ARTICLE IN PRESS

Pathology – Research and Practice 204 (2008) 757–761

www.elsevier.de/prp

TEACHING CASES
Nonbacterial thrombotic endocarditis involving all four cardiac valves
Jan Lacoa,, Ivo Steinera, Eduard Havelb
a
The Fingerland Department of Pathology, Faculty of Medicine and Faculty Hospital, Charles University, Sokolská 581, 500 05
Hradec Králové, Czech Republic
b
Department of Surgery, Faculty of Medicine and Faculty Hospital, Charles University, 500 05 Hradec Králové, Czech Republic

Received 12 November 2007; accepted 4 March 2008

Abstract
Nonbacterial thrombotic endocarditis (NBTE) is a well-known complication of hypercoagulable states, particularly
in patients with malignancies. Its complications comprise thrombembolism rather than valvular dysfunction. We
present a case of a 71-year-old man treated for colonic carcinoma, who died 1 month after tumor resection with clinical
signs of respiratory failure. Ante mortem, there was no suspicion of cardiac disease. The autopsy revealed NBTE
affecting all four cardiac valves simultaneously, as well as multiple systemic and pulmonary thrombemboli.
Microscopically, neither microorganisms nor inflammation were found in the thrombi and/or valve tissues. To the best
of our knowledge, this is the fourth case of quadri-valvular NBTE reported in the English-written literature so far.
r 2008 Elsevier GmbH. All rights reserved.

Keywords: Heart; Nonbacterial thrombotic endocarditis; Colonic carcinoma; Paraneoplastic phenomenon

Introduction Materials and methods

Nonbacterial thrombotic endocarditis (NBTE), de-
fined as a presence of sterile thrombi on cardiac valves,
is known to be often associated with hypercoagulable
states, particularly in patients with various types of
malignant tumors [2]. A known complication of NBTE
is systemic thrombembolism to different sites, including
central nervous system, spleen, kidneys, and extremities,
rather than valvular dysfunction [9].
Herein, we present a unique case of NBTE involving
all four cardiac valves simultaneously. It was compli-
cated by multiple systemic and pulmonary thrombem-
boli. To the best of our knowledge, this is the fourth
such case described in English-written literature.
Corresponding author. Tel.: +420 495 832 548;
fax: +420 495 832 004.
E-mail address: lacoj@lfhk.cuni.cz (J. Laco).
A complete autopsy was performed. Multiple speci-
mens from all routinely examined organs were fixed in
formalin, routinely processed, embedded in paraffin,
and stained with hematoxylin–eosin. For detection of
microorganisms, Gram, Cresyl violet, and Grocott
stainings were used. For fibrin thrombi detection,
Mallory’s phosphotungstic acid hematoxylin (PTAH)
was used.
Results
Clinical history
A 71-year-old man with no relevant previous
medical history underwent stapler resection of colonic

