Mechanical mitral valve replacement remains a life‑saving intervention for patients with advanced mitral valve disease who are not suitable candidates for valve repair or bio prosthetic replacement.  Despite substantial improvements in surgical techniques, prosthesis design, and postoperative management, thrombotic complications continue to represent one of the most serious and potentially fatal long‑term adverse outcomes in this patient population.  Prosthetic valve thrombosis and systemic thromboembolic events are associated with significant morbidity, including stroke, heart failure, valve dysfunction, and mortality, underscoring the critical need for accurate risk stratification and optimized antithrombotic strategies in patients with mechanical mitral valves [1].

The mitral position is inherently associated with a higher thrombotic risk compared with the aortic position due to lower transvalvular flow velocities, larger prosthetic surface area, and greater exposure to blood stasis within the left atrium. Additionally, many patients undergoing mitral valve replacement have concomitant atrial fibrillation, left atrial enlargement, or prior thromboembolic events, all of which further exacerbate the prothrombotic milieu. As a result, lifelong anticoagulation with vitamin K antagonists remains mandatory in patients with mechanical mitral valves; however, thrombotic events may still occur despite apparently adequate anticoagulation, highlighting the multifactorial nature of thrombus formation in this setting [2].

Current guidelines recommend target international normalized ratio (INR) ranges based primarily on prosthesis type and valve position, with limited incorporation of individual patient‑level thrombotic risk factors beyond historical thromboembolism or atrial fibrillation. While INR remains the cornerstone of anticoagulation monitoring, it does not fully capture the dynamic interplay between clinical comorbidities, endothelial dysfunction, inflammation, and hemodynamic factors that contribute to thrombus formation. Consequently, there is growing interest in identifying additional clinical risk assessment tools that may improve prediction of thrombotic events and facilitate personalized management in patients with mechanical heart valves [3].

The CHA₂DS₂‑VASc score was originally developed as a simple and practical clinical tool for estimating the risk of stroke in patients with non‑valvular atrial fibrillation. By incorporating readily available clinical variables—congestive heart failure, hypertension, age, diabetes mellitus, prior stroke or transient ischemic attack, vascular disease, and sex—the score provides a cumulative assessment of systemic thromboembolic risk. Its ease of use and strong prognostic performance have led to widespread adoption in routine clinical practice and inclusion in international guidelines for anticoagulation decision‑making in atrial fibrillation [4].

Beyond its original indication, accumulating evidence suggests that the CHA₂DS₂‑VASc score may have broader applicability as a marker of global thrombotic risk across diverse cardiovascular populations. Several studies have demonstrated its association with adverse thromboembolic outcomes in patients without atrial fibrillation, including those with heart failure, acute coronary syndromes, and structural heart disease. These findings support the concept that the score captures fundamental pathophysiological determinants of thrombosis, such as endothelial dysfunction, vascular inflammation, and impaired hemodynamics, rather than merely reflecting arrhythmia‑related risk [5].

Patients with mechanical mitral valve replacement represent a particularly compelling population in which to explore the utility of the CHA₂DS₂‑VASc score. Many components of the score are highly prevalent in this group, including advanced age, hypertension, diabetes mellitus, heart failure, and vascular disease. Moreover, atrial fibrillation is common both before and after mitral valve surgery, further amplifying thrombotic risk. Despite these overlaps, the CHA₂DS₂‑VASc score has not been systematically integrated into risk assessment frameworks for patients with mechanical valves, and its predictive value for prosthetic valve thrombosis and systemic embolic events remains incompletely defined [6].

Prosthetic valve thrombosis is a complex phenomenon influenced by prosthesis‑related factors, patient‑specific characteristics, and anticoagulation quality. While sub therapeutic INR is a well‑recognized precipitating factor, a substantial proportion of thrombotic events occur in patients with therapeutic or near‑therapeutic anticoagulation levels. This observation suggests that traditional anticoagulation metrics alone are insufficient to fully explain thrombotic risk and that additional clinical variables may play a decisive role. The CHA₂DS₂‑VASc score, by integrating multiple comorbid conditions into a single numerical value, may offer incremental prognostic information beyond INR monitoring alone [7].

