Case Report: Right atrial organized thrombus three years after tricuspid annuloplasty

Background: Occurrence of right atrial masses, especially in patients with history of cardiac surgery, is rare. Differential diagnosis between malignant and non-malignant aetiologies might be cumbersome, and surgery is often required to prevent complications or disease evolution. Case: We report the case of a 16-year-old girl from a rural area of Sudan, who underwent surgery for a modified De Vega’s tricuspid annuloplasty, and mitral and aortic valve replacement with mechanical prostheses. The patient was on regular follow-up but demonstrated a poor compliance to anticoagulation therapy with a time in therapeutic range between 52% and 20%. She remained asymptomatic, but a right atrial mass was diagnosed by transthoracic echocardiography during a follow-up visit 41 months after the first operation. Surgical removal of the mass revealed an organized thrombus arising from the point where the Prolene stitches for the tricuspid annuloplasty were previously passed. The patient recovered from surgery, was discharged home on post-operative day 10 and the first follow-up visit at 30 days after discharge confirmed a good clinical status and a normal transthoracic echocardiography (TTE). Conclusions: This case report describes the diagnostic and therapeutic work-out of a thrombus formation on the suture lines of a tricuspid annuloplasty. Moreover, it highlights the importance of a strict and long follow-up after valvular surgery and of the adherence to anticoagulation therapy, especially for patients living in rural areas of developing countries.


Introduction
Intracardiac masses are not frequent and they may arise in all of the four chambers of the heart. 1 Their aetiologies include thrombi, vegetations, and neoplasms. 1 Despite the pivotal role of echocardiography and other imaging techniques, differential diagnosis might be challenging, and surgery might be indicated to avoid complications and rule out malignancies. Intracardiac masses may arise also in patients that underwent previous cardiac surgery with implantation of valve prosthesis or valve repair. 2, 3 Herein, we report a case of a girl that underwent triple valve surgery and was diagnosed with a right atrial mass more than three years after the indexed operation. This case report follows the CARE guidelines. 13

Case presentation
We present the case of a 16-year-old Black African girl from a rural area of Sudan, with a history of recurrent tonsillitis, chest infections and untreated rheumatic fever. Her symptoms started with shortness of breath on exertion, dry cough, palpitations and lower limb oedema. She was first referred to our hospital due to signs of acute decompensation (raised jugular venous pressure, limb oedema and dyspnoea) when she was 13 years old (body mass index 12.65). Transthoracic echocardiography showed retracted rheumatic mitral and aortic leaflets associated with severe mitral and aortic regurgitation. The left atrium and ventricle were dilated, and a secondary severe tricuspid regurgitation was diagnosed. Indication for urgent surgery was confirmed. The patient underwent mitral valve replacement with a 27 mm SJM Master mechanical prosthesis (Abbott, Burlington, MA USA), aortic valve replacement with a 19 mm SJM Regent mechanical prothesis (Abbott, Burlington, MA USA), and tricuspid annuloplasty with two separate Prolene 4/0 sutures with pledgets. The postoperative period was uneventful, and the patient was discharged home in good general condition on postoperative day 10. The anticoagulation therapy included warfarin with a target international normalized ratio of 2.5-3.5 and was associated with oral aspirin (100 mg/day) as the patient was a woman in fertile age living in a rural area. 4 The predischarge transthoracic echocardiography (TTE) showed a mildly depressed left ventricular systolic function (46%), good result of the tricuspid repair with mild residual regurgitation and good function of the mechanical prostheses. The patient remained in regular follow-up at our outpatient clinic, restarted a normal life and went back to school. Two years after surgery she experienced menorrhagia with severe anaemia (haemoglobin: 5.6 g/dl) and oral aspirin was discontinued. She demonstrated a low compliance with the anticoagulation therapy and a time in therapeutic range (TTR) of 52% during the first year after surgery, 34% during the second year, 34% during the third year and 20% during the first six months of the fourth year. No history of hypercoagulopathy and contraceptive use was reported. The patient remained in sinus rhythm during the whole follow-up.
At the follow-up visit 41 months after surgery (16 years old, body mass index 18.49), the TTE showed a mobile mass measuring 10 Â 15 mm and arising from the atrial wall just above the tricuspid annulus ( Figure 1). The right atrium was normal in size and structure (diameter: 31 mm; area: 15 cm 2 ). The mass appeared mobile with the cardiac cycle, but no interference with the tricuspid valve function was noticed. No other masses or possible thrombi were noticed on the left heart prosthetic valves, nor episodes of systemic or pulmonary embolism were reported. Surgical indication was given based on the significant dimension of the mass, its position close to the tricuspid valve, the risk for embolization and the possible neoplastic nature.
The patient underwent re-sternotomy, cardiopulmonary by-pass was established with bicaval and aortic cannulation, the heart was arrested, and the right atrium was opened. The surgery was completed at arrested heart to reduce the risk of neoplastic embolization in case of malignant diagnosis and allow for a radical removal of the mass. The mass appeared to be attached to the atrial wall between the pectinate muscles and the anterior tricuspid annulus (Figure 2). In detail, the mass was arising from the point where the Prolene stitches for the tricuspid annuloplasty were previously passed but did not involve the valve leaflets. The mass had a curved shape and hard texture with a smooth surface. It was removed from REVISED Amendments from Version 1 We have made minor revisions and clarifications to this revised version to address reviewers' comments. Specifically, we attempted to better characterize the case presentation with further details on the patient's characteristics, surgical approach and medical therapy. First, the patient was better characterized with details such as body mass index at both operations, clinical presentation before the first operation and echocardiographic details that led to the first surgical indication. Second, we added few details about the anticoagulation therapy between the two surgeries and the literature reference to a previous study from our group regarding pregnancy in women with implanted mechanical valves. Finally, we specified that the patient did not experience any other thrombotic event and we exposed the rationale for an operation on crossclamp instead of beating heart.
Any further responses from the reviewers can be found at the end of the article the atrial wall using a knife, the atrium was closed, and the surgery completed. The macroscopic analysis showed a 15 Â 15 Â 8 mm homogenous light brown soft-tissue mass. The microscopic section showed several layers of hyalinized tissue containing red blood cells, scattered mixed inflammatory cells and fibrosis. The histological features were consistent with an organized thrombus.
The post-operative course was uneventful, and the patient was discharged home 12 days after surgery. The first follow-up visit at 30 days after discharge confirmed a good recovery and a normal TTE.

