左心室辅助与抗栓治疗策略(二)| 云彤辅心
LVAD植入患者的长期管理中,抗栓治疗发挥着至关重要的作用,它直接关系到LVAD相关并发症的发生和发展。同时,这些并发症也反过来影响着抗栓治疗的策略选择。本期北京安贞医院刘彤教授将从“出血与血栓栓塞并发症的病理生理学”的角度与大家深入解析和讨论"左心室辅助植入后的抗栓治疗策略"这一主题。
作者:刘彤 首都医科大学附属北京安贞医院
来源:MiHeart
连续流左心室辅助装置(CF-LVAD)植入后,出血或血栓事件的发生可能与多种因素相关,包括患者的个体差异、器械的特性以及外部环境因素(见下图1)。这些因素间的相互作用决定了是否会出现出血或血栓事件。
图1 患者、LVAD和外部因素间的相互关系,引致了特定的血栓形成或出血事件的倾向
(来源:Ann Transl Med. 2021;9(6):521.)
(一)器械类型
正如上篇中所提到的,已有充分的临床证据证实,器械类型是决定出血和血栓事件发生的关键因素。脉动式LVADs虽然在卒中、血栓栓塞事件和器械故障方面的发生率较高,但对于胃肠道出血(Gastrointestinal bleeding/hemorrhage,GIB),其风险并未显著增加[1]。对比之下,轴流式连续流泵CF-LVADs显著降低了卒中、血栓栓塞事件和器械故障的风险[2];但在另一方面,随着脉动性减少,动静脉畸形(Arteriovenous malformation,AVM)的发生发展与复发性GIB成为了新的重要问题[3]。此外,如前篇所述,离心式CF-LVAD(Heartware HVAD)可能会增加卒中的风险。
图2 CF-LVADs可能导致胃肠道出血的机制总结。VEGFR2,血管内皮生长因子受体2;vWF,血管性血友病因子
(来源:Circ Res. 2017 Sep 29;121(8):902-904.)
MOMENTUM 3研究[4]和INTERMACS分析[5]均已证实,全磁悬浮HM-3与既往的第二代轴流式HM-II和磁液悬浮HeartWare HVAD相比,血液相容性显著提升,从而显著降低了泵血栓形成和卒中的发生。即便如此,也要同时看到,这些患者出血并发症的降低幅度有限[4,6],且GIB的发生率并未得到改善[4]。鉴于全磁悬浮HM-3在减少血栓栓塞事件方面的显著效果,临床医生们正在考虑调整抗凝和抗血小板治疗方案,以进一步降低GIB的发生概率[7,8,9]。
图3 MOMENTUM研究的亚组分析,常规剂量阿司匹林组(325mg)和低剂量阿司匹林组(81mg)比较,无出血或血栓事件的生存率没有差异。ASA,阿司匹林;HM3,HeartMate 3;HRAE,血液相容性相关不良事件
(来源:J Heart Lung Transplant. 2020 June; 39(6): 518-525.)
不同LVADs在出血或血栓事件上的差异,取决于多种因素,其中血液相容性是关键。血液相容性指的是器械装置与血液接触时引发的血栓反应。影响LVAD血液相容性的因素包括剪切应力引起的血小板激活[10]、内皮细胞激活[11]、vWF降解[12]和氧化应激[13]。不同LVADs在这些参数上的影响能力各不相同[14-16]。除了LVAD自身的特性,脉动性等其它一些参数也在出血或血栓形成与发展中起着重要作用[17]。
图4 针对HM-3和EVAHEART泵的体外研究示意图,将它们集成在使用健康志愿者全血的双体外泵循环中
(来源:J Heart Cardiovasc Surg. 2019;157:591-9.)
(二)患者个体差异
患者的个体差异在出血或血栓栓塞事件的发展中,也扮演着重要角色。一些不可修改的因素,如年龄、性别和遗传多态性,对这些事件有着显著的影响。例如,年龄较大的患者更易经历出血和血栓事件[18];女性患者则与较高的卒中风险相关[19],等等。
图6 LVAD患者缺血性卒中的风险评分,包括了变量与分数
(来源:JACC Heart Fail. 2017 October;5(10):703-711.)
