Thrombolysis in dysfunctional valve and stroke

Abstract

BACKGROUND

Valvular heart disease affects more than 100 million people worldwide and is associated with significant morbidity and mortality. The prevalence of at least moderate valvular heart disease is 2.5% across all age groups, but its prevalence increases with age. Mitral regurgitation and aortic stenosis are the most frequent types of valvular heart disease in the community and hospital context, respectively. Surgical valve replacement (or mitral valve repair) is the standard of care for treating heart valve disease. However, the replacement of a prosthetic heart valve can lead to complications, either in the peri-procedural phase or in the long-term follow-up period.

CASE SUMMARY

We present a case of a 71-year-old female patient with a history of mitral valve replacement and warfarin anti-coagulation therapy. She was admitted to the intensive care unit due to spontaneously reperfused ischemic stroke of probable cardioembolic etiology. A dysfunctional mitral prosthesis was identified due to malfunction of one of the fixed discs. Furthermore, a possible microthrombotic lesion was suspected. Therefore, systemic thrombolysis was performed with subsequent normalization of mitral disc opening and closing.

CONCLUSION

This case underscores the critical importance of a multidisciplinary approach for timely decision-making in critically ill patients with prosthetic valve complications.

Key Words: Mitral valve thrombolysis; Stroke; Recombinant human plasminogen tissue activator; Heart valve disease; Prosthetic valve-associated thrombosis; Thrombotic dysfunction

Core Tip: We describe the case of a 71-year-old woman with a history of mitral valve replacement who presented with cardioembolic stroke due to prosthetic valve dysfunction and thrombotic obstruction. Advanced imaging confirmed the diagnosis. After careful assessment by neurology, cardiology, and critical care teams, systemic thrombolysis was performed as an alternative to surgery. The intervention successfully restored valve function without complications. This case demonstrates the value of collaborative decision-making and tailored treatment strategies in optimizing outcomes for patients with prosthetic valve thrombosis and associated complications.

INTRODUCTION

Heart valve disease affects more than 100 million people worldwide and is associated with significant morbidity and mortality[1]. The prevalence of at least moderate valvular heart disease is 2.5% and it increases with age. Mitral regurgitation and aortic stenosis are the most frequent types of valvular heart disease within the community and hospital settings, respectively[2]. Surgical valve replacement or mitral valve repair are the standard of care for valvular heart disease treatment[3]; however, prosthetic heart valve replacement can be associated with complications in either the peri- procedural phase or in the long-term follow-up period[4]. After prosthetic implantation, transthoracic or transesophageal echocardiography can detect valve dysfunction secondary to structural damage or thrombosis[5]. Prosthetic valve-associated thrombosis is a serious complication with a high mortality rate; the most common cause is inadequate anticoagulation therapy or other associated pathogenic factors, such as type of prosthesis and atrial fibrillation[6]. Although surgical treatment is usually preferred in cases of prosthetic valve-associated thrombosis, the optimal treatment approach remains controversial. The different therapeutic modalities available for prosthetic valve-associated thrombosis (heparin therapy, fibrinolysis, surgery) are largely influenced by the presence of valvular obstruction, valve location (left or right) and the patient’s clinical status[7].

We present herein the case of a 71-year-old female patient with a history of mitral valve replacement and warfarin anticoagulation therapy. She was admitted to the intensive care unit for neurological monitoring due to spontaneously reperfused ischemic stroke of probable cardioembolic etiology. A dysfunctional mitral prosthesis was documented due to malfunction of one of the fixed discs. Furthermore, a possible microthrombotic lesion was suspected, so systemic thrombolysis was considered through a multidisciplinary approach with subsequent normalization of the opening and closing of the mitral discs.

CASE PRESENTATION

Chief complaints

A 71-year-old woman consulted the emergency department with symptoms of nausea, somnolence and headache.

History of present illness

The patient presented with clinical symptoms over the course of 2 hours characterized by nausea, dizziness and intense headache, which did not improve with analgesic use such as acetaminophen.

History of past illness

The patient has a history of mechanical mitral valve replacement 20 years ago with regular echocardiographic follow-up, last performed a year before admission. Transthoracic echocardiograms documented a normofunctioning prosthetic with adequate transvalvular gradients.

Personal and family history

Patient with a history of atrial fibrillation, warfarin use, and two cerebrovascular events in the last 3 years.

Physical examination

On presentation, the patient was in hypertensive crisis with a blood pressure of 186/90 mmHg and mitral holosystolic murmur. There were no signs of acute heart failure and no neurological findings. NIH Stroke Score, 0 points.

Laboratory examinations

Blood work analysis suggested anemia (hemoglobin: 10.7 g%; normal range: 13-16 g%), leukocytosis (total leukocyte count: 13700; normal range: 4500-11000) with a shift to the left (75% neutrophils), and thrombocytosis (platelets: 4.14 × 10⁵; normal range: 1.50-4.00 × 10⁵). Liver and kidney function tests were within normal limits. The patient had a subtherapeutic international normalized ratio of 1.3 (therapeutic range: 2.0-3.0).