From a mechanistic perspective, each component of the CHA₂DS₂‑VASc score contributes to a prothrombotic state through distinct but interrelated pathways. Heart failure is associated with low cardiac output and blood stasis, hypertension promotes endothelial injury, diabetes, hypertension, diabetes mellitus, heart failure, and vascular disease. Moreover, atrial fibrillation is common both before and after mitral valve surgery, further amplifying thrombotic risk. Despite these overlaps, the CHA₂DS₂‑VASc score has not been systematically integrated into risk assessment frameworks for patients with mechanical valves, and its predictive value for prosthetic valve thrombosis and systemic embolic events remains incompletely defined [6].

Prosthetic valve thrombosis is a complex phenomenon influenced by prosthesis‑related factors, patient‑specific characteristics, and anticoagulation quality. While sub therapeutic INR is a well‑recognized precipitating factor, a substantial proportion of thrombotic events occur in patients with therapeutic or near‑therapeutic anticoagulation levels. This observation suggests that traditional anticoagulation metrics alone are insufficient to fully explain thrombotic risk and that additional clinical variables may play a decisive role. The CHA₂DS₂‑VASc score, by integrating multiple comorbid conditions into a single numerical value, may offer incremental prognostic information beyond INR monitoring alone [7].

From a mechanistic perspective, each component of the CHA₂DS₂‑VASc score contributes to a prothrombotic state through distinct but interrelated pathways. Heart failure is associated with low cardiac output and blood stasis, hypertension promotes endothelial injury, diabetes mellitus induces chronic inflammation and platelet hyperreactivity, and advancing age is linked to impaired fibrinolysis and vascular stiffness. Prior cerebrovascular events reflect an established propensity for thrombosis, while vascular disease signifies systemic atherosclerosis and endothelial dysfunction. These mechanisms are particularly relevant in the context of a mechanical mitral valve, where altered flow dynamics and foreign material further enhance chromogenic potential [8].

Identifying patients at heightened risk for thrombotic complications after mechanical mitral valve replacement has important clinical implications. Enhanced risk stratification may inform closer INR surveillance, more aggressive management of modifiable comorbidities, or consideration of adjunctive antithrombotic strategies in selected individuals. Furthermore, improved prediction of thrombotic events could aid in patient counseling, postoperative follow‑up planning, and early detection of prosthetic valve dysfunction. In this regard, a validated, simple, and widely familiar scoring system such as CHA₂DS₂‑VASc would be particularly attractive for routine clinical use [9].

Despite the theoretical rationale and emerging evidence from related cardiovascular populations, data specifically addressing the association between CHA₂DS₂‑VASc score and thrombotic outcomes in patients with mechanical mitral valves remain limited. Existing studies have often focused on heterogeneous valve positions, mixed prosthesis types, or composite endpoints, making it difficult to draw definitive conclusions for this high‑risk subgroup. Moreover, the potential role of the score in predicting both prosthetic valve thrombosis and systemic thromboembolic events has not been comprehensively evaluated in well‑defined cohorts of mechanical mitral valve recipients [10].

Against this background, evaluating the predictive value of the CHA₂DS₂‑VASc score for thrombotic events following mechanical mitral valve replacement represents an important and clinically relevant research objective. Demonstrating a robust association could support the integration of this score into postoperative risk assessment models and stimulate further studies aimed at refining anticoagulation strategies in this population. Ultimately, such efforts may contribute to reducing the burden of thrombotic complications and improving long‑term outcomes in patients living with mechanical mitral valve prostheses.