0344-0338/$ - see front matter r 2008 Elsevier GmbH. All rights reserved.
doi:10.1016/j.prp.2008.03.007
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758 J. Laco et al. / Pathology – Research and Practice 204 (2008) 757–761
adenocarcinoma diagnosed 5 months ago and treatment
by neoadjuvant chemotherapy (FOLFOX [folinic acid,
5-fluorouracil, and oxaliplatin] and oxaliplatin in
monotherapy). On the third postoperative day, the
patient developed septicemia following anastomosis
dehiscence; a re-operation with creation of terminal
sigmoideostomy and open laparotomy was performed
immediately. The postoperative course was complicated
by adult respiratory distress syndrome (ARDS). The
patient subsequently underwent indwelling of central
venous catheters, parenteral nutrition, tracheostomy,
and continual arteficial ventilation.
Two transthoracic echocardiography (TTE) examina-
tions were performed on the first 2 days after the first
operation. These did not reveal any pathological
findings of the heart. During the further hospitalization
period, there were no clinical signs of cardiac disease.
The patient’s coagulable state was continually mon-
itored. During hospitalization, a prophylactic dose of
low molecular weight heparin (0.4 mL s.c./day) was
given. On the third postoperative day, the patient
developed thrombocytopenia (140 y 5  109/L), which
further continued to decrease. In addition, since the
fourth postoperative day, increasing levels of D-dimers
(9.6 y 20.0 mg/L) appeared.
Fig. 1. (a) Large thrombi (arrows) on all three cusps of the tricuspid valve. (b) Small thrombi (arrows) on both cusps of the mitral
valve. (c) Small thrombus (arrow) on the right cusp of the pulmonary valve. (d) Large thrombi (arrows) on all three cusps of the
aortic valve.
The patient died on the 27th postoperative day with
clinical features of respiratory failure.
Autopsy and microscopic findings
The relevant autopsy findings revealed dehiscence of
the adoral part of rectal stump with purulent inflamma-
tion in the vicinity and residual purulent peritonitis. No
tumor residue was found, but there was a solitary
metastasis in the lower lobe of the right lung. There was
generalized, mild (grades 1–2 of 4) atherosclerosis in the
arterial system.
The heart weighed 590 g. The gross pathological
findings comprised valvular thrombi on all four cardiac
valves and acute transmural myocardial infarction of
the lateral wall of the left ventricle. Basically, the heart
valves showed no underlying disease. All three cusps of
the tricuspid valve (Fig. 1a) and both cusps of the mitral
valve (Fig. 1b) featured on their atrial aspects reddish
thrombi measuring 5–15 mm. Similarly, the right cusp of
the pulmonary valve (Fig. 1c) and all three cusps of the
aortic valve (Fig. 1d) showed on their ventricular aspects
thrombi of the same character and size. The coronary
arteries showed grade 2 atherosclerosis with no lumen
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J. Laco et al. / Pathology – Research and Practice 204 (2008) 757–761
occlusion detected grossly. Furthermore, features of
multiple systemic thrombembolism, i.e., infarctions of
spleen and both kidneys were found. Despite careful
revision, no thrombemboli in relevant supplying arteries
of these organs was detected grossly.
Histologically, all the valve thrombi appeared to be of
recent origin and of the same age (Fig. 2). They were
composed of platelets interwoven with strands of fibrin
(Fig. 2, inset). Neither microorganisms nor inflamma-
tory reactions were detected even with special stainings
(Gram, Cresyl violet, Grocott). The underlying valve
tissues showed neither inflammatory nor age-related
changes, except the mitral valve, which featured mild
myxoid degeneration.
Furthermore, multiple infarctions of recent origin and
of the same age in the myocardium, spleen, and both
kidneys, associated with thrombemboli in small arteries
of similar appearance to the valve vegetations, were
found microscopically. In addition, occasional small
thrombemboli in small branches of the pulmonary
artery without lung infarction formation were detected
