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\begin{document}

\title{Bubbling the diagnosis: Incidental finding of non-bacterial thrombotic
endocarditis in a patient with pancreatic carcinoma}



\author[1]{Johannes Wild}%
\author[2]{Simon Distelmeier}%
\author[3]{Philipp Keil}%
\author[3]{Arndt Weinmann}%
\author[1]{Thomas Münzel}%
\author[3]{Julia Weinmann-Menke}%
\author[3]{Daniel Kraus }%
\affil[1]{University Medical Center Mainz}%
\affil[2]{University Medical Center Mainz          }%
\affil[3]{University Medical Center Mainz Department of Internal Medicine 1}%


\vspace{-1em}



  
  \date{May 07, 2024}


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\selectlanguage{english}
\begin{abstract}
Nonbacterial thrombotic endocarditis (NBTE) is a rare condition which
most often accompanies a malignant disease and involves a
hypercoagulable state. We report the incidental finding of a scarce case
of NBTE affecting the tricuspid valve in a patient with metastatic
pancreatic carcinoma complicated by severe venous and arterial
thromboembolisms.%
\end{abstract}%



\sloppy


\textbf{Introduction}

Diseases of the mitral and tricuspid valve are more and more recognized
as a significant cause of morbidity and mortality and are in the scope
of new treatment strategies for structural heart
interventions\textsuperscript{1,2}. Despite the triumphal march of
cardiac CT and MRT, echocardiography is still the most widely available
first-line imaging modality for the heart. We present a case of the
incidental finding of nonbacterial thrombotic endocarditis of the
tricuspid valve in a patient with metastatic pancreatic carcinoma
detected by point-of-care echocardiography on a non-cardiological ward.

\textbf{Case report}

A 67-year-old female patient with metastatic pancreatic carcinoma was
admitted to the department of gastro-oncology in our university medical
center for the initiation of palliative chemotherapy. The carcinoma was
first detected by CT and diagnosed by confirmatory histology using
ultrasound guided biopsy two weeks prior to the admission. In addition
to the primary tumor, CT-scans had detected multiple liver metastases
(Figure 1), so palliative chemotherapy with FOLFIRINOX (oxaliplatin,
irinotecan, leucovorin and fluorouracil) was recommended. Initially, the
therapy was planed in an outpatient setting, but due to dyspnea and
progressive thrombocytopenia, the patient was admitted to the hospital.

On admission, the patient reported worsening dyspnea for about two weeks
which now met the criteria of NYHA stage III. Furthermore, she reported
that a deep vein thrombosis of the left lower leg had been diagnosed 10
days before admission. Anticoagulant treatment with apixaban 5mg twice
daily had been initiated, but recently discontinued by her family
physician due to severe thrombocytopenia of so far unknown origin. The
patient had no history of cardiovascular disease. During physical exam,
we did not find typical clinical sings of heart failure or deep vein
thrombosis but petechiae on different sites of the skin on both lower
legs.

Laboratory findings confirmed severe thrombocytopenia and highly
elevated D-dimer levels reflecting a hypercoagulatory state. Given the
severe shortness of breath and the deep vein thrombosis, an immediate
CT-angiogramm of the chest was planned to rule out pulmonary embolism.

In order to apply intravenous contrast medium and after multiple
attempts at inserting a peripheral venous catheter had failed, a central
venous catheter was inserted into the right internal jugular vein.
Following insertion, bedside ultrasound was used for confirmation of the
central venous placement by visualizing bubble artifacts in the right
atrium after injection of agitated saline through the distal
port\textsuperscript{3}.

Unexpectedly, during visualization of the right atrium and right
ventricle in subcostal view, transthoracic echocardiography (using a
Philips Affinity 70 ultrasound system) revealed large masses adherent to
the tricuspid valve leaflets (Figure 2 A/B). The differential diagnosis
included thrombi, bacterial vegetations and metastases. A CT was
obtained immediately and demonstrated a hypodense lesion of 28 x 20 mm
with predominantly intra-ventricular and only a small intra-atrial
proportion (Figure 3). The lesion was irregularly configured and showed
multiple stripy foothills to the ventricle walls. Furthermore, bilateral
segmental and subsegmental pulmonary embolisms were detected.

