Discussion
Nonbacterial thrombotic endocarditis (NBTE) is a rare clinical finding
and is likely underdiagnosed, although it is a serious manifestation of
cancer-related hypercoagulability and a potentially life-threatening
source of thromboembolism [5]. NBTE was first described by Ziegler
in 1888 as fibrinous efflorescence on heart valves [6]. In 1936, the
term was renamed ”nonbacterial thrombotic endocarditis” by Gross and
Friedberg [7] and defined as deposition of fibrin and platelets on
heart valves without evidence of microorganisms. Most cases of NBTE are
detected post mortem, and autopsy reports indicate an incidence of 1.2%
[8]. Anatomically, the aortic valve is most commonly affected,
followed by the mitral valve. Pulmonary and tricuspid valves are rarely
affected [8]. Since NBTE is a rare finding, multivalvular NBTE is
even rarer and quadrivaluvular NBTE is a real rarity with very few
published cases [9-11].
The pre-mortem diagnosis of NBTE is usually made on the basis of
clinical and echocardiographic findings in conjunction with exclusion of
an infectious cause of endocarditis. Because an autopsy (required by
german law) was refused by the family, our diagnosis was also made based
on echocardiographic imaging after interdisciplinary discussion and
after negative results of microbiologic diagnostics. All of our
conventional blood cultures and blood culture-negative endocarditis
(BCNE)-diagnostics remained sterile. In addition, we used commercially
available next generation sequencing (NGS)-based diagnostics for
pathogen identification (Noscendo DISQVER®) that can detect bacteria,
DNA viruses, fungi, and parasites in a single assay [12]. This
highly sensitive assay also showed no evidence of a bacterial or fungal
pathogen, so we are confident in diagnosing NBTE in our patient.
Regarding differential diagnoses, cardiac metastasis is also a very rare
disease [13] and involvement of heart valves is an uncommon site for
manifestation [14]. Evidence of cervical cancer metastasizing to the
heart is available from several case reports in recent decades, but none
involved the heart valves which makes the diagnosis very unlikely.
In a prospective study, NBTE was significantly more common in cancer
patients [15]. Among gynecologic malignancies, ovarian cancer is the
most common cancer associated with NBTE [16]. To our knowledge,
neither a case of NBTE in a patient with clear cell cervical cancer nor
a case of quadrivalvular NBTE in any gynecologic malignancy has been
published so far.
Disseminated intravascular coagulation (DIC) can be detected in most
NBTE patients [5], indicating a poor prognosis overall. We would
like to emphasize that in our case, NBTE developed in spite of
pre-existing anticoagulation. Our patient did not meet the criteria for
DIC based on the Overt DIC-score by the International Society for
Thrombosis and Hemostasis [17] consisting of low platelet count,
elevated levels of a fibrin-related marker, prolonged prothrombin time
and decreased fibrinogen levels. Nevertheless, we found high levels of
D-Dimers and thrombin-antithrombin complexes (TAT). The presence of TAT
indicates ongoing, intravascular thrombin formation as well as the
consumption of antithrombin and is associated with DIC [18].
In addition, the patient showed severe venous and arterial thromboses.
Thus, on the one hand, the stroke was likely caused by arterial
thrombosis resulting from dislocated thrombotic material from the NBTE
of the aortic valve. The occurrence of stroke is a disastrous prognostic
sign in NBTE patients with a 6-month lethality of 80% [19]. On the
other hand, the acute pulmonary embolisms can well be attributed to
carryover from the marked thrombotic masses in the area of the tricuspid
and pulmonary valves.