【作者】 丁殿柱；

【导师】 吕柏南；

【作者基本信息】 河北医科大学 ， 外科学， 2012， 硕士

【摘要】 目的：静脉血栓栓塞症（VTE）是胃肠道肿瘤术后一个重要并发症，它的预防越来越引起外科医师的重视，其中应用低分子量肝素（LMWH）预防已逐渐被外科医师所接受，但用药剂量及方法尚没有达成共识。目前我国尚没有关于VTE预防药物剂量的前瞻性研究，尚缺乏足够的循证医学证据。抗-Xa活性测定可以有效的监测LMWH活性。本研究采用发色底物法对两种不同的低分子量肝素钠给药方案抗-Xa活性进行测定，观察不同给药方案对VTE预防的安全性和有效性，进而为胃肠肿瘤术后VTE预防制订个体化方案提供理论依据。方法：选取我院普外二科在2010年10月-2011年12月间，胃肠道肿瘤术后VTE风险高危患者40例，其中男性24例，女性16例，平均年龄55.9岁（34~76岁）。排除标准：（1）年龄<18岁或>80岁;（2）病情危重，或伴有肝肾功能异常（谷丙转氨酶（ALT）、谷草转氨酶（AST）或肌酐、尿素氮高于正常水平）等;（3）有抗凝禁忌证,如活动性溃疡、活动性出血、感染性心内膜炎、恶性高血压[收缩压(SBP)>200mm Hg,或舒张压(DBP)>120mmHg]、3个月内新发脑出血;（4）凝血功能异常。将40例患者分为2组，其中A组16例、B组24例，于术后12小时（如果术后12小时引流液为浓血性且大于200毫升，那么LMWH开始时间可延长至术后24小时）排除抗凝禁忌后分别给予LMWH5000IU皮下注射24小时一次、LMWH5000IU皮下注射12小时一次预防VTE，两组病人均于术后第1、2、7天，在用药3.5h后采血，将所采血样2.7mL迅速注入预先放有0.109mol枸橼酸钠3mL的真空试管内,室温下3000r/min离心15min,用移液管将血浆移至试管中,-80℃保存样本。术后第1-7天每日查体，检查有无VTE症状或体征（沿深静脉走行区压痛、下肢肿胀、Homans征、胸闷、心慌、胸痛、咯血）。如出现上述症状，则随时化验血浆D-二聚体，如未出现上述症状，则于术后第7天化验血浆D-二聚体。(D-二聚体≤300ug/L,排除VTE；D-二聚体>300ug/L，根据患者症状继续检查双下肢深静脉超声或血气分析，必要时查肺动脉螺旋CT（肺动脉CTA)。术后1-7天随时观察有无出血并发症并监测血小板数目。终止事件：（1）任何出血性并发症，如血肿、腹腔出血；（2）出现肝素诱发的血小板减少症（HIT）；（3）出现经深静脉超声证实下肢深静脉血栓（DVT）或经肺动脉CTA证实肺动脉栓塞（PE）。终止实验，但继续给予相应治疗；（4）出现低分子量肝素过敏。最后所有标本用发色底物法测定抗-Xa活性，应用低分子量肝素钠3.5小时后推荐抗Xa因子活性范围为0.5-1.0IU/mL。结果：1.40例患者中，A组有一例患者于术后第7天凌晨出现上消化道出血，考虑为应激性溃疡，予以终止实验。经有效抑酸、止血、输血等治疗后出血停止，病情平稳后顺利出院。该病例为胃癌患者，肿瘤分期T2N0M0，手术方式D2胃癌根治、毕Ⅱ式吻合术，LMWH应用方法：5000IU皮下注射12小时一次。2.术后72小时引流液：两组均为淡血性引流液，A组为（96.69±31.99）mL，B组为（87.96±24.74）mL，两组比较无统计学差异（P>0.05）。剔除消化道出血病例后，两组均无其他并发症，无HIT。3.术后血浆D-二聚体含量：A组为（606.78±276.47）ug/L，B组为(621.25±226.85) ug/L,两组比较无统计学差异（P>0.05）。其中A组有93.7%的患者血浆D-二聚体含量高于300ug/L，B组中有82.6%的患者血浆D-二聚体含量高于300ug/L，两组比较无统计学差异（P>0.05）。两组患者经临床观察及辅助检查确定均未发生VTE。4.术后抗-Xa活性监测结果：第一天A组anti-FXa:(0.66±0.14)IU/mL； B组anti-FXa:(0.69±0.14)IU/mL；第二天A组anti-FXa:(0.68±0.14)IU/mL；B组anti-FXa:(0.69±0.07)IU/mL；第七天A组anti-FXa:(0.70±0.11)IU/mL； B组anti-FXa:(0.73±0.10)IU/mL。均在推荐血药浓度范围0.5-1.0IU/mL之间。两组总体比较无统计学差异（F>0.05），各组间比较均无明显统计学差异（F>0.05）。5.术后第一天A组有95.65%抗-Xa活性值达到有效抗凝（>0.5IU/ml），有一例抗-Xa活性超过1.0IU/ml，但未发生出血并发症，B组有87.50%病例抗-Xa活性值达到有效抗凝（>0.50IU/ml），均未超过1.0IU/ml。两组抗凝有效率比较无统计学差异（P>0.05）。术后第二天A组有95.65%抗-Xa活性值达到有效抗凝（>0.50IU/ml），B组有93.75%抗-Xa活性值达到有效抗凝（>0.50IU/ml），两组抗凝有效率比较无统计学差异（P>0.05）。两组均无超过1.0IU/ml病例。术后第七天两组抗-Xa活性值均达到有效抗凝（>0.5IU/mL），A组有一例抗-Xa活性超过1.0IU/ml，但未发生出血并发症。结论：两种用药方案均可在用药后3.5小时达到有效抗凝强度，随着用药时间的延长（术后第7天），低分子量肝素并无明显累计效应。应用LMWH5000IU皮下注射24小时一次可以安全并有效的预防胃肠道肿瘤术后VTE，应用LMWH5000IU皮下注射12小时一次同样可有效的预防胃肠道肿瘤术后VTE，但似乎增加了出血并发症风险。胃肠道肿瘤术后7天内监测血浆D-二聚体对VTE监测价值不大。更多还原

【Abstract】 Object:venous thromboembolism(VTE) is an importantcomplication after gastrointestinal tumor surgery, surgerns are payingmore and more attention on its prevention. And the way of usinglow-molecular-weight heparin (LMWH) to prevent VTE is graduallyaccepted. But the dosage and method of the drug has not come to thecommon view. At present, there are no prospective researches about thedosage of drug on VTE prophylaxis in our country yet, and also there isnot enough evidence. The determination of anti-Factor Xa can effectivelymonitor the activity of LMWH。