Marantic endocarditis: a multidisciplinary case in which the etymology helps to determine the aetiology

Abstract

Background

Non-bacterial thrombotic endocarditis (NBTE), also known as ‘Marantic’ endocarditis, is a rare and life-threatening condition that involves thrombotic thickening of cardiac structures, most often heart valves, with the potential to cause multiple embolisms. In the literature, NBTE has been reported in association with advanced malignancies, connective tissue disease, and inflammatory disorders. We present a case of marantic endocarditis (ME) related to acute promyelocytic leukaemia (APL) causing visceral organ infarction, notably splenic, renal, and brain, without the development of major sequelae.

Case summary

We report a case of a 43-year-old male with a history of bicuspid aortic valve and aortic coarctation, surgically corrected at an early age, was presented to our service showing signs of deep vein thrombosis, disseminated intravascular coagulation (DIC), and multiple signs of embolism. During diagnostic evaluation, a non-bacterial thrombotic vegetation was identified on the aortic valve, and an early relapse of APL was confirmed. The patient was treated with a standard regimen for APL and anticoagulation therapy. On close follow-up, we observed a reduction in the size of the vegetation without structural cardiac damage and further signs of thromboembolism.

Discussion

As highlighted, in the emerging literature, the presence of multiple systemic emboli, whether cutaneous or involving visceral organs, should prompt clinicians to evaluate for endocarditis and distinguish between infective and non-infective causes. This is particularly essential in setting of malignancy or systemic inflammatory state. The present case underscores the importance of the timely recognition of ME in all cases presenting with DIC, in order to prevent further escalation. In addition, it offers an opportunity to reinforce the understanding of pathophysiological mechanisms and open the window for new insights and further reflections.

Graphical Abstract

Graphical Abstract.

Learning points.

• To demonstrate diagnosis and effective treatment in marantic endocarditis, particularly in the context of haematological malignancy.

• To highlight the importance of prompt recognition of NBTE in the case of systemic embolization.

Introduction

While non-bacterial thrombotic endocarditis (NBTE) remains an uncommon and underdiagnosed ill condition, the direct effects of multiple embolisms caused by partial detachment of sterile valvular vegetation require prompt detection and adequate management. Given the rarity of the phenomenon, most of the scientific literature on NBTE is based on case reports¹ and expert opinions, which explains the lack of established consensus on diagnosis and treatment. In recent years, systematic efforts have attempted to consolidate this fragmented body of evidence and provide a comprehensive overview of diagnostic and therapeutic strategies.^2,3

NBTE is mainly described in association with advanced malignancies particularly mucin-releasing adenocarcinoma,⁴ and autoimmune diseases, such as rheumatoid arthritis⁵ and systemic lupus erythematosus,⁶ referred to as Libman–Sacks endocarditis. In the last decade, however, it has also been reported with other systemic inflammatory conditions related to sepsis, burns, and Covid-19, all of which share a prothrombotic milieu.^7,8 Although thrombo-embolic events are not uncommon in haematological malignancies, the occurrence of NBTE has been rarely documented in the context of myeloproliferative and lymphoproliferative disorders.⁹ To date, only a limited number of cases have been identified worldwide in association with acute promyelocytic leukaemia (APL).^10,11

To the best author’s knowledge, this is the first reported case of NBTE occurring in the context of an early haematological relapse of APL. The presented case illustrates NBTE in a patient with perivascular thrombosis of indwelling central venous catheter (CVC), associated with multiple visceral infarctions (splenic, renal, and cerebral). It highlights the challenges of managing NBTE in the context of APL-related DIC, a condition characterized by both thrombotic and bleeding diathesis (Graphical abstract).

Timeline

Case presentation

A 43-year-old Caucasian male presented to our Emergency Department (ED) with an acute onset of oedema and cyanosis in the right upper limb, which had developed over the previous 24 h. He reported a low-grade fever (37.7°C) and mild pain related to the swelling of the upper limb without complain dyspnoea or other systemic symptoms. On admission, his blood pressure and oxygen saturation were normal, with a regular HR of 112 b.p.m., and a pain score of 2/10 according to visual analogue scale (VAS). On physical examination, the proximal third of patient’s right upper limb was cyanotic and mildly swollen compared to the contralateral arm, with mild venous reticulation over the right hemithorax. The limb was cooler to the touch, though pulse, sensitivity, and motor function were preserved. Cardiovascular examination showed normal heart sounds with no additional murmurs. No focal neurological deficits were identified.

