1 Introduction

Knee arthroplasty(KA) is a standard and efficacious intervention for managing end-stage osteoarthritis, with an annual occurrence of approximately 620,000 procedures in the U.S.^1–3 However, the incidence of deep vein thrombosis (DVT) in post-KA patients reaches as high as 30 %, resulting in prolonged post-operative hospitalization length, increased economic burden, and, in severe cases, patient fatalities due to pulmonary embolism.^4,5 Symptomatic venous thromboembolism (VTE) occurs in about 2 % of patients, even when preventive strategies for VTE are implemented.⁶ FAR ratio indicators have been employed in predictive analytics and research across various medical domains, demonstrating promising outcomes, such as tumor prognosis prediction, the investigation of diabetic neuropathy correlations, and cardiac function assessment.^7–12 However, the current research mainly focuses on the fact that FAR represents a useful indicator of acute phase response after KA, neglecting its potential role in predicting postoperative venous thrombosis.¹³ In contrast, significant correlations and predictive capabilities have been documented in certain vascular obstruction-related conditions, including post-pregnancy venous thrombosis, ischemic stroke, and acute coronary syndrome.^14–16 Clinically utilized methods for identifying patients at high risk for deep vein thrombosis (DVT) include D-dimer assays, DVT risk nomogram, Khorana score, ultrasound imaging, and angiography.^17–19 However, each method presents distinct limitations. The specificity of D-dimer is notably low; evaluation scales impose additional burdens on clinicians, while ultrasound and angiography may pose inconveniences for patients shortly after surgery.²⁰ The fibrinogen to albumin ratio (FAR) has been proposed to indicate disease severity in prothrombotic conditions.^21,22 Fibrinogen and albumin both influence blood clotting, with fibrinogen acting as a clotting factor that enhances thrombocyte aggregation, while albumin inhibits thrombocyte function and thrombus formation.²³ Despite these insights, limited data exist regarding the predictive value of FAR in thrombosis among patients undergoing KA. The association between FAR and thrombosis occurrence in KA patients remains unclear. Therefore, this study aims to elucidate whether early FAR is linked to thrombosis occurrence following KA.

2 Methods

Patients who underwent knee arthroplasty (KA) at our institution between August 2020 and August 2022 were included in this cohort study, dividing into the postoperative DVT group and the non-DVT group. We excluded patients with past DVT, chronic venous disorders, liver and kidney diseases or PTS-related symptoms before surgery. Fifteen patients were excluded from the study, with 2 due to thrombosis before KA and the remaining 13 patients lost to follow-up post-surgeries. The Baseline characteristics and the laboratory findings of the two groups were collected to eliminate the influence of doping factors. In addition, the FAR of the two groups was statistically analyzed to compare their sensitivity to DVT prediction.Biochemical tests were conducted within 1 week before TKA, and ultrasounds were performed to exclude any existing thrombus. All surgeries adhered to standard procedures and were performed by 4 surgeons. A prophylactic regimen of low molecular weight heparin (100IU/kg once daily) commenced 12–24 h after TKA during the first 7 days, and then all patients were taken rivaroxaban orally (10 mg once daily)during the remaining 30 days. Additionally all patients underwent intermittent pneumatic compression in the hospital every day after operation (Twice daily, with each session lasting 30 min). FAR values were also measured two days after surgery to compare with preoperative FAR values. Both groups were followed up by the same physician to determine the presence of DVT diagnosed by ultrasound every follow-up time after KA. The minimum follow-up time was 6 months. Furthermore, If the patient has lower limb swelling or other VTE symptoms within 6 months, the physician will advise these patients for an ultrasound immediately. A comparison between the two groups, those with DVT and those with controls, was conducted regarding baseline characteristics and laboratory findings. FAR was defined as the numerical value of fibrinogen (g/L) divided by the numerical value of albumin (g/L). Continuous variables were presented as mean ± standard deviation, whereas categorical variables were presented as numbers and percentages. Receiver operating characteristics (ROC) curve analysis was employed to determine the cut-off value of FAR as a predictor of DVT. Differences between continuous variables were analyzed using the t-test and one-way analysis of variance, while categorical variables were assessed using the chi-square (χ²) test. The change in mean FAR after KA was calculated using the paired t-test, and the differences in the change of mean FAR between post-operative DVT and no DVT group were calculated using analysis of covariance, adjusted for pre-operative FAR values. The linear-by-linear association chi-square (χ²) test was used to analyze the trend of the frequency of high FAR. Multivariate logistic regression analysis was used to assess predictors of DVT. The variables included in the models were age, sex, operation history, hypertension, other cardiovascular diseases, diabetes, dyslipidemia, degenerative joint disease, prior antiplatelet use, surgical methods, BMI, and FAR. The selection of variables was based on clinical relevance and the results of previous trials.^24,25 All the data and results in this paper have been reviewed by a professional team. All statistical analyses were performed using SPSS 25.0, and a P value of <0.05 was considered statistically significant. The study protocol was approved by the Institutional Review Board (IRB), and the study adhered to the Declaration of Helsinki.