Discussion
Occurrence of right atrial masses, especially in patients with history of cardiac surgery, is rare. This case report describes the diagnostic and therapeutic work-out of a thrombus formation on the tricuspid valve annulus after a modified De Vega's annuloplasty. Moreover, it highlights the importance of a strict follow-up after valvular surgery and of the adherence to anticoagulation therapy, especially for patients living in rural areas of developing countries. To the best of our knowledge, this is the first report of a long-standing thrombus developed on the suture lines of a tricuspid annuloplasty and diagnosed more than three years after surgery. Many types of masses can be found in the right atrium, from benign thrombus to malignant sarcoma. 1 For example, angiosarcoma may infiltrate the right atrioventricular junction, the atrial wall and also the tricuspid valve. 5,6 Lymphoma, hamartoma and pericardial mesothelioma can also affect the right atrium. 7,8 Vegetations on the tricuspid valve can be seen in case of infective endocarditis while non-infective masses have been reported in patients with antiphospholipid antibody syndrome. 9 Calcified masses such as the calcified amorphous tumour have been reported in patients with end stage renal failure, 10 and cardiac hydatid cysts on the tricuspid valve has also been described. 11 In case of previous cardiac surgery, the presence of prosthetic material can orient the aetiological diagnosis toward the presence of a thrombus. 2,3 Nevertheless, all other causes cannot be excluded, especially when the mass presents years after the operation.
Diagnosis is usually made initially by imaging through TTE as first-line modality, and cardiac computed tomography or magnetic resonance to better characterize the tissues. Finally, 18-Flurodeoxyglucose positron emission tomography may identify an increased metabolic activity of tumours. In the case described above, echocardiography was the only diagnostic tool available and precise differentiation among all aetiologies was not possible. However, yearly follow-up visits and TTE were pivotal to diagnose the mass and give surgical indication before the occurrence of any complication.
Finally, direct excision of the mass and subsequent histological analysis revealed the thrombotic origin of the mass. Although right-sided prosthetic materials have demonstrated a higher thrombotic potential than their left-sided ones, there are no specific postoperative antithrombotic management recommendations after tricuspid valve repair, especially in the case of all types of De Vega's annuloplasty techniques. 3 Moreover, the association between tricuspid procedures and other indications for postoperative anticoagulation (e.g., concomitant left-sided mechanical valves like in the case presented) may contribute to the low incidence of this diagnosis, especially in case of infrequent TTE and follow-up contacts with the patient. This may become a problem in rural areas or developing countries where the follow-up programs might be difficult. 12 Moreover, difficult access to the tertiary cardiac surgery centre can reduce the patient's compliance to the anticoagulation therapy as it happened in the presented case. Indeed, she demonstrated a low TTR with a decreasing trend as time passed since the first surgery. We can, thus, speculate that such a low compliance could have favoured the development of a thrombus over the annuloplasty stitches. Further screenings for any hypercoagulopathy could have helped in the characterization of the case but they could not be performed for economical and logistic reasons. In conclusion, this case report highlights the importance of adequate follow-up programs for young patients undergoing valve surgery for rheumatic heart disease in developing countries. Moreover, it shows how tricuspid annuloplasty can carry a certain degree of thrombotic risk, even years after surgery. Further studies are required to investigate the fate of patients receiving tricuspid annuloplasty associated to left-sided valve surgery for rheumatic heart disease.