而在可修改的风险因素中,高血压已被证实与出血性和缺血性卒中的发生有关[20]。优化血流动力学,如使得中心静脉压低于12mmHg、肺动脉楔压低于18mmHg,以及心指数超过2.2l/min/m2,可显著减少患者受到血液相容性不良事件(HRAEs)的影响[21]。
一项小型研究发现,LVAD植入后3月内出现的显著主动脉瓣关闭不全(AI)与HRAEs有关系[22]。此外,肺动脉舒张压和肺毛细血管楔压的不匹配,可致右心衰恶化,也与HRAEs相关。这种相关性可能与泵功能停滞、肝脏充血、随后的炎症反应和凝血级联反应失衡,以及AVM的发展有关。
图7 根据显著主动脉瓣反流是否存在(A)(定义为反流分数>30%)和分层(B),来比较其与HRAEs的关系
(来源:J Card Fail. 2019 October;25(10):787-794.)
(三)外部环境因素
外源性因素在出血或血栓事件的发展中,也起着至关重要的作用,尤其是与抗凝和抗血小板治疗强度和策略密切相关的因素。在CF-LVAD患者中,最常见的出血事件风险因素是过度抗凝。INR的升高,即与出血事件紧密相关,特别是当其超过3.5时,出血事件显著增加。另一方面,较高的基线INR值也与出血事件相关,这可能暗示了该患者潜在的肝脏功能障碍,或由右心力衰引起的继发性肝充血[23]。
其他影响因素还包括:抗血小板药物、血小板减少或功能障碍(无论是由CF-LVAD引起或其它原因)、获得性von Willebrand综合征、肾功能损害、LVAD植入前的体外膜肺氧合(Extracorporeal membrane oxygenation,ECMO)支持以及感染并发症。患者对药物的依从性、药物间的相互作用以及不良生活习惯如烟草,也均可影响血栓/出血事件[24]。
图8 LVAD患者早期、晚期出血性和缺血性卒中的多变量预测因素
(来源:Journal of Heart and Lung Transplantation, http://dx.doi.org/10.1016/j.healun.2016.12.010.)
器械的特性、患者的个体差异以及外部因素的相互作用,在每位患者中形成了一个独特的组合。这就要求我们必须采取个性化的策略来预防出血/血栓事件。例如,遗传变异可能使得患者对华法林、阿司匹林和氯吡格雷产生不同的药物反应,及早识别无反应患者,对制定预防出血/血栓栓塞事件的策略亦很重要[25]。
往期推荐
刘彤 教授
引用文献:
1. Eric A. Rose, Annetine C. Gelijns, Alan J. Moskowitz, et al. Long-term use of a left ventricular assist device for end-stage heart failure. N Engl J Med. 2001;345:1435-1443.
2. Andreas R. de Biasi, Keefe B. Manning, Arash Salemi. Science for surgeons: understanding pump thrombogenesis in continuous-flow left ventricular assist devices. J Thorac Cardiovasc Surg. 2015;149:667-73.
3. Emma J. Birks. Stopping LVAD bleeding. A piece of the puzzle. Circ Res. 2017 Sep 29;121(8):902-904.
4. Mandeep R. Mehra, Nir Uriel, Yoshifumi Naka, et al. A fully magnetically levitated left ventricular assist device-final report. N Engl J Med. 2019;380:1618-1627.
5. Jeffery J. Teuteberg, Joseph C. Cleveland, Jennifer Cowger, et al. The Society of Thoracic Surgeons Intermacs 2019 Annual Report: The Changing Landscape of Devices and Indications. Ann Thorac Surg. 2020;109:649-60.
6. Robert L. Kormos, Christiaan F.J. Antonides, Daniel J. Goldstein, et al. Updated definitions of adverse events for trials and registries of mechanical circulatory support: a consensus statement of the mechanical circulatory support academic research consortium. J Heart Lung Transplant. 2020 Aug;39(8):735-750.
7. Mandeep R. Mehra, Ivan Netuka, Nir Uriel, et al. Aspirin and hemocompatibility events with a left ventricular assist device in advanced heart failure. The ARIES-HM3 randomized clinical trial. JAMA. 2023;330(22):2171-2181.
8. Omar Saeed, Paolo C. Colombo, Mandeep R. Mehra, et al. Effect of aspirin dose on hemocompatibility-related outcomes with a magnetically levitated left ventricular assist device: an analysis from the MOMENTUM 3 study. J Heart Lung Transplant. 2020 June ; 39(6): 518–525. doi:10.1016/j.healun.2020.03.001.
9. Ivan Netuka, Peter Ivak, Zuzana Tucanova, et al. Evaluation of low-intensity and anti-coagulation with a fully magnetically levitated centrifugal-flow circulatory pump-the MAGENTUM 1 study. J Heart Lung Transplant. 2018;37:579-586.