3 Results

During the research period, a total of 316 patients were assessed for eligibility. Among them, 38 patients (12.0 %) received a diagnosis of DVT. The mean follow-up time was 12 ± 3 months (range 6–18). There were 250 females and 66 males, with a mean age of 67.0 ± 7.2 years (range 44–86). TKA was performed in 230 patients, and UKA was performed in 86 patients. The mean length of hospital stay was 6.5 ± 2.0 days (range 6–21). The baseline characteristics of the study patients are presented in Table 1. No significant differences were observed in baseline characteristics between the post-operative DVT and no DVT groups. Additionally, there were no significant differences in pre- and post-operative laboratory tests between both groups. Furthermore, post-operative FAR and change in mean FAR value after KA did not exhibit significant differences between the two groups. However, the pre-operative FAR was significantly higher in patients with post-operative DVT compared to those without DVT (0.077 ± 0.007 vs. 0.067 ± 0.012, P < 0.001) (Table 2). Drawing on clinical rationale, we selected twelve putative risk factors for multivariable logistic regression modeling. The results demonstrated that female (OR = 1.83, 95 %CI: 0.66–5.06, P = 0.244), Age (years) (OR = 0.99, 95 %CI: 0.94–1.04, P = 0.619), Previous surgery(OR = 0.67, 95 %CI: 0.27–1.68, P = 0.398), Hypertension(OR = 1.22, 95 %CI: 0.54–2.72, P = 1.217), Other cardiovascular diseases(OR = 1.05, 95 % CI: 0.18–6.02, P = 0.960), Diabetes(OR = 1.35, 95 %CI: 0.49–3.70, P = 0.565), Dyslipidemia(OR = 1.31, 95 %CI: 0.61–2.84, P = 0.491), BMI (kg/m2) (OR = 1.05, 95 %CI: 0.97–1.13, P = 0.237), Degenerative joint disease(OR = −, 95 %CI: , P = 0.999), Prior antiplatelet use(OR = 0.26, 95 %CI: 0.30–2.23, P = 0.218), Surgical methods(OR = 1.01, 95 %CI: 0.45–2.30, P = 0.975) and Pre-operative FAR(OR = 1.12, 95 %CI: 1.06–1.17, P=<0.001).The multivariate analysis identified pre-operative FAR as the sole independent predictor of post-operative DVT events (OR = 1.12, 95 %CI: 1.06–1.17, P < 0.001) (Table 3). There is a significant correlation between preoperative FAR and DVT, and it remains significant even under the interference of confounding factors. Therefore, we believe that FAR has predictive power for the early stage of DVT, and Higher values may indicate an increased risk of thrombosis. However, this hypothesis requires further validation with additional data and prospective studies.ROC curve analysis showed that a pre-operative FAR of 0.070 was the best cut-off value for predicting DVT events, with a sensitivity of 94.7 %, specificity of 51.1 %, and an area under the curve of 0.732) (Fig. 1).

