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.