Consent
Written informed consent for data collection and publication was obtained from the patient and the patient's mother, as legal guardian. We confirm that we have obtained permission to use images included in this presentation from the patient and the mother, as legal guardian.

Data availability
Underlying data All data underlying the results are available as part of the article and no additional source data are required.

Open Peer Review
surgery.
The article is well written, but few points should be clarified. I would like the authors to comment on the following points The author should provide some information about the preoperative symptoms and the preoperative echocardiographic finds at the time of the first operation.
Which was the anticoagulation therapy at discharge?
The author states that aspirin was discontinued two years after the surgery. Why was aspirin needed two years after the surgery? Probably due to the low compliance to anticoagulation therapy. But since the compliance to anticoagulation was low at the third and fourth year was the aspirin reintroduced? I notice that the author uses two specific mechanic valves in aortic and mitral position. On the market is available a different mechanical valve prosthesis, that can be used in both mitral and aortic position. For this specific mechanical valve the anticoagulation therapy can be carried out with a lower INR in combination with aspirin. Has the author thought to change the used mechanical valves in consideration to the special social contest in which he practices and the difficulties for the patients to adhere to the needed anticoagulation therapy?
The author states that the patient had a low compliance with regard to the anticoagulation therapy, but no information is given if the patient had trombi on the mitral and aortic valves or if she had peripheral embolism.
To remove the mass in the right atrium, the patient underwent a second surgery and the heart was arrested. Why the author used this surgical approach? This kind of surgery can be performed as well with a beating heart. Since the patient had a mildly depressed left ventricular systolic function (46%), why to expose this heart to ischaemic time when it was possible to avoid it? I think the the article can be deemed suitable for indexing with minor corrections

Are enough details provided of any physical examination and diagnostic tests, treatment given and outcomes? Yes
Is sufficient discussion included of the importance of the findings and their relevance to future understanding of disease processes, diagnosis or treatment? Yes

Is the case presented with sufficient detail to be useful for other practitioners? Yes
Competing Interests: No competing interests were disclosed.

Reviewer Expertise: Endocarditis
I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard, however I have significant reservations, as outlined above.

Salvatore Lentini
We are grateful for the opportunity to submit a revised version of our manuscript "Case Report: Right atrial organized thrombus three years after tricuspid annuloplasty" to F1000 Research and are thankful for the very constructive and helpful comments of the Reviewers. In addition to responding to the comments, we revised the manuscript, and hope that the changes and responses satisfy the Editors and Reviewers` requests.

Reviewer 2 I would like to gratulate the author for reporting this interesting and rare case of a patient with a thrombus formation on the tricuspid valve annulus after a modified De
Vega's annuloplasty. The patient underwent surgery with removal of the thrombus and discharged home 12 days after surgery. The article is well written, but few points should be clarified. I would like the authors to comment on the following points. We are grateful to the Reviewer for the very constructive and helpful comments. In addition to responding to the comments, we revised the manuscript, and hope that the changes and responses satisfy the Reviewers` requests.
The author should provide some information about the preoperative symptoms and the preoperative echocardiographic finds at the time of the first operation. We thank the Reviewer for this suggestion. We added a brief description of the preoperative symptoms and echocardiographic findings.

