肝硬化伴脾亢患者血小板減少癥臨床研究進(jìn)展-感染科課件

1、血小板減少癥臨床研究進(jìn)展 齊魯制藥有限公司 于海玲2010年12月7日血小板減少癥病因血小板數(shù)量減少是出血性疾病最常見的病因。血小板減少癥按病因分為：血小板破壞增加：免疫性血小板減少性紫癜（ITP）彌散性血管內(nèi)凝血（DIC）肝素誘發(fā)的血小板減少癥其他藥物誘發(fā)血小板減少癥血小板生成減少AA，AL，放化療骨髓抑制，感染干擾素治療慢性乙型病毒性肝炎所致骨髓抑制，白細(xì)胞及血小板減少是其常見的不良反應(yīng)之一，約有25%30%的患者因此原因須暫?；蛑兄怪委?血小板分布異常：脾亢阮長耿. 血小板減少癥的研究進(jìn)展. 中華醫(yī)學(xué)會(huì)第八次全國血液學(xué)學(xué)術(shù)會(huì)議論文匯編;2004年 血小板計(jì)數(shù)與出血程度Gaydos la,

2、 Freirich ej, Mantel n. The quantitative relation between platelet count and hemorrhage in patients with acute leukemia. N Engl J Med. 1962 May 3;266:905-9.102030400.5151050100Platelet count (x109/L)% Days with hemorrhage血小板減少癥的治療病因治療：如ITP應(yīng)用糖皮質(zhì)激素、丙種球蛋白等2007年美國ASH血小板輸注指南介紹：預(yù)防性血小板輸注的閾值為患者血小板計(jì)數(shù)10109/L。

3、化療、骨髓移植、骨髓自身因素(如再生障礙性貧血或骨髓增生異常綜合征)引起的血小板減少腦部手術(shù)時(shí)要求血小板計(jì)數(shù)不低于100109/L其他侵入性操作或是創(chuàng)傷手術(shù)時(shí)要求血小板計(jì)數(shù)在50100109/L水平血小板生長因子：刺激造血細(xì)胞的增殖和分化其它 血小板生長因子IL-1IL-3IL-6白細(xì)胞介素-11（rhIL-11，巨和粒）血小板生成素（rHuTPO，特比澳）羅米司亭（Romiplostim，Nplate ）艾曲波帕（Eltrombopag，Promacta）巨核細(xì)胞生長因子（MGDF）血小板生長因子白細(xì)胞介素（IL-11）白介素-11(interleukin11，IL-11)是由造血微環(huán)境基質(zhì)

4、細(xì)胞和部分間葉細(xì)胞產(chǎn)生的多效性細(xì)胞因子：成熟的IL-11編碼178個(gè)氨基酸，分子量為19.2kDa為4-螺旋束型結(jié)構(gòu)，每個(gè)功能域由7個(gè)反平行的折疊片層組成IL-11通過與受體(IL-11R)結(jié)合促進(jìn)信號(hào)傳導(dǎo)Dimitri HARMEGNIES, el. Characterization of a potent human interleukin-11 agonist. Biochem. J. (2003) 375, 2332N C位點(diǎn)I位點(diǎn)III位點(diǎn)IIIL-11介導(dǎo)的信號(hào)傳導(dǎo)通路IL-11通過復(fù)雜的信號(hào)通路介導(dǎo)，通過一系列的信號(hào)級(jí)聯(lián)反應(yīng)，作用于細(xì)胞核內(nèi)特異的DNA片段，調(diào)控靶基因的轉(zhuǎn)錄，直接

5、影響細(xì)胞的增殖、分化和凋亡 GP130IL-11RIL-11RSypJAK2GRB2SOSRASSTATsMAPKpp90rskPhospholipase DPhosphatidicAcidPrimary Response Genes(gene expression)IL-11STAT：信號(hào)傳導(dǎo)和轉(zhuǎn)錄活化因子MAPK：促進(jìn)細(xì)胞分裂蛋白激酶IL-11rhIL-11劑量耐受性試驗(yàn)16例乳腺癌患者入組，接受大劑量化療IL-11療效呈劑量依賴性，劑量越高，療效越好（p0.05）外周血骨髓巨核細(xì)胞染色體倍數(shù)檢測(cè)顯示，劑量25g/kg時(shí)，巨核細(xì)胞倍數(shù)大大增加，血小板數(shù)明顯增多IL-11藥物最大耐受劑量(M

6、DT)為75g/kg，推薦劑量為25g/kg -50g/kgMichael S. Gordon, Worta J. et al. A Phase I Trial of Recombinant Human Interleukin-11 in Women With Breast Cancer Receiving Chemotherapy. Blood, Vol 87, No 9 (May 1). 1996: pp 3615-3624days of treatment （circle 0）mg/dl3 pts 75 g6 pts 50 g3 pts 25 g3 pts 10 gAdministrat

7、ionsat Day1-14白介素-11治療肝硬化伴脾功能亢進(jìn)患者血小板減少IL-11不僅可以提升肝硬化患者的血小板，同時(shí)對(duì)患者可能存在的肝功能損害和黏膜糜爛有好處IL-11對(duì)肝炎患者肝臟炎癥和纖維化過程有保護(hù)作用1在內(nèi)毒素血癥中可減少肝臟損傷2肝硬化引起的血小板減少癥患者每天皮下注射rhlL-11 3mg，不僅使得患者血小板計(jì)數(shù)提高，同時(shí)ALT、AST在治療期間也有明顯下降3ong J P，Younossi Z MManaging the hematologic side effects of antiviral therapy for chronic hepatitis C：anemia。

