重组人可溶性血栓调节蛋白治疗脓毒症合并弥散性血管内凝血临床疗效的Meta分析

doi:10.3877/cma.j.issn.1674-6880.2023.02.006

目的

系统评价重组人可溶性血栓调节蛋白（rhTM）治疗脓毒症合并弥散性血管内凝血（DIC）的临床疗效。

方法

检索PubMed、Embase、Cochrane Library、Sinomed、中国知网、万方数据库、维普数据库自建库至2022年7月发表的关于rhTM治疗脓毒症合并DIC患者的临床研究。对照组使用肝素、安慰剂治疗或空白对照；试验组使用rhTM治疗。由2名研究人员独立筛选文献、数据提取及质量评价后，使用RevMan 5.4软件进行Meta分析。

结果

共纳入7篇文献、合计1 913例患者，其中试验组937例，对照组976例。Meta分析显示，试验组患者28 d病死率显著低于对照组[相对危险度（RR）= 0.83，95%置信区间（CI）（0.71，0.97），Z = 2.40，P = 0.02]，DIC缓解率显著高于对照组[RR = 1.34，95%CI（1.09，1.66），Z = 2.75，P = 0.006]，而两组患者间不良事件数比较差异没有统计学意义[RR = 1.01，95%CI（0.58，1.75），Z = 0.02，P = 0.98]。

结论

rhTM能够降低脓毒症合并DIC患者的28 d病死率，提高DIC缓解率，且不会增加不良事件的发生，具有较好的临床使用价值。

关键词: 脓毒症, 弥散性血管内凝血, 血栓调节蛋白, Meta分析

Objective

To systematically evaluate the clinical efficacy of recombinant human soluble thrombomodulin (rhTM) in sepsis-induced disseminated intravascular coagulation (DIC).

Methods

Clinical studies on rhTM for the treatment of sepsis-induced DIC were searched in PubMed, Embase, Cochrane Library, Sinomed, China National Knowledge Infrastructure, Wanfang database and VIP database published up to July 2022. The control group was treated with heparin, placebo or blank control. The experimental group was treated with rhTM. Two reviewers independently screened articles, extracted data and evaluated the quality of included studies. The RevMan 5.4 software was used to perform meta-analysis.

Results

Seven clinical studies involving 1 913 patients were included, with 935 patients in the experimental group and 978 patients in the control group. Meta-analysis showed that the 28-day mortality in the experimental group was much lower than that in the control group [relative risk (RR) = 0.83, 95% confidence interval (CI) (0.71, 0.97), Z = 2.40, P = 0.02], the remission rate of DIC was much higher [RR = 1.34, 95%CI (1.09, 1.66), Z = 2.75, P = 0.006], and no significant difference in the number of adverse events was found between the two groups [RR = 1.01, 95%CI (0.58, 1.75), Z = 0.02, P = 0.98].

Conclusion

rhTM can reduce the 28-day mortality and improve the remission rate of DIC in patients with sepsis-induced DIC, and it does not increase the occurrence of adverse events, showing good clinical application value.

Key words: Sepsis, Disseminated intravascular coagulation, Thrombomodulin, Meta-analysis

图1 纳入研究的偏倚风险评估图注：a图为偏倚风险构成比；b图为各纳入研究的偏倚风险

表1 纳入研究的基本信息

第一作者	例数		干预措施		随访时间（d）	观察指标
第一作者	试验组	对照组	试验组	对照组	随访时间（d）	观察指标
Aikawa等^[16]	42	38	0.06 mg·kg^-1·d^-1持续6 d	肝素（8 U·kg^-1·h^-1）	28	①②③
Ogawa等^[17]	41	45	0.06 mg·kg^-1·d^-1持续6 d	空白对照	90	①③
Vincent等^[18]	370	371	0.06 mg·kg^-1·d^-1持续6 d	安慰剂	28	①②③
Vincent等^[19]	395	405	0.06 mg·kg^-1·d^-1持续6 d	安慰剂	90	①
Yamakawa等^[20]	20	45	0.06 mg·kg^-1·d^-1持续6 d	空白对照	28	①③
Hagiwara等^[21]	47	45	0.06 mg·kg^-1·d^-1持续6 d	空白对照	90	①②③
Ushizawa等^[22]	22	27	0.06 mg·kg^-1·d^-1持续6 d	安慰剂	28	①

表1 纳入研究的基本信息

第一作者	例数		干预措施		随访时间（d）	观察指标
第一作者	试验组	对照组	试验组	对照组	随访时间（d）	观察指标
Aikawa等^[16]	42	38	0.06 mg·kg^-1·d^-1持续6 d	肝素（8 U·kg^-1·h^-1）	28	①②③
Ogawa等^[17]	41	45	0.06 mg·kg^-1·d^-1持续6 d	空白对照	90	①③
Vincent等^[18]	370	371	0.06 mg·kg^-1·d^-1持续6 d	安慰剂	28	①②③
Vincent等^[19]	395	405	0.06 mg·kg^-1·d^-1持续6 d	安慰剂	90	①
Yamakawa等^[20]	20	45	0.06 mg·kg^-1·d^-1持续6 d	空白对照	28	①③
Hagiwara等^[21]	47	45	0.06 mg·kg^-1·d^-1持续6 d	空白对照	90	①②③
Ushizawa等^[22]	22	27	0.06 mg·kg^-1·d^-1持续6 d	安慰剂	28	①

