
==== Front
Zhong Nan Da Xue Xue Bao Yi Xue Ban
Zhong Nan Da Xue Xue Bao Yi Xue Ban
zndx
Journal of Central South University Medical Sciences
1672-7347
中南大学出版社 湖南省长沙市湘雅路110号湘雅医学院

39311777
1672-7347(2024)06-0825-07
230575
10.11817/j.issn.1672-7347.2024.230575
Topics on Endocrine and Metabolic Disease
库欣综合征高凝状态与静脉血栓栓塞风险
Hypercoagulable state and risk of venous thromboembolism in Cushing syndromehttp://orcid.org/0009-0006-4466-0037
刘 宇珂 LIU Yuke
唐 宇 TANG Yu
http://orcid.org/0000-0002-0451-8283
谭 惠文 TAN Huiwen
李 建薇 LI Jianwei
四川大学华西医院内分泌代谢科，垂体瘤及相关疾病诊疗中心 成都 610041
Department of Endocrinology and Metabolism, Center of Pituitary Adenoma and Related Diseases, West China Hospital, Sichuan University Chengdu 610041 China
彭 敏宁 executive-editor
谭惠文，Email: huiwent2016@scu.edu.cn, ORCID: 0000-0002-0451-8283
刘宇珂，Email: liuyuke0809@163.com, ORCID: 0009-0006-4466-0037

28 6 2024
49 6 825831
18 12 2023
©Journal of Central South University (Medical Science). All rights reserved.
2024
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库欣综合征(Cushing syndrome，CS)是以高皮质醇血症为特征的内分泌代谢疾病，高皮质醇血症可诱发高凝状态，导致静脉血栓栓塞(venous thromboembolism，VTE)风险增加。无论是垂体来源的库欣病(Cushing disease，CD)，还是肾上腺来源的非促肾上腺皮质激素(adrenocorticotropic hormone，ACTH)依赖性CS，手术均是一线治疗选择。在手术和疾病本身的双重影响下，VTE风险进一步增加，甚至导致肺栓塞，严重威胁患者生命安全。此外，高凝状态的CS患者的心血管病和VTE发生率乃至病死率均高于正常人群，未经治疗的活动性CS患者的VTE发生率较普通人群升高了17.8倍。近年来，CS高凝状态与VTE之间的关系引起了越来越多临床医师的重视。进一步了解CS高凝状态的临床流行病学特点、病理生理机制和VTE及肺栓塞的临床防治，可以为CS患者预防性抗凝药物规范化使用提供参考。

Cushing syndrome (CS) is an endocrine-metabolic disorder characterized by hypercortisolism. Elevated cortisol levels can induce a hypercoagulable state, increasing the risk of venous thromboembolism (VTE). Both pituitary-origin Cushing disease (CD) and adrenal-origin non-adrenocorticotropic hormone (ACTH)-dependent CS are primarily treated with surgery. The dual impact of surgery and the underlying disease further elevates the risk of VTE, potentially leading to pulmonary embolism, which poses a severe threat to patient survival. Additionally, CS patients in a hypercoagulable state have a higher incidence of cardiovascular diseases and VTE, and even mortality compared with the general population. Untreated active CS patients have a 17.8-fold increased risk of VTE compared to the general population. In recent years, the relationship between the hypercoagulable state in CS and VTE has garnered increasing attention from clinicians. A better understanding of the clinical epidemiological characteristics, pathophysiological mechanisms, and clinical prevention and treatment of VTE and pulmonary embolism in CS can provide valuable references for the standardized use of prophylactic anticoagulant therapy in CS patients.