His past medical history included a bicuspid aortic valve, surgically corrected aortic coarctation at the age of four (with mild residual stenosis), hypertension, and a prior diagnosis of APL treated with a standard regimen,¹² based on all-trans retinoic acid (ATRA), arsenic trioxide (ATO), idarubicin, and hydroxyurea, 1 year before the presentation. The patient achieved molecular remission at the end of the first cycle and maintained it. He also had a tunnelled indwelling CVC placed in the subclavian vein (SCV) to facilitate long-term intravenous treatment (Timeline).

Initial laboratory investigations showed thrombocytopenia (platelet count, 54 × 10⁹/L), moderate leucocytosis (WBC, 11 × 10⁹/L) with 12% promyelocytes and 5% blasts on peripheral smear, and normal C-reactive protein. Fibrinogen level was significantly reduced (1.6 g/L) and D-dimer markedly elevated (86 mg/L). Prothrombin time (PT) prolonged (48%; INR 1.6), while activated partial thromboplastin time (APTT) was within normal range (29 s). Renal and hepatic function tests were normal. Electrocardiography revealed sinus tachycardia with no additional abnormalities. After 24 h, the D dimer further increased (94 mg/L) with a sharp decline in fibrinogen level (0.8 g/L). According to ISTH score system,¹³ these findings and timing were consistent with early phase of thrombotic compensated disseminated intravascular coagulation (DIC).

Given the elevated D-dimer, tachycardia, and upper-limb swelling, a contrast-enhanced computed tomography (CT) scan of the chest and abdomen was performed to evaluate the extension of thrombo-embolic disease and vein patency. The CT images revealed thrombosis of the right axillary and SCVs around the indwelling catheter, as well as a 4-cm wedge-shaped splenic infarct and a similar hypodense area ∼2 cm in size at the middle third of the right kidney, both suggestive of embolic infarction (Figure 1) (Timeline).

Figure 1.

CT thoracic/abdomen scans: (A) a wedge-shaped infarct of the splenic parenchyma ∼4 cm of diameter and (B) hypodense area ∼2 cm in size at the middle third of the right kidney.

Management

In view of patient’s history of APL, the presence of complex coagulopathy with clinical and laboratory features of DIC, as well as circulating promyelocytes and blasts in the blood smear, an early relapse of APL (within 6 months from the end of first-line treatment) was highly suspected. Thus, lifesaving treatment with ATRA, hydroxyurea, and high-dose intravenous prednisone was initiated promptly to induce promyelocytic maturation. Bone marrow biopsy subsequently confirmed the diagnosis. Fibrinogen supplementation was administered to correct hypofibrinogenemia (nadir 0.8 g/L). Despite thrombocytopenia (54 × 10⁹/L) and bleeding risk, anticoagulation with unfractionated heparin (UFH) was started. However, achieving therapeutic APTT levels proved difficult due to consumptive coagulation, leading to a switch to low-molecular-weight heparin (LMWH), which resulted in progressive reduction of upper-limb oedema. Removal of the indwelling catheter was discussed but deferred to prioritize urgent haematological treatment with intravenous chemotherapy (antracyclines). As part of the standard pre-therapy evaluation before chemotherapy, a transthoracic echocardiogram (TTE) was performed 48 h after presentation. The exam revealed a vegetation affecting the posterior cusp of the bicuspid aortic valve (8–9 mm) with a broad-based, elongated lesion and mild-to-moderate aortic regurgitation (Figure 2). Left ventricular systolic function was preserved. A previous TTE performed six months earlier had shown no valvular abnormalities.

Figure 2.

(A, B) Transthoracic echocardiogram: vegetation of the posterior cusp on the bicuspid aortic valve (8–9 mm).

Given the evidence of systemic embolization, differential diagnosis between infective and NBTE was considered. While awaiting for microbiological results, empirical broad-spectrum antibiotic therapy with piperacillin/tazobactam was initiated, considering the patient’s immunocompromised status. Following consultation with an infectious-disease specialist, additional serological testing for pathogens commonly associated with infective endocarditis (IE) was performed, all yielding negative results. In the absence of microbiological and clinical evidence of infection, NBTE was deemed the most probable diagnosis, and antibiotic therapy was discontinued.

