Author + information
- Received September 30, 2014
- Revision received February 13, 2015
- Accepted March 3, 2015
- Published online April 27, 2015.
- Eduardo De Marchena, MD∗,
- Julian Mesa, MD∗∗ (, )
- Sydney Pomenti, BS∗,
- Christian Marin y Kall, MD∗,
- Ximena Marincic, BS∗,
- Kazuyuki Yahagi, MD†,
- Elena Ladich, MD†,
- Robert Kutys, MS†,
- Yaar Aga, BS∗,
- Michael Ragosta, MD‡,
- Atul Chawla, MD§,
- Michael E. Ring, MD|| and
- Renu Virmani, MD†
- ∗International Medicine Institute, Department of Medicine, Division of Cardiology, University of Miami Miller School of Medicine, Miami, Florida
- †CVPath Institute, Gaithersburg, Maryland
- ‡Division of Cardiology, University of Virginia, Charlottesville, Virginia
- §Division of Cardiology, Iowa Heart Center, Des Moines, Iowa
- ||Division of Cardiology, Providence Spokane Heart Institute, Providence Sacred Heart Medical Center and Children’s Hospital, Spokane, Washington
- ↵∗Reprint requests and correspondence:
Dr. Julian Mesa, University of Miami Miller School of Medicine, Cardiovascular Division, Dominion Towers, 1400 NW 10th Avenue, Suite 206A, Miami, Florida 33136.
Objectives This paper reviews the published data and reports 3 cases of thrombosis involving CoreValve (Medtronic, Minneapolis, Minnesota) and 1 involving Edward Sapien (Edwards Lifesciences, Irvine, California) devices. Three of these cases had pathological findings at autopsy.
Background Only a limited number of cases of valve dysfunction with rapid increase of transvalvular aortic gradients or aortic insufficiency post-transcatheter aortic valve replacement (TAVR) have been described. This nonstructural valvular dysfunction has been presumed to be because of early pannus formation or thrombosis.
Methods Through reviews of the published reports and 4 clinical cases, pathological and clinical findings of early valve thrombosis are examined to elucidate methods for recognition and identifying potential causes and treatments.
Results This paper presents 4 cases, 2 of which had increasing gradients post-TAVR. All 3 pathology cases showed presence of a valve thrombosis in at least 2 TAV leaflets on autopsy, but were not visualized by transthoracic echocardiogram or transesophageal echocardiogram. One case was medically treated with oral anti coagulation with normalization of gradients. The consequence of valve thrombosis in all 3 pathology patients either directly or indirectly played a role in their early demise. At least 18 case reports of early valve thrombosis have been published. In 12 of these cases, the early treatment with anticoagulation therapy resolved the thrombus formation and normalized aortic pressures gradients successfully.
Conclusions These 4 cases elucidate the occurrence of valve thrombosis post-TAVR. Consideration should be given to treatment with dual antiplatelet therapy and oral anticoagulation in patients post-TAVR with increasing mean pressure gradients and maximum aortic valve velocity. Further research should be conducted to create guidelines for antithrombotic therapy following TAVR procedure.
Calcific aortic stenosis (AS) remains the most prevalent valvular disease in the elderly population, and the prevalence of AS continues to grow as our population ages (1–3). Transcatheter aortic valve replacement (TAVR) has become the therapy of choice for patients with severe AS clinically deemed to be at high risk or considered nonsurgical for conventional surgical aortic valve replacement (SAVR) (1,4–10). Although limited TAVR procedures to date have shown a similar rate of failure to those individuals treated with surgical aortic valve (11–14). However, there has been insufficient time to track full outcomes of TAVR procedures (≥5 years) due to the introduction and approval of this procedure spanning just over a decade.
Only a limited number of cases of early valvular dysfunction with rapid increase of transvalvular aortic gradients or aortic insufficiency (AI) have been described (15–17). These valve failures have been presumed to be because of either early pannus formation or thrombosis. This paper reviews the published data and reports 4 additional cases, of which 3 had further autopsy pathology reports. The first patient treated with a CoreValve bioprosthesis (Medtronic, Inc., Minneapolis, Minnesota) manifested with early post-procedure elevation in transvalvular gradient and insufficiency, requiring treatment with a second valve-in-valve TAVR (Figure 1). In 2 other patients, valve failure was noted at autopsy. The patient that underwent the valve-in-valve procedure died 1 month after the procedure, and an autopsy was performed that elucidates the mechanisms of early valvular failure, whereas the other 2 died 48 days (Sapien, Edwards Lifesciences, Irvine, California) and 15 days (CoreValve) after the procedure. The last case had post-TAVR severe AS 10 months following implantation (CoreValve) that was treated medically with oral anticoagulation.