库欣综合征
高凝状态
静脉血栓栓塞
Cushing syndrome
hypercoagulable state
venous thromboembolism
四川省科技厅重点项目2023SFY0039┫。This work was supported by the Major Project of Science and Technology Department of Sichuan Province China ┣2023SFY0039
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pmc高凝状态是由机体循环系统凝血异常引起的动脉或静脉血栓形成倾向，也称为易栓症或血栓前状态[1]。高凝状态的形成有多因素参与，发病机制复杂，目前尚无统一的诊断标准，诸多生理和病理因素都能够影响凝血系统，包括血小板活化、血浆凝血相关因子的改变(凝血因子的升高、抗凝因子和纤维蛋白溶解活性的降低)、血黏滞度增加和/或血管内皮损伤状态等[2]。库欣综合征(Cushing syndrome，CS)是一种以高皮质醇血症为特征的内分泌疾病，患者病情复杂，长期高皮质醇血症可导致高血压、骨质疏松、向心性肥胖、糖脂代谢紊乱、消化道溃疡等，并且还可引发高凝状态[3-4]。相较于普通人群，CS患者的心血管并发症发生率和死亡风险较高，主要死因包括心血管事件[急性心肌梗死(acute myocardial infarction，AMI)和充血性心力衰竭(heart failure，HF)]、静脉血栓栓塞(venous thromboembolism，VTE)和肺栓塞(pulmonary thromboembolism，PE)等[5]。无论是垂体来源的库欣病(Cushing disease，CD)，还是肾上腺来源的非促肾上腺皮质激素(adrenocorticotropic hormone，ACTH)依赖性CS，手术是一线治疗选择，但手术本身可能加重CS患者VTE风险，甚至导致PE，严重威胁患者生命安全[6]。笔者现围绕CS高凝状态的临床流行病学、病理生理机制和CS相关VTE的临床防治进行综述。

1 CS高凝状态的临床流行病学特点

目前国内CS患者高凝状态或VTE发生率尚不清楚[7-9]。多项临床研究[10-15]均表明CS患者无论处于疾病活动期还是缓解期，VTE的发生率为2.6%~5.6%，而非CS患者的VTE发生率仅为0.9%[16]，CS患者发生VTE的风险显著高于正常人群，甚至高达一般人群的17.8倍[15]。CS中最常见的是CD，约占患者总数的70%，而非ACTH依赖性CS患者肾上腺切除术后发生VTE的风险未增加[14]，说明CD对凝血功能的影响更为显著。

值得注意的是，尽管CS患者术后可以实现生化缓解，但VTE风险不仅在术后第1周增加，而且在术后2~3个月甚至数年内同样增加，这一现象考虑与高皮质醇血症解除缓慢有关，也有学者认为高凝状态存在延迟可逆性[17]。一项单中心回顾性队列研究[18]显示：在接受外科手术和药物治疗的208例CS患者中，39例(18.8%)经历56例次VTE，其中21例次(37.5%)为深静脉血栓、15例次(26.8%)为脑血管意外、12例次(21.4%)为心肌梗死和8例次(14.3%)为PE，并且有41.1%(23例次)的VTE发生在术后60 d内。该研究[18]还显示：接受经蝶窦垂体瘤切除术(transsphenoidal adenomectomy，TSS)的CD患者术后VTE发生率明显高于相同手术治疗的无功能垂体腺瘤(non-functioning pituitary adenomas，NFPA)患者。此外，肾上腺切除术也显著增加了CS患者发生VTE的风险，且有证据表明CS术后VTE的高风险是由皮质醇所介导的[2, 3, 7, 17]。因此，对于CS患者不论是否合并VTE风险因素，术前和术后预防及监测VTE并发症都非常重要[19]。

2 CS高凝状态的发病高危因素

CS高凝状态的发病机制比较复杂，目前认为由促凝和抗凝途径活性失衡所致，主要表现为血栓活性增加和纤维蛋白溶解系统的补偿性激活[8]。CS高凝状态的病理生理机制主要包括：血小板活化、促凝血因子[血管性血友病因子(von Willebrand factor，vWF)与凝血因子-8(coagulation factor Ⅷ，FⅧ)等]浓度升高和纤溶系统受抑制[1]。另外，肥胖、感染、卧床、侵入性操作[如岩下窦采血(inferior petrosal sinus sampling，IPSS)]、药物和手术等也可能促进CS患者的高凝状态，增加其VTE风险[20]。

2.1 血小板活化

人类血小板上存在糖皮质激素受体(glucocorticoid receptor，GR)，糖皮质激素与之结合可促进血小板进入循环池，导致血小板增多[21]。一项研究[22]表明暴露于高皮质醇血症的CS患者的血栓素B2(thromboxane B2，TXB2)水平显著升高，而TXB2是反映血栓素A2(thromboxane A2，TXA2)合成情况的重要血浆标志物，TXB2升高表明TXA2合成增加，TXA2可引起血小板释放、活化和聚集[23]，进而造成机体的高凝状态。