Material and methods

Study Design: This research was conducted as a case–control study at Shahid Madani Heart Center, affiliated with Tabriz University of Medical Sciences (Tabriz, Iran). The study period extended from early 2017 to late 2021. Patients who had undergone mechanical mitral valve replacement and were regularly followed in the hospital’s cardiac surgery and anticoagulation clinics were considered for inclusion. The study was designed to explore the association between the CHA₂DS₂‑VASc score and the occurrence of prosthetic valve thrombosis or systemic thromboembolic events during long‑term follow‑up.

Sampling: Sampling was performed through census sampling (complete enumeration) of all eligible patients meeting the inclusion criteria during the defined period. The final sample size comprised 100 patients, including both cases (patients who developed documented thrombotic events after surgery) and controls (patients without any thrombotic complications). Data were collected retrospectively from hospital records and verified through clinical visits and echocardiographic findings.

Inclusion and Exclusion Criteria

Eligible participants were adult patients (≥18 years) who had undergone mechanical mitral valve replacement and had completed regular postoperative follow‑up at the study center for at least 12 months. Patients were required to have available clinical, echocardiographic, and laboratory data, as well as a recorded CHA₂DS₂‑VASc score derived from their baseline characteristics.

Exclusion criteria included individuals with bio prosthetic or mixed valve replacement, incomplete medical documentation, poor adherence to anticoagulation therapy, coexistent mechanical aortic valve, active malignancy, severe infection or autoimmune disease, and known coagulation disorders unrelated to anticoagulation management. Patients with valve reoperation, endocarditis, pregnancy, or loss to follow‑up were also excluded to maintain uniformity and reduce confounding effects.This comprehensive filtering ensured a homogenous sample representative of patients with isolated mechanical mitral valve replacement under standard care conditions.

Procedures

In the first phase, all enrolled patients were identified through the hospital’s cardiac surgery registry and anticoagulation clinic database. Demographic variables (age, sex), clinical comorbidities (heart failure, hypertension, diabetes mellitus, prior stroke or transient ischemic attack, vascular disease), and details of anticoagulation management (INR values, warfarin dosage, and frequency of monitoring) were extracted systematically. The CHA₂DS₂‑VASc score was calculated retrospectively for each patient at baseline using these parameters.

In the second phase, postoperative outcomes were reviewed to identify thrombotic events, including confirmed prosthetic valve thrombosis, systemic embolism, or stroke. Diagnosis was based on clinical presentation, transthoracic or trans esophageal echocardiography findings, and radiologic confirmation when available. For valve thrombosis, visualization of restricted leaflet motion, increased transvalvular gradient, or visible thrombus on imaging was required. Cases and controls were matched for age and sex to minimize confounding. In the third phase, data were anonymized and validated independently by two cardiologists to ensure accuracy and consistency. Discrepancies in classification were resolved by consensus. Relevant hematologic parameters, including INR trend, hemoglobin, and platelet counts, were recorded. Duration since valve replacement and overall follow‑up time were noted for all subjects.

Statistical Analysis

Data analysis was performed using SPSS software, version 26 (IBM Corp., Armonk, NY, USA). Continuous variables were expressed as mean ± standard deviation or median with interquartile range, depending on normality assessed by the Kolmogorov–Smirnov test. Categorical variables were reported as frequencies and percentages.

Comparisons between case and control groups were made using independent t‑tests or Mann–Whitney U tests for continuous data and chi‑square or Fisher’s exact tests for categorical variables. The association between CHA₂DS₂‑VASc score and thrombotic events was evaluated using binary logistic regression, both in univariate and multivariate frameworks, adjusting for potential confounders such as sex, age, and time since surgery. A p‑value < 0.05 was considered statistically significant. Receiver operating characteristic (ROC) curve analysis was conducted to determine the optimal cutoff value of the CHA₂DS₂‑VASc score predicting thrombosis.

