应用他克莫司治疗的肝移植术后患者凝血功能变化及意义

临床研究应用他克莫司治疗的肝移植术后患者凝血功能变化及意义

徐长志 林维真 李晓杰 胡波

目的 探讨应用他克莫司免疫治疗的肝移植患者术后凝血功能的变化及意义。方法 【摘要】回顾性分析2012年5月至2014年12月在中山大学附属第三医院行肝移植治疗的63例患者临床资料。其中男51例，女12例；平均年龄（45±15）岁。所有患者均签署知情同意书，符合医学伦理学规定。采用他克莫司+吗替麦考酚酯+肾上腺皮质激素三联用药方案。于术前、术后当天、术后1～5 d测定患者PT、血浆纤维蛋白原（Fib）、活化部分凝血活酶时间（APTT）、凝血酶时间（TT）和Plt。检测数×109/L、×109/L，术后1～5 d分别为（73±21）据的比较采用t检验。结果 患者术前平均Plt为（104±37）

×109/L、×109/L、×109/L，×109/L、（64±20）（50±17）（52±17）与术前比较，差异有统计学意义（60±19）

P<0.05）。其他凝血功能检测指标（PT、Fib、APTT、TT）较（t=－3.768，－4.462,－4.584，－2.048,－2.934；术前逐渐改善。结论 肝移植患者术后凝血功能的恢复过程中可能会发生持续性Plt降低，应用他克莫司时应警惕血小板变化。

血小板； 他克莫司结合蛋白质类【关键词】 肝移植；

Changes of coagulation function in patients when using tacrolimus after liver transplantation and its significance Xu Changzhi, Lin Weizhen, Li Xiaojie, Hu Bo. Department of Laboratory, Lingnan Hospital, the Third Affiliated Hospital of Sun Yat-sen University, Guangzhou 510630, ChinaCorresponding author:Hu Bo,Email:hubo96073@hotmail.com

【Abstract】 Objective To investigate the changes of coagulation function in patients receiving

tacrolimus immunotherapy after liver transplantation and its significance. Methods Clinical data of 63 patients undergoing liver transplantation in the Third Affiliated Hospital of Sun Yat-sen University between May 2012 and December 2014 were retrospectively studied. Among the 63 patients, 51 were males and 12 were females with the average of (45±15) years old. The informed consents of all patients were obtained and the local ethical committee approval had been received. The triple medication regimen of tacrolimus + mycophenolate mofetil + adrenocortical hormone was utilized. Prothrombin time (PT), fibrinogen (Fib), activated partial thromboplastin time (APTT), thrombin time (TT) and platelets count (Plt) were tested before surgery, on the day of surgery and on 1-5 d after surgery. The comparisons of the data were conducted using t test. Results The average Plt before surgery was (104±37)×109/L and the average Plt on 1-5 d after surgery was respectively (73±21)×109/L, (60±19)×109/L, (64±20)×109/L, (50±17)×109/L and (52±17)×109/L, and significant difference was observed (t=－3.768, －4.462, －4.584, －2.048, －2.934; P<0.05). The other coagulation function indexes (PT, Fib, APTT and TT) were gradually improved when compared with those before surgery.

DOI : 10.3877/cma.j.issn.2095-3232.2015.05.013基金项目： 广东省自然科学基金（2014A030313095）

作者单位： 510630 广州，中山大学附属第三医院岭南医院检验科通讯作者：胡波，Email：hubo96073@hotmail.com

312

中华肝脏外科手术学电子杂志2015年10月第4卷第5期 Chin J Hepat Surg(Electronic Edition), October 2015, Vol. 4, No. 5Conclusion During the recovery of coagulation function after liver transplantation, continuous Plt decrease may occur. Plt changes should be on alert when tacrolimus is used.

【Key words】 Liver transplantation; Blood platelets; Tacrolimus binding proteins

肝移植是终末期肝病唯一有效的治疗手段，围手术期他克莫司等免疫抑制剂的广泛应用显著提高了移植器官的存活率

[1-3]

thromboplasting time，APTT）、凝血酶时间（thrombin time，TT）和Plt。

三、统计学方法

应用GraphPad Prism 5统计软件进行数据x分析。患者凝血功能检测数据以 s 表示，比较 ±

采用t检验。以P＜0.05为差异有统计学意义。

。最新研究发现

他克莫司对患者的凝血功能有一定的影响，但应用他克莫司肝移植患者术后凝血功能变化规律尚不清楚[4-6]。

资料与方法

一、一般资料

回顾性研究2012年5月至2014年12月在中山大学附属第三医院肝移植中心行肝移植治疗的63例患者临床资料。纳入标准：（ 1）行改良背驮式原位肝移植术；（ 2）采用他克莫司+吗替麦考酚酯+肾上腺皮质激素三联用药方案

