:1330-5,Cascade of events leading to formation of HIT antibodies and prothrombotic components,www.thrombosite.com,Bleeding and Clotting,the most feared consequence in these patients with a low platelet count is not bleeding but clotting present with mucocutaneous bleeding, ranging from petechiae and ecchymoses to life-threatening gastrointestinal and intracranial hemorrhage,Thrombosis,thrombosis is mostly venous not arterial may result in bilateral deep venous thrombosis of the legs pulmonary embolism venous gangrene of fingers, toes, penis, or nipples myocardial infarction, stroke mesenteric arterial thrombosis limb ischemia and amputation,Circulation 1999;100:587-93 Am J Med 1996;101:502-7 Thromb Haemost 1993;70:554-61,Other Clinical Features,Skin lesions at heparin injection site Skin necrosis Acute platelet activation Acute inflammatory reactions (fever, chills, etc.),Skin Necrosis,Used with permission from Warkentin TE. Br J Haematol. 1996;92:494497.,Venous Limb Gangrene,Used with permission from Warkentin TE, Elavathil LJ, Hayward CPM, Johnston MA, Russett JI, Kelton JG. Ann Intern Med. 1997;127:804812.,Morbidity and Mortality,HIT-associated mortality is high (about 18%) 5% of affected patients require limb amputation Overt bleeding or bruising is rare even with severe thrombocytopenia Appropriate management can limit morbidity and mortality,HIT Syndrome,Type I nonimmunologic mechanisms (mild direct platelet activation by heparin) associated with an early (within 4 days) and usually mild decrease in platelet count (rarely 100 x 109/L) typically recovers within 3 days despite continued use of heparin not associated with any major clinical sequelae occurs primarily with high dose iv heparin,HIT Syndrome,Type II induced by immunologic mechanisms substantial fall in platelet count ( 50%) count in the 50,000 - 80,000 /mm range typical onset of 4-14 days occurs with any dose by any route potential for development of life-threatening thromboembolic complications rarely causes bleeding,Risks for HIT,Type I intravenous high-dose heparin Type II varies with dose of heparin unfractionated heparin LMWH bovine porcine surgical medical patients,Diagnosis of HIT,absence of another clear cause for thrombocytopenia the timing of thrombocytopenia the degree of thrombocytopenia adverse clinical events (most often thrombocytpenia) positive laboratory tests for HIT antibodies,Pathogenesis of Drug-induced thrombocytopenia,Certain drugs (quinine, quinidine, sulfa antibiotics) link non-covalently to platelet membrane glycoproteins very rarely, IgG antibodies are produced that recognize these drug-glycoprotein complexes macrophages remove the complexes causing severe thrombocytopenia,Comparison of HIT and other Drug-Induced Thrombocytopenia,HIT Quinine/Sulfa Frequency 1/100 1/10,000 Onset 5-8 days 7 days Platelet count 20-150x109/L 20x109/L Sequelae Thrombosis Bleeding Laboratory Immunoassay Platelet- (heparin/PF4) associated IgG,Unusual Clinical Events Suspicious for HIT,mild to moderate thrombocytopenia, often in conjunction with thrombosis adrenal hemorrhagic infarction (caused by adrenal vein thrombosis) warfarin-induced venous limb gangrene fever, chills, beginning 5 to 30 minutes after an IV heparin bolus heparin-induced skin lesions associated with HIT antibodies, even in the absence of thrombocytopania,Other Clinical Features Suspicious for HIT,a rapid drop in platelets may also be indicative of HIT, particularly if the patients received heparin within the previous 3 months a fall in platelet count of 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,Common Laboratory Tests for HIT,Test