A case of tricuspid valvular nonbacterial thrombotic endocarditis associated with advanced ovarian cancer

Abstract

Nonbacterial thrombotic endocarditis (NBTE) is characterized by the deposition of thrombi on the heart valves without bacteremia and predominantly affects patients with hypercoagulable state. Since the lesion of NBTE often exists in the left-sided valves, involvement of the tricuspid valve (TV) is rare. We herein report a 34-year-old woman with advanced ovarian cancer and pulmonary embolization showing NBTE on the TV. Plasma D-dimer level was markedly elevated and echocardiography showed highly mobile masses on the TV with moderate to severe regurgitation. After the initiation of heparin therapy, reduction of plasma D-dimer levels along with shrinkage of the TV vegetations was observed. However, she was forced to discontinue the heparin because its supply was interrupted in association with coronavirus disease 2019. Coupled with systemic metastasis of ovarian cancer, elevated plasma D-dimer level and exacerbation of NBTE were observed. Thereafter, she resumed subcutaneous injection of heparin, resulting in re-improvement.

Learning objective

Involvement of tricuspid valve (TV) by nonbacterial thrombotic endocarditis (NBTE) is rare, especially when they are associated with advanced cancer. Our case underlines the importance of listing the NBTE as a differential diagnosis in cancer patients showing valve vegetations even in the TV.

Introduction

Nonbacterial thrombotic endocarditis (NBTE) is characterized by the deposition of thrombi on heart valves without a bacterial infection in the blood [1] and predominantly affects patients in hypercoagulable state as represented by malignancy, connective tissue diseases, and disseminated intravascular coagulation [2]. Its management has not been established whereas anticoagulation therapy by using heparin is highly effective to reduce the size of vegetation [3]. Since the lesion of NBTE often exists in the left-sided valves, involvement of the tricuspid valve (TV) is rare, especially in malignancy-associated NBTE [2]. We herein report a case of NBTE associated with advanced ovarian cancer in whom vegetations on TV showed expansion and reduction of their size during the management.

Case report

A 34-year-old woman with an abdominal tumor was referred to the cardiology section because of elevated plasma D-dimer level. On physical examination, marked right lower leg edema was observed whereas jugular vein distension and cardiac murmur were not. Her body temperature was 36.9 °C. Laboratory data showed slightly increased white blood cell count (9400/μL), normal platelet counts (17.1 × 10⁴/μL), markedly elevated D-dimer concentration (36.4 μg/mL), increased C-reactive protein (CRP) level (5.26 mg/mL), and lactate-dehydrogenase (LDH) (488 U/L). Carbohydrate antigen (CA) 19-9 and CA125 levels were elevated to 188.6 U/mL (normal range: 0.0 to 37.0 U/mL) and 732.4 U/mL (normal range: 0.0 to 35.0 U/mL), respectively, while rheumatoid factor and antinuclear antibody were negative. Blood culture was also negative. Thoracic and abdominal computed tomography revealed a huge abdominal mass along with thrombus in the right lower lobe pulmonary artery and beyond the right femoral vein (Fig. 1). Transthoracic echocardiography showed slight enlargement of the right ventricle and increase in peak tricuspid regurgitation (TR) velocity (3.5 m/s). Surprisingly, it also revealed highly mobile masses attached to the TV with moderate to severe TR (Fig. 2A, Video 1).

Fig. 1.

Contrast-enhanced computed tomography showing thrombi in the right pulmonary artery (A, arrow), a large tumor in the pelvis (B, asterisk), and deep vein thrombosis in the right femoral vein (C, arrow head).

Fig. 2.

Mid-systolic two-dimensional echocardiographic images and corresponding color Doppler images in the parasternal four-chamber view before the initiation of heparin infusion (A), on the 18th day (B), 137th day (C), 220th day (D), and 285th day (E) after the initial therapy. During the heparin therapy, shrinkage of the tricuspid valvular vegetation (arrows) along with reduction of tricuspid valve regurgitation was observed at once (A to C) from 5.7 × 2.7 mm (A) to 3.8 × 2.5 mm (B) and 1.0 × 0.8 mm (C). Although they recurred with the size of 13.6 × 7.5 mm after the discontinuation of heparin (D), re-improvement with a shrinkage of the size to 2.8 × 2.9 mm was demonstrated after re-administration of the heparin (E).