[5-7]

结 果

术后当天患者的PT、Fib、APTT、TT和Plt检

测数据与术前相比差异无统计学意义（t=－0.379，P＞0.05）；术后1～5 d0.575，－0.912，－0.569，－0.493；患者PT、Fib、APTT、TT和Plt数据与术前相比差异t=－6.401，具有统计学意义（1 d：2.206，－2.774， t=－5.642，－3.048，－3.768；2 d：3.857，－3.341， t=－4.901，－4.816，－4.462；3 d：3.857，－3.341， t=－6.453，－3.725，－4.584；4 d：4.702，－3.848， t=－6.429，－4.203，－2.048；5 d：3.750，－3.934， P＜0.05；－5.478，－2.934；表1）。

；

（3）术后1周内他克莫司的血浓度谷值维持在（ 1）行肝肾联合7.08 ng/ml左右[8-10]。排除标准：

移植术者；（2）接受再次肝移植者；（ 3）术后他克莫司血药浓度不稳定者。其中男51例，女12例；

平均年龄（45±15）岁。原发病：肝细胞癌24例，肝硬化34例，肝豆状核变性、多囊肝、先天性胆道先天性胆道扩张和胆管癌患者各1例。所闭锁、

有患者均签署由医院伦理委员会批准的患者知情同意书，符合医学伦理学规定。

二、研究方法

术前、术后当天、术后1～5 d采集患者静脉血3 ml,采用HITACHI-7170A全自动生化分析仪（日本日立公司）测定PT、血浆纤维蛋白原（fibrinogen, Fib）、活化部分凝血活酶时间（activeated partial

表1

时间

手术前术后当天术后1 d术后2 d术后3 d术后4 d术后5 d

PT（s）26±824±816±416±517±4 15±4 15±4

讨 论

肝移植患者术前存在不同程度的凝血功能障碍，无肝期、大量输血等均会对患者的凝血功能造成影响，新肝植入后凝血功能恢复为新肝发挥功能的重要指标，直接影响患者术后恢复。因此，术后监测凝血功能非常重要

[11]

。本研究发现

肝移植患者PT、Fib、APTT和TT在术后5 d内逐说明移植肝在受者体内步恢复至接近正常水平，

发挥正常生理功能，逐渐合成各种凝血因子。

肝移植前后患者的凝血功能（x）Fib（g/L）1.4±0.41.6±0.51.9±0.6 2.5±0.72.4±0.72.4±0.82.2±0.6

APTT（s）55±1949±1538±10 37±936±1134±933±8

TT（s）23±622±521±6 19±618±317±318±3

Plt（109/L）104±37103±3773±21 60±1964±2050±1752±17

注：Fib为血浆纤维蛋白原，APTT为活化部分凝血活酶时间，TT为凝血酶时间

中华肝脏外科手术学电子杂志2015年10月第4卷第5期 Chin J Hepat Surg(Electronic Edition), October 2015, Vol. 4, No. 5313

本研究发现，患者的Plt在术后1～5 d逐渐下降，凝血功能受影响。研究认为肝移植术后2周是肝动脉内血栓形成的高危期，可应用低分子量肝素维持适度的低凝状态，以降低肝动脉血栓的发生率，且研究证实低分子量肝素不会引起Plt降低，推测本研究中肝移植患者术后Plt减低的发生可能与他克莫司的应用有关[12-13]。他克莫司是一种钙调磷酸酶抑制剂，主要通过抑制钙调磷酸酶的去磷酸活性，抑制Ｔ细胞活化，发挥免疫抑制作用

[14-16]

pediatric liver transplantation:a single-center experience[J]. Pediatr Transplant, 2014, 18 (1):58-63.[9]

Xu W, Ling P, Zhang T. Toward immunosuppressive effects on liver transplantation in rat model: tacrolimus loaded poly(ethylene glycol)-poly(D,L-lactide) nanoparticle with longer survival time[J]. Int J Pharm, 2014, 460 (1/2):173-180.[10]

Liu YY, Li C, Cui Z, et al. The effect of ABCB1 C3435T polymorphism on pharmacokinetics of tacrolimus in liver transplantation: a meta-analysis[J]. Gene, 2013, 531(2):476-488.[11]