on microscopy. The remaining tissues showed neither
thrombemboli nor ischemic necroses.
A careful microscopic examination failed to demon-
strate the presence of fibrin thrombi diagnostic of
disseminated intravascular coagulation (DIC), even with
the use of Mallory’s PTAH.
Fig. 2. Large thrombus on the atrial aspect of the septal cusp
of the tricuspid valve. The valve tissue itself features no
pathological changes (hematoxylin–eosin, histotopogram).
Inset: The thrombus is composed of strands of fibrin and
platelets with no inflammatory cells (hematoxylin–eosin,
200  ).
759
The lung tissue showed a subacute to chronic stage of
diffuse alveolar damage, i.e., hyalin membrane forma-
tion and fibrosis, consistent with the clinical signs of
ARDS.
Discussion
NBTE, previously known as marantic endocarditis, is
characterized by the presence of sterile thrombi on
previously undamaged heart valves [9]. Although de-
scribed by Ziegler [13] already in 1888, the term NBTE
has been used since 1936 when coined by Gross and
Friedberg [4]. The precise pathogenesis of the lesion
remains incompletely understood. The most important
factor in the formation of the vegetations is a hypercoa-
gulable state usually associated with various types of
malignancies (paraneoplastic) and their treatment [2].
The most frequent histologic types of the underlying
neoplasms are adenocarcinomas originating in the
abdominal organs (pancreas, stomach, large bowel,
gallbladder/bile ducts, and ovary) and adenocarcinoma
of the lung [3]. Squamous cell carcinomas and hemato-
logic malignancies are much less common. Interestingly,
the small cell carcinoma, commonly associated with
paraneoplastic phenomena, has not yet been reported in
relation to NBTE. The factors associated with cancer
treatment include chemo/radiotherapy, hormonal ther-
apy, immobilization, and indwelling of central catheters
[7]. Simultaneous coagulation abnormalities, manifesting
as pulmonary thrombembolism or DIC, may be detected
in about one-fifth of the patients with NBTE [9]. Thus,
our patient exhibited several risk factors for NBTE-
colonic adenocarcinoma, chemotherapy, immobilization,
and clinical features of DIC syndrome with consumption
of thrombocytes and increased fibrinolytic activity.
The exact incidence of NBTE is unknown. In one
large autopsy series [3], an incidence of 1.6% in the adult
autopsy population was reported. NBTE may occur in
any age group, affecting mostly patients in the 4–8
decades [2]. There seems to be a slight female
predominance [10], although some authors reported no
gender predilection [2].
The most affected valves (in descending frequency)
are the aortic valve, the mitral valve, and the combina-
tion of both aortic and mitral valve [2]. However, in a
large study, a mitral valve predominance (64%) was
reported, followed by aortic valve (24%) and aortic plus
mitral valve (9%) [10]. The involvement of tricuspid and
pulmonary valves is much less common [9]. The
simultaneous quadri-valvular NBTE is extremely rare
[6], with only three cases being previously reported so
far (Table 1)[1,11,12].
Microscopically, the thrombi are composed of platelets
and fibrin strands. By definition, no microorganisms and
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Table 1
Case no. Gender Age Diagnosis
[reference] (years)
1 [11] Male 59 Autopsy
2 [1] Female 64 TEE
3 [12] Female 58 Autopsy
4 [this case] Male 71 Autopsy
DIC ¼ disseminated intravascular coagulation, NBTE ¼ nonbacterial thrombotic endocarditis, TEE ¼ transesophageal echocardiography.
inflammatory reactions are present. The underlying valve
tissue does not show any inflammatory changes [9].
The main clinical symptoms of NBTE are systemic
or pulmonary thrombembolism, the former appearing in
about 50% patients with NBTE [2]. The common
sites of systemic embolization include spleen, kidneys,
and extremities. However, the most serious event
for the patient is embolization in the central nervous
system, resulting in potentially debilitating cerebral
stroke. In our case, the patient exhibited myocardial,
splenic, and renal infarctions visible on gross
examination. Furthermore, occasional thrombemboli
