Diagnosis and treatment of thrombosis during the perioperative period of joint replacement

doi:10.3969/j.issn.2095-4344.2013.48.017

Abstract

Abstract:

BACKGROUND: The coagulation function of patients after joint replacement is enhanced during the perioperative time, the coagulation disorder can easily lead to the deep vein thrombosis, which will seriously affect the rehabilitation and prognosis of patients. The embolus falling off from venous thrombosis can lead to acute pulmonary embolism, severe cases can be life-threatening. So the early diagnosis of postoperative deep vein thrombosis and acute pulmonary embolism is very important.
OBJECTIVE: To review the research progress of clinical diagnosis of thrombosis in the perioperative patients after orthopaedic joint replacement.
METHODS: A computer-based retrieve in PubMed database and CNKI database were conducted by the first author for the articles on the clinical diagnosis of thrombosis in the perioperative patients after orthopaedic joint replacement from January 2008 to May 2013 with the key words of “arthroplasty, deep venous thrombosis, pulmonary artery embolism, risk factor, diagnostic approach, anticoagulant, perioperative period, research progress” in English and Chinese. A total of 165 articles were screened out, and finally 50 articles were included according to the inclusion criteria.
RESULTS AND CONCLUSION: After joint replacement surgery, various risk factors were associated with the etiology and pathogenesis of deep venous thrombosis, such as vascular and tissue impairments, limb fixation, pain stress, and hemorrhagic fluid caused coagulation disorder, were the main reasons to thrombosis. Deep vein thrombosis and pulmonary embolism had variety of clinical manifestations, many diagnostic approaches were widely applied in clinic, but each one has its laminations. So the positive diagnosis intervention should be performed according to the common clinical manifestations, generally begin from the routine examinations of ultrasound and electrocardiogram, and the combination of various methods was preferred if necessary in order to increase the positive diagnosis rate to the maximum extent, and take drug intervention immediately after diagnosis to avoid the happening of adverse events. Several new types of oral anticoagulants appear in clinical trials, and the outcomes are very promising, but the widely clinical application needs further observation.

Key words: arthroplasty, replacement, venous thrombosis, pulmonary embolism, perioperative care

CLC Number:

R318

Li Shao-fei, Zhao Jian-ning, Guo Ting . Diagnosis and treatment of thrombosis during the perioperative period of joint replacement[J]. Chinese Journal of Tissue Engineering Research, 2013, 17(48): 8401-8406.