Changes: case presentation
Her symptoms started with shortness of breath on exertion, dry cough, palpitations and lower limb oedema. She was first referred to our hospital due to signs of acute decompensation (raised jugular venous pressure, limb oedema and dyspnoea) when she was 13 years old (body mass index 12.65). Transthoracic echocardiography showed retracted rheumatic mitral and aortic leaflets associated with severe mitral and aortic regurgitation. The left atrium and ventricle were dilated, and a secondary severe tricuspid regurgitation was diagnosed.

Which was the anticoagulation therapy at discharge?
The Reviewer pointed out an interesting clinical detail. We modified the manuscript adding details about the anticoagulation therapy at discharge:

Changes: case presentation
The anticoagulation therapy included warfarin with a target international normalized ratio of 2.5-3.5 and was associated with oral aspirin (100 mg/day).
The author states that aspirin was discontinued two years after the surgery. Why was aspirin needed two years after the surgery? Probably due to the low compliance to anticoagulation therapy. But since the compliance to anticoagulation was low at the third and fourth year was the aspirin reintroduced? We thank the reviewer for this interesting question. Aspirin was associated with warfarin as the patient was a woman in fertile age living in a rural area. Thus, the patient was at higher risk of low compliance for the anticoagulation therapy and a possible pregnancy would have required association with anti-platelet therapy as previously reported in a study from our group on pregnancy outcomes in women with mechanical valve prostheses using vitamin K antagonist therapy (PMID: 35899137), and following guidelines (PMID: 33342587). After the menorrhagia experienced by the patient, aspirin was not re-introduced despite the low compliance due to the previous bleeding event.

Changes: case presentation
The anticoagulation therapy included warfarin with a target international normalized ratio of 2.5-3.5 and was associated with oral aspirin (100 mg/day) as the patient was a woman in fertile age living in a rural area.
I notice that the author uses two specific mechanic valves in aortic and mitral position. On the market is available a different mechanical valve prosthesis, that can be used in both mitral and aortic position. For this specific mechanical valve the anticoagulation therapy can be carried out with a lower INR in combination with aspirin. Has the author thought to change the used mechanical valves in consideration to the special social contest in which he practices and the difficulties for the patients to adhere to the needed anticoagulation therapy? The Reviewer is correct and, indeed, the On-X valve was evaluated for possible use in our patients. Despite the possible better outcomes in our patients, the costs of this valve are higher compared to the valve which are currently used at the Salam Center. The Salam Center is financially supported by the local government and by an NGO called "Emergency". Based on the limited financial resources available, unfortunately the routine use of the On-X valve was not possible and, thus, was limited to very few selected patients (i.e. redo patients).
The author states that the patient had a low compliance with regard to the anticoagulation therapy, but no information is given if the patient had trombi on the mitral and aortic valves or if she had peripheral embolism. We thank the Reviewer for this remark. We specified in the case presentation that the patient did not have any clot formations nor embolism events.

Changes: case presentation
No other masses or possible thrombi were noticed on the left heart prosthetic valves, nor episodes of systemic or pulmonary embolism were reported. To remove the mass in the right atrium, the patient underwent a second surgery and the heart was arrested. Why the author used this surgical approach? This kind of surgery can be performed as well with a beating heart. Since the patient had a mildly depressed left ventricular systolic function (46%), why to expose this heart to ischaemic time when it was possible to avoid it? We agree with the Reviewer on the fact that operations on the right heart could be completed with a beating heart approach. Indeed, this is the approach used at Salam Centre for most surgeries on tricuspid valves. However, in this case, a possible diagnosis of malignant tumour could not be ruled out before surgery. Therefore, the heart was stopped to reduce the risk of tumour embolization resulting from mass manipulation and allow for a radical removal of the mass in case of malignant diagnosis.

Is the background of the case's history and progression described in sufficient detail? Yes
Are enough details provided of any physical examination and diagnostic tests, treatment given and outcomes? Yes Is sufficient discussion included of the importance of the findings and their relevance to future understanding of disease processes, diagnosis or treatment? Yes Is the case presented with sufficient detail to be useful for other practitioners? Yes