Imaging examinations

A simple cranial computed tomography (CT) scan was performed to rule out acute ischemic events and a cerebral magnetic resonance imaging showed right temporal punctate infarcts with recanalization, in addition to several old ischemic lesions.

Transthoracic echocardiogram was initially performed and identified high transvalvular gradients, with a mean gradient of 6 mmHg. However, it did not allow for adequate visualization of the valve prosthesis. Therefore, a transesophageal echocardiogram was subsequently performed. Three-dimensional evaluation revealed a thickened prosthesis with altered mobility of one of the discs, generating an increase in transvalvular gradients and moderate insufficiency, compatible with thrombotic dysfunction (Figure 1).

Figure 1 Dysfunctional mitral valve prosthesis in transthoracic echocardiography. A: Mitral valve prosthesis viewed from the atrium demonstrating the opening of only one of the two hemidiscs (arrows); B: Elevated mitral transvalvular gradient. Mean gradient of 6.4 mmHg.

MULTIDISCIPLINARY EXPERT CONSULTATION

Cardiology assessment was requested and, together with the neurocritical care service, thrombolysis was decided.

FINAL DIAGNOSIS

Cardioembolic etiology was suspected.

TREATMENT

We consulted the Neurology and Critical Medicine Departments on thrombolysis as an alternative treatment to surgery. We requested a cardiology assessment, and together with the neurocritical care service decided to perform thrombolysis.

Prior to the procedure, warfarin reversal with prothrombin complex is required. We confirmed that there was no residual anticoagulant effect at the time of tissue plasminogen activator administration, which was administered at a dose of 0.9 mg/kg, the initial 10% as a bolus and the remaining infusion for 60 minutes. The infusion was completed without complications, without major bleeding nor changes in clinical status.

OUTCOME AND FOLLOW-UP

A transesophageal echocardiogram was performed 24 hours after thrombolysis and demonstrated normalization of the opening of the hemidiscs of the mitral valve prosthesis, reduction of the transvalvular gradients and reduction of the insufficiency to mild residual (Figure 2).

Figure 2 Post-thrombolysis corrected mitral valve prosthesis in transthoracic echocardiography. A: Mitral valve prosthesis viewed from the atrium with two open hemidiscs (arrows); B: Transvalvular mitral valve gradient after thrombolysis. Mean gradient of 1.8 mmHg.

An additional CT scan of the skull showed no signs of bleeding. Anticoagulation therapy was restarted the day after thrombolysis.

The patient was transferred to a general hospital with adequate neurological evolution under anticoagulation therapy with unfractionated heparin. Warfarin was started for long-term anticoagulation and management of cardiovascular comorbidities. The patient was discharged without complications.

DISCUSSION

The worldwide incidence of prosthetic valve thrombosis is 0.03% in bioprosthetic valves, 0.5% to 8% in mechanical valves in the mitral and aortic positions, and up to 20% in mechanical tricuspid valves[8]. In contrast, a previous study found that 1.2% of patients in a 402 person cohort had mitral valve disease[9]. Periprosthetic valve-associated thrombosis is not very common but is one of the most frequent complications of mechanical or biological valve prostheses. Thrombotic phenomena account for 11% of valve dysfunction[10]. Another study by the same group found that in a study of 575 patients with rheumatic mitral valve disease, acute cardioembolic phenomena occurred in 16.3% of patients[11]. Mitral valve dysfunction can occur through several mechanisms: Reduced leaflet motion, impaired leaflet coaptation, leaflet thickening, reduction or enlargement of the prosthetic orifice, leading to stenosis or insufficiency. These changes cause disruptions to the transvalvular gradients that may or may not co-occur with other associated symptoms[12]. Although inadequate anticoagulation is the main cause of this phenomenon, other comorbidities or associated factors contribute, including atrial fibrillation, mechanical prostheses, and prosthesis location. Finally, thrombin generation can be induced through tissue factor and contact coagulation pathway activation, increasing thrombotic risk through proatherogenic and proinflammatory mechanisms[13].

Patients with prosthetic valve dysfunction with or without thrombosis may present with variable symptoms ranging from progressive dyspnea and signs of heart failure or systemic embolization. It is sometimes even asymptomatic with non-obstructive thrombi. These patients are at an increased risk of developing cerebral embolism, manifesting as transient ischemic attack or stroke[13]. The preferred diagnostic tool remains transthoracic or transesophageal echocardiography. With current techniques, three-dimensional reconstruction of the prosthetic valve can aid in the assessment of disc mobility and define the etiology of prosthetic dysfunction. These assessments are important to determine the type of treatment required. It is most useful in asymptomatic patients with sub-therapeutic levels of anticoagulation. When a more detailed assessment of the valve, thrombus size and prosthetic valve body motion is required, transesophageal echocardiography and transthoracic echocardiography is recommended for hemodynamic assessment. Multimodality imaging has a class I-b indication in patients with suspected mechanical prosthetic valve thrombosis to assess valve function and presence of thrombus[14].

