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\begin{document}

\title{Recurrent Bioprosthetic Mitral Valve Thrombosis Treated with
Anticoagulation}



\author[1]{Robin Fernandes}%
\author[2]{Anubodh Varshney}%
\author[1]{Jayashri Aragam}%
\affil[1]{Boston VA Medical Center}%
\affil[2]{Brigham and Women's Hospital Division of Cardiology}%


\vspace{-1em}



  
  \date{May 22, 2024}


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\selectlanguage{english}
\begin{abstract}
Bioprosthetic valve thrombosis (BPVT) is more common than previously
thought and likely underreported. BPVT can be accurately diagnosed with
cardiac imaging and treated successfully with anticoagulation, thus
preventing re-operation. We hereby report a case of recurrent BPVT in
the mitral position successfully treated with anticoagulation along with
review of literature.%
\end{abstract}%



\sloppy


\textbf{Introduction:}

The mechanism of Bioprosthetic valve (BPV) dysfunction is predominantly
due to structural deterioration. Bioprosthetic valve thrombosis (BPVT)
has traditionally been considered a rare event. However, recent data
suggest that BPVT is not uncommon and in fact an increasingly recognized
entity. The true incidence of BPVT may be underestimated as most cases
remain under diagnosed. The diagnosis can be challenging due to low
general awareness of the condition. A high degree of clinical suspicion
and formal echocardiographic criteria can accurately diagnose BPVT.
Early diagnosis remains crucial as it can be successfully treated with
anticoagulation.

\textbf{Case Report:}

A 72-year-old male presented to the emergency room with one-week history
of progressive exertional dyspnea and lower extremity edema. His past
medical history included mitral valve replacement (MVR) eight years ago
{[}27mm Carpentier-Edward (CE) Magna{]} for severe mitral regurgitation
(MR) due to myxomatous mitral valve disease, paroxysmal atrial
fibrillation (pAF), and non-ischemic cardiomyopathy with LVEF 30-35\%
s/p dual chamber implantable cardioverter-defibrillator (ICD). Two years
prior to the current admission, he presented with multiple ICD shocks
secondary to atrial tachycardia. Work up revealed multiple echodensities
on the mitral bioprosthetic valve with BPV stenosis and a transmitral
mean gradient of 7mm Hg at heart rate 61 beats per min (bpm). After a
detailed workup he was diagnosed with non-bacterial thrombotic
endocarditis \textbf{{[}Figure 1, Video 1-2{]}.} He was treated with
unfractionated heparin (UFH) for two weeks. However, due to lack of
improvement, he underwent re-do MVR with a similar valve (27mm CE Magna)
and was discharged on warfarin with international normalized ratio (INR)
goal 2-3. One month prior to the current presentation, warfarin was
interrupted perioperatively for total right hip replacement surgery.

At the time of his current admission, physical examination revealed a
chronically ill appearing man with blood pressure 121/94 mmHg,
irregularly irregular rhythm with heart rate of 84 bpm, normal S1 and S2
without murmurs, jugular venous pressure 12 cm of water, bibasilar
crackles, and bilateral 4+ pitting pedal edema. He was started on
intravenous (IV) diuretics and admitted to the cardiology inpatient
service. Laboratory evaluation included normal blood counts and
metabolic panel, elevated B-type natriuretic peptide (2,751 pg/ml) and
INR (2.3). Transthoracic echocardiogram (TTE) showed LVEF 30-35\%,
mitral BPV leaflet thickening with mean gradient of 10 mmHg at heart
rate of 65bpm, and multiple echo densities suspicious for vegetation or
thrombus \textbf{{[}Figure 2A \& 2B, Video 3{]}.} Transesophageal
echocardiogram (TEE) revealed severe BPV leaflet thickening with
restricted motion, a large echo density encompassing both leaflets with
a mobile component measuring 1.4 x 0.4 cm and a mean gradient of 9.2
mmHg at heart rate of 67 bpm \textbf{{[}Figure 2C, 2D, 3A, 3B, Video
4-6){]}.} A detailed laboratory work-up including infectious,
rheumatologic, immunologic, and allergic (for bovine pericardial valve)
tests was unremarkable. Given echocardiographic findings of BPV stenosis
and echodensities and an extensive negative work up for other
etiologies, he was treated empirically for BPVT with UFH and eventually
transitioned to warfarin with an increased INR goal of 2.5-3.5. After
three months of uninterrupted anticoagulation, a repeat TEE showed
complete resolution of BPV thickening and echo density with significant
reduction in the mean transvalvular gradient to 4 mmHg at heart rate of
65 bpm \textbf{{[}Figure 4, and Video 7-8{]}} , indicating that the
cause of the patient's initial presentation was likely BPVT. The patient
is currently asymptomatic and is followed clinically and with regular
surveillance TTE.

