Published online: 2019-08-17 1590 Theme Issue Article Thrombogenicity and Antithrombotic Strategies in Structural Heart Interventions and Nonaortic Cardiac Device Therapy—Current Evidence and Practice Tobias Geisler1 Rezo Jorbenadze1 Aron-Frederik Popov2 Karin L. Mueller1 Dominik Rath1 Michal Droppa1 Juergen Schreieck1 Peter Seizer1 Robert F. Storey3 Steen D. Kristensen4 Andrea Rubboli5 Diana Gorog6,7 Daniel Aradi8,9 Dirk Sibbing10,11 Kurt Huber12,13 Meinrad Gawaz1 Jur Ten Berg14 1 Department of Cardiology and Angiology, University Hospital, Address for correspondence Tobias Geisler, MD, MHBA, Department Eberhard-Karls University of Tübingen, Tübingen, Germany of Cardiology and Angiology, University Hospital, Eberhard-Karls 2 Department of Thoracic and Cardiovascular Surgery, University University of Tübingen, Tübingen, Germany Medical Center Tübingen, Eberhard-Karls University of Tübingen, (e-mail: [email protected]; [email protected]). Tübingen, Germany 3 Department of Infection, Immunity and Cardiovascular Disease, University of Sheffield, Sheffield, United Kingdom 10Department of Cardiology, LMU München, Munich, Germany 4 Department of Cardiology, Aarhus University Hospital, Aarhus, Denmark 11DZHK (German Centre for Cardiovascular Research), partner site 5 Division of Cardiology, Department of Cardiovascular Disease– Munich Heart Alliance, Munich, Germany AUSL Romagna, Ospedale S. Maria delle Croci, Ravenna, Italy 123rd Department of Medicine, Cardiology and Intensive Care 6 National Heart and Lung Institute, Imperial College London, Medicine, Wilhelminenhospital, Vienna, Austria London, United Kingdom 13Medical Faculty, Sigmund Freud University, Vienna, Austria 7 University of Hertfordshire, Hertfordshire, United Kingdom 14Department of Cardiology, St Antonius Hospital, Nieuwegein, 8 Heart Center Balatonfured, Balatonfured, Hungary The Netherlands 9 Heart and Vascular Center, Semmelweis University, Budapest, Hungary Thromb Haemost 2019;119:1590–1605. Abstract As the number of, and the indications for, structural heart interventions are increasing worldwide, the optimal secondary prevention to reduce device thrombosis is becoming more important. To date, most of the recommendations are empiric. The current review discusses mechanisms behind device-related thrombosis, the available evidence Keywords with regard to antithrombotic regimen after cardiac device implantation, as well as ► patent foramen ovale providing an algorithm for identification of risk factors for device thrombogenicity and ► left atrial appendage for management of device thrombosis after implantation of patent foramen ovale and ► MitraClip left atrial appendage occluders, MitraClips/transcatheter mitral valve replacement, ► left ventricular assist pacemaker leads, and left ventricular assist devices. Of note, the topic of antithrom- device botic therapy and thrombogenicity of prostheses in aortic position (transcatheter ► device-related aortic valve replacement, surgical, mechanical, and bioprostheses) is not part of the thrombosis present article and is discussed in detail in other contemporary focused articles. This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited. Introduction Following device implantation, thrombotic events associated Michal Droppa’s ORCID is https://orcid.org/0000-0001-5807- with cardiac devices can be attributed to thrombosis that 7615. occurs either by direct contact activation on the device received © 2019 Georg Thieme Verlag KG DOI https://doi.org/ April 12, 2019 Stuttgart · New York 10.1055/s-0039-1694751. accepted after revision ISSN 0340-6245. June 21, 2019 Thrombogenicity and Antithrombotic Strategies in Structural Heart Interventions and LVAD Geisler et al. 1591 surface (device thrombosis) or indirectly as a result of cardiac negatively charged hydrophilic surfaces that act indepen- thromboembolism provoked by changed hemodynamics and dently from blood flow velocity.1 Fibrinogen, fibronectin, flow characteristics after device implantation (device-relat- and von Willebrand factor (vWF) primarily adhere to the ed thrombosis [DRT]). In the following review, we shall surface of devices and lead to activation and adhesion of briefly discuss the mechanisms of device thrombosis and platelets. Negatively charged surfaces further activate factor DRT and give an overview of the clinical problems, epidemi- XII to factor XIIa, thus initiating the intrinsic pathway. Factor ological evidence, and management strategies of cardiac XIIa also induces complement activation leading to thrombin device thrombosis. A separate paragraph will provide an amplification. Leukocytes, in particular neutrophils, also update about the mechanisms of left ventricular assist device adhere to fibrinogen