8、neutropenia，and thmmbocytopeniaJCleve Clin J Med，2004，71(Suppl 3)：S17-21halib RRecombinant human interleukin11 improves thromboeytopenia in patients with cirrhosisJHepatology，2003，37：1165-1171Maeshima K, Takahashi T, Nakahira K, et a1A protective role of interleukin 11 on hepatic injury in acute end

9、otoxemiaJShock, 2004，21(2):134-138Interleukin-11 for Treatment ofHepatitis C-Associated ITPWallace H. Coulter Platelet Laboratory, Division of ematology/Oncology, Department of Medicine,University of Miami, Miller School of Medicine, Miami, Fla. , USAVincenzo Fontana Pamela Dudkiewicz Wenche Jy Larr

10、y Horstman Yeon S. AhnActa Haematol 2008;119:126-132.Results: Hepatitis C Viral LoadLiverTreatment pre- post- pre- post-Vincenzo Fontana, et al. Interleukin-11 for Treatment of Hepatitis C-Associated ITP. Acta Haematol 2008;119:126-132.In group 1, the HCV-RNA titer decreased with treatment in all pa

11、tients, falling to mean of 16% of initial value in 1-10 weeksIn group 2, the change of HCV-RNA was not statistically significantResults: Anti-Platelet Antibodies (aPlt-Ab)Treatment pre- post- pre- post-Vincenzo Fontana, et al. Interleukin-11 for Treatment of Hepatitis C-Associated ITP. Acta Haematol

12、 2008;119:126-132.In group 1, mean IgG decreased from 4.01 to 2.04 (p=0.05), after 48 weeksIn group 2, the changes were not statistically significant (p=0.68)重組人白介素-11在肝硬化脾功能亢進(jìn)患者中的術(shù)前應(yīng)用溫州醫(yī)學(xué)院附屬第二醫(yī)院朱寶玲 姚榮欣 夏軼姿 金栗名實(shí)用醫(yī)學(xué)雜志2008年第24卷第10期重組人白介素-11在肝硬化脾功能亢進(jìn)患者中的術(shù)前應(yīng)用繼發(fā)性脾功能亢進(jìn)患者N=22rhIL-11 50g/kgd, d 1-1020例患者為乙型

13、肝炎后肝硬化，2例為酒精性肝硬化患者擬行手術(shù)的病因包括：胃癌8例，結(jié)腸癌5例，卵巢腫瘤2例，股頸骨折l例，食管癌2例，乳房癌1例，膽道結(jié)石2例，大隱靜脈曲張1例研究終點(diǎn)：觀察重組人白介素-11(rhlL-11)在肝硬化脾功能亢進(jìn)患者中升高血小板的療效及其副作用實(shí)用醫(yī)學(xué)雜志2008年第24卷第10期研究結(jié)果血小板計(jì)數(shù)變化比較國際醫(yī)藥衛(wèi)生導(dǎo)報(bào)2008年第14卷第22期研究結(jié)果兩組血小板輸注情況比較國際醫(yī)藥衛(wèi)生導(dǎo)報(bào)2008年第14卷第22期結(jié)論對(duì)于需要進(jìn)行手術(shù)或有創(chuàng)性操作的肝硬化脾功能亢進(jìn)患者，術(shù)前使用IL-11不失為一種新的好方法術(shù)前升高血小板，利于患者渡過病情危險(xiǎn)期，進(jìn)一步實(shí)行介入性治療、外科手

14、術(shù)與侵入性檢查，如肝穿刺、內(nèi)鏡檢查、特殊內(nèi)鏡檢查等項(xiàng)目在用于準(zhǔn)備手術(shù)治療的肝硬化脾功能亢進(jìn)患者時(shí)，應(yīng)提早7-15d使用ong J P，Younossi Z MManaging the hematologic side effects of antiviral therapy for chronic hepatitis C：anemia。neutropenia，and thmmbocytopeniaJCleve Clin J Med，2004，71(Suppl 3)：S17-21halib RRecombinant human interleukin11 improves thromboeyto

15、penia in patients with cirrhosisJHepatology，2003，37：1165-1171Maeshima K, Takahashi T, Nakahira K, et a1A protective role of interleukin 11 on hepatic injury in acute endotoxemiaJShock, 2004，21(2):134-138小 結(jié)血小板計(jì)數(shù)和rhIL-11的關(guān)系Platelet increases usually begin 5-9 days after the initiation of rhIL-11For m

16、aximum therapeutic benefit, it must be started within 24h of chemotherapy completion, Continued for at least 7-10 daysMonica Bha. The role of interleukin-11 to prevent chemotherapy-induced thrombocytopenia in patients with solid tumors, lymphoma, acute myeloid leukemia and bone marrow failure syndro

17、mes. Leukemia and Lymphoma, 2007, 48:1,9-15美國腫瘤護(hù)理學(xué)會(huì)(ONS 2009V3 )推薦IL-11用于化療或生物治療所致的血小板減少癥的治療心房撲動(dòng)與心房顫動(dòng)（Atrial Flutter and Atrial Fibrillation）研究報(bào)道1，IL-11會(huì)增加中老年患者心房纖維顫動(dòng)發(fā)生的頻率，且呈年齡依賴性，年齡越大，發(fā)生率越高Several reports have indicated that the prevalence of AF increases with age, commencing after the age of 40, with a sharp increase after 65既往應(yīng)用蒽環(huán)類藥物的患者，需密切監(jiān)視（ONS 2009V3）對(duì)心肺功能低下的患者，建議減少rhIL-11每天用量2Age-Dependent Atrial Remodeling Induced by RecombinantHuman Interleukin-11: Implications for Atrial Flutter/Fibrillation傅強(qiáng), 王雅杰, 等. 重組