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1、,金润铭,血小板减少症的临床诊治,Platelets,Adult form of the same undifferentiated stem cell as the RBC and the WBCThrombopoietin(hormone)specializes the stem cell into the thrombocyteDisc shaped without a nucleusHelp slow blood loss from damaged vessels by forming a plugAlso excrete a chemical the enhances more cl
2、ot formation,Platelets,Life spanUsually 5-9 daysAged and dead platelets are removed in the liver and spleen by fixed macrophagesNormal amountsBetween 100,000 and 300,000 in each microliter of blood2-4 micrometers in diameter,血小板减少的原因,血小板生成减少或无效死亡遗传性获得性:药物、恶性肿瘤、感染、电离辐射、再障、MDS等损伤造血干细胞或影响其在骨髓中增殖所致。这些因素
3、可影响多个造血细胞系统，常伴有不同程度贫血，白细胞减少，骨髓巨核细胞减少(2)血小板破坏过多先天性获得性：免疫性和非免疫性。免疫性血小板破坏过多常见的有特发性血小板减少和药物性血小板减少。非免疫性血小板减少包括感染、弥漫性血管内凝血、血栓性血小板减少等(3)血小板在脾内滞留过多：脾功能亢进,重症感染的发病过程,感染,感染严重征象-血小板计数,ICU中，血小板减少的病人住院时间长且死亡率高有人发现23%的危重病人至少有一次血小板计数10万/mm3,10%的病人5万/mm3外科急诊ICU血小板减少的病人38%死亡，而对照组仅为20%,严重脓毒症(Severe sepsis),定义：合并有器官功能障
4、碍、低灌注或低血压器官功能障碍:动脉氧分压低(氧合指数PO2/FIO2 2.0mg/dl；凝血功能异常(INR1.5或APTT60秒)；血小板减少(血小板计数2.0mg/dl或35mmol/L)组织灌注指标:高乳酸盐血症(2mmol/L)血液动力学指标:动脉血压过低(收缩压SBP 40 mm Hg),小儿最常见的出血性疾病，也是最常见的血小板异常性疾病。主要临床特点为血循环中存在抗血小板抗体，使血小板破坏过多，血小板减少引起皮肤、粘膜自发性出血；骨髓巨核细胞数正常或增多，出血时间延长，血块收缩不良，束臂试验阳性。,免疫性血小板减少性紫癜(ITP),基本情况 发病率高（40100/10万），没有
5、明显的地域和种族差别；中国13亿人口中每年发病人数将超过50万，其中急性ITP在儿童多见，发病高峰年龄2-5岁，无性别差异，常在冬春季病毒感染高峰期发病较多。慢性ITP 则多见于20-50岁的成人，女性较男性发病率高3-4倍，发病无季节性，但近年来儿童慢性ITP的发病有增多趋势，研究显示部分ITP的发病与幽门螺旋杆菌(HP)、人类巨细胞病毒(hCMV)等感染有关。,诊断依据,（1）血小板计数100109/L（2）骨髓巨核细胞增多或正常，有成熟障碍。成熟障碍主要表现为幼稚型和（或）成熟型且无血小板释放的巨核细胞比例增加，巨核细胞颗粒缺乏，胞质少。（3）皮肤出血点、淤斑和（或）粘膜出血等临床表现。
6、（4）急性型脾脏多无肿大（5）具有以下4项中任何1项糖皮质激素治疗有效；脾切除有效；血清血小板相关抗体（PAIg或PAC3）阳性；血小板寿命缩短（6）排除其他可引起血小板减少的疾病，如再生障碍性贫血、白血病、骨髓增生异常综合征（MDS）、其他免疫性疾病以及药物性因素,临床分型,急性型 起病急，常有发热，出血一般较重，血小板计数常20109/L，病程6个月 慢性型 起病隐匿，出血一般较轻，血小板计数常为（3080）109/L，病程6个月,病情分度,轻度 血小板计数（BPC）50109/L，一般无自发出血，仅外伤后易发生出血或术后出血过多中度 25109/LBPC50109/L，有皮肤粘膜出血点或
7、外伤后淤斑、血肿、外伤出血延长，但无广泛出血重度（具备下列一项者即可）10109/LBPC25109/L，皮肤广泛出血、淤斑或多发血肿，粘膜活动性出血（齿龈渗血、口腔血泡、鼻出血）；消化道、泌尿道或生殖道暴发出血或发生血肿压迫；视网膜出血或咽后壁出血；外伤处出血不止，经一般治疗无效极重度（具备下列一项即可）BPC10109/L或几乎查不到，皮肤粘膜广泛自发性出血、血肿或出血不止；危及生命的严重出血（包括颅内出血）,等级 出血严重程度及生活质量 临床干预,一级 少量出血，紫癜100个，和/或5个、建议观察 直径3cm的小瘀斑，无粘膜出血二级 轻微出血，紫癜100个，和/或5个、观察或选择性治疗