Initial TAVR procedure
A 68-year-old woman presented with symptomatic severe AS, with a previous medical history of congestive heart failure, moderate chronic obstructive pulmonary disease (COPD), stage IV chronic kidney disease, chronic iron deficiency anemia, and a New York Heart Association (NYHA) functional class III. The patient had been deemed inoperable by 4 cardiac surgeons because of a calcified ascending aortic root. The patient’s screening transthoracic echocardiogram (TTE) revealed severe AS with a calculated mean pressure gradient (Pmean) of 43.5 mm Hg, a maximum aortic valve velocity (Vmax) of 4.3 m/s, and an aortic valve area (AVA) of 0.4 cm2. Her calculated Society of Thoracic Surgeons (STS) mortality score was 4%, and her EuroSCORE (European System for Cardiac Operative Risk Evaluation) was 3.5%. There were no unusual findings regarding the aortic root’s characteristics, with normal size sinus of Valsalva (SOV), that would predispose to a thrombotic setting. Under general anesthesia, she underwent a successful TAVR, with a 26-mm CoreValve bioprosthesis implanted through a left subclavian approach due to severe peripheral vascular disease. The valve was mounted by usual characteristics and deployed by fluoroscopy guidance on the first attempt with an implantation depth of 8 mm. There was no evidence of AI and post-dilation was not considered necessary. On follow-up TTE, there was evidence of mild AI.
Post-TAVR TTE measurements revealed a Pmean of 16 mm Hg, a Vmax of 2.8 m/s, and an AVA of 1.3 cm2. The patient had a 5-day hospital stay in which she had worsening anemia, with a hemoglobin decrease from 11.9 mg/dl to 8.6 mg/dl, requiring a transfusion of 2 units of packed red blood cells. She also developed transient thrombocytopenia, with a platelet count of 6 × 103 platelets/μl. A possible heparin-induced thrombocytopenia was suspected, so heparin and clopidogrel were discontinued. Platelet factor 4 was ordered, and the results were negative. On discharge, the TTE values were in normal ranges with a Pmean of 15.1 mm Hg, a Vmax of 2.7 m/s, and an AVA of 1.3 cm2. The patient was discharged home on antiplatelet monotherapy of aspirin 81 mg/day due to her bleeding risk.
At 1-month follow-up post-TAVR, the patient referred to be “feeling better,” but still required oxygen support because of her COPD. Her NYHA functional class improved from III to II. Her cardiovascular physical examination revealed an aortic outflow murmur, with preserved second heart sounds and no indication of AI. TTE revealed an increase in Pmean to 43 mm Hg, as well as an increase in Vmax to 4.3 m/s, and a decrease of the AVA to 0.5 cm2. Mild perivalvular AI was seen on TTE. Although a high transvalvular velocity was documented, the clinical presentations showed improvement and the physical examination did not support the echocardiographic findings. Because the patient’s symptoms were improved, she was followed up clinically and continued on the same antiplatelet monotherapy.
At 6-month follow-up, there was worsening of the NYHA functional class to III. The patient’s TTE revealed a Pmean of 50 mm Hg, a Vmax of 4.6 m/s, and an AVA of 0.6 cm2, with moderate AI. The patient was evaluated with a cardiac catheterization that confirmed moderate to severe AS of the bioprosthesis as well as a 2+ AI with a central jet. The CoreValve dysfunction was presumed to be from early pannus formation. On the basis of hemodynamic evidence of early valve failure, it was decided to perform a valve in valve TAVR.
Second TAVR procedure
A transesophageal echocardiogram was performed before the second TAVR implantation, revealing a nodular thickening at the aortic side of the CoreValve leaflet (Figure 1).