2.2 促凝血因子浓度升高

CS患者的凝血因子-5(coagulation factor Ⅴ，FⅤ)、FⅧ、凝血因子-9(coagulation factor Ⅸ，FⅨ)等多种促凝因子水平升高[24]。研究[25]显示CS患者血浆vWF水平与普通人群相比有显著升高，甚至亚临床CS患者的vWF水平同样显著高于普通人群。但vWF水平的增加并非CS的固有特征，其对糖皮质激素的反应是由基因决定的，取决于vWF基因启动子中是否存在特定的多态性。而糖皮质激素对纤维蛋白原、vWF、FVIII、纤溶酶原激活物抑制剂-1(plasminogen activator inhibitor-1，PAI-1)、凝血酶激活的纤溶抑制物(thrombin activatable fibrinolysis inhibitor，TAFI)等因子的产生有直接刺激作用，但目前尚未发现CS患者高皮质醇血症的严重程度与VTE风险之间存在正相关[26]。

2.3 纤溶系统受抑制

CS患者凝血酶激活纤溶抑制物，包括PAI-1、TAFI、α2-抗纤溶酶(α2-antiplasmin，α2-AP)、纤溶酶原激活物抑制物(纤维蛋白原和α2-纤溶酶抑制物等)水平均有所升高[27]，同时，蛋白C、蛋白S和抗凝血酶III水平也升高，这可能是CS患者高凝状态的代偿机制所致[27]，而皮质醇直接作用于血管内皮导致内皮功能障碍，可能与GR介导的相关基因转录上调相关[28]，但其具体机制尚未阐明。

2.4 其他高危因素

除过度分泌的皮质醇介导的凝血系统变化外，其他相关因素也可能导致CS患者VTE风险增加[29]，如垂体或肾上腺手术成功后，皮质醇水平突然下降(亦称为“糖皮质激素撤退综合征”)可能导致炎症反应，从而激活凝血级联反应[14, 17, 29]。年龄、制动卧床、既往发生过心血管事件、午夜唾液皮质醇水平升高和活化部分凝血活酶时间(activated partial thromboplastin time，APTT)缩短等[30]也是VTE发生的常见危险因素；此外，用于鉴别诊断的IPSS等操作或潜在的神经内分泌肿瘤等疾病本身也会导致VTE风险升高[16, 30]。CS患者在手术后或者经药物治疗诱导的短期生化缓解(即3个月)后凝血参数仍持续异常，这可能是CS患者术后随访中仍存在较高VTE风险的原因[31-32]。持续性腹部肥胖与血浆纤维蛋白原、vWF和PAI-1水平升高有关，是凝血因子长期升高的原因之一[33]，但其他可能的机制尚不清楚。

3 VTE的临床防治

目前关于CS患者血栓预防策略的文献很少，有3项评估经蝶鞍手术和/或肾上腺切除术后CS患者抗凝预防血栓形成效果的回顾性研究[5, 34-35]，结果表明术后血栓预防可以减少VTE发生，但这些研究纳入的CS患者人数较少且异质性大，可靠性仍有待进一步验证。

3.1 VTE高危人群的筛查和临床预测模型

VTE风险评估工具主要包括Caprini风险评估模型和Padua评估量表等，前者侧重于外科围手术期的VTE风险评估，后者侧重于内科患者血栓风险评估[36-37]；而Wells或Geneva评估表则侧重对疑似急性PE患者进行评估[38-39]。Caprini风险评估模型是一种用于量化和分类患者的VTE风险评分工具，一般用于评估大多数外科患者围手术期VTE的风险。根据Caprini风险评估模型，绝大多数接受手术的CS患者处于VTE中度风险，部分为高风险。Zilio等[36]回顾性分析176例内源性CS患者后，提出了CS-VTE评分，这项评分系统是专门为疾病活跃期的CS患者设计的风险评估工具，以3分作为预测VTE的切点值，敏感性为85%，特异性为95%，然而这一模型暂未在其他研究中得到验证[36]。目前仍是通过血栓风险分层来确定高危患者，以做好VTE的有效预防，降低CS患者的VTE风险[36-39]。也有研究[40]采用D-二聚体和血栓弹力图(thromboela-stogram，TEG)预测VTE的发生风险，未来仍需要更多的前瞻性研究评估CS血栓预防的最佳时机、持续时间和类型，以降低VTE相关的发病率和病死率。