Close

Fig. 1 ROC curve of pre-operative FAR for predicting post-KR deep vein thrombosis events. AUC, area under the curve; FAR, fibrinogen-albumin ratio; ROC, receiver operating characteristic; KA, knee arthroplasty.

Export to PPT

4 Discussion

The main findings of this study can be summarized as follows: (1) the incidence of DVT after KA was 12.0 %, which is notably lower than previously reported results.^26–28 This discrepancy may be attributed to the relatively short follow-up time or the potential influence of various surgical methods. (2) Pre-operative FAR was significantly higher in patients who developed DVT, and a high FAR emerged as an independent predictor of DVT following KA. The fundamental pathophysiological processes underlying deep vein thrombosis (DVT) formation encompass venous stasis, alterations in venous blood flow patterns, and complex interactions between blood components, endothelial cells, and inflammation.²⁹ Following KA, venous stasis inevitably occurs (due to impaired mobility), while endothelial injury and inflammation are also unavoidable. Consequently, the incidence of post-KA DVT remains persistently high.^30–32 Established risk factors for acute DVT in patients undergoing KA include advanced age, a history of malignant tumors, and pre-existing cardiovascular pathologies.^43–45 Current research on the Fibrinogen - Albumin Ratio (FAR) is primarily concentrated on its utility in prognostic assessment for malignancies and cardiovascular diseases.^7,8,11,12,15 FAR demonstrates unique predictive value, particularly as an independent prognostic factor for overall survival (OS) and disease-free survival (DFS) in malignant tumors.³³ Albumin is recognized as an indicator not only reflecting nutritional status but also integral to assessment systems related to inflammatory responses.³⁴ Hypoalbuminemia can lead to immune compromise in cancer patients, reducing treatment efficacy and increasing mortality.^35,36 Numerous observations indicate complex interactions between fibrinogen, fibrin, components of the fibrinolytic system, and cancer growth and metastasis.³⁷ Simply stated, elevated plasma fibrinogen promotes a hypercoagulable state, facilitates tumor cell adhesion and survival, and enhances metastatic potential.³⁸ Therefore, FAR plays a significant role in predicting the prognosis of malignant tumors.Fibrinogen, the precursor to fibrin, is itself a recognized precursor to thrombus formation. Inflammatory responses during cardiovascular disease often induce structural modifications in fibrinogen, rendering it more resistant to fibrinolysis.³⁹ Beyond reflecting chronic inflammation, albumin also has distinct pathophysiological roles in thrombogenesis.⁴⁰ Among inflammatory biomarkers, albumin uniquely predicts short-term mortality, aligning with prior studies showing hypoalbuminemia as a predictor of poor outcomes in cardiovascular disease patients.^41,42 Consequently, FAR is not merely a bystander to sustained inflammation but likely has an active pathophysiological role in cardiovascular disease.Crucially, t Crucially, the pathogenesis of post-TKA deep vein thrombosis involves three concurrent pathophysiological processes: plasma hypercoagulability, systemic inflammatory activation, and generation of thrombogenic precursors.⁴⁶ Therefore, we hypothesize that shared pathophysiological pathways likely exist between DVT formation and the mechanisms implicated in malignancies and cardiovascular pathologies. This mechanistic convergence establishes the biological plausibility of FAR as a novel predictive biomarker for post-KA DVT development, warranting clinical validation of its prognostic utility.However, research specifically investigating FAR in the context of DVT prediction remains notably scant. Substantial prospective studies are required to rigorously validate this hypothesis.

To the best of our knowledge, this study represents the first report illustrating the potential utility of FAR as a simple and valuable biomarker for predicting post-operative DVT events.The most likely source of pulmonary artery thrombus is an embolism of deep veins in the leg. Approximately one-third of patients diagnosed with DVT progress to pulmonary embolism (PE).⁴⁷The annual incidence of PE ranges from 39 to 115 cases per 100,000 people, while that of DVT falls between 53 and 162 cases per 100,000 people. Acute PE stands as the third most common cardiovascular disease, following coronary heart disease and stroke.⁴⁸ Overall, the mortality rate associated with PE is alarmingly high, contributing to 100,000 deaths in the United States.⁴⁹ Doppler ultrasound is the preferred diagnostic test for DVT, offering high sensitivity and specificity. However, assessing DVT in the calf vein poses challenges during ultrasound examinations, and post-operative examinations can be inconvenient for patients.⁵⁰ Therefore, exploring additional diagnostic measures becomes crucial in enhancing our ability to detect and manage these potentially life-threatening conditions.