A transoesophageal echocardiogram (TOE) was deferred due to thrombocytopenia (PLTS < 50 × 10⁹/L) and DIC-related bleeding risk.

On hospital day 3, as part of APL diagnostic work-up to exclude central nervous system involvement prior to lumbar puncture, a non-contrast CT brain followed by MRI was performed. Imaging revealed multiple ischaemic lesions in the left temporal cortex, right centrum semiovale, right caudate nucleus, and right cerebellar hemisphere, consistent with embolic phenomena (Figure 3A–C). Despite these findings, the patient remained neurologically asymptomatic, and neurologic consultant confirmed the absence of focal deficits. LMWH therapy was continued cautiously, with temporary discontinuation during phase of severe thrombocytopenia (<30 × 10⁹/L). No major bleeding events occurred.

Figure 3.

Diffusion weighted imaging sequence magnetic resonance imaging brain: small foci of diffusion restriction in left temporal cortex (A), right caudate nucleus (B), and right cerebellar hemisphere (C).

Outcome and follow-up

Follow-up echocardiograms performed at 2, 3, and 6 months after diagnosis showed first a reduction (Figure 4) and then a complete disappearance of the vegetations supporting the diagnosis of NBTE. Follow-up brain MRI demonstrated resolution of prior cerebellar ischaemia without new ischaemic lesions (Figure 5). Follow-up abdominal CT scan demonstrated residual splenic scarring (32 × 21 mm²) and mild ischaemic changes in the right kidney. After normalization of blood counts normalized, especially platelets, LMWH was replaced with Apixaban 5 mg twice daily. The anticoagulant therapy was continued for a total of three months and subsequently discontinued, as the thrombotic episode was considered provoked and resolved following morphological remission of APL. The clinical course was favourable. Following induction and maintenance therapy, the patient underwent to autologous stem cell transplantation.

Figure 4.

Follow-up transthoracic echocardiogram: reduction of the vegetation.

Figure 5.

Follow-up brain MRI showed resolution of previous ischaemic lesion in the right cerebellar hemisphere.

Discussion

Overall, patients with NBTE have a poor prognosis, and the antemortem diagnosis remains rare and challenging. In-hospital mortality is estimated at ∼36%, reaching higher rates of 56% when associated with malignancy.¹

Over the past two decades, however, NBTE has gained increasing recognition, particularly within the specialized field of cardio-oncology, contributing to improved survival rates and cancer patient care.²

NBTE is frequently observed in patients with hypercoagulable states, often triggered by malignancy-associated procoagulants, including tumour necrosis factor and interleukins (IL), which disrupt the host immune response and create a prothrombotic inflammatory environment.² This predisposition to thrombosis increases the risk of venous thromboembolism, DIC, and thrombotic microangiopathy.

The present report illustrates a unique case of NBTE as a complication of early relapse of APL presenting with catheter-related thrombosis CVC-related thrombosis and DIC.

APL represents a distinct subtype of acute myeloid leukaemia accounting for ∼10%–15% of all cases. It is classically characterized by the chromosomal translocation between t(15;17) (q24;q21), which results in differentiation arrest at the promyelocyte stage. Although current regime combining ATRA and ATO has dramatically improved overall survival, a significant number of patient might exhibit relapse. Given high risk of haemorrhagic and thrombotic complications, APL constitutes a medical emergency.¹⁴

Clinically, marantic endocarditis may remain silent, or present with mild symptoms such as fever, malaise, and fatigue, or being detected incidentally, most often postmortem.¹⁵ In the present case, valvular vegetation was identified during echocardiographic evaluation performed as part of the APL work-up, despite embolic signs already evident on initial imaging studies.

Valvular vegetations in NBTE are generally small (ranging from <0.1 to >2 cm) and less stable compared to IE, making them more prone to systemic embolization. Unlike IE, NBTE rarely causes significant valvular dysfunction or audible murmurs, thus a challenge in early recognition.

Systemic embolization remains the hallmark feature¹ of NBTE, with cerebrovascular accidents occurring in up to 70% of cases and stroke-like symptoms as the most frequent manifestation. The presence of DIC is observed in 71% of individuals² contribute to significant morbidity and complex management challenges.