The venous thromboembolism was considered to be associated with the advanced cancer. Also, the mobile masses on the TV were suspected to be vegetations due to NBTE associated with intrapelvic cancer because of the lack of evidence of infective endocarditis or connective tissue diseases. Anticoagulation therapy with intravenous heparin was started for thromboembolism, and an inferior vena cava filter was placed to prevent secondary embolization from the large residual venous thrombus. Thereafter, D-dimer concentration gradually decreased to 3.4 μg/mL on the 4th day followed by 0.63 μg/mL on the 18th day. As well, CRP and LDH levels decreased to 1.70 mg/mL and 282 U/L, respectively, on the 18th day. Repeated echocardiography on the 18th day showed reduction of the size of the vegetations (Fig. 2B, Video 2). On the 20th day, she underwent surgical resection of the left ovary and greater omentum. The histopathological evaluation confirmed well-differentiated clear cell carcinoma in the ovary.

Based on the clinical course showing the reduction of vegetation size by continuous heparin infusion, the diagnose of NBTE was confirmed. Anticoagulation therapy was then switched from intravenous to subcutaneous administration and the intermittent chemotherapy was continued based on home recuperation. On the 137th day, echocardiography revealed further reduction of the TV vegetation as well as reduced TR (Fig. 2C, Video 3). However, she was unfortunately forced to discontinue the subcutaneous injection of heparin on the 159th day because its supply was interrupted in association with coronavirus disease (COVID-19). Moreover, peritoneal dissemination of the ovarian cancer, liver metastasis, and abdominal lymph node metastasis were found and alternative intermittent chemotherapy was continued with home recuperation. Anticoagulant therapy was then switched to direct oral anticoagulant for thromboembolism. Echocardiography on the 220th day showed enlarged vegetation on the TV (Fig. 2D). After that, supply of the subcutaneous heparin resumed and thus anticoagulation therapy was returned to subcutaneous heparin and chemotherapy was continued. Echocardiography on the 285th day demonstrated substantial reduction of the vegetation again (Fig. 2E).

Discussion

NBTE, formerly known as marantic endocarditis, was first described by Ziegler in 1888 as fibrin thrombi on normal or degenerated cardiac valves. Although the pathogenesis of the vegetation is not completely elucidated, hypercoagulable state caused by malignancy or autoimmune diseases and endocardial injury are postulated to trigger platelet-fibrin interaction, resulting in formation of the vegetation [2], [4]. Tissue factor expressed by malignant tissues and mononuclear cells in response to inflammatory cytokines has been considered to become a trigger for the vegetation formation [4]. Post-mortem, the histological diagnosis of NBTE is defined by the presence of a mixture of platelets and fibrin on the valvular leaflet without microorganisms [2]. In clinical practice, however, definitive diagnosis of NBTE is difficult because a histological approach is not possible in most cases [1]. Although there have not been established criteria for definitive diagnosis of NBTE, it has been reported that ruling out of infective endocarditis as well as response to heparin therapy could be a certain basis of the diagnosis [1], [4]. Consistently, the diagnosis of our case was confirmed according to the changes in the echocardiographic findings after the initiation of heparin infusion.

Regarding the location of NBTE lesions, the aortic valve is most often affected, followed by the mitral valve and a combination of them [2]. In contrast, the tricuspid or pulmonary valves are rarely involved. In the NBTE including all causes, the frequency of TV involvement is reported to be only 3.6 % [2], in which most cases were associated with antiphospholipid syndrome [5], [6], [7]. Notably, the report of TV NBTE associated with malignancy is limited to only one case [8]. Therefore, this is the second report showing TV involvement by NBTE in advanced cancer. In addition, because the size of vegetation might depend on the duration of active disease state and the patient could have suffered from the malignancy and subsequent NBTE for a substantial duration based on the size of the ovarian cancer, the present case might have shown large vegetations at the initial evaluation. Our case underlines the importance of listing NBTE as a differential diagnosis in cancer patients showing valve vegetations even in the TV. When we found mobile masses of TV, we need to take into account the possibility of NBTE, and consider heparin therapy if infective endocarditis was excluded, especially in a patient complicated with advanced malignancy. In addition, this particular patient was forced to discontinue the subcutaneous heparin infusion due to the current COVID-19 problem, resulting in recurrence of NBTE. We need to overcome this worldwide problem of healthcare to prevent such unmet need. In conclusion, we present a rare case of NBTE associated with ovarian cancer affecting the TV, in whom size of vegetation drastically changed according to the management status.

The following are the supplementary data related to this article.

Video 1

Two-dimensional echocardiographic image of parasternal four-chamber view before the initiation of heparin.

Video 2

Two-dimensional echocardiographic image of parasternal four-chamber view on the 18th day after the initiation of heparin.

Video 3

Two-dimensional echocardiographic image of parasternal four-chamber view on the 137th day after the initiation of heparin.

Declaration of competing interest

The authors have nothing to be disclosed regarding this case report.