8、直径3cm的小瘀斑，无粘膜出血三级 中等量出血，明显的粘膜出血 临床干预使患儿 病情达一/二级 四级 粘膜出血或怀疑有内部出血 紧急临床干预,Primary ITP Primary ITP is an autoimmune disorder characterized by isolated thrombocytopenia(peripheral blood platelet count100 x109/L)in the absence of other causes or disorders that maybe associated with thrombocytopenia.The di
9、agnosis of primary ITP remains one of exclusion;no robust clinical or laboratory parameters are currently available to establish its diagnosis with accuracy.The main clinical problem of primary ITP is an increased risk of bleeding,although bleeding symptoms may not always be present.Secondary ITP Al
10、l forms of immune-mediated thrombocytopenia except primary ITP*,Proposed definitions of disease,BLOOD,12 MARCH 2009 VOLUME 113,NUMBER 11,Standardization of terminology,definitions and outcome criteria in immune thrombocytopenic purpura of adults and children:report from an international working grou
11、p,*The acronym ITP should be followed by the name of the associated disease(for thrombocytopenia after exposure to drugs,the terms“drug-induced”should be used)in parentheses:for example,“secondary ITP(lupus-associated),”“secondary ITP(HIV-associated),”and“secondary ITP(drug-induced).”For manuscript
12、titles,abstracts,and so on,definitions such as lupus-associated ITP or HIV-associated ITPcan also be used.,BLOOD,12 MARCH 2009 VOLUME 113,NUMBER 11,Phases of the disease 1.Newly diagnosed ITP within 3 months from diagnosis2.Persistent ITP between 3 to 12 months from diagnosis.Includes patients not r
13、eachingspontaneous remission or not maintaining complete response off therapy.3.Chronic ITP lasting for more than 12 months4.Severe ITP Presence of bleeding symptoms atpresentation sufficient to mandate treatment,or occurrence of new bleeding symptoms requiringadditional therapeutic intervention wit
14、h a different platelet-enhancing agent or an increased dose,BLOOD,12 MARCH 2009 VOLUME 113,NUMBER 11,难治性ITP的诊断标准,国际协作组：脾切除无效或有效后复发存在严重的ITP或需要治疗(包括但不局限于低剂量的皮质激素)的严重出血。仅需单独应用常规或附加治疗的病人不是难治性的除外其他引起血小板减少的疾病。国内采用的标准:病程6个月,正规皮质激素治疗无效及达那唑、其它常用免疫抑制剂或脾切除无效,血小板计数 30109/L。除外继发性免疫性血小板减少性紫癜,如系统性红斑狼疮、抗磷脂抗体综合征、骨髓增
15、生异常综合征等。George JN等认为，只有脾切除无效的ITP患者才能被诊断为难治性ITP，因为牌切除是治疗ITP最有效、最持久的方法,Refractory ITPDefinition(all should be met)Failure to achieve at least R or loss of R after splenectomy*Need of treatment(s)(including,but not limited to,low dose of corticosteroids)to minimize the risk of clinically significant bl