This research is to monitor the activity ofanti-Factor Xa of two different dosage regimen by chromogenic substrateassay，and at the same time, we observe the safety and efficacy of VTEprophylaxis by different dosage regimen. So that we would provide someevidence based proof for VTE prevention after gastrointestinal tumorsurgeries.Methods:Randomly selected October2010to December2011postoperative patients who are at high or the highest risk of VTE40casesfrom gastrointestinal surgery in our hospital, which include24male casesand16female cases, is at a average age of55.9years (34~76years).Exclusion criteria:1.Younger than18years or older than80years;2.Seriously ill, or hepatic insufficiency or renalinsufficiency(Aspartate-aminotransferase (ALT) orAlanine-aminotransferase (AST) or creatinine or urea nitrogen is higherthan normal level);3.Anticoagulation contraindications, for example,active peptic ulcer disease, active hemorrhage, Infective endocarditis,accelerated hypertension [systolic pressure (SBP)>200mmHg or diastolic pressure (DBP)>120mmHg], cerebral hemorrhage with thepast3months;4.Blood coagulation disorders.40cases were randomlydivided into2groups,16cases in group A and24cases in group B. Allthe patients were given the LMWH prophylaxis for VTE12hours afteroperation(if the volume of abdominal drainage exceed200mL12hoursafter operation and was strong bloody ascites, then the start time could beextended to24hours after operation) after eliminating anticoagulationcontraindications. Group A were giver LMWH5000IU per24hours andgroup B wer given LMWH5000IU per12hours. All the patients’ bloodsamples were collected at the first day、second day and seventh day afteroperation,3.5hours after receiving LMWH. The2.7mL blood sampleswere immediately inject into3mL vacuum test tubes which contained0.109mol sodium citrate. and then centrifuged15minutes at the speed of3000r/min at the room temperatures, and then transfer the plasma toanother tube with pipettes. All the samples were stored at the lowtemperature of-80℃。We checked every case from the first day toseventh day after operation, checked whether there was tenderness alongthe deep vein, whether the legs were swelling, whether HomansSyndrome was positive, whether the patients had the symptom ofdyspnea、palpitation、chest pain or hemoptysis. If these symtoms appeared,took the d-dimer test immediately, if they did’t appeared, took thed-dimer test at the seventh day after operation［.if d-dimer≤300ug/L, VTEexcluded; if d-dimer>300ug/L， lower limb compression venousultrasonography（CUS） or arterial blood gas analysis(ABG) would betaken, and pulmonary artery CT would also be taken if necessarily］.Thecomplication of haemorrhage and platelet count were strictly monitored.Termination events:(1)any hemorrhagic complications, such as hematoma,abdominal bleeding and so on；（2） hepain inducedthrombocytopenia(HIT)；（3）deep vein thrombosis(DVT) confirmed byCUS and pulmonary embolism(PE) by pulmonary artery CT, the researchwould be stopped, and the standard treatment would be given.