图2 rhTM对脓毒症合并DIC患者28 d病死率影响的森林图注：rhTM.重组人可溶性血栓调节蛋白；DIC.弥漫性血管内凝血；RR.相对危险度；CI.置信区间；试验组予以rhTM治疗，对照组予以肝素、安慰剂治疗或空白对照

图3 rhTM对脓毒症合并DIC患者DIC缓解率影响的森林图注：rhTM.重组人可溶性血栓调节蛋白；DIC.弥漫性血管内凝血；RR.相对危险度；CI.置信区间；试验组予以rhTM治疗，对照组予以肝素、安慰剂治疗或空白对照

图4 rhTM对脓毒症合并DIC患者不良事件发生影响的森林图注：rhTM.重组人可溶性血栓调节蛋白；DIC.弥漫性血管内凝血；RR.相对危险度；CI.置信区间；试验组予以rhTM治疗，对照组予以肝素、安慰剂治疗或空白对照

图5 rhTM对脓毒症合并DIC患者28 d病死率影响的Meta分析文献发表偏倚漏斗图注：rhTM.重组人可溶性血栓调节蛋白；DIC.弥漫性血管内凝血；RR.相对危险度

1	Singer M, Deutschman CS, Seymour CW, et al. The third international consensus definitions for sepsis and septic shock (sepsis-3)[J]. JAMA, 2016, 315 (8): 801-810.
2	Rudd KE, Johnson SC, Agesa KM, et al. Global, regional, and national sepsis incidence and mortality, 1990-2017: analysis for the Global Burden of Disease Study[J]. Lancet, 2020, 395 (10219): 200-211.
3	Xie J, Wang H, Kang Y, et al. The epidemiology of sepsis in Chinese ICUs: a national cross-sectional survey[J]. Crit Care Med, 2020, 48 (3): e209-e218.
4	中华医学会急诊医学分会，中华危重病急救医学杂志编辑委员会，脓毒症并发弥散性血管内凝血诊治急诊专家共识专家组.脓毒症并发弥散性血管内凝血诊治急诊专家共识[J].实用检验医师杂志，2017，9（3）：129-132.
5	宋立成,韩志海.脓毒症相关凝血功能障碍机制及治疗的研究进展[J/CD].中华危重症医学杂志（电子版），2017，10（2）：125-129.
6	Iba T, Nagaoka I, Boulat M. The anticoagulant therapy for sepsis-associated disseminated intravascular coagulation[J]. Thromb Res, 2013, 131 (5): 383-389.
7	Dellinger RP, Levy MM, Rhodes A, et al. Surviving sepsis campaign: international guidelines for management of severe sepsis and septic shock, 2012[J]. Intensive Care Med, 2013, 39 (2): 165-228.
8	Rhodes A, Evans LE, Alhazzani W, et al. Surviving sepsis campaign: international guidelines for management of sepsis and septic shock: 2016[J]. Intensive Care Med, 2017, 43 (3): 304-377.
9	Ito T, Thachil J, Asakura H, et al. Thrombomodulin in disseminated intravascular coagulation and other critical conditions-a multi-faceted anticoagulant protein with therapeutic potential[J]. Crit Care, 2019, 23 (1): 280.
10	Levi M, Van Der Poll T. Thrombomodulin in sepsis[J]. Minerva Anestesiol, 2013, 79 (3): 294-298.
11	Yamakawa K, Aihara M, Ogura H, et al. Recombinant human soluble thrombomodulin in severe sepsis: a systematic review and meta-analysis[J]. J Thromb Haemost, 2015, 13 (4): 508-519.
12	Bone RC, Balk RA, Cerra FB, et al. Definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis. The ACCP/SCCM Consensus Conference Committee. American College of Chest Physicians/Society of Critical Care Medicine[J]. Chest, 1992, 101 (6): 1644-1655.
13	Kobayashi N, Maekawa T, Takada M, et al. Criteria for diagnosis of DIC based on the analysis of clinical and laboratory findings in 345 DIC patients collected by the Research Committee on DIC in Japan[J]. Bibl Haematol, 1983 (49): 265-275.
14	Taylor FB Jr, Toh CH, Hoots WK, et al. Towards definition, clinical and laboratory criteria, and a scoring system for disseminated intravascular coagulation[J]. Thromb Haemost, 2001, 86 (5): 1327-1330.
15	Gando S, Iba T, Eguchi Y, et al. A multicenter, prospective validation of disseminated intravascular coagulation diagnostic criteria for critically ill patients: comparing current criteria[J]. Crit Care Med, 2006, 34 (3): 625-631.
16	Aikawa N, Shimazaki S, Yamamoto Y, et al. Thrombomodulin alfa in the treatment of infectious patients complicated by disseminated intravascular coagulation: subanalysis from the phase 3 trial[J]. Shock, 2011, 35 (4): 349-354.
17	Ogawa Y, Yamakawa K, Ogura H, et al. Recombinant human soluble thrombomodulin improves mortality and respiratory dysfunction in patients with severe sepsis[J]. J Trauma Acute Care Surg, 2012, 72 (5): 1150-1157.
18	Vincent JL, Ramesh MK, Ernest D, et al. A randomized, double-blind, placebo-controlled, phase 2b study to evaluate the safety and efficacy of recombinant human soluble thrombomodulin, ART-123, in patients with sepsis and suspected disseminated intravascular coagulation[J]. Crit Care Med, 2013, 41 (9): 2069-2079.