16、eeding.Need of on-demand oradjunctive therapy alone does not qualify the patient as refractory.Primary ITP confirmed by excluding other supervened causes of thrombocytopeniaDefinition of on-demand therapy Any therapy used to temporarily increase the platelet count sufficiently to safelyperform invas
17、ive procedures or in case of major bleeding or traumaDefinition of adjunctive therapy Any non-ITP specific therapy that may decrease bleeding(eg,antifibrinolyticagents,hormonal agents,DDAVP,recombinant factor VIIa,fibrin sealants).Platelet transfusion is also included.Definition of response to thera
18、py in refractory ITP Ability to maintain a platelet count sufficient to prevent clinically significant bleeding Ability to decrease toxic therapy(eg,corticosteroids)does not qualify forresponse but should be reportedDefinition of response to on-demand therapy Control of bleeding in the specific situ
19、ation Achievement of a platelet count sufficient to perform procedure or minimizebleeding from trauma,Timing of assessment of response to ITP treatments Variable,depends on the type of treatment Duration of response Measured from the achievement of CR or R to loss of CR or R Measured as the proporti
20、on of the cumulative time spent in CR or R during the period under examination as well as the total time observed from which the proportion is derived,BLOOD,12 MARCH 2009 VOLUME 113,NUMBER 11,转 归,儿童ITP大部分呈急性、自限性过程，据美国血液协会（American Society of Hematology，ASH）统计，不予治疗的儿童病人血小板好转占83%，在6月内恢复的儿科病人占70-80%。然而
21、有一小部分病人血小板持续低于20109/L，伴有一个以上部位出血，称之为重症ITP，这部分病人往往对治疗的反应不佳,重症治疗措施,一线治疗糖皮质激素可触发淋巴细胞凋亡，抑制T、B细胞的活性及巨噬细胞Fc受体的产生，减少自身血小板相关抗体的产生 常规用法 泼尼松 12mg/kgd1-2w短期冲击 地塞米松40 mg/(m2d)4d，14天/循环4（近期有效率85.6，15个月缓解率81）甲强龙30 mg/(kgd)3d-20 mg/(kgd)4d，月/循环6 英国指南推荐对难治性病例使用地塞米松片，4mg/kg/d4d,Corticosteroid-dependence The need for
22、 ongoing or repeated doses administration of corticosteroids for at least 2 months to maintain a platelet count at or above 30 x109/L and/or to avoid bleeding(patients with corticosteroid dependence are considered nonresponders)Supplemental outcomes(whenever possible)Bleeding symptoms measured by a
23、validated scale(requires additional studies)Health-related quality of life assessment measured by a validated instrument(requires additional studies),一线治疗,IVIG 抗独特型抗体效应，封闭单核巨噬细胞系统的Fc受体，上调抑制性FcRB的表达，加速血小板抗体的清除，减少Fc介导的单核巨噬细胞对血小板的吞噬作用 400mg/kg/dX5d 1g/kg/d,36w/循环X68 总有效率60%80%,一线治疗,抗-Rh(D)免疫球蛋白 最早应用于治疗