The second valve was also a 26-mm CoreValve bioprosthesis implanted through a left subclavian approach. The valve was mounted by usual characteristics and deployed by fluoroscopy guidance on the first attempt with an implantation depth of 4 mm. Post-dilation was not considered necessary.
Post-implantation measurements under fluoroscopy revealed no significant AS, no residual AI, and a Pmean of 9 mm Hg. TTE performed the day following the second TAVR procedure, showed a Pmean of 20 mm Hg, a Vmax of 3.02 m/s, and an AVA of 1.5 cm2. These values indicate a resolution of her severe AS. The patient underwent an uneventful post-operative stay and was discharged home on day 3.
The patient was discharged home on antiplatelet therapy of clopidogrel at the time of TAVR and remained on therapy until her death. Following discharge, the patient returned to her daily activities, and her AS symptoms had significantly improved. Sixteen days after the second valve implantation, the patient developed nausea and vomiting for 24 h due to food poisoning and had a witnessed sudden cardiac death. An autopsy was performed to determine the cause of death.
Valve-in-valve Medtronic CoreValve devices were visualized in the aortic position and calcification of the underlying native aortic valve leaflets was noted with mild left coronary artery calcification. The heart weighed 538 g with attached aortic arch. There was evidence of left ventricular hypertrophy, with no evidence of myocardial fibrosis or necrosis. The coronary arteries revealed mild to moderate hemodynamically insignificant coronary artery disease.
The inner CoreValve (second valve) appeared well seated without paravalvular leaks. The valve leaflets showed the presence of mural thrombus on the aortic surface involving the right and the noncoronary leaflets, which limited their mobility (Figure 1). The left coronary cusp was freely movable and there was an absence of valve calcification or thrombus. The coronary ostia were wide open. Histologically, the noncoronary and the right aortic leaflets showed presence of organizing fibrin thrombus on the aortic surface near the commissural attachment site with the underlying valve pericardial collagen intact, without degeneration. Scattered, minimal fragments of fibrin thrombus were adherent to the left coronary cusp. Mild inflammatory infiltrate was noted and consisted of a single to a few layers of palisading macrophages, lymphocytes, and rare neutrophils focally lining the leaflet surfaces and were located beneath the valve thrombus (Figure 1). The outer CoreValve (first valve) showed the presence of thrombus in the area of the valve leaflets, which were compressed on the valve frame. Sections of the valve leaflets did not show any presence of a pannus but organizing thrombus on all 3 leaflets without inflammation or degeneration; however, the noncoronary leaflet showed significantly larger thrombus (Figure 1).
The autopsy revealed evidence of severe COPD, hypertensive changes in the kidneys, and fatty changes in the liver. There was no evidence of systemic or pulmonary emboli.
An 88-year-old woman presented with symptomatic severe AS with a history of coronary artery disease with stenting of the left circumflex artery, atrial flutter with pacemaker implantation, hypertension, hypercholesterolemia, breast cancer, COPD, and cerebrovascular disease with possible transient ischemic attack and post-carotid endarterectomy. The screening TTE revealed severe AS with a calculated Pmean of 59.7 mm Hg, an aortic AVA of 0.61 cm2, and left ventricular ejection fraction of 60%. The STS mortality score was 8.3%. There were no unusual findings regarding the aortic root’s characteristics, with normal size SOV, that would predispose to a thrombotic setting. The patient underwent a successful transfemoral TAVR, with a 23-mm Edwards Sapien aortic valve, with an immediate post-procedure Pmean of 9 mm Hg. There was presence of trace AI and post-dilation was performed with an additional 1 cc of contrast added to the balloon due to a paravalvular leak.
On follow-up the patient’s symptoms had improved to NYHA functional class I; Pmean remained 9 mm Hg; and the valve appeared to function normally on TTE. The patient was prescribed dual antiplatelet therapy (aspirin and clopidogrel) at the time of TAVR and remained on therapy until her death due to a cerebral hemorrhage 48 days later.
