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中华危重症医学杂志(电子版) ›› 2016, Vol. 09 ›› Issue (05) : 300 -308. doi: 10.3877/cma.j.issn.1674-6880.2016.05.004

所属专题： 文献；

论著

重组人血小板生成素治疗脓毒症相关血小板减少症患者的临床研究
章渭方1, 方君俊1, 王国彬1, 倪昀岚1, 李惠1, 龚仕金2, 虞意华2, 方堃3, 舒伟峰3, 潘孔4, 寒林玲4, 郑树森1,†()   
  1. 1. 310003　杭州，浙江大学医学院附属第一医院重症医学科
    2. 310013　杭州，浙江医院重症医学科
    3. 310003　杭州，杭州市红十字会医院重症医学科
    4. 310020　杭州，浙江大学附属邵逸夫医院重症医学科
  • 收稿日期:2016-08-19 出版日期:2016-10-01
  • 通信作者: 郑树森
  • 基金资助:
    浙江省自然基金资助项目(LY15H150001)

Clinical study of recombinant human thrombopoietin in patients with sepsis-associated thrombocytopenia

Weifang Zhang1, Junjun Fang1, Guobin Wang1, Junlan Ni1, Hui Li1, Shijin Gong2, Yihua Yu2, Kun Fang3, Weifeng Shu3, Kong Pan4, Linling Han4, Shusen Zheng1,†()   

  1. 1. Department of Intensive Care Unit, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China
    2. Department of Intensive Care Unit, Zhejiang Hospital, Hangzhou 310013, China
    3. Department of Intensive Care Unit, Hangzhou Red Cross Hospital, Hangzhou 310003, China
    4. Department of Intensive Care Unit, Sir Run shaw Hospital, Zhejiang University School of Medicine, Hangzhou 310020, China
  • Received:2016-08-19 Published:2016-10-01
  • Corresponding author: Shusen Zheng
  • About author:
    Coresponding author: Zheng Shusen, Email:
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引用本文：

章渭方, 方君俊, 王国彬, 倪昀岚, 李惠, 龚仕金, 虞意华, 方堃, 舒伟峰, 潘孔, 寒林玲, 郑树森. 重组人血小板生成素治疗脓毒症相关血小板减少症患者的临床研究[J]. 中华危重症医学杂志(电子版), 2016, 09(05): 300-308.

Weifang Zhang, Junjun Fang, Guobin Wang, Junlan Ni, Hui Li, Shijin Gong, Yihua Yu, Kun Fang, Weifeng Shu, Kong Pan, Linling Han, Shusen Zheng. Clinical study of recombinant human thrombopoietin in patients with sepsis-associated thrombocytopenia[J]. Chinese Journal of Critical Care Medicine(Electronic Edition), 2016, 09(05): 300-308.

目的

评估重组人血小板生成素（rhTPO）对严重脓毒症患者伴发血小板减少症患者的疗效。

方法

将2013年10月至2015年9月期间收治的严重脓毒症合并血小板减少症的患者66例分成实验组（35例）和对照组（31例）。所有患者均予以治疗原发病及积极控制感染，实验组患者于血小板下降的第1天给予rhTPO治疗，300 U·kg-1·d-1，皮下注射，当血小板计数绝对值升高≥ 50 × 109/L时即停用，疗程一般不超过14 d。检测所有患者治疗前即刻、治疗后1、2、3、5、7、9、14 d血小板计数、C反应蛋白及丙氨酸转氨酶（ALT）水平。比较两组患者血小板输注例数、急性病生理学和长期健康评价（APACHE）Ⅱ评分、体温下降至正常时间、临床症状消失时间、肺部影像学恢复时间、ICU治疗后28 d病死率及住院时间。记录不良反应发生情况，并比较实验组患者治疗前后活化部分凝血活酶时间、ALT水平、C反应蛋白水平及总胆红素水平。

结果

实验组患者仅血小板计数治疗后3、5 d较对照组明显升高[（56 ± 19）× 109/L vs.（42 ± 18）× 109/L，t = 3.112，P < 0.05；（67 ± 22）× 109/L vs.（54 ± 21）× 109/L，t = 2.520，P< 0.05]，且实验组患者血小板输注例数明显低于对照组患者（5/35 vs. 11/31，χ2 = 4.022，P = 0.045）。两组患者治疗后的APACHEⅡ评分（t = 0.692，P< 0.05）、体温下降至正常的时间（t = 0.510，P< 0.05）、临床症状消失时间（t = 0.262，P< 0.05）、肺部影像系统恢复至正常时间（t = 0.685，P< 0.05）、28 d病死率（χ2 = 0.001，P< 0.05）及ICU平均住院天数（t = 0.637，P< 0.05）比较，差异均无统计学意义。同时，研究中没有观察到rhTPO所致的药物不良反应，且经rhTPO治疗前后实验组患者活化部分凝血活酶时间（t = 0.697，P< 0.05）、ALT（t = 0.478，P< 0.05）、C反应蛋白（t = 0.110，P< 0.05）及总胆红素（t = 1.634，P< 0.05）比较，差异亦均无统计学意义。

结论

针对脓毒症合并血小板减少症的患者，在传统治疗手段的基础上联合rhTPO治疗可以显著地提升血小板计数，减少输注血制品带来的风险以及医疗资源的消耗，改善患者预后。

关键词: 重组人血小板生成素, 脓毒症, 血小板减少
Objective

To evaluate the efficacy of recombinant human thrombopoietin (rhTPO) in patients with severe sepsis and thrombocytopenia.