TTE remains the first-line imaging modality in suspected NBTE, with its inherent limitations in detecting small vegetations (<2–3 mm) that fall below its resolution threshold. In such cases, TOE is recommended. The advent of three-dimensional (3D) echocardiography has enhanced the visualization of valvular lesions, although its role in NBTE assessment remains an area of ongoing research.¹⁶

Management strategies of NBTE typically focus on two parallel objectives: Treatment of the underlying disease (in this case, APL) and prevention of further thrombo-embolic events. In the setting of DIC poses significant clinical challenges due to the interplay among coagulopathy, thrombo-embolic risk, and potential bleeding complications. Although data are limited, UFH or LMWH is generally preferred over vitamin K antagonists or direct oral anticoagulants (DOACs) during the acute phase, given their more predictable effect on DIC. This case also showed the challenge of achieving therapeutic levels with UFH in the setting of consumptive coagulopathy. The role of DOACs and the optimal duration of anticoagulation remain subject of ongoing debate.¹⁷ The role of anticoagulation in reducing NBTE vegetation, in the context of antiphospholipid antibody syndrome, appears to be controversial.¹⁸ Lifelong anticoagulation is considered reasonable unless the underlying disease is proved to be cured. Ultimately and most importantly, anticoagulation should be carefully tailored and individualized according to patient-specific factors such as age, renal function, and bleeding risk.¹⁹

While NBTE rarely causes severe valvular damage, it is crucial assessing the need for surgical intervention. In selected cases of valvular dysfunction surgical intervention may be indicated.

This case underscores a well-recognized clinical dilemma, previously reported in various contexts²⁰ regarding the potential for haemorrhagic transformation of cerebral ischaemic lesions during the acute post-stroke phase, particularly within the first 48 h. Fortunately, no haemorrhagic complications occurred in this patient. These observations suggest that anticoagulation therapy may be judiciously implemented in the presence of minor, albeit multiple, ischaemic lesions.

Finally, the management of CVC-related thrombosis in patients requiring intravenous chemotherapy presents a significant clinical challenge. Decisions regarding catheter retention must balance the risk of further thromboembolism vs. the need to preserve vascular access.

Conclusion

This case is remarkable in several aspects, illustrating a rare occurrence of NBTE secondary to early relapse of APL complicated by CVC-related thrombosis and DIC. The coexistence of thrombocytopenia, hypercoagulability, and systemic embolization reflects the complex pathophysiology underlying APL. It highlights the therapeutic challenges and the need for a multidisciplinary approach integrating haematological, infectious disease, and cardiovascular perspectives. Given the paucity of literature, it exposes therapeutic limitations in relation to anticoagulation in contraindicated cases such as DIC, severe thrombocytopenia, or the risk of haemorrhagic transformation following embolic ischaemic stroke. As our case demonstrates, NBTE may remain clinically silent or being identified incidentally, underscoring the importance of suspecting marantic endocarditis in all patients presenting with unexplained systemic emboli, particularly in the context of solid or haematological malignancies. Despite advances in the field of cardio-oncology, future research is required to address existing knowledge gaps regarding the optimal management of NBTE in patients with haematological malignancies.

Lead author biography

Stefano Di Gregorio graduated from the Medical faculty of the University of Turin in 2006. He is currently completing a residency in general internal medicine. He completed a Postgraduate diploma in Public Health at the University of Manchester and an MA in Medical Anthropology at the School of Oriental and African Studies (SOAS, University of London).

Author contributions

Stefano Di Gregorio (Conceptualization [lead]; Investigation [lead]; Methodology [lead]; Writing—original draft [lead]), Unal Tokkuzun (Conceptualization [equal]; Data curation [equal]; Investigation [equal]; Methodology [equal]), Angelo Di Simone (Investigation [supporting]; Methodology [supporting]; Validation [supporting]; Writing—review & editing [supporting]), Andrea Menafoglio (Conceptualization [supporting]; Supervision [supporting]; Writing—review & editing [supporting]), and Andrea Demarchi (Conceptualization [lead]; Supervision [lead]; Writing—review & editing [lead])

Consent: The authors confirm that written consent for submission and publication of this case report including images and associated text has been obtained from the patient in line with COPE guidance.

Funding

None.

Data availability

The data underlying this case report can be made available upon reasonable request to the corresponding author.

Primary specialties involved other than cardiology

Hematology, Internal Medicine, Infectious disease, Neurology.