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Leaflet Thrombosis in SurgicallyExplanted or Post-Mortem TAVR Valves

Fernanda M. Mangione, MD,a Tannas Jatene, MD,a Alexandra Gonçalves, MD, PHD, MMSC,a Gregory A. Fishbein, MD,b

Richard N. Mitchell, MD, PHD,b Marc P. Pelletier, MD,c Tsuyoshi Kaneko, MD,c Pinak B. Shah, MD,a

Charles B. Nyman, MBBCH,d Douglas Shook, MD,d Ron Blankstein, MD,a Robert F. Padera, MD, PHD,b

Deepak L. Bhatt, MD, MPHa

LEAFLET THROMBOSIS IS CURRENTLY ONE OF THE GREATEST CONCERNS RELATED TO TRANSCATHETER

aortic valve replacement (TAVR). Symptomatic valve thrombosis is a rare occurrence, but reduced leafletmotion, diagnosed by computed tomography, seems to be a more common finding (1).

We screened our pathology registries for patients with a prior TAVR who underwent a post-mortem exami-nation or who had a TAVR device surgically explanted in an attempt to understand better the causes of TAVRfailure. Of 13 valves studied, we found 4 cases of leaflet thrombosis diagnosed only on pathological examination(Figures 1 to 4, Online Videos 1, 2, and 3). Two of the patients had a valve-in-valve TAVR (Figures 1 and 3), and in 3cases, there was incomplete expansion or asymmetry of the valve (Figures 1, 2, and 4). None of the patients wereon anticoagulation. There were also 2 cases of endocarditis, 1 coronary obstruction, and 2 cases of paravalvularleak. The other 4 patients had no substantial valve findings.

TAVR valve thrombosis is underdiagnosed, and the mechanisms for its development might be associatedwith underexpansion and asymmetry of the valve. Valve-in-valve TAVR may be associated with these featuresmore often and might be a risk factor for leaflet thrombosis.

From the aBrigham andWomen’s Hospital Heart & Vascular Center and Harvard Medical School, Boston, Massachusetts; bBrigham

and Women’s Hospital Department of Pathology and Harvard Medical School, Boston, Massachusetts; cBrigham and Women’s

Hospital Department of Surgery and Harvard Medical School, Boston, Massachusetts; and dBrigham and Women’s Hospital

Department of Anesthesiology and Harvard Medical School, Boston, Massachusetts. Dr. Gonçalves has received funds from the

Portuguese Foundation for Science and Technology, Grant HMSP-ICS/007/2012. Dr. Pelletier is a consultant for St. Jude

Medical. Dr. Kaneko is a consultant for Edwards Lifesciences. Dr. Shah is a proctor for Edwards Lifesciences; and a course

director for Edwards Lifesciences and St. Jude Medical. Dr. Nyman has received educational honoraria and holds stock in

Edwards Lifesciences. Dr. Shook has received education honoraria from Edwards Lifesciences, Sorin Group, and Boston

Scientific; and is a consultant for Edwards Lifesciences. Dr. Padera is a pathology consultant for Medtronic, Direct Flow, and

Boston Scientific. Dr. Bhatt is on the advisory boards of Cardax, Elsevier Practice Update Cardiology, Medscape Cardiology, and

Regado Biosciences; is on the board of directors of Boston VA Research Institute and the Society of Cardiovascular Patient

Care; chairs the American Heart Association Quality Oversight Committee; is on data monitoring committees for Duke Clinical

Research Institute, Harvard Clinical Research Institute (including for his role as DMC Chair of the PORTICO trial), Mayo Clinic,

and the Population Health Research Institute; has received honoraria from the American College of Cardiology (Senior

Associate Editor, Clinical Trials and News, ACC.org), Belvoir Publications (Editor-in-Chief, Harvard Heart Letter), Duke Clinical

Research Institute (clinical trial steering committees), Harvard Clinical Research Institute (clinical trial steering committee),

HMP Communications (Editor-in-Chief, Journal of Invasive Cardiology), Journal of the American College of Cardiology (Guest

Editor; associate editor), Population Health Research Institute (clinical trial steering committee), Slack Publications (Chief

Medical Editor, Cardiology Today’s Intervention), Society of Cardiovascular Patient Care (secretary/treasurer), and WebMD

(CME steering committees); has other relationships with Clinical Cardiology (Deputy Editor), NCDR-ACTION Registry Steering

Committee (Vice-Chair), and VA CART Research and Publications Committee (Chair); has received research funding from

Amarin, Amgen, AstraZeneca, Bristol-Myers Squibb, Eisai, Ethicon, Forest Laboratories, Ischemix, Medtronic, Pfizer, Roche,

Sanofi Aventis, and The Medicines Company; has received royalties from Elsevier (Editor, Cardiovascular Intervention: A

Companion to Braunwald’s Heart Disease); has been a site coinvestigator for Biotronik, Boston Scientific, and St. Jude Medical;

is a trustee of the American College of Cardiology; and has performed unfunded research for FlowCo, PLx Pharma, and

Takeda. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.

Manuscript received August 23, 2016; revised manuscript received November 14, 2016, accepted November 16, 2016.

