Marantic Endocarditis as a Rare Complication of Metastatic Pancreatic Adenocarcinoma: Case Report and Literature Review

1. Introduction

Cancer patients have an increased risk of hypercoagulability that depends on multiple factors,  classified by the European Society of Cardiology (ESC) as patient related factors, cancer-related factors and treatment related factors. (1) The thrombotic and thromboembolic events are more common in patients with pulmonary, ovarian and gastrointestinal sites. A malignant disease can be hidden by the presence of multiple events of venous or arterial thrombosis that can have lethal manifestations on patients. (2)

Nonbacterial thrombotic endocarditis (NBTE), also known as marantic endocarditis, occurs through the presence of sterile fibrin-platelets conglomerates that may form vegetations on the heart valves leading to paradoxical emboli in peripheral organs. (3)

The epidemiology data about NBTE are poor and post mortem series provide the majority of information. An autoptic study revealed a prevalence of 3,7%, three times higher than infective endocarditis. (4) In high-risk groups, such as cancer patients or those with autoimmune conditions, the prevalence rises dramatically and can reach 15% according to  one large echocardiographic study (5).

In patients with chronic diseases, disseminated intravascular coagulation, mucin-producing metastatic cancers (such as those of the lung, stomach, or pancreas), or chronic infections (like tuberculosis, pneumonia or osteomyelitis), large thrombotic vegetations may develop on heart valves, leading to significant emboli that can affect the brain, kidneys, spleen, mesentery, limbs, and coronary arteries. These vegetations are more likely to form on congenital heart valve abnormalities or those damaged by rheumatic fever. (3) Thus, it is an underdiagnosed manifestation of this prothrombotic state that can cause substantial morbidity in affected patients, most notably recurrent or multiple ischemic cerebrovascular strokes. (6)

The clinical manifestations of NBTE consist of decompensations caused by embolic events. The patients may present with manifestations of deep venous thrombosis, pulmonary embolism (dyspnea, chest pain, cough), ischemic stroke (hemiparesis, motor, sensory and language disorders), depending on the site of the affected vessel. (7) To confirm the diagnosis, serial blood cultures and echocardiography should be performed. A negative blood culture result combined with the presence of valvular vegetations supports this diagnosis. Additionally, examination of embolic fragments obtained during embolectomy can assist in confirming the diagnosis. (6)

Distinguishing noninfective endocarditis from culture-negative infective endocarditis can be challenging, but it is crucial. Regarding treatment strategies, anticoagulation is necessary in noninfective endocarditis, while it is generally avoided in infective endocarditis unless there is an underlying condition, such as a mechanical valve. To identify potential causes of true noninfective endocarditis, tests for hypercoagulability, antinuclear antibodies and antiphospholipid syndrome should be conducted. (3)

We aim to report a rare case of marantic endocarditis in a patient diagnosed with stage IV pancreatic cancer, from our medical practice. We also conducted a review of cases reported in the literature of  NBTE associated with pancreatic cancer. Through this article, we want to highlight the importance of recognizing the main symptoms, the benefit of the early diagnosis, as well as the appropriate treatment and therapeutic management carried out in a multidisciplinary team.

2. Case report

We report the case of a 62 year-old male patient, heavy smoker (40 pack/year) without any family history, who was investigated for an episode of deep venous thrombosis (DVP). The Dopple ultrasound showed a thrombus in the left popliteal vein and the patient received anticoagulant therapy (Rivaroxaban 10 mg, twice/day). Because the patient had lost 5 kg of weight in the last two months, a CT scan of the chest, abdomen and pelvis was performed at that time, showing a pancreatic tumor and liver metastases (Figure 1).