\textbf{Discussion:}

The true incidence of BPVT remains uncertain; estimates range from less
than 0.5\% to over 6\% of BPV recipients depending on the mode of
diagnosis (pathology vs imaging) and length of follow
up\textsuperscript{1}. BPV dysfunction due to thrombosis is commonly
mistaken with `valve degeneration', leading to underreporting. Though
rare, BPVT is a clinically important entity and can occur in all four
valve locations. BPVT is distinguished from BPV degeneration based on
various echocardiographic criteria. BPVT presents with increased cusp
thickness, reduced cusp mobility, and less severe regurgitation, whereas
BPV degeneration is associated with calcified cusps, reduced mobility,
and significant regurgitation.

The mechanisms underlying BPVT are incompletely understood, but involve
blood flow perturbation resulting in high wall shear stress and
increased blood stasis, plasma protein adsorption leading to activation
of hemostatic factors, and patient related factors including
hypercoagulable states, anemia, renal insufficiency, obesity, diabetes
mellitus, smoking, low cardiac output and periprocedural trauma.
Suboptimal anticoagulation in patients taking oral anticoagulation (OAC)
and pAF are additional risk factors for BPVT \textsuperscript{1}.

BPVT presentation may vary from incidental imaging findings without
symptoms to syncope, dyspnea, heart failure, or cardiogenic shock from
valve obstruction. Diagnosis is typically made by echocardiography. A
model consisting of three echocardiographic predictors increased the
sensitivity and specificity of diagnosing BPVT in the setting of
concordant clinical features: 1) 50\% increase in transvalvular
gradients compared with baseline within five years of surgery, in the
absence of a high cardiac output state; 2) increased cusp thickness
(\textgreater{}2 mm), especially on the downstream aspect of the valve;
and 3) abnormal cusp mobility \textsuperscript{2}. Although TTE is
helpful, performing TEE is strongly recommended when clinical suspicion
is high to facilitate expeditious diagnosis.

Although current 2017 ACC/AHA and ESC guidelines recommend oral
anticoagulation for only the first three months following surgical BPV
replacement in the absence of risk factors\textsuperscript{34}, our case
highlights the fact that risk of BPVT is not limited to first three
months after implantation. Several studies have reported that BPVT may
occur late after initial implantation and should be suspected in the
appropriate clinical scenario. Among 149 patients who underwent mitral
BPV implantation at a single center, a retrospective review of TEE's
identified 9 patients (6\%) with BPVT and median time from implantation
to diagnosis was 12 months \textsuperscript{5}. Another study identified
46 cases (11.6\%) of histologically proven BPVT among 397 patients who
underwent BPV explantation. The median time to explantation was 24
months, with 15\% of cases occurring more than 5 years after valve
placement \textsuperscript{2}.

Anticoagulation is the mainstay treatment for BPVT in hemodynamically
stable patients. Early diagnosis of BPVT is crucial as most patients
respond to anticoagulation and BPVT resolves completely, thus avoiding
need for repeat valvular intervention. Several studies have reported
successful resolution of BPVT when treated with VKA (vitamin K
antagonist) \textsuperscript{5678}. A prospective evaluation of warfarin
showed that anticoagulation was effective in 83\% of patients with
suspected BPVT, and most responded within 3 months \textsuperscript{7}.
A recent study by Petrescu et al. reported long term outcomes of
anticoagulation in 83 patients treated with warfarin for suspected BPVT.
Echocardiographic parameters normalized in 75\% of patients within three
months. However, warfarin-treated patients had significant higher rates
of major bleeding compared with matched controls. Additionally, BPVT
recurred in 23\% of warfarin responders after a median of 23 months, and
all but one patient with recurrent BPVT responded to anticoagulation.
Thus, longer term or even indefinite anticoagulation with warfarin could
be considered after an initial BPVT episode while balancing bleeding
risks \textsuperscript{8}. In retrospect, we believe that our patient's
presentation of BPV stenosis two years prior to the current presentation
was likely BPVT. At that time, an extended trial of anticoagulation may
have obviated the need for redo MVR.

While current 2017 ACC/AHA guidelines do not recommend routine
surveillance with TTE until after 10 years of bioprosthetic valve
implantation in the absence of symptoms, our case highlights that early
diagnosis and management of BPVT is critical. Thus, consideration should
be given to regular TTE monitoring for the development of BPVT in high
risk cohorts. Determining the optimal frequency of TTE monitoring for
BPV recipients requires further investigation.