(4)allergy to LMWH. Finally, all blood samples were detected anti-FXa bychromogenic substrate assay. The recommended anti-FXa of3.5hoursafter injection was0.5-1.0IU/mL.Result:1In40cases,1case in group A suffered upper gastrointestinalhemorrhage, which was considered to be stress ulcer. The research wasimmediately stopped. This patient was cured after effective treatment, anddischarged well. This case was a gastric cancer patient, which tumorstaging was T2N0M0, and did the operation of standard D2gastrectomywith the anastomosis of Billroth Ⅱ. Therapeutic schedule：LMWH5000IU subcutaneous injection per12hours.2Abdominal drainage volume of72hours after operation: group Awas (96.69±31.99）mL，group B was (87.96±24.74）mL. The differencesbetween the two groups had no statistical significance(P>0.05). Afterrejecting the case of alimentary tract hemorrhage, there were no othercomplications.3D-dimer results: group A was（606.78±276.47）ug/L, group B was(621.25±226.85) ug/L, with no significant statistical difference. Therewere15cases (93.7%)in group A whose d-dimer was higher than300ug/L, and19cases (82.6%)in group B. There was no significantstatistical difference about the constituent ratio of twogroups(P>0.05).There was no VTE cases in this whole research.4Monitoring result of anti-FXa: in the first day, group A was(0.66±0.14)IU/mL, group B was (0.69±0.14)IU/mL; in the second day,group A was (0.68±0.14)IU/mL, group B was (0.69±0.07)IU/mL; in theseventh day, group A was (0.70±0.11)IU/mL, group B was(0.73±0.10)IU/mL. All the result was between0.5and1.0IU/mL whichwas the recommended blood concentration。There was no significantstatistical difference with two groups.5In the first day after operation, anticoagulation efficient of group Awas87.50%(14/16), with no cases’ anti-FXa greater than1.0IU/mL. Anticoagulation efficient of group B was95.65%(22/24),with one case’santi-FXa greater than1.0IU/mL, but with no bleeding complicationshappened to him. There was no significant statistical difference ofanticoagulation efficiency between two groups(P<0.05). In the secondday after operation, anticoagulation efficient of group A was93.75%(15/16), with no cases’ anti-FXa greater than1.0IU/mL.Anticoagulation efficient of group B was95.65%(22/24),with no case’santi-FXa greater than1.0IU/mL.There was no significant statisticaldifference of anticoagulation efficiency between two groups. In theseventh day, all the cases of two groups had achieved the effectiveanticoagulation, with one case’s anti-FXa greater than1.0IU/ml in groupA, but with no bleeding complications.Conclusion:Both of two regimens could achieve the effective anticoagulation3.5hours after injection, and with treatment’s going on until the seventhday after operation, there was no obvious pharmacodynamicaccumulation. The regimen of LMWH subcutaneous injected per24hours could prevent perioperative VTE effectively and safely. Theregimen of LMWH subcutaneous injected per12hours could also preventperioperative VTE effectively, but it may also increase the risk ofbleeding complications. It make no sense to monitor plasma d-dimer in7days after gastrointestinal tumor surgery.更多还原