Methods

Sixty-six patients with severe sepsis and hrombocytopenia between October 2013 and September 2015 were divided into the experiment group (35 cases) and control group (31 cases). All patients received primary treatment and infection control. And patients in the experiment group received rhTPO 300 U·kg-1·d-1 by hypodermic injection, and withdraw when platelet count (PLT) ≥ 50 × 109/L, and the course did not exceed 14 d. Levels of PLT, C-reactive protein and alanine aminotransferase (ALT) were detected before and after the treatment on 1, 2, 3, 5, 7, 9 ans 14 d. The platelet transfusion cases, acute physiology and chronic health evaluation Ⅱ(APACHEⅡ), the time of temperature dropped to normal, time of clinical symptom disappearance, pulmonary imaging recovery time, 28-day fatality rate and length of ICU stay were compared between the two groups. The adverse reactions were recorded, and the activated partial thromboplastin time, levels of ALT, C-reactive protein and total bilirubin were compared before and after treatment in the experiment group.

Results

The PLT only increased markedly on 3 and 5 d after treatment in the experiment group as compared with those in the control group [(56 ± 19) × 109/L vs. (42 ± 18) × 109/L, t = 3.112, P < 0.05; (67 ± 22) × 109/L vs. (54 ± 21) × 109/L, t = 2.520, P < 0.05]. The platelet transfusion rate in the experiment group was much lower than that in the control group (5/35 vs. 11/31, χ2 = 4.022, P = 0.045). However, the APACHEⅡ scores (t = 0.692, P < 0.05), the time of temperature dropped to normal (t = 0.510, P < 0.05), time of clinical symptom disappearance (t = 0.262, P < 0.05), pulmonary imaging recovery time (t = 0.685, P < 0.05), 28-day fatality rate (χ2 = 0.001, P < 0.05) and length of ICU stay (t = 0.637, P < 0.05) all showed no significant differences between the two groups after treatment. Meanwhile, there was no adverse reactions happened, and the activated partial thromboplastin time (t = 0.697, P < 0.05), levels of ALT (t = 0.478, P < 0.05), C-reactive protein (t = 0.110, P < 0.05) and total bilirubin (t = 1.634, P < 0.05) in the experiment group also showed no significant differences before and after the treatment.

Conclusions

The use of rhTPO combined with conventional treatment in patients with sepsis-associated thrombocytopenia is safe. It can significantly enhance the platelet count, reduce platelet transfusion and improve patient's prognosis.

Key words: Recombinant human thrombopoietin, Sepsis, Thrombocytopenia
表1 两组感染性疾病合并血小板减少症患者实验室检查指标各时间点的比较（±s）
指标 组别 例数 治疗前 治疗后1 d 治疗后2 d 治疗后3 d
血小板计数(× 109/L) 实验组 35 37 ± 8 40 ± 8 40 ± 7 56 ± 19a
对照组 31 39 ± 10 39 ± 9 39 ± 8 42 ± 18
C反应蛋白(μmol/L) 实验组 35 77 ± 35 80 ± 37 75 ± 31 74 ± 37
对照组 31 72 ± 38 78 ± 34 76 ± 35 72 ± 39
ALT(U/L) 实验组 35 39 ± 21 38 ± 15 49 ± 20 51 ± 31
对照组 31 39 ± 24 39 ± 16 46 ± 18 49 ± 31
指标 组别 例数 治疗后5 d 治疗后7 d 治疗后9 d 治疗后14 d
血小板计数(× 109/L) 实验组 35 67 ± 22a 102 ± 48 124 ± 35 178 ± 47
对照组 31 54 ± 21 90 ± 45 109 ± 30 157 ± 49
C反应蛋白(μmol/L) 实验组 35 74 ± 40 70 ± 38 71 ± 46 76 ± 33
对照组 31 70 ± 39 70 ± 39 70 ± 39 71 ± 34
ALT(U/L) 实验组 35 45 ± 27 33 ± 18 38 ± 28 37 ± 18
对照组 31 45 ± 28 31 ± 17 39 ± 26 42 ± 22
表2 两组感染性疾病合并血小板减少症患者疾病危重程度评估（±s）
组别 例数 APACHEⅡ评分（分） 体温下降正常的时间(d) 临床症状消失时间(d) 肺部影像学恢复所需时间(d)
实验组 35 17 ± 3 4.4 ± 2.1 8±4 10 ± 3
对照组 31 17 ± 3 4.1 ± 2.3 8±5 10 ± 4
t值 ? 0.692 0.510 0.262 0.685
P值 ? 0.091 0.183 0.398 0.267
表3 实验组感染性疾病合并血小板减少症患者治疗前后肝肾功能影响（±s）
组别 例数 活化部分凝血活酶时间(s) ALT(U/L) C反应蛋白μmol/L） 总胆红素(μmol/L)
治疗前 35 39 ± 7 39 ± 21 77 ± 35 19 ± 8
治疗后 35 40 ± 8 37 ± 18 876 ± 33 22 ± 8
t值 ? 0.697 0.478 0.110 1.634
P值 ? 0.121 0.145 0.387 0.138
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