血栓分子标志物在下肢骨折血栓中的诊断价值

刘卓超; 韩守江; 肖继龙

doi:10.12404/j.issn.1671-1815.2506014

科学技术与工程 ›› 2026, Vol. 26 ›› Issue (22) :9481-9486 DOI: 10.12404/j.issn.1671-1815.2506014

医药、卫生

血栓分子标志物在下肢骨折血栓中的诊断价值

刘卓超 ¹ ,
韩守江 ²^,^* ,
肖继龙 ³

作者信息 +

Diagnostic Value of Thrombus Molecular Markers in Thrombosis Following Lower Extremity Fractures

Author information +

文章历史 +

摘要

为观察下肢骨折患者术前及术后凝血酶-抗凝血酶复合物(thrombin-antithrombin complex, TAT)、纤溶酶-α₂抗纤溶酶复合物(plasmin-α₂-plasmin inhibitor complex, PIC)、组织型纤溶酶原激活物-纤溶酶原激活物抑制剂复合物(tissue plasminogen activator-plasminogen activator inhibitor complex, t-PAIC)和血栓调节蛋白(thrombomodulin, TM)水平变化,并分析其与术后静脉血栓栓塞症(venous thromboembolism, VTE)发生的关系。通过选取2025年1—7月在本院手术的100例下肢骨折患者,依据术后是否发生VTE分为非VTE组(76例)和VTE组(24例),检测两组术前、术后第1天及术后第3天的TAT、PIC、t-PAIC、TM以及纤维蛋白原(fibrinogen, FIB)、D-二聚体(D-dimer, D-D)水平,分析各指标与VTE的相关性,并通过多因素Logistic回归探讨术后VTE的危险因素,利用受试者工作特征曲线(receiver operating characteristic curve, ROC)评估血栓分子标志物对术后VTE的预测价值。结果表明:与非VTE组相比,VTE组的FIB、D-D水平均升高(P<0.05);VTE组术前、术后第1天及第3天的TAT、PIC、t-PAIC、TM水平亦均高于非VTE组(P<0.05)。相关性分析显示,TAT、PIC、t-PAIC、TM与VTE发生呈正相关(P<0.05)。多因素Logistic回归分析提示,FIB、D-D、TAT、PIC、t-PAIC、TM是影响下肢骨折术后VTE发生的主要因素(P<0.05)。ROC曲线分析表明,TAT、PIC、t-PAIC、TM联合检测对术后VTE具有较高的预测价值(P<0.05)。可见下肢骨折手术患者血栓分子标志物水平升高与VTE形成密切相关,联合检测这些指标对预测术后VTE发生具有较好的临床效果。

Abstract

In order to investigate the perioperative changes in the levels of TAT (thrombin-antithrombin complex), PIC (plasmin-α₂-plasmin inhibitor complex), t-PAIC (tissue plasminogen activator-plasminogen activator inhibitor complex), and TM (thrombomodulin) in patients with lower extremity fractures, and to analyze their relationship with the occurrence of postoperative VTE (venous thromboembolism), a study was conducted on 100 patients who underwent surgery between January and July 2025. The patients were divided into a non-VTE group (76 cases) and a VTE group (24 cases) based on whether VTE occurred postoperatively. The levels of TAT, PIC, t-PAIC, TM, as well as FIB (fibrinogen) and D-D (D-dimer), were measured preoperatively and on postoperative days 1 and 3 in both groups. Correlations between these indicators and VTE were analyzed, multivariate logistic regression was used to explore risk factors for postoperative VTE, and ROC (receiver operating characteristic) curve analysis was performed to assess the predictive value of these thrombotic molecular markers for postoperative VTE. The results show that compared with the non-VTE group, the levels of FIB and D-D are elevated in the VTE group (P<0.05). Additionally, the levels of TAT, PIC, t-PAIC, and TM in the VTE group are significantly higher than those in the non-VTE group preoperatively and on postoperative days 1 and 3 (P<0.05). Correlation analysis reveales that TAT, PIC, t-PAIC, and TM were positively correlated with the occurrence of VTE (P<0.05). Multivariate logistic regression analysis indicates that FIB, D-D, TAT, PIC, t-PAIC, and TM are the main factors influencing the occurrence of VTE after lower extremity fracture surgery (P<0.05). ROC curve analysis demonstrates that the combined detection of TAT, PIC, t-PAIC, and TM had a high predictive value for postoperative VTE (P<0.05). It is concluded that elevated levels of thrombotic molecular markers in patients undergoing lower extremity fracture surgery are closely related to VTE formation, and the detection of these markers is clinically effective for predicting the occurrence of postoperative VTE.