Ethical Considerations: The study protocol was reviewed and approved by the Ethics Committee of Tabriz University of Medical Sciences under the code IR. TBZMED.1400.1256. All patient data were kept strictly confidential and analyzed anonymously. The investigation was performed in accordance with the Declaration of Helsinki ethical standards. This research forms part of a postgraduate thesis project (Thesis No. 67370) and represents the first specific objective (Objective No. 1) of that dissertation. Written informed consent was obtained from all participants or their legal guardians prior to inclusion.

Results

In this cohort of 100 patients receiving mechanical mitral valve replacements, the mean age was slightly higher in the non‑thrombosis group (56.3 ± 10.31 years) compared to the thrombosis group (51.5 ± 14.68 years), though the difference did not reach statistical significance (p=0.148). Gender distribution was similar between groups, with females comprising 62.82% in the non‑thrombosis group and 59.09% in the thrombosis group (p = 0.944), indicating no association between sex and thrombotic events.

Regarding comorbidities, hypertension was observed in 33.33% of patients without thrombosis compared to 22.73% in those with thrombosis (p = 0.491). Diabetes mellitus was slightly more frequent among patients with thrombosis (27.27%) than in those without (20.51%), but not statistically significant (p=0.701). Heart failure prevalence was comparable between groups (50.0% vs. 43.59%, p=0.771). Interestingly, prior cerebrovascular accident was less frequent in the thrombosis group (9.09%) compared to the non‑thrombosis group (26.92%), yet this difference also failed to reach statistical significance (p=0.142) (figure 1). Overall, no baseline demographic or clinical variable demonstrated a significant association with postoperative thrombotic events in this sample.

 Table1. Baseline Characteristics of Patients with Mechanical Mitral Valve Prostheses

Figure 1. Baseline Comorbidities by Thrombotic Status

Among the study population, 94 patients (94%) had mechanical leaflet valves, while only 6 patients (6%) had mechanical monoleaflet valves. The mean left ventricular ejection fraction (EF) was 44.94% ± 10.39, with no statistically significant difference observed between the thrombosis and non‑thrombosis groups (p=0.723) (Table 2‑4). The time elapsed since valve replacement surgery was 100 ± 87.64 months in patients without thrombosis and 127 ± 83.38 months in those with thrombosis, showing no significant intergroup difference (p=0.149).

Warfarin dosage did not differ significantly between the two groups (p=0.447) (figure 2). Similarly, the mean of the three most recent international normalized ratio (INR) measurements was comparable between patients with and without thrombosis, with no statistically significant difference detected (p=0.620).

Comparison of CHA₂DS₂‑VASc individual components revealed no statistically significant differences between patients with and without thrombotic events following mechanical mitral valve replacement. Advanced age demonstrated similar distribution across groups: only two patients were aged ≥75 years, both without thrombosis, and age ≥65 years occurred in 20.5% of the non‑thrombosis group and 22.7% of those with thrombosis (P=1.000 for both age criteria). A history of cerebrovascular accident or transient ischemic attack was more frequent in patients without thrombosis (26.9% vs. 9.1%), but this difference did not reach statistical significance (P=0.142) (table 2).

Other comorbid contributors to the CHA₂DS₂‑VASc score also showed comparable patterns between groups. Hypertension (33.3% vs. 22.7%, P=0.491) and diabetes mellitus (20.5% vs. 27.3%, P=0.701) were similarly distributed, indicating no differential burden of these risk factors in patients with thrombosis. Heart failure, the most prevalent item, was present in half of the thrombosis group and 43.6% of the non‑thrombosis group (P=0.771). Likewise, female sex and vascular disease showed no meaningful group differences (P=0.814 and P=0.502, respectively). Overall, none of the CHA₂DS₂‑VASc components individually demonstrated a significant association with postoperative thrombotic events in this population (table 2).

  Table 2. Distribution of CHA₂DS₂‑VASc Score Components in Patients with Mechanical Mitral Valve Prostheses, Stratified by Thrombotic Status