FIGURE 1 Undiagnosed Valve-in-Valve Leaflet Thrombosis Related to Incomplete TAVR Expansion Leading to Surgical Aortic Valve Replacement

An 82-year-old man, who previously underwent surgical aortic valve replacement, developed very rapid stenosis of the bioprosthetic valve 2 years after

the surgery. He underwent a successful TAVR, but after 6 months, his new valve also developed stenosis. Transesophageal echocardiography showed the

transcatheter valve with diffuse thickening inside the bioprosthetic surgical valve. No thrombus was seen (Online Videos 1 and 2). The mean pressure

gradient was 56 mm Hg (A). The patient had been chronically treated with aspirin and clopidogrel. He underwent a successful surgical aortic valve

replacement. Post-explantation assessment of the valves showed a very calcified surgical valve (B, arrow). The Edwards Sapien valve (Edwards Life-

sciences, Irvine, California) had a low position of implantation (B) and incomplete expansion causing deformation of the leaflets (C). There was thrombus

in the outflow of all 3 cusps resulting in restriction of motion and subsequent stenosis (C, arrows). Microscopic image showing the Sapien cusp with a

thrombus (D, arrow). TAVR ¼ transcatheter aortic valve replacement.

FIGURE 2 Early Leaflet Thrombosis Related to Asymmetry of the TAVR

An 88-year-old man underwent TAVR complicated by aortic regurgitation and

refractory hypotension, that resolved after additional balloon expansion. One

week after, the patient developed acute peripheral artery occlusion and under-

went left superficial femoral artery thrombectomy with stent placement. He was

receiving dual antiplatelet therapy, and heparin was added. Immediately post-

procedure, his hematocrit significantly dropped, and after 3 hours, he had a

sudden cardiac arrest. Autopsy findings showed the Edwards Sapien device in the

aortic position with a distorted oval shape, likely related to the severe athero-

sclerosis and calcification of the aorta. Due to this configuration, the left and

right coronary leaflets were unable to coapt fully, resulting in an abnormal flow

that may have predisposed to the formation of an organizing thrombus behind

the right coronary leaflet (arrow). The autopsy also revealed signs of significant

upper gastrointestinal hemorrhage. TAVR ¼ transcatheter aortic valve

replacement.

J A C C : C A R D I O V A S C U L A R I M A G I N G , V O L . 1 0 , N O . 1 , 2 0 1 7 Mangione et al.J A N U A R Y 2 0 1 7 : 8 2 – 5 TAVR Leaflet Thrombosis

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FIGURE 3 Valve-in-Valve Leaflet Thrombosis Associated With Severe Cardiac Amyloidosis

An 83-year-old man underwent transfemoral TAVR. A few days after the procedure, he developed symptoms of heart failure, and transesophageal echocardiography

revealed moderate-to-severe aortic regurgitation (A and B). An Edwards Sapien valve-in-valve was placed, and a smaller leak was closed successfully using an

Amplatzer Vascular Plug (C, black arrow). One month later, he underwent subtotal colectomy due to a colitis, and his warfarin was discontinued. He was discharged with

aspirin, and approximately 30 days after that, he developed severe respiratory failure and expired. Autopsy findings revealed the transcatheter valve without any

evident structural or mechanical defects. Thrombus with subacute organization was found in both atrial appendages and ventricles, attributed to stasis due to poor

cardiac function in the setting of severe amyloid-induced restrictive physiology. A thrombus with minimal organization was also present on 2 of the cusps of the TAVR

contributing to functional aortic stenosis (C to F, red arrows). TAVR ¼ transcatheter aortic valve replacement.

Mangione et al. J A C C : C A R D I O V A S C U L A R I M A G I N G , V O L . 1 0 , N O . 1 , 2 0 1 7

TAVR Leaflet Thrombosis J A N U A R Y 2 0 1 7 : 8 2 – 5

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FIGURE 4 Early Leaflet Thrombosis Related to Asymmetry and Underexpansion of the TAVR

A 75-year-old woman underwent transfemoral TAVR immediately complicated by a left bundle branch block. The patient was discharged 3 days later on aspirin and

clopidogrel. One day after discharge, she was admitted with chest pressure, pulmonary edema, and new-onset atrial fibrillation. Transthoracic echocardiography

showed diffuse thickening of the transcatheter valve (A, arrow) (Online Video 3), but no increase in the mean pressure gradient (10 mm Hg [B]) and severe decrease in

left ventricle ejection fraction (from 50% to 30%) with new anterior and septal segmental dysfunction. Her hospital course was complicated by hemodynamic

instability, and she expired after 24 h of hospitalization. Autopsy findings showed low implantation of the Edwards Sapien 3 valve, impinging on the basal surface of

the myocardium and compressing the AV node (C). The valve showed asymmetry due to incomplete expansion and presence of thrombus on the valve leaflets (D and

E). There was multifocal acute ischemic damage to cardiomyocytes. AV ¼ atrioventricular; TAVR ¼ transcatheter aortic valve replacement.

J A C C : C A R D I O V A S C U L A R I M A G I N G , V O L . 1 0 , N O . 1 , 2 0 1 7 Mangione et al.J A N U A R Y 2 0 1 7 : 8 2 – 5 TAVR Leaflet Thrombosis

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REPRINT REQUESTS AND CORRESPONDENCE: Dr. Deepak L. Bhatt, Brigham and Women’s Hospital Heart &Vascular Center and Harvard Medical School, 75 Francis Street, Boston, Massachusetts 02115. E-mail:dlbhattmd@post.harvard.edu.

RE F E RENCE

1. Makkar RR, Fontana G, Jilaihawi H, et al. Possiblesubclinical leaflet thrombosis in bioprosthetic aorticvalves. N Engl J Med 2015;373:2015–24.

KEY WORDS aortic stenosis, autopsy,pathology, TAVR, thrombosis

APPENDIX For supplemental videos,please see the online version of this article.