Graphical abstract

关键词

下肢骨折 / 血栓分子标志物 / 静脉血栓栓塞症 / 凝血酶-抗凝血酶复合物

Key words

lower limb fracture / thrombus molecular marker / venous thromboembolism / TAT

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刘卓超, 韩守江, 肖继龙. 血栓分子标志物在下肢骨折血栓中的诊断价值[J]. 科学技术与工程, 2026, 26(22): 9481-9486 DOI:10.12404/j.issn.1671-1815.2506014

LIU Zhuo-chao, HAN Shou-jiang, XIAO Ji-long. Diagnostic Value of Thrombus Molecular Markers in Thrombosis Following Lower Extremity Fractures[J]. Science Technology and Engineering, 2026, 26(22): 9481-9486 DOI:10.12404/j.issn.1671-1815.2506014

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下肢骨折在临床骨折类型中具有较高发病率,临床主要进行手术治疗,但手术创伤可激活凝血系统,造成血液凝结^[1]。手术本身作为一种创伤,术中肌肉牵拉、关节旋转、骨钻磨以及植入物的使用,均可能造成血管内皮损伤,暴露胶原蛋白和组织因子(tissue factor, TF),从而启动外源性凝血途径^[2]。内皮细胞、血小板和白细胞的激活,以及组织因子的表达和中性粒细胞胞外诱捕网(neutrophil extracellular traps,NETs)的形成,均促进凝血激活并捕获更多细胞(如红细胞),最终导致血栓形成和增长。术后长期卧床进一步加剧了静脉血流淤滞,静脉瓣膜袋内的血流缓慢且缺氧,形成一个高凝微环境,血栓可在2 h内于瓣膜尖端形成^[3]。尤其在麻醉和长期制动状态下,肌肉泵功能减弱,静脉回流减慢,部分氧压降低,进一步促进血栓形成。术后深静脉血栓形成(deep venous thrombosis,DVT)的总体发生率约为48%,其中约30%的病例在术前已存在,且88%的DVT为远端DVT。值得注意的是,股骨骨折患者的DVT风险更高,且手术延迟超过48 h会使DVT风险增加五倍,而肺栓塞的发生率约为0.3%^[4]。目前,D-二聚体是临床静脉血栓栓塞症(venous thromboembolism, VTE)筛查中应用最为广泛的指标,其敏感性可达 95% 以上,但特异性仅为 20%~40%,且易受炎症、感染、手术等多种因素干扰,临床诊断效能受限。因此,单一依赖 D-二聚体指标难以实现对 VTE 的精准预测。TAT、PIC、t-PAIC、TM血栓分子标志物,对血栓性疾病具有重要诊断与预测价值,在疾病早期识别、风险分层评估及治疗全程监测中均发挥关键作用。TAT可精准反映机体内凝血酶的浓度水平,PIC能够客观体现机体纤溶功能的强弱程度,t-PAIC、TM均可有效反映患者内皮功能的损伤程度及损伤水平,检测患者体内TAT、PIC、t-PAIC、TM,可用于血栓形成的判断^[5]。临床研究中涉及血栓分子标志物联合预测下肢骨折患者术后发生VTE的研究较少,基于此,现检测血栓分子标志物指标的水平,并探讨其对下肢骨折术后VTE发生的预测价值,为临床工作中预测下肢静脉血栓形成提供基础理论支撑。

1 资料与方法

1.1 一般资料

选取2025年1—7月在华北医疗健康集团峰峰总医院院手术的100例下肢骨折患者,根据手术后VTE发生情况分非VTE组76例VTE组24例。患者及家属均知情并签署同意书,且经华北医疗健康集团峰峰总医院医学伦理委员会审核批准,审批编号:2025B11。