10.Filippo Consolo, Giulia Sferrazza, Giulia Motolone, et al. Platelet activation is a preoperative risk factor for the development of thromboembolic complications in patients with continuous-flow left ventricular assist device. European Journal of Heart Failure (2018)20,792-800.
11.Alice Apostoli, Valentina Bianchi, Nina Bono, et al. Prothrombotic activity of cytokine-activated endothelial cells and shear-activated platelets in the setting of ventricular assist device support. J Heart Lung Transplant. 2019 June ; 38(6): 658–667. doi:10.1016/j.healun.2019.02.009.
12.Choon-Sik Jhun, Christopher Siedlecki, Lichong Xu, et al. Stress and exposure time on von Willebrand factor degradation. Artif Organs. 2019 Feb;43(2):199-206.
13.Nandan K. Mondal, Zengsheng Chen, Jaimin R. Trivedi, et al. Oxidative stress induced modulation of platelet integrin α2bβ3 expression and shedding may predict the risk of major bleeding in heart failure patients supported by continuous flow left ventricular assist device. Thromb Res. 2017 October ; 158: 140–148. doi:10.1016/j.thromres.2017.09.006.
14.Zachary B.K. Berk, Jiafeng Zhang, Zengsheng Cheng, et al. Evaluation of in vitro hemolysis and platelet activation of a newly developed MagLev LVAD and two clinically used LVADs with human blood. Artif Organs. 2019 September;43(9):870-879.
15.Ivan Netuka, Tomas Kvasnicka, Jan Kvasnicka, et al. Evaluation of von Willebrand factor with a fully magnetically levitated centrifugal continuous-flow left ventricular assist device in advanced heart failure. J Heart Lung Transplant. 2016;35:860-867.
16.Rashad Zayat, Ajay Moza, Oliver Grottke, et al. In vitro comparison of the hemocompatibility of two centrifugal left ventricular assist devices. J Thorac Cardiovasc Surg. 2019;157:591-9.
17.Omar Wever-Pinzon, Craig H. Selzman, Stavros G. Drakos, et al. Pulsatility and the risk of nonsurgical bleeding in patients supported with the continuous-flow left ventricular assist device HeartMate II. Circ Heart Fail. 2013 May;6(3):517-26.
18.Caren Taylor, Krystle Bittner, Nicholas Bartell, et al. Outcomes of gastrointestinal bleeding in patients with left ventricular assist devices: a tertiary care experience. Endoscopy International Open. 2020;08:E301-E309.
19.Deepak Acharya, Renzo Loyaga-Rendon, Charity J. Morgan, et al. INTERMACS analysis of stroke during support with continuous flow left ventricular assist devices: risk factors and outcomes. JACC Heart Failure. 2017 October;5(10):703-711.
20.Alberto Pinsino, Francesco Castagna, Amelia M. Zuver, et al. Prognostic impications of serial outpatient blood pressure measurements in patients with anaxial continuous-flow left ventricular assist device. J Heart Lung Transplant. 2019;38:396-405.
21.Teruhiko Imamura, Ann Nguyen, Gene Kim, et al. Optimal haemodynamics during left ventricular assist device support are associated with reduced haemocompatibility-related adverse events. Eur J heart Fail. 2019 May;21(5):655-662.
22.Teruhiko Imamura, Gene Kim, Daisuke Nitta, et al. Aortic insufficiency and hemocompatibility-related adverse events in patients with left ventricular assist devices. J Card Fail. 2019 October;25(10):787-794.
23.Saadia Sherazi, Peter Kouides, Charles Francis, et al. Prospective analysis of bleeding events in left ventricular assist device patients. Int J Artif Organs. 2018 May;41(5):269-276.
24.Jennifer A. Frontera, Randall Starling, Sung-Min Cho, Amy S. Nowacki, Ken Uchino, M. Shazam Hussain, Maria Mountis and Nader Moazami, Risk Factors, Mortality and Timing of Ischemic and Hemorrhagic Stroke with Left Ventricular Assist Devices, Journal of Heart and Lung Transplantation, http://dx.doi.org/10.1016/j.healun.2016.12.010.
25.A. Montalto, M. Comisso, A. Cammardella, et al. Early Aspirin nonresponders identification by routine use of aggregometry test in patients with left ventricle assist devices reduces the risk of pump thrombosis. Transplant Proc. 2019 Nov;51(9):2986-2990.
微信扫码关注该文公众号作者