Yoshida EM, Lilly LB, Marotta PJ, et al. Canadian national retrospective chart review comparing the long term effect of cyclosporine vs. Tacrolimus on clinical outcomes in patients with post-liver transplantation hepatitis C virus infection[J]. Ann Hepatol, 2013, 12 (2):282-293.[12]

De Simone P, Beckebaum S, Koneru B, et al. Everolimus with reduced tacrolimus in liver transplantation[J]. Am J Transplant, 2013, 13 (5):1373-1374.[13]

Rao V, Haywood S, Abecassis M, et al. A non-induction renal sparing approach after liver transplantation: high dose mycophenolate mofetil with delayed, low-dose tacrolimus[J]. Transplant Proc, 2013, 45 (1):320-322.[14]

Guy-Viterbo V, Scohy A, Verbeeck RK, et al. Population pharmacokinetic analysis of tacrolimus in the first year after pediatric liver transplantation[J]. Eur J Clin Pharmacol, 2013, 69 (8):1533-1542.[15]

Pratschke S, Eder M, Heise M, et al. Protocol TOP-Study (tacrolimus organ perfusion): a prospective randomized multicenter trial to reduce ischemia reperfusion injury in transplantation of marginal liver grafts with an ex vivo tacrolimus perfusion[J]. Transplant Res, 2013, 2 (1):3.[16]

Tempestilli M, Di Stasio E, Basile MR, et al. Low plasma concentrations of albumin influence the affinity column-mediated immunoassay method for the measurement of tacrolimus in blood during the early period after liver transplantation[J]. Ther Drug Monit, 2013, 35 (1):96-100.[17]

Li C, Wen TF, Yan LN, et al. Risk factors for abdominal bleeding after living-donor liver transplant[J]. Exp Clin Transplant, 2014, 12 (5):424-428.[18]

Takada Y, Kaido T, Asonuma K, et al. Randomized, multicenter trial comparing tacrolimus plus mycophenolate mofetil to tacrolimus plus steroids in hepatitis C virus-positive recipients of living donor liver transplantation[J]. Liver Transpl, 2013, 19 (8):896-906.[19]

Nacif LS, David AI, Pinheiro RS, et al. An analysis of tacrolimus-related complications in the first 30 days after liver transplantation[J]. Clinics, 2014, 69 (11):745-749.

（收稿日期：2015-07-09）

（本文编辑：郭宇

。

有文献报道他克莫司可能引起Plt的降低[17-19]。其确切机制尚不清楚，需要进一步大量研究证实。

综上所述，肝移植患者术后凝血功能的恢复过程中可能会发生持续性Plt降低，应用他克莫司时应警惕血小板变化。

参 考 文 献

[1]

Wang J, Xu M, Luo B. Chronic renal disease and reversible posterior leukoencephalopathy syndrome after liver transplantation[J]. West Indian Med J, 2013, 62 (9):869-872.[2]

Wimmer CD, Angele MK, Schwarz B, et al. Impact of cyclosporine versus tacrolimus on the incidence of de novo malignancy following liver transplantation: a single center experience with 609 patients[J]. Transpl Int, 2013, 26 (10):999-1006.[3]

Howell J, Sawhney R, Testro A, et al. Cyclosporine and tacrolimus have inhibitory effects on toll-like receptor signaling after liver transplantation[J]. Liver Transpl, 2013, 19 (10):1099-1107.[4]

Cardet JC, Boyce JA. Addition of mycophenolate mofetil to tacrolimus is associated with decreases in food-specific IgE levels in a pediatric patient with liver transplantation-associated food allergy[J]. J Allergy Clin Immunol Pract, 2013, 1 (1):104-106.[5]

Durand P, Debray D, Kolaci M, et al. Tacrolimus dose requirement in pediatric liver transplantation: influence of CYP3A5 gene polymorphism[J]. Pharmacogenomics, 2013, 14 (9):1017-1025.[6]

Weiler N, Thrun I, Eberlin M, et al. Tacrolimus effects and side effects after liver transplantation: is there a difference between immediate and extended release?[J]. Transplant Proc, 2013, 45 (6):2321-2325.[7]

Rojas LE, Herrero MJ, Boso V, et al. Meta-analysis and systematic review of the effect of the donor and recipient CYP3A5 6986A>G genotype on tacrolimus dose requirements in liver transplantation[J]. Pharmacogenet Genomics, 2013, 23 (10):509-517.[8]

Xie M, Rao W, Sun LY, et al. Tacrolimus-related seizure after

杨扬）

徐长志，林维真，李晓杰，等．应用他克莫司治疗的肝移植术后患者凝血功能变化及意义[J/CD]．中华肝脏外科手术学电子杂志，2015，4(5)：311-313.