immobilized on the device surface via (LVAD) thrombosis and give guidance on treatment CD11b/CD18 (macrophage-1 antigen 1 [MAC-1]).2 Following strategies. adhesion and activation, platelets interact with leucocytes mainly via cross-linking of P-selectin with P-selectin glyco- α Mechanisms of Device Thrombosis protein ligand-1 and MAC-1 with glycoprotein 1b . Leuco- cyte degranulation contributes to a prothrombotic and Implantable devices usually contain a prothrombotic surface proinflammatory milieu by generating free radicals, releas- that lead to activation of the coagulation system by a ing interleukins and tumor necrosis factor α, and activating complex interplay between blood cells and plasma proteins. monocytes, leading to induction of tissue factor expression This process is characterized by enhanced adsorption of and consequent initiation of the coagulation cascade proteins, adhesion of platelets, leukocytes, and red blood (►Fig. 1). Attempts to reduce protein adsorption on the cells, activation of the extrinsic coagulation cascade leading device surface have been mainly driven by the reduction of to thrombin generation, and activation of the complement electrostatic and hydrophobic interactions between plasma system. Thrombogenicity is further enhanced by the under- proteins and the artificial surface. Synthetic and natural lying cardiac disease, particularly heart failure (HF), leading materials that hamper this process include polyethylene to disturbances in endothelial function and impaired blood oxide, phosphorylcholine, pyrolytic carbon, albumin, and flow and composition. Protein adsorption is caused by elastin-inspired protein polymers.1 This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited. Fig. 1 Mechanism of contact activation on artificial surface leading to device thrombosis (figure was composed by using Adobe Stock vectors). DTI, direct thrombin inhibitor; IL, interleukin; MAC-1, macrophage-1 antigene; PSGL1, P-Selectin glycoprotein ligand-1; TF, tissue factors; TNF, tumor necrosis factor; VKA, vitamin k antagonists; vWF, von Willebrand factor. Thrombosis and Haemostasis Vol. 119 No. 10/2019 1592 Thrombogenicity and Antithrombotic Strategies in Structural Heart Interventions and LVAD Geisler et al. Methods device and the time of follow-up was usually lower compared – with the medical arm in recent trials.5 7,9 It is difficult to We performed a systematic search regarding device throm- determine association with device thrombosis as, in some bosis and DRT and antithrombotic management after cardiac studies, different occluder devices were used7 and systematic device therapy in the international guidelines, including the transesophageal echocardiography (TOE) follow-up was per- guidelines and position papers of the European Society of formed in only few trials. Of note, there havebeen observations Cardiology (ESC)3,4 and the American Heart Association/ that stroke occurred even if there was no detection of device American Stroke Association. thrombosis nor device leakage,10,11 highlighting the impor- In addition, we searched for relevant ongoing clinical trials tance of careful risk assessment to first clarify the causality of in the registry of clinical trials (clinicaltrials.gov) using key- paradoxical embolism and second defining the residual stroke words “Mitral interventions,”“left atrial appendage (LAA) risk after PFO occluder. occlusion,”“antithrombotic treatment,” and “patent foramen PFO closure device thrombosis is a rare event and has been ovale/PFO.” A review of current literature was performed using described in ranges from 0.4 to 1.2% depending on the type of the search terms “device related thrombosis,”“antithrombotic occluder and duration of follow-up (►Fig. 2).12,13 In a system- therapy after cardiac devices,”“thrombolytic therapy for device atic series of 620 patients treated with the AMPLATZER thrombosis,”“patent foramen ovale / PFO,”“cardiac occluder,” PFO occluder for secondary prevention of paradoxical embo- “LAA,”“Amplatzer Cardiac Plug and thrombosis,”“Amplatzer lism, 6-month follow-up revealed only two cases showing small Amulet and thrombosis,”“Watchman and thrombosis,”“pace- thrombi on the atrial disk.14 Although thrombi at the right atrial maker related thrombosis,”“ICD related thrombosis,” and disc have been usually reported, there are single reports of “LVAD thrombosis” in pubmed.gov. organized thrombi at the left atrial disc (example of echocar- diographic finding in ►Fig. 3C and ref. 15). It is a matter of debate Risk Factors for Patent Foramen Ovale whether PFO occluder thrombosis is related to the device itself ClosureDeviceThrombosis or rather due to a hypercoagulable state as a consequence of alteration in hemodynamics