3.2 VTE防控的时机和高危因素管理

国内CS患者血栓预防和抗凝的相关研究相对缺乏[6-8]。2022年，van Haalen等[41]绘制了欧洲罕见内分泌疾病参考网络(Endo-ERN)的CS患者血栓管理实践图。不同中心血栓预防的指征、起始时间、终止时间均是个体化的，无统一标准[35, 41]。目前，最好的方法可能是在活动期和术后对CS患者实施个体化的血栓预防方案，同时需考虑血栓形成的其他危险因素，如年龄、VTE病史、肥胖程度、活动能力、雌激素或口服避孕药的使用情况，还要考虑出血并发症的风险[18]。既往有VTE病史、严重高皮质醇血症、活动能力受限是启动血栓预防的三大因素[35]。2项回顾性研究[42-43]显示：与未接受血栓预防的患者相比，接受血栓预防的患者VTE发生率较低。除血栓预防外，术前降低皮质醇水平也可降低VTE风险，但尚有争议[44]。虽然临床上尚未就如何预防性使用抗凝药物达成共识或颁布指南，但一般认为拟行垂体手术或IPSS的CD患者需常规应用抗凝药物(最好使用低分子量肝素)，可以考虑在手术前暂时停止女性患者的雌激素治疗。TSS术前应停止血栓预防治疗，以尽量降低术中出血的风险，但应在手术后早期进行低剂量肝素治疗[41, 45]。术后建议延长血栓预防时间，即4~8周，尤其是高危患者[41]。此外，术后早期下床活动(行走)和使用弹力袜是预防VTE的有效支持措施[42-43]。间歇性动态压力疗法如间歇充气压力泵(intermittent pneumatic compression，IPC)等非药物预防策略，可实现下肢腿部被动运动和定期足背屈练习，也取得了良好的效果[46]。

3.3 VTE 抗凝治疗药物选择

VTE抗凝治疗药物包括肠外抗凝剂，如肝素、华法林及口服的Xa因子抑制剂(利伐沙班等)。目前研究[41]认为，在无抗凝治疗禁忌的前提下，抗凝药物的种类应首选低分子量肝素或小剂量普通肝素，华法林次之，关于其用量仍存在争议；而其他种类抗凝药物尚无相关研究。Huckhagel等[46]的研究显示围手术期予以CD患者40 mg/d依诺肝素皮下注射，仍有6.7%的患者出现VTE，但该研究样本量少，证据力度有限。一项纳入307例CS患者的回顾性研究[43]提示：预防性使用抗凝药物(肝素或华法林)可以显著降低CS患者血栓并发症的发生率并且不增加其出血风险。与对照组相比，预防性使用抗凝药物的CS患者术后VTE发生率由10%降至4%，因VTE所致的病死率则由10%降至0.4%。而直接口服抗凝剂，如阿匹沙班、利伐沙班、达比加特兰和艾多沙班等被推荐用于各种骨科手术以预防血栓形成[47]，但尚缺乏在CS背景下的有效性和安全性的研究报告。

目前临床实践[2]表明血栓预防的启动时间、持续时间和类型存在相当大的异质性：大多数医学中心对患者进行了血栓药物预防，但只有一个中心制订了血栓标准化预防方案；血栓预防均首选低分子量肝素，但治疗持续时间差异很大。关于抗凝药物的用法和时机，通常推荐一旦CS诊断明确便立即开始预防性用药，在围手术期停药(最少用至术后1个月，最多不超过出院后4周)。目前最佳的术后预防时间尚未达成共识，特别是CS生化缓解后血栓预防的持续时间是一个有争议的问题[47]。多数医生主张抗凝治疗维持至出院后大约1个月，也有学者认为术后30~60 d血栓风险较高，建议继续预防至术后60 d，特别是在难治性CD患者双侧肾上腺切除术后。而研究[47]表明高皮质醇血症患者的高凝状态可持续至术后6个月。是否继续延长术后抗凝时间仍需进一步探索。尽管不同研究之间存在一些时间异质性，但手术后前3个月患者VTE的风险最高。建议制订个体化预防性使用抗凝药物方案的同时，也要考虑CS患者VTE发生的高危因素(如高龄、肥胖、手术操作等)和其出血风险，在两者之间寻找一个平衡[48]。