After an interdisciplinary discussion of the echocardiography and CT
results, we interpreted the tricuspid mass as most consistent with
non-bacterial thrombotic endocarditis. We explained the findings to the
patient and outlined the risks and benefits of initiating the planned
chemotherapy. Specifically, we were concerned that chemotherapy might
destabilize the intracardial mass, causing massive pulmonary embolism On
the other hand, anticoagulative therapy was deemed riskful because of
the marked thrombocytopenia. Finally, not acting at all would allow the
tumor to grow in an uncontrolled manner. The patient opted for the
chemotherapy which was initiated the next day. During the treatment,
several sets of blood cultures as well as serum procalcitonin were
negative indicating no hint for infectious endocarditis. Therapeutic
anticoagulation was not possible due to persistent severe
thrombocytopenia and spontaneous intracutaneous and catheter-related
bleeding.

Several days later, the patient developed arterial thromboses in both
lower extremities with critical ischemia, reflecting an overall deranged
coagulation with parallel hypercoagulation and bleeding disorder
consistent with disseminated intravascular coagulation. We performed a
short time echocardiographic control after the first course of
chemotherapy.

Unfortunately, the masses covering the tricuspid valve leaflets
increased with signs of valve dysfunction and severe tricuspid
insufficiency (Figure 4). Despite severe thrombozytopenia, continuous
heparin and alprostadil were started. Within a few days, the thrombocyte
count reached normal levels, and serum D dimer levels declined.
Naturally, toe necroses did not resolve. The patient was discharged on
low molecular-weight heparin in order to continue palliative
chemotherapy in the outpatient department.

\textbf{Discussion}

Nonbacterial thrombotic endocarditis (NBTE, formerly known as marantic
endocarditis) has first been described by Ziegler in 1888, as fibrin
thrombi on normal or degenerated cardiac valves\textsuperscript{4}.
Postmortem, the histological diagnosis of NBTE is defined by the
presence of a mixture of platelets and fibrin on the valvular leaflet
without detecting micro-organisms destructing the valve. In clinical
routine, NBTE is rarely diagnosed antemortem and is likely to be
underdiagnosed and overlooked\textsuperscript{5} as a definitive
histological diagnosis is not possible in most cases. In the presented
case, a histological confirmation was also not feasible as it would have
endangered the patient without affecting the further management. So, the
diagnosis was based on appropriate imaging (echocardiography and CT)
combined with the clinical findings. We resigned from additional MRI
imaging as it would not have changed the clinical management of the
patient.

A large autopsy study from 1976 reports an incidence of 1.6 \% of NBTE
in the adult autopsy population\textsuperscript{6}. Coagulation
abnormalities suggestive of disseminated intravascular coagulation were
present in 18.5 \% of the cases\textsuperscript{6}. Other autopsy
studies described the significantly higher prevalence of NBTE in
patients with malignancies than in patients without
cancer\textsuperscript{7,8}. The condition is predominantly seen in
patients suffering from pancreatic cancer in comparison with other
carcinomas. As exemplified by our case, NBTE is significantly more
common with more than 10\% of all pancreatic cancer patients presenting
histological features of the disease in autopsy
studies\textsuperscript{7}.

Regarding the anatomical site, the aortic valve is most often affected,
followed by the mitral valve and a combination of both the aortic and
mitral valves. Affections of the tricuspid or pulmonary valve are very
rare reflecting only 3.6\% (tricuspid valve) or 0.9\% (pulmonary valve)
of all cases\textsuperscript{9}. When the tricuspid valve is affected,
the vegetations are typically present on the atrial surface and occuring
at the coapting edge of the leaflets but without altering valve
function\textsuperscript{9}. In the first echocardiography, our patient
did not suffer from severe tricuspid insufficiency, but unfortunately in
a noticeably short span of time, the regurgitation increased, indicating
functional impairment of the valve by the growing mass.

Systemic embolization is known to be the main cause of morbidity in NBTE
patients, not only affecting the heart valves but also peripheral
intravascular thromboses. Arterial thrombosis with infarction have been
described in many peripheral organs, whereas spleen and kidneys were
most frequent.\textsuperscript{6} Our patient suffered from venous
thromboembolism (deep vein thrombosis and subsequent pulmonary embolism)
in the early stage of the disease and additionally developed peripheral
arterial thrombosis most probably driven by the coagulopathy.