In this case study, our patient presented with a cardioembolic ischemic stroke. Echocardiogram analysis suggested that the stroke was caused by mitral mechanical prosthesis dysfunction with thrombotic lesion leading to mitral valve dysfunction. Left atrial thrombi are the most likely embolic source in these patients. Barbetseas et al[14] found that patients with ischemic stroke had a higher rate of mitral valve replacement and atrial fibrillation and increased left atrial size compared to patients with transient ischemic attack. However, none of these differences were statistically significant; the presence of left atrial thrombus, visualized by transesophageal echocardiography, was the only parameter that differentiated between patients with ischemic stroke and transient ischemic attack.

Antithrombotic treatments indicated in prosthetic valve thrombosis and thromboembolic events after prosthetic heart valve replacement can be broadly classified according to their mechanisms of action as antiplatelet-based strategies (aspirin and/or a P2Y12 receptor inhibitor) and anticoagulant-based strategies [using vitamin K antagonists (VKAs) or direct oral anticoagulants][1].

VKAs are the primary preventative treatment against thrombosis due to prosthetic valve dysfunction, with dosing adjusted to maintain INRs of 2 to 3 and 2.5 to 3.5 for mechanical heart valves implanted in the aortic and mitral positions, respectively; for bioprosthetic heart valves, anticoagulation with VKA is recommended for the 1^st 3 months after the procedure, with a target INR between 2.0 and 3.0, regardless of prosthesis position (aortic, mitral or right)[3,15,16].

In recent years, thrombolytic therapy has become an alternative to surgery in the treatment of obstructive prosthetic valve thrombosis[4]. Fibrinolytic therapy has a success rate of over 80%[15]. The appropriate management for obstructive prosthetic valve thrombosis has remained debatable. Some guidelines [e.g., European Society of Cardiology (ESC)] recommend surgery for all patients regardless of clinical status, while others (Heart Valve Disease Society) recommend thrombolytic therapy for all patients without contraindications[17,18]. However, the current update of the ESC/EACTS guidelines still considers surgery as the first-line approach[19].

Due to its high fibrin specificity, recombinant tissue-type plasminogen activator (tPA) is widely used in managing prosthetic heart valve thrombosis. However, streptokinase remains the drug of choice in low-income countries due to its relatively lower cost, while other agents such as tenecteplase and urokinase have also been used, with similar safety and efficacy compared to streptokinase[4,19].

CONCLUSION

The ESC guidelines recommend the standard dose (recombinant tissue plasminogen activator 10 mg bolus to 90 mg over 90 minutes with unfractionated heparin) of fibrinolytic therapy (class IIa) based on a meta-analysis of seven trials[20]. The American College of Cardiology and American Heart Association guidelines recommend the use of slow infusion, low-dose (25 mg tPA over 6 hours to 24 hours without bolus) fibrinolytic therapy as a comparable initial approach (Class I)[5]. Comparison of complication rates between the study groups showed a statistically lower combined complication rate in the slow infusion low-dose tPA group[21]. The ultra-slow PROMETEE trial demonstrated that ultra-slow (25 hours) infusion of low-dose (25 mg) tPA without bolus dosing is associated with fairly low non-fatal complications and mortality without loss of efficacy, except for those with NYHA class IV[22].

For a patient with prosthetic valve thrombosis, stroke may be the initial symptom resulting in cerebral embolism or may be secondary to thrombolysis therapy, with rates as high as 5%-6% for left-sided prosthetic heart valve thrombosis[23]. The recommended RTPA dose according to the ischemic stroke guideline is 0.9 mg/kg over 60 minutes, with a bolus of 10% of the total dose over 1 minute[24].

Simple cranial CT scan is essential to exclude intracranial hemorrhage and to define the administration of thrombolytic agents[25]. There are no protocols for thrombolytic therapy in patients presenting with stroke associated with cardiac valvular prosthesis. However, accelerated thrombolytic therapy regimens may complicate treatment[25]. In their case report, Özka et al[24] demonstrated that prolonged low-dose infusion of thrombolytic therapy and its continuation for the treatment of acute cerebral ischemic complications induced thrombolysis and limited the risk of hemorrhage and embolization. It resulted in subsequent normal mitral valve function with no evidence of residual thrombus, as assessed by echocardiography. However, there is no consensus on the best thrombolytic therapy strategy or specific agent. Therefore, thrombolysis in ischemic stroke associated with prosthetic heart valve thrombosis may be an effective therapy in selected cases[26].

ACKNOWLEDGEMENTS

We thank Dr. Nohra Piedad Romero Vanegas and the Echocardiography Service, Hospital Universitario Fundación Santa Fe De Bogotá, Bogotá, Colombia. We also thank the Neurology Service, Hospital Universitario Fundación Santa Fe De Bogotá, Bogotá, Colombia. During the final review and approval of the manuscript, our professor Jose del Carreño passed away. May he rest in peace.