A biopsy was obtained through EUS-guided FNA from the pancreatic lesion and the histopathological examination showed a G2 adenocarcinoma. Given the good performance status, palliative polychemotherapy (PCT) with mFOLFIRINOX was initiated. Before the second cure of PCT, the patient presented with dysarthria and paresthesias in the right upper limb. A cerebral CT scan was performed, and it revealed an ischemic stroke (Figure 2). The patient was admitted in the department of neurology where he suffered another stroke. Antiplatelet therapy with Aspirin 75 mg/day and anticoagulant treatment with enoxaparin twice a day were added to the treatment.

Figure 1. Abdominal CT scan showing multiple hypodense liver lesions and the pancreatic tumor

Figure 2. Cerebral CT scan showing small hypodense areas at the level of the white matter adjacent to the posterior horn of the left lateral ventricle (VL).

Neurologically, the patient’s evolution was favorable for a few days until the language disorder and motor deficit worsened. A brain MRI was performed at that time and multiple subacute ischemic strokes were visualized in the temporal lobe, parietal lobe and cerebellum (Fig 3a,b). Also, the inflammatory biomarkers were increased (C-reactive protein= 179 mg/L, WBC= 20.000/mcL), so a thoracic and abdominal CT scan was performed to exclude a possible pulmonary infection.  Multiple renal infarcts were observed localized at the lower pole of the right kidney and at the upper pole of the left kidney, also to the lower pole of the spleen (Fig 4). Blood and urine cultures were taken and a cardiology check-up was requested. The urine culture was positive for Pseudomonas spp, so it was initiated antibiotic treatment with Meropenem 1g every 8 hours and Vancomicin 1g twice a day.

A transesophageal cardiac ultrasound was performed and it showed a round oval hypoechogenyc formation attached to the anterior mitral valve towards the atrial face, without mobility, but with an appearance suggestive of vegetation with embolic risk. The blood cultures were also negative, thus the diagnosis of marantic endocarditis was established.

Figure 3. Brain MRI showing subacute stroke in the vascular territory of the left middle cerebral artery (ACM) (left); Brain MRI showing chronic ischemic stroke- occipital, parietal and frontal on the left side (right)

 Figure 4. Abdominal CT scan showing a hypodense lesion in the spleen suggestive of splenic infarction; hypoechoic lesions at the lower pole of the right kidney and at the upper pole of the left kidney consistent with renal infarction

The patient was discharged stable, conscious with predominantly expressive mixed aphasia in remission, right facial paresis in remission, right brachial monoparesis score 4/5 MRC, no apparent superficial sensitivity disorder. He received treatment at home with  Apixaban 5 mg twice a day. Despite the anticoagulant treatment, another thrombotic episode ocurred, a deep thrombosis localized at the left femoral artery and the popliteal artery. Unfortunately, the patient passed away after two weeks.

3. Discussion and literature review

Based on this rare case in our medical practice, who had a difficult management and an unpredictable evolution, we conducted a review of the literature to assess the prevalence of marantic endocarditis in patients with pancreatic cancer. The literature search was performed in four major databases: PubMed, Google Scholar, Web of Science and Science Direct, using the filters “Case report”, “2014-2024” and the key words “pancreatic cancer”, “marantic endocarditis”, “hypercoagulability”, “metastatic disease”. We aimed to find similar cases published during the years, having the pancreas as primary tumor, metastatic or not, complicated with marantic endocarditis during the evolution of the disease. We had as exclusion criteria any other sites of the primary tumor or the presence of NBTE that was not related to cancer patients. We analyzed each case, and we found 16 articles relevant to the mentioned criteria and a total of 18 cases.

We summarized the content of the studies in Table 1 and we observed several similarities between our case and the cases selected in the review.

Regarding the onset of symptoms, the patients presented with manifestations caused by ischemic cerebral strokes (n= 8), thrombotic episodes of deep vein thrombosis (n=2) and pulmonary embolism (n= 3) or the association of both of them (n= 3) and few of them had some nonspecific symptoms. The majority of thromboembolic events and the diagnose of the NBTE occurred before the diagnosis of cancer (n=13), one of them was diagnosed at the autopsy. Most patients were diagnosed with stage IV of pancreatic cancer (n= 17); only one patient had locally advanced disease.