\textbf{Conclusion}

We present a rare case of severe nonbacterial thrombotic endocarditis
affecting the tricuspid valve. Unfortunately, the patient developed
severe tricuspid insufficiency in a noticeably short period despite
ongoing non-surgical treatment. We want to highlight the unusual and
incidental detection of the NTBE in our case by bedside ultrasound on a
non-cardiological ward. Our case might emphasize that basic
echocardiography even when done in a bedside, point-of care setting
without following a formal protocol, can provide insights that help to
improve patient management.

\textbf{Figure Legends}

\textbf{Figure 1}

Computed tomography (CT) scan of the abdomen demonstrating excessive
hepatic metastasis (arrows for examples) of the pancreas carcinoma.

\textbf{Figure 2}

\textbf{(A)} Bedside two-dimensional transthoracic echocardiography.
Parasternal short-axis view showing a large masse adhering to the
tricuspid valve. TV = tricuspid valve, RA = Right atrium, RV = Right
ventricle, LA= Left atrium.

\textbf{(B)} Color doppler echocardiography reflecting tricuspid
insufficiency which was estimated as non-severe by the given limited
quality of the imaging in the point-of care setting.

\textbf{Figure 3}

Cardiac CT scan demonstrating a 28 x 20 mm measuring hypodense lesion
with predominantly intra-ventricular and a small intra-atrial
proportion. TV = tricuspid valve, RA = Right atrium, RV = Right
ventricle, LA= Left atrium, LV = Left ventricle, PA = Pulmonary artery.

\textbf{Figure 4}

\textbf{(A)} Two-dimensional transthoracic echocardiography,\textbf{(B)}
X-plane imaging and \textbf{(C)} color doppler echocardiography.
Optimized apical four chamber view to demonstrate the NTBE of the
tricuspid valve. TV = tricuspid valve, RA = Right atrium, RV = Right
ventricle, LA= Left atrium, LV = Left ventricle.

\textbf{Author contributions}

JW: Imaging, concept and drafting of the article; SD: Imaging, critical
revision of the article; PK: imaging; AW/TM/JWM: critical revision of
article; DK: Drafting and revision of the article.

\textbf{Conflict of interest:} none

\textbf{References}

1. Kalbacher D, Schafer U, RS VB, et al. Long-term outcome, survival and
predictors of mortality after MitraClip therapy: Results from the German
Transcatheter Mitral Valve Interventions (TRAMI) registry. \emph{Int J
Cardiol.} 2019;277:35-41.

2. Lurz P, Stephan von Bardeleben R, Weber M, et al. Transcatheter
Edge-to-Edge Repair for Treatment of Tricuspid Regurgitation. \emph{J Am
Coll Cardiol.} 2021;77(3):229-239.

3. Meggiolaro M, Scatto A, Zorzi A, et al. Confirmation of correct
central venous catheter position in the preoperative setting by
echocardiographic ''bubble-test''. \emph{Minerva
Anestesiol.}2015;81(9):989-1000.

4. E. Z. Ueber den Bau und die Entstehung der endocaridtischen
Efflorescenzen. \emph{Ver Kong Inn Med.} 1888;7: 339-- 343.

5. el-Shami K, Griffiths E, Streiff M. Nonbacterial thrombotic
endocarditis in cancer patients: pathogenesis, diagnosis, and
treatment.\emph{Oncologist.} 2007;12(5):518-523.

6. Deppisch LM, Fayemi AO. Non-bacterial thrombotic endocarditis:
clinicopathologic correlations. \emph{Am Heart J.} 1976;92(6):723-729.

7. Gonzalez Quintela A, Candela MJ, Vidal C, Roman J, Aramburo P.
Non-bacterial thrombotic endocarditis in cancer patients. \emph{Acta
Cardiol.} 1991;46(1):1-9.

8. Kuramoto K, Matsushita S, Yamanouchi H. Nonbacterial thrombotic
endocarditis as a cause of cerebral and myocardial infarction. \emph{Jpn
Circ J.} 1984;48(9):1000-1006.

9. Lopez JA, Ross RS, Fishbein MC, Siegel RJ. Nonbacterial thrombotic
endocarditis: a review. \emph{Am Heart J.} 1987;113(3):773-784.

\textbf{Hosted file}

\verb`Figures Case.ppt`  available at \url{https://authorea.com/users/399154/articles/511705-bubbling-the-diagnosis-incidental-finding-of-non-bacterial-thrombotic-endocarditis-in-a-patient-with-pancreatic-carcinoma}

\selectlanguage{english}
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