Figures/Tables 1

2.1 围手术期深静脉血栓/肺动脉栓塞高危因素 2.1.1 手术组织损伤关节置换为骨科大手术，创伤大，时间长，术中出血多，置换过程可导致软组织血管壁及内皮细胞损伤，导致组织因子等促凝物质释放，启动内外源性凝血途径，假体植入过程中骨髓脂肪颗粒、骨水泥单体等可逆行入血导致血液中出现不溶物质，上述多种因素均可导致患者凝血功能紊乱[4]。 2.1.2 置换后卧床、患肢固定患者置换后一般卧床3 d，高龄患者可能卧床时间更久，该过程即可造成全身血液缓滞，红细胞聚集力增强，血黏度增高，部分患者卧床期间穿防旋鞋制动，或因疼痛而不敢活动肢体，使下肢肌肉的收缩减弱，静脉血回流失去了肌肉的泵作用，加之肢体创伤肿胀，压迫深静脉，致使局部血液瘀滞，堆积的凝血因子激活凝血系统，促使血栓形成[5]。虽有医生鼓励患者卧床期间积极功能锻炼，但文献报道在髋关节置换后住院期间进行床上锻炼似乎并没有额外的好处[6-7]。 2.1.3 置换后疼痛患者置换后疼痛、应激过程及情绪波动，导致内分泌异常，促使肾上腺素、内皮素、5-羟色胺等大量分泌，上述激素类物质可在一定程度上导致患者置换后高凝状态持续加重。并易诱发深静脉血栓和肺动脉栓塞的发生[8]。 2.1.4 置换后补液根据文献报道，当患者置换后每日补液量超过1 000 mL，相当于70 kg成年人体内血液稀释20%以上，会显著促成患者置换后高凝状态，具体机制尚未阐明[9]。有学者研究认为，在血液稀释的情况下，凝血酶与抗凝血酶的动态平衡被打破，而抗凝血酶功能受稀释影响更大。置换后第1天，患者排气后即可进食，鼓励早期进食，补充能量和液体量，利于置换后恢复[10]。 2.1.5 置换后置管静脉内留置导管是深静脉血栓重要的致病原因，尤其是中心静脉插管和起搏器。静脉导管置入后对静脉造成的损伤、局部淤血、导管周围血栓形成等，最终引起置管静脉阻塞。此外，导管口径、穿刺次数、导管放置时间和经导管注药成分等因素与深静脉血栓的发病风险相关[11-12]。 2.2 深静脉血栓和肺动脉栓塞临床表现特征 2.2.1 急性深静脉血栓患者临床表现呈多样性，且差异性较大，根据易巍等[13]报道，通过影像科确诊的126例急性深静脉血栓患者中各种临床症状的发生率依次为：①胀感77%。②疼痛：73.8%。③浅静脉怒张73%。④下肢肿胀71.4%。⑤凹陷性水肿67.5%。⑥皮肤暗红及皮温升高67.5%。⑦Homans征 64.3%。⑧Neuhof征 41.3%。⑨心悸22.2%。⑩股三角区压痛17.5%。沉重感 15.1%。发热 15.1%。临床症状虽然多样，但特异性不高，可与很多血管性疾病混淆，故实验室及其他相关临床检查手段在深静脉血栓确诊中起主要作用。 2.2.2 肺动脉栓塞临床表现从无症状到猝死，呈多样性，没有特异性，呼吸困难、气促心动过速、胸闷、胸痛/胸膜性胸痛、晕厥、发绀、发热、咳嗽、及咯血是肺栓塞的常见临床表现，占96%以上[14]，据尹春琳等[15]分析132例肺动脉栓塞患者临床表现，比例依次为：呼吸困难(89.4%)、胸闷(62.1%)、发热(10.6%)、胸痛/胸膜性胸痛(26.5/2.3%)、咳嗽(23.5%)、晕厥(22%)、发绀(9.1%)、咯血(6.8%)、头晕(18.2%)、乏力(4.5%)、黑朦(6.8%)、出汗(22.7%)。 2.3 深静脉血栓及肺动脉栓塞临床诊断方法 2.3.1 胸部X射线片肺动脉栓塞患者在发病后12-36 h或数天内即可出现线胸片的改变，田治海等[16]对确诊的29例肺栓塞患者胸部X射线表现进行分析结果发现肺栓塞早期线表现多样并以肺缺血 Westermark征为典型表现，明莫瑜[17]对55例肺栓塞患者行正侧位X射线胸片检查，其中肺炎样改变38.2%，胸腔积液21.8%，肺动脉高压征象20%以及20%无阳性表现说明肺栓塞患者X射线胸片虽无特异性改变，但通过对比患者术前术后X射线平片可为肺栓塞诊断提供线索[18]。 2.3.2 D-二聚体血浆D-二聚体浓度升高对诊断深静脉血栓/肺动脉栓塞均有一定参考价值[19-20]，但为非特异性指标。以血浆D-二聚体的0.5 mg/L为阳性界点，诊断肺动脉栓塞的敏感性、特异性分别为89.9%，67.2%[21]，该检验的阳性结果反映了血管内有纤维蛋白的存在，可用于血栓筛查。除血栓疾病外，肝脏疾病、炎症、恶性肿瘤、怀孕、创伤及近期手术均可使其升高[22]。该检测结果还受血栓的大小范围、出现症状后检测时间及抗凝治疗的影响。仅凭D-二聚体水平不能确诊肺栓塞，但阴性有助于排除肺栓塞。