The most common site of metastasis was the liver (n=17) and three of the patients had multiple metastases: lung (n= 2), spleen (n=1), kidney (n=1), adrenal glands (n=1).

Concerning the location of vegetations at the heart valves, it was observed in the cases that we studied, univalvular disease: mitral valve (n=8), aortic valve (n=3) and tricuspide valve (n=1) and bivalvular disease (n=4). The treatment was based on anticoagulant therapy, LMWH (n=11), UFH (n= 3) and DOAC (n=4). Just one case published by Savarapu et al had the chance to achieve both chemical and mechanical fibrinolysis. (8)

About the evolution of the patients after the embolic episodes, more than half of the cases mention the death of the patients (n=10), while the rest of them have overcome the complications of the NBTE episode (n= 8).

There is another important point of view concerning the presence of marantic endocarditis, namely the presence of embolic recurrences despite the optimal anticoagulant therapy that patients receive. In the cases included in the review, the recurrence of the thromboembolic events was frequent (n=13/18).

It is important to raise awareness regarding the timing of the embolic events related to cancer diagnosis. The prognosis is poor, not because of the heart injury caused by the presence of the vegetations on the heart valves, but because of the underlying disease. There is ongoing discussion about the fact that NBTE patients should get a thorough diagnostic work-up for occult cancer. Also, the key of the discussion is about giving or not prophylactic anticoagulant treatment for the patients in risk categories.

Table 1- The summary of the clinical cases included in the review

4. Conclusion

In conclusion, oncological patients have a high risk of prothrombotic events, and the diagnosis of neoplastic diseases may be obscured by the neurological manifestations of the marantic endocarditis. Therefore, we must be aware of the fatal nature of this condition which can have multi-organ consequences due to the presence of the spreading emboli. Consequently, it is imperative to early diagnose and treat through a multidisciplinary approach this rare complication, so we can improve mortality and morbidity rates of the patients.

Abbreviations

ACM – middle cerebral artery

AMV – anterior mitral valve

CT – computer tomography

DVP – deep venous thrombosis

DOAC – direct oral anticoagulant

EUS – endoscopic ultrasound

FNA – fine needle aspiration;