4 结 语

CS患者的凝血特征具有异质性，不同年龄段患者的凝血状态有所不同。这可以用患者个体特征和凝血常规测定方法的差异来解释，但并没有在每个CS患者中观察APTT、促凝因子和抗凝因子的血浆浓度变化。高皮质醇血症和手术等与CS患者的VTE风险增加有关，其所致的高凝状态已越来越引起临床和基础工作者的重视，因此进行了更多的研究与探索，这不仅有助于揭示其分子机制，增进对CS相关性VTE的了解，也可为临床上预防性使用抗凝药提供指导，以改善CS患者预后。但目前尚无CS患者术前或术后血栓预防的标准方案，未来的研究应侧重于CS高凝状态的发病机制，并根据临床特征(可能还要基于凝血参数，甚至单核苷酸多态性)预测哪些CS亚组发生VTE的风险更高。迄今为止，尚未发表关于活动性CS和术后血栓预防的疗效、持续时间和类型的前瞻性研究或指南[2-3]。CS的高凝状态需要更多的前瞻性临床研究，以获得能够指导CS患者VTE预防的起始时间、持续时间和类型的数据。评估危及生命的血栓形成事件的风险预测模型和最佳切点尚需更有针对性的研究，以降低CS患者高凝状态VTE的发生率和病死率。

基金资助

四川省科技厅重点项目(2023SFY0039)。This work was supported by the Major Project of Science and Technology Department of Sichuan Province, China (2023SFY0039).