Cosmi等[23]研究表明，肺栓塞患者接受抗凝治疗后，若D-二聚体恢复正常，其复发肺栓塞的概率仅为4.4%/年，对预后评价有较高参考价值[24]。 2.3.3 超声现为主流检测下肢静脉血栓手段，非侵入性检测，无放射性，分加压超声成像和多普勒超声，加压超声在诊断下肢近端血栓的灵敏度为89%- 96%，特异度约94%-99%[25]，该检查主要从以下几个方面评估深静脉血栓的可能性：①静脉血管的压缩性，当静脉中存在固体血栓时压缩性下降。②血流特性改变，部分或全部阻塞时异于正常情况。③血流相位性消失。当深静脉血栓存在时，最可靠的表现是静脉压缩性降低，加压超声在小腿深静脉血栓的诊断中可靠性不高[26]，但结合了血流多普勒信号及超声图像的二维超声提高了诊断小腿深静脉血栓的准确率[27]。 2.3.4 计算机断层造影该检查一般应用非离子型含碘对比剂碘普罗胺为对比剂，一次检查可一起同时检测肺动脉栓塞和深静脉血栓[28]，当增强后CT净增值100 Hu后从设定的感兴趣区触发扫描，一般为肺动脉平面开始，延迟3-35 min后可从小腿中部向上扫描，把扫描后获得的薄层数据载入后处理工作站，采用容积重建获得带骨的血管图像，然后采用去骨技术，获得去骨后的完整肺动脉及下肢静脉血管图，用最大密度投影显示血管的全貌，从而直观地了解血管内有无栓塞情况。该检查缺点：①需要静脉注射含碘对比剂，有0.01%严重过敏反应发生率。②大覆盖范围联合检查无疑会增加患者的X射线辐射剂量，对单纯疑诊深静脉血栓的患者，仍推荐使用下肢多普勒超声检查作为首选的筛查手段[29]，现计算机断层造影一般在患者有明确的下肢肿胀或呼吸困难等栓塞症状且常规检查结果不确定的情况下应用[30]，或在患者需介入治疗前为获取更多的解剖学资料时必要时使用[31-32]。 2.3.5 磁共振静脉成像磁共振静脉成像是近几年刚开发的新技术，该检查可通过影像直接发现血栓病变，并且可以诊断出血栓在血管内是静止的还是运动的栓子[33]。在对比剂作用下计算机可较短时间内完成血栓及其所在血管的3D重建[34]，对细小血管成像更优[35]，可发现血栓的具体病变部位及大小占位情况。磁共振静脉成像在深静脉血栓的诊断价值与对比静脉造影相仿，该检查可准确发现超声检查难以发现的盆腔血栓，对肺动脉栓塞也有极高的诊断价值。但是磁共振静脉成像并未广泛应用[36]。磁共振静脉成像缺点有：①费用较高，仪器昂贵。②患者体内有磁性植入物为该检查禁忌。③检查过程患者需较高配合度。④造影剂(含金属钆)可能与中晚期肾病患者肾脏纤维化有关联，患者合并肾脏疾病需慎用。 2.4 诊断深静脉血栓/肺动脉栓塞发展新方向 2.4.1 放射性同位素造影检查可用放射性同位素125I标记患者的纤维蛋白原，当体内有新鲜血栓形成时，局部放射性增强，可准确诊断出深静脉血栓的位置及形态。最新临床应用的同位素为99Tc。Tc-99m-apcitide为一种同位素标记的肽链，与Ⅱb/Ⅲa的糖蛋白受体高度结合且特异性高，该受体高表达于因新生血栓激活的血小板上。最近一项关于99Tc与静脉造影在深静脉血栓患者诊断准确率比较的实验[37]，该实验共统计了280例患者，实验结论：99Tc在深静脉血栓诊断上灵敏度90.6%，特异度83.9%，与静脉造影结论一致率为87.3%，同位素检查为深静脉血栓的诊断方法提供了新的思路。 2.4.2 血栓弹力图血栓弹力图是一种可以直接检测全血凝血功能的检测手段[38]，现已广泛应用于检测血液高凝、低凝、纤维蛋白溶解、血块强度以及抗凝药物疗效等，现已有相关研究应用血栓弹力图监测高凝状态及提示血栓发生过程。最近一项关于血栓弹力图文献系统性回顾研究的资料显示[39]，关于血栓弹力图下高凝状态的定义尚无统一标准，在收集的共10个统计的实验中，6项实验主张用血栓最大幅度值(MA)> 68-70 mm为高凝(有血栓倾向)的界限。余下4项实验以凝血综合指数(CI)>3.0为高凝界限。实验结果的波动性较大，根据上述标准统计，血栓弹力图检测深静脉血栓的灵敏度在69%-80%之间，特异度在62%-92%之间，介于统计资料较少，尚无法进行Meta分析，血栓弹力图在诊断血栓方面仍需进一步探究。但关节置换后常规血栓弹力图监测可早期发现患者血液高凝状态，指导临床进行早期的抗凝治疗，从而避免血栓形成的进展过程。 