19	Vincent JL, Francois B, Zabolotskikh I, et al. Effect of a recombinant human soluble thrombomodulin on mortality in patients with sepsis-associated coagulopathy: the SCARLET randomized clinical trial[J]. JAMA, 2019, 321 (20): 1993-2002.
20	Yamakawa K, Fujimi S, Mohri T, et al. Treatment effects of recombinant human soluble thrombomodulin in patients with severe sepsis: a historical control study[J]. Crit Care, 2011, 15 (3): R123.
21	Hagiwara A, Tanaka N, Uemura T, et al. Can recombinant human thrombomodulin increase survival among patients with severe septic-induced disseminated intravascular coagulation: a single-centre, open-label, randomised controlled trial[J]. BMJ Open, 2016, 6 (12): e12850.
22	Ushizawa H, Isotani E, Sera T, et al. Randomized controlled trial of novel recombinant human soluble thrombomodulin for sepsis with DIC patients in Japan[J]. Crit Care Med, 2011, 39 (12): 108.
23	刘小荣.儿童血栓性微血管病的诊断及治疗进展[J].中华实用儿科临床杂志，2016，31（17）：1292-1295.
24	Thompson EA, Salem HH. Inhibition by human thrombomodulin of factor Xa-mediated cleavage of prothrombin[J]. J Clin Invest, 1986, 78 (1): 13-17.
25	Abeyama K, Stern DM, Ito Y, et al. The N-terminal domain of thrombomodulin sequesters high-mobility group-B1 protein, a novel antiinflammatory mechanism[J]. J Clin Invest, 2005, 115 (5): 1267-1274.
26	Nagato M, Okamoto K, Abe Y, et al. Recombinant human soluble thrombomodulin decreases the plasma high-mobility group box-1 protein levels, whereas improving the acute liver injury and survival rates in experimental endotoxemia[J]. Crit Care Med, 2009, 37 (7): 2181-2186.
27	Suzuki K, Kusumoto H, Deyashiki Y, et al. Structure and expression of human thrombomodulin, a thrombin receptor on endothelium acting as a cofactor for protein C activation[J]. EMBO J, 1987, 6 (7): 1891-1897.
28	Mohri M, Sugimoto E, Sata M, et al. The inhibitory effect of recombinant human soluble thrombomodulin on initiation and extension of coagulation-a comparison with other anticoagulants[J]. Thromb Haemost, 1999, 82 (6): 1687-1693.
29	Umemura Y, Yamakawa K, Ogura H, et al. Efficacy and safety of anticoagulant therapy in three specific populations with sepsis: a meta-analysis of randomized controlled trials[J]. J Thromb Haemost, 2016, 14 (3): 518-530.
30	Moll S, Lindley C, Pescatore S, et al. Phase Ⅰ study of a novel recombinant human soluble thrombomodulin, ART-123[J]. J Thromb Haemost, 2004, 2 (10): 1745-1751.
31	Tsuruta K, Yamada Y, Serada M, et al. Model-based analysis of covariate effects on population pharmacokinetics of thrombomodulin alfa in patients with disseminated intravascular coagulation and normal subjects[J]. J Clin Pharmacol, 2011, 51 (9): 1276-1285.
32	Yamakawa K, Murao S, Aihara M. Recombinant human soluble thrombomodulin in sepsis-induced coagulopathy: an updated systematic review and meta-analysis[J]. Thromb Haemost, 2019, 119 (1): 56-65.
33	高洁，靳英辉，吴荷宁，等.脓毒症相关弥漫性血管内凝血患者使用重组人可溶性血栓调节蛋白疗效的Meta分析[J/CD].中华危重症医学杂志（电子版），2015，8（6）：361-365.
34	Saito H, Maruyama I, Shimazaki S, et al. Efficacy and safety of recombinant human soluble thrombomodulin (ART-123) in disseminated intravascular coagulation: results of a phase Ⅲ, randomized, double-blind clinical trial[J]. J Thromb Haemost, 2007, 5 (1): 31-41.

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Clinical efficacy of recombinant human soluble thrombomodulin in sepsis-induced disseminated intravascular coagulation: a meta-analysis

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Clinical efficacy of recombinant human soluble thrombomodulin in sepsis-induced disseminated intravascular coagulation: a meta-analysis