\textbf{Conclusions:}

BPVT may occur late after valve implantation and should not be confused
for valve degeneration. BPVT should be suspected in patients with
clinical or echocardiographic evidence of BPV dysfunction, especially
when presenting within five years after valve implantation. Elevated
transvalvular gradients can be the first clue in diagnosing subclinical
BPVT. Anticoagulation should be instituted in hemodynamically stable
patients without contraindications before pursuing repeat valve
replacement. Surgery should be reserved for non-responders to
anticoagulation or patients in whom hemodynamic status precludes further
delay. Although the optimal duration of anticoagulation is not known,
long-term anticoagulation should be considered. In the event of
cessation of oral anticoagulation, antiplatelet therapy and frequent
echocardiographic surveillance can be considered.

\textbf{References:}

1. Puri R, Auffret V, Rod\selectlanguage{ngerman}és-Cabau J: Bioprosthetic Valve Thrombosis. J
Am Coll Cardiol. 2017; 24;69(17):2193--211.

2. Egbe AC, Pislaru SV, Pellikka PA, et al: Bioprosthetic Valve
Thrombosis Versus Structural Failure: Clinical and Echocardiographic
Predictors. \emph{J Am Coll Cardiol} . 2015;66(21):2285-2294.

3. Nishimura RA, Otto CM, Bonow RO, et al: 2017 AHA/ACC Focused Update
of the 2014 AHA/ACC Guideline for the Management of Patients With
Valvular Heart Disease: A Report of the American College of
Cardiology/American Heart Association Task Force on Clinical Practice
Guidelines. \emph{J Am Coll Cardiol} . 2017;70(2):252-289.

4. Baumgartner H, Falk V, Bax JJ, et al: 2017 ESC/EACTS Guidelines for
the management of valvular heart disease. \emph{Eur Heart J} .
2017;38(36):2739-2791.

5. Butnaru A, Shaheen J, Tzivoni D, et al: Diagnosis and treatment of
early bioprosthetic malfunction in the mitral valve position due to
thrombus formation. \emph{Am J Cardiol} . 2013;112(9):1439-1444.

6. Oliver JM, Gallego P, Gonzalez A, et al: Bioprosthetic mitral valve
thrombosis: Clinical profile, transesophageal echocardiographic
features, and follow-up after anticoagulant therapy. \emph{Journal of
the American Society of Echocardiography} . 1996;9(5):691-699.

7. Egbe AC, Connolly HM, Pellikka PA, et al: Outcomes of Warfarin
Therapy for Bioprosthetic Valve Thrombosis of Surgically Implanted
Valves: A Prospective Study. \emph{J Am Coll Cardiol Intv} .
2017;10(4):379-387.

8. Petrescu I, Egbe AC, Ionescu F, et al: Long-Term Outcomes of
Anticoagulation for Bioprosthetic Valve Thrombosis. \emph{J Am Coll
Cardiol} . 2020;75(8):857-866.

\textbf{Figure legends:}

Figure 1: \textbf{Echocardiogram demonstrating mitral BPV echodensities
(previous admission)}

Mitral BPV thickening and echodensities seen on (A) TTE (red arrow); (B)
TEE (blue arrow); (C) 3D TEE and (D) TEE Transmitral gradients.

Figure 2 \& 3: \textbf{Echocardiogram demonstrating mitral BPV
thrombosis (current admission)}

Mitral BPV thickening and echodensities seen on (2A) TTE (red arrow);
(2B) TTE Transmitral gradients; (2C) TEE (blue arrow); (2D) TEE
Transmitral gradients; (3A \& 3B) 3D TEE.

Figure 4: \textbf{Echocardiogram demonstrating complete resolution of
mitral BPV thrombosis after anticoagulation}

Resolution of mitral BPV thickening and thrombosis after anticoagulation
(A) TEE; (B) 3D TEE (C) TEE Transmitral gradients.

BPV= Bioprosthetic valve

TTE= Transthoracic echocardiogram

TEE= Transesophageal echocardiogram

LV = Left ventricle; RV= Right ventricle; LA= Left atrium; RA = Right
atrium.

\textbf{Video legends:}

Video 1: TEE mid-esophageal four chamber view demonstrating mitral BPV
thickening with mobile echodensities.

Video 2: 3D TEE mid-esophageal four chamber view showing mitral BPV
thickening with mobile echodensity.

Video 3: TTE apical four chamber view showing mitral BPV thickening with
mobile echodensities.

Video 4: TEE mid-esophageal four chamber view showing mitral BPV
thickening with mobile echodensity.

Video 5: 3D TEE mid-esophageal four chamber view demonstrating mitral
BPV thickening with mobile echodensity.

Video 6: 3D TEE mid-esophageal four chamber view demonstrating mitral
BPV thickening with mobile echodensity.

Video 7: TEE mid-esophageal four chamber view demonstrating complete
resolution of mitral BPV thrombosis after anticoagulation.

Video 8: 3D TEE mid-esophageal four chamber view demonstrating complete
resolution of mitral BPV thrombosis after anticoagulation.

\textbf{Consent:} A written informed consent was obtained from the
patient.\selectlanguage{english}
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