利益冲突声明

作者声称无任何利益冲突。

作者贡献

刘宇珂、唐宇 资料收集，论文撰写与修改；谭惠文 论文设计、指导与修改；李建薇 论文指导。所有作者阅读并同意最终的文本。

原文网址

http://xbyxb.csu.edu.cn/xbwk/fileup/PDF/202406825.pdf

http://dx.chinadoi.cn/
==== Refs
参考文献

1 Coelho MC , Vieira Neto L , Kasuki L , Rotation thromboelastometry and the hypercoagulable state in Cushing’s syndrome[J]. Clin Endocrinol, 2014, 81 (5 ): 657-664. 10.1111/cen.12491.
2 Feelders RA , Nieman LK . Hypercoagulability in Cushing’s syndrome: incidence, pathogenesis and need for thromboprophylaxis protocols[J]. Pituitary, 2022, 25 (5 ): 746-749. 10.1007/s11102-022-01261-9. 35881275
3 Simion C , Campello E , Bensi E , Use of glucocorticoids and risk of venous thromboembolism: a narrative review[J]. Semin Thromb Hemost, 2021, 47 (6 ): 654-661. 10.1055/s-0040-1722270. 33893633
4 St-Jean M , Lim DST , Langlois F . Hypercoagulability in Cushing’s syndrome: From arterial to venous disease[J]. Best Pract Res Clin Endocrinol Metab, 2021, 35 (2 ): 101496. 10.1016/j.beem.2021.101496. 33795197
5 郝娜娜, 谭惠文, 王椿, 等. 库欣病合并肺栓塞一例并文献复习[J]. 中国呼吸与危重监护杂志, 2023, 22 (8 ): 587-590. 10.7507/1671-6205.202210004.
HAO Nana , TAN Huiwen , WANG Chun , Cushing’s disease complicated with pulmonary embolism: a case report and literature review[J]. Chinese Journal of Respiratory and Critical Care Medicine, 2023, 22 (8 ): 587-590. 10.7507/1671-6205.202210004.
6 Koraćević G , Stojanović M , Petrović S , Cushing’s syndrome, a risk factor for venous thromboembolism is a candidate for guidelines[J]. Acta Endocrinol, 2020, 16 (2 ): 123-128. 10.4183/aeb.2020.123.
7 吴晓谦, 林群力 . 库欣综合征及肥胖症患者凝血功能的改变及影响因素[J]. 中国药物与临床, 2019, 19 (4 ): 580-582. 10.11655/zgywylc2019.04.020.
WU Xiaoqian , LIN Qunli . Changes and influencing factors of coagulation function in patients with Cushing’s syndrome and obesity[J]. Chinese Remedies & Clinics, 2019, 19 (4 ): 580-582. 10.11655/zgywylc2019.04.020.
8 吴遐, 高路, 幸兵 . 库欣综合征所致高凝状态的研究进展[J]. 基础医学与临床, 2016, 36 (1 ): 121-124. 10.16352/j.issn.1001-6325.2016.01.027.
WU Xia , GAO Lu , XING Bing . Research progress on hypercoagulable state in Cushing’s syndrome[J]. Basic & Clinical Medicine, 2016, 36 (1 ): 121-124. 10.16352/j.issn.1001-6325.2016.01.027.
9 王薇, 王佳宁, 虞巍, 等. 肾上腺性库欣综合征与无功能腺瘤患者的凝血功能比较及其影响因素[J]. 北京大学学报(医学版), 2023, 55 (6 ): 1062-1067. 10.19723/j.issn.1671-167X.2023.06.017.
WANG Wei , WANG Jianing , YU Wei , Comparison of coagulation function between adrenocorticotropic hormone independent Cushing syndrome and nonfunctional adrenal adenoma and its influence factors[J]. Journal of Peking University. Health Sciences, 2023, 55 (6 ): 1062-1067. 10.19723/j.issn.1671-167X.2023.06.017.38101790
10 Johannesdottir SA , Horváth-Puhó E , Dekkers OM , Use of glucocorticoids and risk of venous thromboembolism: a nationwide population-based case-control study[J]. JAMA Intern Med, 2013, 173 (9 ): 743-752. 10.1001/jamainternmed.2013.122. 23546607
11 Limumpornpetch P , Morgan AW , Tiganescu A , The effect of endogenous cushing syndrome on all-cause and cause-specific mortality[J]. J Clin Endocrinol Metab, 2022, 107 (8 ): 2377-2388. 10.1210/clinem/dgac265. 35486378
12 van Zaane B , Nur E , Squizzato A , Hypercoagulable state in Cushing’s syndrome: a systematic review[J]. J Clin Endocrinol Metab, 2009, 94 (8 ): 2743-2750. 10.1210/jc.2009-0290. 19454584
13 Papakokkinou E , Olsson DS , Chantzichristos D , Excess morbidity persists in patients with Cushing’s disease during long-term remission: a Swedish nationwide study[J]. J Clin Endocrinol Metab, 2020, 105 (8 ): dgaa291. 10.1210/clinem/dgaa291. 32436951
14 Stuijver DJ , van Zaane B , Feelders RA , Incidence of venous thromboembolism in patients with Cushing’s syndrome: a multicenter cohort study[J]. J Clin Endocrinol Metab, 2011, 96 (11 ): 3525-3532. 10.1210/jc.2011-1661. 21880802
15 Wagner J , Langlois F , Lim DST , Hypercoagulability and risk of venous thromboembolic events in endogenous Cushing’s syndrome: a systematic meta-analysis[J]. Front Endocrinol, 2018, 9 : 805. 10.3389/fendo.2018.00805.