纳入标准:①符合《中国骨科大手术静脉血栓栓塞症预防指南》^[6]中诊断标准;②经X线、CT检查确诊;③年龄≥ 18 岁, 连续住院时间≥ 5 d,并伴有创伤性下肢骨折的患者。下肢骨折包括髋部骨折、股骨干骨折、股骨远端骨折、髌骨骨折、胫骨平台骨折、胫腓骨骨干骨折、踝关节骨折和足部骨折。

排除标准:①为病理性骨折;②患有凝血功能障碍、血液系统疾病;③合并免疫性疾病;④合并心肝肾功能障碍;⑤存在感染性疾病;⑥合并代谢性骨病;⑦合并精神类疾病。

1.2 指标观察

1.2.1 一般资料收集

采集患者一般资料,包括性别(男,女)、年龄、饮酒史(是,否)、吸烟史(是,否)、骨折程度(轻中度,重度)、骨折原因(摔伤,车祸,坠落,其他),活化部分凝血活酶时间(activated partial thromboplastin time,APTT)、凝血酶原时间(prothrombin time,PT)、凝血酶时间(thrombin time,TT)、纤维蛋白原(fibrinogen,FIB)、D-二聚体(D-dimer,D-D)。

1.2.2 血栓分子标志物指标检测

采集术前、术后24 h、术后3 d患者早晨空腹静脉血2 mL,用离心机(产地:湖南沪康离心机有限公司,型号:L550)15 min,3 500 r/min,进行操作,分离上层清液,于-80 ℃冰箱内存储,待用。采用万孚全自动化学发光免疫分析仪(产地:广州,型号:I2900)检测TAT、PIC、t-PAIC、TM水平。

1.3 统计学处理

使用SPSS 19.0软件进行数据分析,计量资料以

$\stackrel{-}{x}\pm s$

表示,组间比较采用独立样本t检验,计数资料以%表示,组间比较采用χ²检验;衡量两个变量的相关程度采用Pearson分析。将结果分析中P<0.05的变量作为多因素条件进行Logistics回归分析,诊断效能分析采用受试者工作特征(receiver operating characteristic,ROC)曲线,获取曲线下面积、置信区间、敏感度、特异度及准确度值,P<0.05为差异有统计学意义。

2 结果分析

2.1 两组患者一般资料对比

如表1所示,基线特征均衡性分析,两组性别、年龄、饮酒史、吸烟史、骨折程度、骨折原因、骨折类型、APTT、PT、TT水平对比,差异无统计学意义(P>0.05);两组凝血功能指标的差异性分析,与非VTE组相比,VTE组FIB、D-D水平升高,差异具有统计学意义(P<0.05)。

2.2 两组患者血栓分子标志物指标对比

如表2所示,与非VTE组相比,VTE组术前、术后24 h、3 d TAT、PIC、t-PAIC、TM水平升高,差异具有统计学意义(P<0.05)。

2.3 血栓分子标志物指标与VTE发生的相关性

如表3所示,以VTE为分类变量,以非VTE=1,VTE=2做相关性分析,结果显示,TAT、PIC、t-PAIC、TM与VTE的发生呈正相关,差异具有统计学意义(P<0.05)。

2.4 下肢骨折手术后VTE发生的多因素Logistic回归分析

如表4所示,选择单因素分析中P<0.05的变量作为自变量赋值,将术后VTE的发生作为因变量(未发生=0;发生=1),进行多因素Logistic回归分析,结果显示FIB、D-D、TAT、PIC、t-PAIC、TM为影响下肢骨折手术后VTE发生的独立危险因素(P<0.05)。