in small branches of pulmonary artery were found
microscopically. The microscopical appearance of the
emboli was consistent with their origin from the valve
vegetations.
In general, the diagnosis of NBTE is difficult because
of no pathognomonic features, little intervention with
valve function, and a large variety of symptoms
resulting from different sites of potential embolism.
Cardiac murmurs occur infrequently, presenting even-
tually as soft systolic murmurs located at the left lower
sternal border. Therefore, appearance of a new murmur
in a patient with malignancy should give rise to
suspicion of NBTE [2]. Regarding detection of the valve
thrombi, transesophageal echocardiography is more
sensitive than TTE [5]. In our case, two subsequent
TTEs performed 1 month before death did not reveal
any pathological findings. However, the age of the
vegetations as assessed by microscopy was considerably
lower.
The peripheral embolism from left-sided NBTE may
result in a neurological deficit, in hematuria, in
abdominal pain caused by splenic or bowel infarctions;
arterial occlusion of the extremities may feature as
cyanotic, cold, and pulseless limbs. Rarely, dyspnea due
to pulmonary embolism from right-sided vegetations
may be the symptom. Unfortunately, the diagnosis of
NBTE still remains an autopsy-related one.
The treatment of NBTE comprises both anticancer
therapy and systemic anticoagulation. While heparins
Sites of embolism Associated Coagulation
malignancy disorder
Brain, kidneys Carcinoma of Pulmonary
pancreas embolism
Brain, kidneys None DIC
Heart, spleen, right None None
kidney, brain, lungs
Heart, spleen, kidneys, Colonic DIC
lungs carcinoma
seem to be most effective in the treatment of NBTE,
vitamin K antagonists should be avoided, as recurrent
thrombembolic events following warfarin treatment are
common [8].
Acknowledgment
Supported by the Research Project of the Ministry of
Health of the Czech Republic MZO No. 00179906.
References
[1] D.G. Blauchard, R.S. Ross, H.C. Dittrich, Nonbacterial
thrombotic endocarditis: assessment by transesophageal
echocardiography, Chest 102 (1992) 954–956.
[2] K. el-Shami, E. Griffiths, M. Streiff, Nonbacterial
thrombotic endocarditis in cancer patients: pathogenesis,
diagnosis, and treatment, Oncologist 12 (2007) 518–523.
[3] A. Gonzalez-Quintela, M.J. Candela, C. Vidal, J. Roman,
P. Aramburo, Non-bacterial thrombotic endocarditis in
cancer patients, Acta Cardiol. 46 (1991) 1–9.
[4] L. Gross, C.K. Friedberg, Nonbacterial thrombotic
endocarditis. Classification and general description, Arch.
Int. Med. 58 (1936) 620–640.
[5] R.J. Lee, T. Bartzokis, T.K. Yeoh, H.R. Grogin, D. Choi,
I. Schnittger, Enhanced detection of intracardiac sources
of cerebral emboli by transesophageal echocardiography,
Stroke 22 (1991) 734–739.
[6] J.A. Lopez, R.S. Ross, M.C. Fishbein, R.J. Siegel,
Nonbacterial thrombotic endocarditis: a review, Am.
Heart J. 113 (1987) 773–784.
[7] P. Prandoni, A. Falanga, A. Piccioli, Cancer and venous
thromboembolism, Lancet Oncol. 6 (2005) 401–410.
[8] L.R. Rogers, E.S. Cho, S. Kempin, J.B. Posner, Cerebral
infarction from non-bacterial thrombotic endocarditis:
clinical and pathological study including the effects of
anticoagulation, Am. J. Med. 83 (1987) 746–756.
[9] M.D. Silver, A.I. Gotlieb, F.J. Schoen, Cardiovascular
Pathology, Churchill Livingstone, New York, 2001,
pp. 447–449.
 ARTICLE IN PRESS
J. Laco et al. / Pathology – Research and Practice 204 (2008) 757–761 761

[10] I. Steiner, Nonbacterial thrombotic versus infective
endocarditis: a necropsy study of 320 cases, Cardiovasc.
Pathol. 4 (1995) 207–209.
[11] A.M.C. Tsanaclis, F. Robert, Cerebral embolism in
nonbacterial thrombotic endocarditis associated with
carcinoma: a clinico-pathological study, Acta Neurol.
Latinoam. 22 (1976) 86–103.
[12] R. Vassallo, E.D. Remstein, J.E. Parisi, J. Hudson III.,
R.D. Brown Jr., Multiple cerebral infarctions from
nonbacterial thrombotic endocarditis mimicking cerebral
vasculitis, Mayo Clin. Proc. 74 (1999) 798–802.
[13] E. Ziegler, Ueber den Bau und die Entstehung der
endocarditischen Efflorescenzen, Ver. Kong. Inn. Med.
7 (1888) 339–343.