24、Rh血型不合导致的溶血反应。Rh(D)抗原阳性的急性重症ITP患者输注抗-Rh(D)免疫球蛋白后，致敏红细胞和抗体包被的血小板竞争性结合单核巨噬细胞膜Fc受体，可以明显减少单核巨噬细胞对血小板的吞噬。国外的多个治疗指南均将抗-Rh(D)免疫球蛋白列为重型ITP 的一线治疗。近期有效率70%90%，未切脾者疗效更佳。常用剂量为2550g/kg/次X30 min,二线治疗,免疫抑制剂 CsA T淋巴细胞调节剂，特异性地抑制Th活性，通过IL-2受体阻断细胞毒T细胞激活后释放IL-2，抑制T细胞生成干扰素（IFN）-等造血负调控因子，使抗血小板抗体（PAIgG）的产生下降，从而减少对血小板的破坏 3
25、-5mg/kg/d分次口服，血药浓度200-400ng/ml，疗程36个月，有效率65%80%,免疫抑制剂,长春新碱 0.020.075 mg/kg(2 mg/次)(41%)环磷酰胺 23 mg/kg/d tid X 8w;1.5g/m2/d iv q4w X 4(76.9%90%)硫唑嘌呤 23mg/kg/d 霉氛酸脂(MMF)2040mg/kg/d,二线治疗,其他药物 达那唑 抑制巨噬细胞对致敏血小板的破坏（成人单用取得67%的近期效果，远期有效率46%10-15mg/kg/dX23月 氨磷汀 400mg/d5d 干扰素 调节机体体液免疫和促进骨髓巨核细胞造血，一方面抑制B淋巴细胞产生抗血
26、小板抗体，另一方面能提高机体促血小板生成素水平，促进巨核细胞增殖、分化及血小板的产生 3106u/m2/次,皮下或肌肉注射,3次/周X4周,单克隆抗体 利妥昔单抗（美罗华，Rituximab，抗-CD20）清除循环中的自身免疫B细胞，减少抗血小板抗体的产生、减少血小板的破坏。成人近期有效率50-70%，远期缓解率超过30%，对脾切除后复发的患者仍有效果。儿童难治性ITP的总有效率为69%375 mg/m2,q1w X 14,其他药物,其他药物,促血小板生长因子类似物重组人血小板生成素（rhTPO）:刺激巨核细胞系生长、分化及成熟，治疗早期可提升血小板（皮下注射300U/kg，每日一次，疗程14
27、天）TPO受体激动剂 romiplostim、eltrombopag、AKR-501 氨苯砜（DDS）2mg/kgd，持续数周，60%的病人血小板回升，不良反应轻微，在停药后迅速好转,研究结果特比澳（rhTPO）起效较快且停药后作用可持续一周以上,中华内科杂志，2004，43（8）：608-610,研究结果特比澳有效率85.3%,中华内科杂志，2004，43（8）：608-610,其他药物,重组人白细胞介素-11（rhIL-11）多功能细胞因子，促进骨髓造血细胞增殖，诱导巨核细胞的成熟分化，促进巨核细胞和血小板生长，具有较好的提升血小板作用 rhIL-11 50g/kgd，H X 714d,脾
28、 切 除,适应症,病程 1年 年龄 5岁 血小板持续 30 109/L 长期或间断处于重度出血 药物治疗无效或需长期大剂量激素维持,Individual agents for treatment of ITP and the time to the first and peak responses Agent/treatment Reported dose range Time to initial response*Time to peak response*Pred.1-4 mg/kg po/dx1-4 w 4-14 d 7-28 dDex.40 mg po or iv/dx4 d(4-6
29、 courses every 14-28 d)2-14 d 4-28 dIVIg 0.4-1 g/kg per dose iv(1-5 doses)1-3 d 2-7 dAnti-D 75 g/kg per dose iv 1-3 d 3-7 dRituximab 375 mg/m2 per dose iv(4 weekly doses)7-56 d 14-180 dSplenectomy Laparoscopic 1-56 d 7-56 dVincristine up to 2 mg/dose iv(4-6 weekly doses)7-14 d 7-42 dVinblastine 0.1
30、mg/kg per dose iv(6 weekly doses)7-14 d 7-42 dDanazo 400-800 mg po daily 14-90 d 28-180 dAzathioprine 2 mg/kg po daily 30-90 d 30-180 dAMG5316 3-10 g/kg weekly sc 5-14 d 14-60 dEltrombopag 50-75 mg po daily 7-28 d 14-90 d,BLOOD,12 MARCH 2009 VOLUME 113,NUMBER 11,Thank you very much for your attention！,武汉协和医院儿童血液科,