16 Babic B , De Roulet A , Volpe A , Is VTE prophylaxis necessary on discharge for patients undergoing adrenalectomy for cushing syndrome?[J]. J Endocr Soc, 2019, 3 (2 ): 304-313. 10.1210/js.2018-00278. 30652131
17 Kastelan D , Dusek T , Kraljevic I , Hypercoagulable state in Cushing’s syndrome is reversible following remission[J]. Clin Endocrinol, 2013, 78 (1 ): 102-106. 10.1111/j.1365-2265.2012.04479.x.
18 Suarez MG , Stack M , Hinojosa-Amaya JM , Hypercoagulability in Cushing syndrome, prevalence of thrombotic events: a large, single-center, retrospective study[J]. J Endocr Soc, 2020, 4 (2 ): bvz033. 10.1210/jendso/bvz033. 32064411
19 Koutroumpi S , Daidone V , Sartori MT , Venous thromboembolism in patients with Cushing’s syndrome: need of a careful investigation of the prothrombotic risk profile[J]. Pituitary, 2013, 16 (2 ): 175-181. 10.1007/s11102-012-0398-4. 22585010
20 Ferrante E , Serban AL , Clerici M , Evaluation of procoagulant imbalance in Cushing’s syndrome after short- and long-term remission of disease[J]. J Endocrinol Investig, 2022, 45 (1 ): 9-16. 10.1007/s40618-021-01605-5. 34115342
21 Wurth R , Rescigno M , Flippo C , Inflammatory biomarkers in the evaluation of pediatric endogenous Cushing syndrome[J]. Eur J Endocrinol, 2022, 186 (4 ): 503-510. 10.1530/EJE-21-1199. 35171827
22 Isidori AM , Minnetti M , Sbardella E , Mechanisms in endocrinology: The spectrum of haemostatic abnormalities in glucocorticoid excess and defect[J]. Eur J Endocrinol, 2015, 173 (3 ): R101-R113. 10.1530/EJE-15-0308. 25987566
23 Erem C , Nuhoglu I , Yilmaz M , Blood coagulation and fibrinolysis in patients with Cushing’s syndrome: increased plasminogen activator inhibitor-1, decreased tissue factor pathway inhibitor, and unchanged thrombin-activatable fibrinolysis inhibitor levels[J]. J Endocrinol Invest, 2009, 32 (2 ): 169-174. 10.1007/BF03345709. 19411818
24 Tripodi A , Ammollo CT , Semeraro F , Hypercoagulability in patients with Cushing disease detected by thrombin generation assay is associated with increased levels of neutrophil extracellular trap-related factors[J]. Endocrine, 2017, 56 (2 ): 298-307. 10.1007/s12020-016-1027-1. 27448294
25 Tirosh A , Lodish M , Lyssikatos C , Coagulation profile in patients with different etiologies for cushing syndrome: a prospective observational study[J]. Horm Metab, 2017, 49 (5 ): 365-371. 10.1055/s-0043-100113.
26 Coelho MCA , Santos CV , Vieira Neto L , Adverse effects of glucocorticoids: coagulopathy[J]. Eur J Endocrinol, 2015, 173 (4 ): M11-M21. 10.1530/EJE-15-0198. 25971647
27 Manetti L , Bogazzi F , Giovannetti C , Changes in coagulation indexes and occurrence of venous thromboembolism in patients with Cushing’s syndrome: results from a prospective study before and after surgery[J]. Eur J Endocrinol, 2010, 163 (5 ): 783-791. 10.1530/EJE-10-0583. 20696792
28 Hacioglu A , Firat ST , Caglar AS , Cardiovascular evaluation and endothelial dysfunction in Cushing syndrome following remission: a prospective study[J]. J Endocrinol Invest, 2024, 47 (3 ): 645-653. 10.1007/s40618-023-02183-4. 37648907
29 Moore MD , Agrusa C , Ullmann TM , Risk factors for venous thromboembolism (VTE) after adrenalectomy for adrenal cortical neoplasms[J]. J Surg Oncol, 2022, 126 (7 ): 1176-1182. 10.1002/jso.27059. 35997946
30 Obuobie K , Davies JS , Ogunko A , Venous thrombo-embolism following inferior petrosal sinus sampling in Cushing’s disease[J]. J Endocrinol Invest, 2000, 23 (8 ): 542-544. 10.1007/BF03343772. 11021772
31 Miljic P , Miljic D , Cain JW , Pathogenesis of vascular complications in Cushing’s syndrome[J]. Hormones, 2012, 11 (1 ): 21-30. 10.1007/BF03401535. 22450342
32 Fukuoka H , Takeuchi T , Matsumoto R , D-dimer as a significant marker of deep vein thrombosis in patients with subclinical or overt Cushing’s syndrome[J]. Endocr J, 2014, 61 (10 ): 1003-1010. 10.1507/endocrj.ej14-0102. 25100148