2.4.3 抗人血小板单克隆抗体的研究用121锢标记血小板特种单克隆抗体(P256)进行诊断下肢深静脉血栓的研究[40]，P256能清楚地显示整个下肢深静脉血栓形成的过程，经血管造影证实，下肢深静脉血栓和肺栓塞诊断准确性一致，目前对P256的临床应用还没有进行系统的评估，尚未进行临床运用检测，近年来利用与血栓形成相关的特异性单克隆抗体，成功地进行了血栓导向显像诊断、溶栓治疗以及新型抗栓和抗血小板药物的研究，这些研究结果显示了血栓导向单抗对血栓性疾病的诊断有着良好的前景。 2.4.4 溶血磷脂酸溶血磷脂酸属于脂类小分子物质，是又称多功能“磷脂信使”，是一种由活化血小板生产的生物活性磷脂，越来越多证据表明，溶血磷脂酸与动脉粥样硬化和血栓形成密切相关[41]，该物质可在血栓形成早期由血小板产生，是检测血栓形成的标志物之一[42]。Cui[43]发现在深静脉血栓血浆中溶血磷脂酸水平显著高于未并发深静脉血栓患者，证实了在血栓形成早期溶血磷脂酸已经释放，此时检测溶血磷脂酸早期筛查对深静脉血栓诊断有临床意义。 2.5 围手术期血栓药物预防及发展方向参照《预防骨科大手术深静脉血栓形成指南》[44]，置换后抗凝治疗一般不应少于7-10 d，必要时延长至28-35 d。近50年来，低分子肝素和维生素K拮抗剂类(以华法林为代表)为主要的围手术期抗凝药物，虽疗效得到肯定，可明显降低置换后深静脉血栓发生率[45]，但应用却受到诸多因素限制，低分子肝素为非口服类，不适合非住院期间及长期治疗，华法林为间接口服抗凝药物，半衰期长，用药5-7 d药效才能稳定，治疗期间需严格把握剂量，定期监测国际标准化比值(INR)，且药物代谢受饮食、饮酒及多种药物等影响，若患者术后5 d出院，则应用大为不便，因此，临床需要一种可以口服，无需临床监测并可在家中长期服用的新型抗凝药物，下文介绍最新的2种现已得到临床广泛应用的抗凝剂及代表药物。 2.5.1 凝血酶直接抑制剂(代表药物：达比加群) 前体药物为达比加群酯，经口服后在体内转换成有活性的达比加群，作用机制：凝血酶是细胞外胰岛素样丝氨酸蛋白酶，在凝血过程中具有重要作用[46]，一方面，其能使纤维蛋白原裂解成为纤维蛋白，后者参与构成不溶性血栓基质；另一方面，其能诱导血小板活化和聚集，进而引发一系列次级凝血级联反应。达比加群直接抑制凝血酶从而达到抗凝血作用，该药口服生物利用度约5%，半衰期14-17 h，肝脏清除率低，以肾脏排出为主[47]，根据临床相关实验(RE-MODEL)，在关节置换后血栓预防作用方面，每天150 mg、225 mg剂量达比加群效果不亚于40 mg依诺肝素(皮下注射)组，且关节置换后出血的不良反应发生率差异无显著性意义。最新实验(RE-COVER)比较了该药与华法林在术后6个月内血栓预防作用，结果发现达比加群效果不亚于华法林组[48]，所以该药完全可以胜任长期血栓预防治疗，且治疗过程无需监测INR等凝血功能。该药不良反应以出血为主，且有明显的剂量相关性。综合来讲，达比加群是一种应用前景广阔的骨科术后抗凝药物。 2.5.2 活性X因子直接抑制剂(代表药物：利伐沙班)因子Xa是凝血酶形成的内外源通路的共同交叉点。利伐沙班选择性抑制因子Xa阻断凝血酶生成的爆炸样放大效应，高效、安全地抑制血栓形成[49]。该药的生物利用度可达80%以上，快速起效(给药后2-4 h血药浓度达峰值)，终末半衰期为4-9 h，与药物之间作用小，经胆道和肾脏双通道排泄，多次给药后无蓄积且不受食物影响，且无需监测凝血功能。RECORD实验比较全髋关节置换后患者短期内皮下注射依诺肝素和置换后5周内长期口服FXa因子抑制剂利伐沙班在预防血栓预防作用。结果显示，利伐沙班组严重深静脉血栓发生率均显著低于依诺肝素组，大出血和一般出血事件的发生率在2组中相似。与依诺肝素短期用药相比，利伐沙班长期预防对全髋关节置换患者可更有效地预防深静脉血栓[50]。RECORD研究旨在比较利伐沙班和依诺肝素每天1次对全膝关节成形患者的疗效和安全性，共随机纳入2 531例患者，利伐沙班对减少严重静脉血栓栓塞更有效，可使相对危险度降低62%。利伐沙班组症状性静脉血栓栓塞发生率低于依诺肝素组。大出血和一般出血的发生率在利伐沙班组(0.6%)和依诺肝素组(0.5%)相似，其他不良事件的发生率也相似。治疗期间利伐沙班组无死亡或肺栓塞发生，依诺肝素组有2例死亡和4例肺栓塞。利伐沙班关节置换后预防血栓治疗效果显著，且安全性高，值得大规模应用。 2.5.3 新型口服抗凝药物的优点 ①高选择性，不良反应少。②临床起效快，可用于急性和慢性血栓治疗。③无明显食物影响，药物相互作用少。④多次给药无蓄积，⑤可预见性高，无需监测凝血功能。"

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