LMWH – low molecular weight heparin

MRC – muscle power scale

MRI – magnetic resonance imaging

NBTE – non -bacterial trombotic endocarditis

PE – pulmonary thrombembolism

SC – subcutaneous

TAP – toraco-abdominal-pelvis

UFH – unfractionated heparin

WBC –  white blood cells

References

1. ESC Guidelines on cardio-oncology. Lyon Alexander R, Lopez-Fernandez Teresa et al. 2022, European Heart Journal, p. 4303.
2. Bartosz, Chmielowski and Territo, Mary C. Manual of Clinical Oncology 8th edition. Philadelphia : Wolters Kluwer, 2017.
3. Noninfective endocarditis. Armstrong, Guy P. Waitemata, Auckland : MSD, Cardiovascular disoreders, 2024.
4. Overview and Comparison of Infectious Endocarditis and Non-Infectious Endocarditis: A Review of 814 Autoptic Cases. Bussani, R., De-Giorgio, F. and Pesel, G. doi:10.21873/invivo.11638, s.l. : In Vivo, 2019, Vols. 33: 1565-1572 (2019).
5. Antiphospholipid Syndrome and the Relationship between Laboratory Assay Positivity and Prevalence of Non-Bacterial Thrombotic Endocarditis: A Retrospective Cohort Study. . Lenz, C.J., Mankad, R. and Klarich, K.ș. 1408-1414, Rochester : J Thromb Haemost., 2020, Vol. 18. DOI: 10.1111/jth.14798 .
6. Diagnostic Work-Up in Patients with Nonbacterial thrombotic endocarditis. Tonutti, A and Scarfo, I. 5819, Rozzano, Italy : Journal of Clinical Medicine, 2023, Vol. 12.
7. Development of Nonbacterial Thrombotic endocarditis while on systemic anticoagulationin pancreatic cancer: A case report. Wang, J, Monga, N and et al. 2020, Cureus 12(10): e10967.
8. Cancer-Related Non-Bacterial Thrombotic Endocarditis Presenting as Acute Ischemic. Savarapu, P, Abdelazeem, B and Isa, S et al. 2021, Cureus 13(5): e14953.
9. Nonbacterial thrombotic endocarditis with bivalvular regurgitation. Assaf, Sohiub N. and Taylor, John et al. 2023, Cardiovascular imaging case reports, pp. 168-173.
10. Nonbacterial thrombotic endocarditis. Fournier, John B et al. 2019, The New England Journal of Medicine.
11. Non-bacterial thrombotic endocarditis in a patient with pancreatic carcinoma. Wild, Johannes and Distelmeier, Simon et al. 2021, Wiley Echocardiography.
12. Non- bacterial thrombotic endocarditis: a rare presentation and literature review. Patel, Maulin J and Elzweig, Joel et al. 2020, BMJ Case reports.
13. Reversibility of valve regurgitation due to cancer- related non- bacterial thrombotic endocarditis after switching direct oral anticoagulation for heparin. Lepour, Maxence and Wieers, Gregoire J FG et al. 2022, BMJ Case reports.
14. Non-bacterial thrombotic endocarditis. Report of one case. Salinas, Alejandra G et al. 2017, Revista Medica de Chile, pp. 1353-1358.
15. Non-bacterial thrombotic endocarditis in pancreatic cancer and other high-risk malignancies: the case for prophylactic treatment. Spurgeon, Laura and Ispouglou, Sissi. 436-439, Manchester : Oxford Medical Case Reports, 2021.
16. A rare case of metastatic pancreatic adenocarcinoma presenting as a pulmonary embolism from nonbacterial thrombotic endocarditis. Kania, B, Mekheal, E and et al. 2022, Elsevier, pp. 3097-3102.
17. Severe Nonbacterial Thrombotic Endocarditis Resulting in Aortic Valve Insufficiency and Multiple Small Strokes in a Patient With Metastatic Pancreatic Cancer: Lessons for Optimal Management. Collien, Maike and et al. 2020, Clinical Colorectal Cancer.
18. Synchronous cardiopulmonary consquences of the hypercoagulable state associated with cancer. Guerra, Martin JM and et al. 2018, Archivos de Bronconeumologia.
19. Marantic endocarditis associated with pancreatic cancer: A case series. Jameson, Gayle S and et al. 2009, Case reports in Gastroenterology.
20. Acute Subdural Hemorrhage Associated With Both Metastatic Adenocarcinoma of the Dura and Minor Head Trauma: A Case Report and Review of the Literature. Julson, Janet R and et al. 2018, ACADEMIC FORENSIC PATHOLOGY: THE OFFICIAL PUBLICATION OF THE NATIONAL ASSOCIATION OF MEDICAL EXAMINERS , pp. 769-776.
21. Guidelines for the Early Management of Patients with Acute Ischemic Stroke: 2019 Update to the 2018 Guidelines for the Early Management of Acute Ischemic Stroke. Powers, William J and et al. North Carolina : American Heart Association, 2019.
22. Pancreatic cancer with multiple liver metastasis complicating multi-organ infarcts from marantic endocarditis and Trousseau’s syndrome. Rahman, Mir and et al. 2022, Royal College of Physicians.
23. Marantic endocarditis: incidental infarcts leading to diagnosis of pancreatic cancer. Starobinska, Ella and et al. 2018, BMJ case reports.
24. Multiple thrombi in the heart in Tousseau Syndrome caused by pancreeatic carcinoma. Takeshita, Shao and et al. 2017, Journal of Stroke and Cerebrovascular Diseases.