2.5 ROC曲线分析血栓分子标志物指标对下肢骨折手术后VTE发生的预测价值

如表5和图1所示,ROC分析显示,TAT、PIC、t-PAIC、TM联合检测对下肢骨折手术后VTE发生的预测价值较高,差异具有统计学意义(P<0.05)。

3 讨论与结论

骨折易导致肌腱损伤、神经损伤、关节脱位。患者手术后,需卧床休息,影响患者的生活质量^[7-9]。患者长时间卧床,可导致下肢肿胀,影响静脉血流,造成内皮细胞活化,促使血小板、白细胞的黏附,形成中性粒细胞胞外陷阱,激活患者凝血功能,促使血栓的形成,体内静脉血栓脱落后,栓子可进入血液,堵塞患者肺动脉,导致肺栓塞,严重时可引发患者死亡^[10-12]。VTE发生早期,临床无特异症状,随着疾病的发生,患者可出现疼痛、下肢肿胀、静脉曲张,临床治疗不及时,可造成栓子脱落,威胁患者生命安全。临床需在血栓形成早期进行治疗,促使术后康复。机体内血栓形成较为复杂,可受到凝血系统的影响,骨折可损伤机体内血管壁,损伤患者血管内膜,激活内外源性凝血途径,使机体凝血功能处于亢进状态,导致血液高凝^[13-14]。FIB为肝脏合成的蛋白质,可参与血液凝块的形成,FIB转化为纤维蛋白后,可促使血小板的聚集,使血液处于高凝状态,形成血栓,增加VTE发生风险^[15]。D-D为特异性分子标志物,可显示出纤溶酶激活状态,并反映出交联蛋白形成情况^[16]。研究结果显示,术后VTE患者体内FIB、D-D水平高于非VTE患者,表明下肢骨折术后患者FIB、D-D水平越高,VTE发生风险越高。

临床研究显示^[17-18],体内凝血因子激活后,凝血系统形成的凝血酶与抗凝血酶结合,可形成TAT,检测体内TAT水平,可反映出凝血系统激活强度,并显示出血液高凝状态,与血栓的形成具有较大联系。TM为内皮细胞细胞膜上蛋白,机体内皮细胞发生损伤,可促使TM进入血液循环,并经肾脏排泄,检测血清中TM水平,可反映出血管内皮细胞损伤程度、肾脏代谢功能^[19-20]。研究结果显示,VTE患者术前、术后24 h、3 d 体内TAT、TM水平高于非VTE患者,且预测VTE发生的准确度为73.00%、75.00%,表明术前检测TAT、TM水平,可用于VTE发生的预测,临床应用效果较好。

PIC为纤溶系统激活后形成的复合物,可反映出纤溶系统的亢进程度,机体内PIC水平升高,可影响术中、术后出血^[21-22]。t-PAIC为纤溶系统标志物,可反映出体内PIC活性,PIC水平升高,表明机体内血栓形成风险增加^[23]。研究结果显示,与非VTE患者相比,VTE患者术前、术后24 h、3 d 体内TAT、TM水平升高,与VTE的形成呈正相关关系,且检测TAT、TM水平,对术后VTE发生的具有较高的预测敏感度、特异度,表明临床可通过早期检测TAT、TM水平,用于VTE发生的预测。原因可能为,骨折后,可损伤静脉内皮,导致血小板、凝血因子聚集于损伤处,且血小板释放的血管活性物质,可促使血小板聚集,形成血栓,体内血液长期处于高凝状态,可加重血栓程度,升高PIC水平,促使VTE的形成。

多因素Logistic回归分析显示,下肢骨折手术后VTE发生可受到FIB、D-D、TAT、PIC、t-PAIC、TM的影响,为下肢骨折手术后VTE发生的危险因素。ROC曲线分析显示,TAT、PIC、t-PAIC、TM联合检测,对下肢骨折手术后VTE发生的预测敏感度为95.83%,特异度为77.63%,准确度为82.00%,临床具有较高的预测价值,表明检测TAT、PIC、t-PAIC、TM水平,可动态观察下肢骨折手术后血栓形成,可早期用于术后VTE发生的预测,及时进行干预治疗,控制疾病的发展,使用价值较高。

综上所述,在下肢骨折手术后VTE患者血清中,TAT、PIC、t-PAIC、TM表达水平升高,与VTE的形成呈正相关关系,为导致VTE发生的危险因素,联合检测TAT、PIC、t-PAIC、TM表达,可用于下肢骨折手术后VTE发生的预测。但因样本量较少,后续研究需进一步分析证实,判断血栓分子标志物(TAT、PIC、t-PAIC、TM)指标在下肢骨折手术后VTE形成预测中的应用价值。

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