An Edwards Sapien aortic valve was present in the aortic position without any fracture, but with underlying native aortic valve calcification. Only the Edwards Sapien valve, the surrounding aorta, and underlying native aortic valve were received for evaluation. The valve appeared to be well seated in the aortic root although the frame had been previously opened along the anterior aspect. The native aortic valve showed calcification beneath the frame. Both the left and right coronary ostia were widely patent. There were no paravalvular gaps. The valve leaflets were generally pliable, with the exception of the noncoronary cusp, which demonstrated compromise of the mobility due to thrombus covering 90% of the aortic surface of the valve leaflet (Figure 2). The left coronary cusp also showed basal deposition of thrombus on the aortic surface, which covered only 20% of the valve leaflet. There was mild platelet-fibrin thrombus adherent on the aortic surface of the right coronary cusp near the commissure. No cusp tears or perforations were identified. On the ventricular surface, mild adherent platelet-fibrin thrombi were seen as well as mild focal chronic inflammation composed of macrophages and lymphocytes, which were observed on all 3 valve leaflets on the aortic and ventricular surfaces.
A 90-year-old man presented with calcific severe AS. The patient presented with dyspnea and had NYHA functional class III for a duration of 6 months. The patient's ejection fraction had deteriorated significantly within the weeks leading to his TAVR and had worsened from 30% to 15% to 20% at the time of TAVR. Aortic root anatomy appeared normal with normal size SOV. He underwent a successful transfemoral TAVR, with a 29-mm Medtronic CoreValve bioprosthesis. The valve was mounted by usual characteristics and deployed by fluoroscopy guidance on the first attempt. There was no evidence of AI and post-dilation was not considered necessary.
The patient was on dual antiplatelet therapy (aspirin and clopidogrel) during and following the TAVR procedure. The initial Pmean post-TAVR implantation was 5.7 mm Hg. One hour post-operatively, the patient lost sensation and movement on his left side, and a computed tomography scan demonstrated a left occipital cerebral infarction. He had a previous history of a right occipital cerebral infarction following a coronary artery bypass graft 20 years previously. On day 7, Pmean increased to 7.3 mm Hg, although ejection fraction increased from ∼20% to 30%. The patient subsequently developed pneumonia and expired 15 days post-implantation.
The CoreValve device was present in aortic position with severe underlying calcification of the native aortic valve leaflets and marked mitral annular calcification (Figure 3). Pacemaker leads were present in the right ventricle and right atrial appendage. The heart weighed 675 g including the ascending aorta. There was a C-shaped mitral annular calcification with extension onto the anterior mitral valve leaflet. The stent frame did not show any coverage by intimal tissue above the valve cusps. Valve leaflets are brown-tan with roughened surfaces and adherent dark red blood clot and fibrin, predominantly on aortic surfaces (Figure 3). The valve appeared well positioned without grossly apparent paravalvular gaps; however, the valve leaflets had limited mobility and sections of the CoreValve leaflets show fibrin thrombus, predominantly on aortic surfaces and to a lesser extent on ventricular surfaces, on all valve leaflets (Figure 3). The right coronary cusp had the largest amount of thrombus with areas of palisading macrophages seen on all 3 valve cusps, more on the aortic side than the ventricular side.
An 85-year-old woman presented with symptomatic severe AS and NYHA functional class III with a history of hypertension, peripheral vascular disease, and mild COPD. The screening TTE revealed severe AS with a calculated Pmean of 43 mm Hg and left ventricular ejection fraction of 35%. Calculated STS mortality score was 7.7%. The SOV diameter was more than adequate to accommodate a 29-mm valve. There was only mild to moderate calcium at the leaflet level and the SOV area did not have any calcium. There was fluoroscopic evidence of annular calcium that was not considered of great concern. The patient underwent a successful transfemoral TAVR, with a 29-mm Medtronic CoreValve bioprosthesis, with an immediate post-procedure Pmean of 9 mm Hg. The placement of the valve was achieved with the first attempt and deployed at an average depth of 6 mm with no need for post-dilation. Immediate paravalvular leak was mild on transesophageal echocardiogram and mild on aortic root injection.
The patient was discharged with dual antiplatelet therapy for 3 months followed by monotherapy with ASA. At 1-month follow-up, the patient’s symptoms had improved to NYHA functional class I and Pmean increased to 22.5 mm Hg. From a clinical standpoint, the patient’s symptoms had improved. On TTE performed 6 months after TAVR, there was a marked increase in Pmean to 42 mm Hg. During the following 3 months, the Pmean values remained high (as seen in Figure 4). Due to the possibility of valve thrombosis, the patient was placed on oral anticoagulation with warfarin, which consequently led to a decrease in Pmean values with complete normalization 3 months later. The clinical course of the patient remained uneventful and symptom free on anticoagulation therapy.