Advantages Disadvantages PAA Rapid and simple Low sensitivity - not suitable for testing multiple samples SRA Sensitivity 90% Washed platelet (technically demanding), needs radiolabeled material 14C HIPA Rapid, sensitivity 90% Washed platelets ELISA High sensitivity, High cost, lower specificity for clinically significant HIT,Thromb Haemost 1998;79:1-7,platelet aggregation assay (PAA) serotonin release assay (SRA) heparin induced platelet activation (HIPA),Functional Assay,Platelet aggregation assay (PAA) performed by many laboratories incubate platelet-rich plasma from normal donors with patient plasma and heparin limited by poor sensitivity and specificity because heparin can activate platelets under these conditions, even in the absence of HIT antibodies,Antigen Assay,Antibodies against heparin/PF4 complexes (the major antigen of HIT) are measured by colorimetric absorbance Two ELISA have been developed Stago GTI limited by high cost,Management of HIT,risk for thrombosis is high in HIT, prevention of thrombosis is the goal of intervention heparin is contraindicated in patients with HIT discontinuation of heparin - all sources of heparin must be eliminated most patients will require treatment with an alternate anticoagulant for initial clinical problem HIT induced thrombosis,HIT 处理措施,药物 可用 禁用 评价 华法令 x warfarin in the absence of an anticoagulant can precipitate venous limb gangrene 补充血小板 x infusing platelets merely “adds fuel to the fire” 静脉滤器 x often results in devastating caval, pelvic, and lower leg venous thrombosis 低分子肝素 x low molecular weight heparin usually cross- react with unfractionated heparin after HIT or HITTS (HIT thrombosis syndrome) has occurred 水蛭素/阿加曲班 x Beware renal insufficiency, antibody formation 血浆置换 x removes micro-particles formed from platelet activation; not a standard indication 阿司匹林 x can inhibit platelet activation by HIT 氯吡格雷 x antibodies Gp2b/3a受体 x 阻滞剂,Steps to Prevent HIT,porcine heparin preferred over bovine heparin LMWH preferred over unfractionated heapirn oral anticoagulation should be started as early as possible to reduce the duration of heparin exposure intravenous adapters should not be flush with heparin monitoring serial plate counts for developing thrombocytopenia,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,HIT监测血小板计数,接受治疗剂量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),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),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,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危险0.1%），建议临床医师不常规使用血小板监测(2C级),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),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（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）。,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）,HIT治疗,VKAs 高度怀疑或确诊HIT的患者 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）,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）,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）,HIT治疗,特殊患者群 有HIT病史，HIT抗体阴性，需要接受心脏手术的患者，建议使用UFH，而不使用非肝素类抗凝剂（1C级） 注：术前和术后抗凝治疗应使用非肝素抗凝剂,HIT治疗,特殊患者群 急性HIT 急性HIT（血小板减少，HIT抗体阳性），需要接受心脏手术的患者，建议采用下列措施（优选药物以降序排列）： 推迟手术（如果可能），直到HIT抗体转为阴性1C级 体外循环下CABG中抗凝使用比伐卢定1C级 或无需体外循环下的CABG中抗凝使用比伐卢定1C级,HIT治疗,特殊患者群 急性HIT 使用来匹卢定术中抗凝（患者的肾功能正常）1C级； 使用UFH加抗血小板药物，使用依前列醇（如果无ECT监测条件或患者肾功能不全）2C级； 使用UFH加抗血小板药物，替罗非班（2C级）； 或术中使用达那肝素抗凝（如果可监测抗Xa因子）2C级）,HIT治疗,特殊患者群 亚急性HIT 亚急性HIT（血小板计数恢复，HIT抗体阳性）建议推迟手术（如果可能）直到HIT抗体转为阴性，然后使用肝素1C级。或者建议使用非肝素类抗凝剂2C级 急性或既往有HIT病史，需要接受心脏导管治疗或PCI的患者，建议选用其他抗凝剂，如阿加曲班（1C级），比伐卢定（1C级），来匹卢定（1C级），或达那肝素（2C级），而不使用肝素,HIT的预防,减少HIT抗体形成 整形外科术后患者建议使用LMWH，而不使用UFH。 血栓形成患者的治疗，不建议使用牛UFH，可使用猪UFH或LMWH（1A级） 心脏手术患者术中抗凝，建议使用猪UFH，而不用牛UFH（1B级）,Thanks You,