33 Birdwell L , Lodish M , Tirosh A , Coagulation profile dynamics in pediatric patients with Cushing syndrome: a prospective, observational comparative study[J]. J Pediatr, 2016, 177 : 227-231. 10.1016/j.jpeds.2016.06.087. 27496264
34 Waqar M , Chadwick A , Kersey J , Venous thromboembolism chemical prophylaxis after endoscopic trans-sphenoidal pituitary surgery[J]. Pituitary, 2022, 25 (2 ): 267-274. 10.1007/s11102-021-01195-8. 34843070
35 Boscaro M , Sonino N , Scarda A , Anticoagulant prophylaxis markedly reduces thromboembolic complications in Cushing’s syndrome[J]. J Clin Endocrinol Metab, 2002, 87 (8 ): 3662-3666. 10.1210/jcem.87.8.8703. 12161492
36 Zilio M , Mazzai L , Sartori MT , A venous thromboembolism risk assessment model for patients with Cushing’s syndrome[J]. Endocrine, 2016, 52 (2 ): 322-332. 10.1007/s12020-015-0665-z. 26113424
37 Segon YS , Summey RD , Slawski B , Surgical venous thromboembolism prophylaxis: clinical practice update[J]. Hosp Pract, 2020, 48 (5 ): 248-257. 10.1080/21548331.2020.1788893.
38 Bartlett MA , Mauck KF , Stephenson CR , Perioperative venous thromboembolism prophylaxis[J]. Mayo Clin Proc, 2020, 95 (12 ): 2775-2798. 10.1016/j.mayocp.2020.06.015. 33276846
39 Nendaz M , Spirk D , Kucher N , Multicentre validation of the Geneva Risk Score for hospitalised medical patients at risk of venous thromboembolism. Explicit ASsessment of Thromboembolic RIsk and Prophylaxis for Medical PATients in SwitzErland (ESTIMATE)[J]. Thromb Haemost, 2014, 111 (3 ): 531-538. 10.1160/TH13-05-0427. 24226257
40 Lopes V , Marques O , De Sousa Lages A . Preventive strategies for hypercoagulation in Cushing’s syndrome: when and how[J]. Thromb J, 2023, 21 (1 ): 72. 10.1186/s12959-023-00515-1. 37400845
41 van Haalen FM , Kaya M , Pelsma ICM , Current clinical practice for thromboprophylaxis management in patients with Cushing’s syndrome across reference centers of the European Reference Network on Rare Endocrine Conditions (Endo-ERN)[J]. Orphanet J Rare Dis, 2022, 17 (1 ): 178. 10.1186/s13023-022-02320-x. 35505430
42 孙旭, 卢琳, 冯铭, 等. 库欣综合征伴围手术期肺栓塞临床特点分析[J]. 中国现代神经疾病杂志, 2021, 21 (3 ): 177-184. 10.3969/j.issn.1672-6731.2021.03.009.
SUN Xu , LU Lin , FENG Ming , Analysis of clinical characteristics of Cushing’s syndrome complicated with pulmonary embolism during perioperative period[J]. Chinese Journal of Contemporary Neurology and Neurosurgery, 2021, 21 (3 ): 177-184. 10.3969/j.issn.1672-6731.2021.03.009.
43 Barbot M , Daidone V , Zilio M , Perioperative thromboprophylaxis in Cushing’s disease: What we did and what we are doing?[J]. Pituitary, 2015, 18 (4 ): 487-493. 10.1007/s11102-014-0600-y. 25239557
44 Daidone V , Boscaro M , Pontara E , New insight into the hypercoagulability of Cushing’s syndrome[J]. Neuroendocrinology, 2011, 93 (2 ): 121-125. 10.1159/000323765. 21304226
45 Gadelha M , Wildemberg LE . Alternative approach to BIPSS in the differential diagnosis of ACTH-dependent Cushing’s syndrome[J]. J Clin Endocrinol Metab, 2023: dgad676. 10.1210/clinem/dgad676.
46 Huckhagel T , Atlihan G , Langer F , Prevalence of perioperative asymptomatic venous thromboses of the lower extremity in 30 consecutive patients undergoing transsphenoidal surgery for Cushing’s disease[J]. Sci Rep, 2023, 13 (1 ): 3217. 10.1038/s41598-023-30070-8. 36828936
47 Clayton RN , Jones PW , Reulen RC , Mortality in patients with Cushing’s disease more than 10 years after remission: a multicentre, multinational, retrospective cohort study[J]. Lancet Diabetes Endocrinol, 2016, 4 (7 ): 569-576. 10.1016/S2213-8587(16)30005-5. 27265184
48 Fleseriu M , Varlamov EV , Hinojosa-Amaya JM , An individualized approach to the management of Cushing disease[J]. Nat Rev Endocrinol, 2023, 19 (10 ): 581-599. 10.1038/s41574-023-00868-7. 37537306