Case Reports of Transcatheter Aortic Valve Thrombosis
At least 18 case reports of early valve thrombosis have been published (Table 1). The mean age of presentation was 79 ± 5 years. Eleven patients (61.1%) were male, whereas 5 (31.2%) were female. Two case reports did not describe sex characteristics. There are 17 Edwards Sapien TAV bioprostheses and 1 Medtronic CoreValve bioprosthesis that developed increasing gradients from 3 days to 24 months post-implantation. TTE evidence of thrombosis restricting the TAV leaflet mobility was suggested in the majority of cases dictating treatment. Twelve of the 18 patients were treated with varying anticoagulation therapy with either heparin or warfarin, or a combination. Nine of those 12 patients had a decrease in Pmean and had symptomatic improvement or were asymptomatic (16–21). One patient was treated with dual antiplatelet therapy and had symptomatic relief (22). Three patients had retrieval of the TAVR bioprosthesis followed by SAVR with further pathology workup that showed thrombus formation (15,23,24). In case 4, even though there was no evidence of TAV thrombosis, the increase in Pmean suggested a valve dysfunction that was treated successfully with oral anticoagulation.
Our current understanding of TAVR post-implantation management is based on the history and outcomes of SAVR. The recommendations proposed to cover treatment for SAVR have assisted in establishing guidelines for percutaneous interventional treatments. Post-TAVR dysfunction can be divided into 2 groups, structural valve deterioration and nonstructural dysfunction (11). Structural valve deterioration is related to changes within the valve and its adjoining structures, whereas nonstructural dysfunction includes components not directly associated with the valve such as a pannus or paravalvular aortic regurgitation (11).
Thrombotic stenosis of an aortic valve bioprosthesis after surgical replacement is an unusual complication (25–27). The incidence of bioprosthetic thrombosis is 0.03% per year (26). This frequency may be underestimated because early echocardiographic assessments are not routinely done. As mentioned in the review of the published reports, treatment for bioprosthetic thrombosis ranges from surgery to thrombolysis and oral anticoagulation (25,27).
During the presentation of these cases, there were no guidelines to base a proper treatment for valve dysfunction secondary to early thrombosis. Different mechanisms of thrombus formation after TAVR, such as pertinent antithrombotic treatment, suboptimal stenting due to valve malposition, and coagulation disorders that predispose patients to thrombus formation, have been described (15,17,18,23,24). In cases 1 and 4, there was evidence of rapid early increase in transvalvular gradients evidenced on TTE, although there was no direct visualization of valve thrombosis. Pathology work-up in case 1 revealed valve thrombosis. In cases 2 and 3, even though pathology work-up revealed evident valve thrombosis, there was no evidence of valve dysfunction clinically or with TTE, probably due to the short period—48 and 15 days—the patients lived following TAVR. Because there was no evidence of bioprosthesis cusp calcifications in either of the 3 cases with pathology work-up, structural deterioration or obvious morphological abnormalities of the valves was unlikely (25). In case 1, because the second inner CoreValve bioprosthesis skirt acted as a barrier to the outer CoreValve bioprosthesis, the thrombi seen in both valves may suggest a patient predispositioned to thrombus formation.
All leaflets from these 3 autopsy cases where re-reviewed to reconfirm the absence of microinjury or leaflet degeneration that may have been present at the time of implantation. Therefore, it is unlikely that valve thrombosis was caused by leaflet injury. Furthermore, the aortic surface of the valve leaflets with thrombosis revealed macrophage presence underneath the thrombus. A mildly greater inflammatory cell infiltrate was observed in the Edwards Sapien valve. Pathology review also revealed the presence of many inflammatory cells within the thrombus, therefore it is likely that the valve leaflet was not the culprit. There was no indication of excessive lymphocytic infiltrate that would suggest an autoimmune rejection.
There are no clinically tested guidelines describing appropriate therapy following thrombus formation. Although the cause of thrombus formation in case 1 could have been from the lack of dual antiplatelet therapy after the procedure, another potential cause could be a possibly unrecognized hypercoagulable state. It is important to note that although the patients in cases 2 and 3 had been on dual antiplatelet therapy right after TAVR, both developed valve thrombosis.
Current antiplatelet therapy recommendations after CoreValve bioprosthesis implantation consist of dual antiplatelet therapy with clopidogrel and aspirin for the first 6 months, and then continuous use of aspirin (16). Conversely, in 1 study, there was no significant difference seen between groups treated with dual antiplatelet therapy versus aspirin alone after TAVR (28). Further consideration could be given to detection of thrombosis on computed tomography (21).
A diagnosis of valve thrombosis must be considered with a progressive increase in transvalvular gradients and reappearance of symptoms (17). It is important to clarify that an increase in Pmean can range from days to months. From our 3 cases and subsequent review of the published reports, in cases of early valve dysfunction, oral anticoagulation treatment should be started regardless of a visualized thrombus on TTE (16–21).
The 4 cases discussed elucidate the occurrence of valve thrombosis post-TAVR, following 3 CoreValve replacements at 15 days, 7 months, and 10 months and 1 Edward Sapien valve at 48 days. As reported in the 4 cases, thrombus formation presenting as stenosis of a TAVR bioprosthesis was detected days to months after implantation. Several of the published reports reviewed cases and 2 of our 4 cases elucidated an increase in transvalvular gradient. Although not clearly demonstrated in all 4 cases, this finding suggests that rapid change in Doppler-derived estimates in transvalvular gradients may be a hallmark of valve thrombosis even without clinical symptoms. The frequency of thrombosis post-TAVR may be underestimated because clinical signs could be masqueraded by comorbidities. Another reason for possible underestimation of the frequency is that early echocardiographic assessments are not uniformly done on follow-up. Our findings indicate that consideration should be given to treatment with dual antiplatelet therapy and oral anticoagulation in a patient’s post-TAVR with increasing Pmean and Vmax and decreasing AVA. Valve-in-valve TAVR or SAVR can be performed if attempts to dissolve the clot are not successful. Current antithrombotic therapy post-TAVR is empirically based on presumed thrombotic milieu and patient observation. Further research should be conducted to create guidelines for antithrombotic therapy following TAVR procedures.
At least 18 case reports of early valve thrombosis with development of increasing gradients while on antithrombotic therapy have been previously published with little consensus on or scientific inquiry into the appropriate treatment. This study adds pathologic confirmation of thrombus and pannus formation in cases with a progressive increase in transvalvular gradients along with anecdotal success of dual antiplatelet therapy and oral anticoagulation in patients with increasing TTE aortic gradients. Clinically tested guidelines describing appropriate antithrombotic therapy following thrombus formation are needed to improve our knowledge base.
Dr. De Marchena has served on the advisory boards or panels of Tendyne Medical Inc., Aegis, Integene International Holdings Inc., and St. George Medical; owns stock in Tendyne Medical Inc., Aegis, Integene International Holdings Inc., and St. George Medical; and has received grants or research support from Medtronic, Inc. Dr. Chawla has served as a proctor for CoreValve (Medtronic, Inc.). Dr. Ring has served on the medical advisory board for Boston Scientific Corp. Dr. Virmani has received research support from Abbott Vascular, BioSensors International, Biotronik, Boston Scientific, Medtronic, MicroPort Medical, OrbusNeich Medical, SINO Medical Technology, and Terumo Corporation; has speaking engagements with Merck; receives honoraria from Abbott Vascular, Boston Scientific, Lutonix, Medtronic, and Terumo Corporation; and is a consultant for 480 Biomedical, Abbott Vascular, Medtronic, and W. L. Gore. All other author have reported that they have no relationships relevant to the contents of this paper to disclose.
- Abbreviations and Acronyms
- aortic insufficiency
- aortic stenosis
- aortic valve area
- chronic obstructive pulmonary disease
- New York Heart Association
- mean pressure gradient
- surgical aortic valve replacement
- sinus of Valsalva
- Society of Thoracic Surgeons
- transcatheter aortic valve replacement
- transthoracic echocardiogram
- maximum aortic valve velocity
- Received September 30, 2014.
- Revision received February 13, 2015.
- Accepted March 3, 2015.
- American College of Cardiology Foundation
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