The FAR is readily accessible, cost-effective, and easily calculable. Our study demonstrates a significant association between elevated Fibrinogen-Albumin Ratio (FAR) levels and preoperative deep vein thrombosis (DVT) risk in elderly patients with end-stage osteoarthritis (OA). Utilizing an optimal FAR cutoff value of 0.070 derived from our analysis, we observed substantially reduced data dispersion beyond this threshold. These findings support FAR's potential utility as a preoperative risk-stratification tool for lower-extremity DVT.Crucially, FAR demonstrated superior sensitivity (94.7 %) and specificity (51.1 %) compared to D-dimer assays (p < 0.001). This enhanced diagnostic performance positions FAR as a valuable biomarker for identifying high-risk patients requiring escalated prophylactic therapy regimens.

Clinically, our anticoagulation strategy consists of 7 days of low molecular weight heparin (100IU/kg once daily) 12–24 h after knee surgery, followed by oral rivaroxaban (10 mg once daily) for the remaining 30 days. In addition, all patients received intermittent pneumatic compression. We used FAR to predict the results of thrombus in some patients and found that the results of postoperative ultrasound were consistent in 90 % of patients. When a patient's preoperative FAR exceeded 0.070, therapeutic doses of heparin or rivaroxaban were administered. Later, Then, we asked these patients to review the color ultrasound one week after surgery, and 90 % of the patients treated showed old thrombosis, which verifies the accuracy of FAR. On this basis, we conducted this retrospective study. However, our statistical results showed that the prediction results of this index have the problems of high sensitivity and low specificity. Although its specificity has far exceeded that of D-dimer, we still think that its specificity can continue to improve. We analyzed this result and concluded that liver function has a great influence on this index. When we removed some indicators of abnormal liver function, its specificity was greatly improved. Thereafter, we will add prospective medical records to validate the results. If the results are reliable, it is believed that preoperative FAR can be used as a reliable indicator for postoperative thrombosis prediction.

This study found that two patients experienced symptoms of PE, and notably, both instances occurred in patients with DVT. This observation suggests a potential association between the occurrence of PE and DVT. However, the extent of this correlation remains unclear, and findings across various reports are inconsistent.^47–50 Following the transition to therapeutic doses of anticoagulants, no patients reported symptoms of PE during the follow-up period. This suggests that despite the use of heparin for thromboprophylaxis, venous thromboembolism (VTE) remains a relatively common event, but therapeutic doses of heparin can effectively ameliorate thrombotic symptoms. This study has several limitations. Firstly, the relatively short follow-up time for patients, coupled with a certain rate of loss to follow-up, may impact the accuracy of the results. Secondly, being a retrospective, single-center study, additional data from prospective studies is necessary for a more comprehensive understanding. Thirdly, although the effect of liver and kidney diseases was excluded, the effect of liver function on the results was ignored. Since the statistical results showed a significantly low specificity of this indicator, the research team believed that it was related to liver function. To fill this gap, we will continue to add prospective studies to confirm it and take liver function values into account. In summary, the potential role of high FAR values in inducing DVT, particularly in patients with thrombophilia, requires further confirmation through extended observation, given the exploratory nature of this study.

5 Conclusions

Our study suggests that pre-operative FAR is an important predictor of lower extremity DVT. However, larger prospective studies are needed to confirm these results.

Guardian/patient's consent

As this article is a retrospective study, there was no informed consent from the patients.

Consent for publication

Not Applicable.

Clinical trial number

Not Applicable.

Availability of data and materials

Data openly available in a public repository.

Human ethics and consent to participate declarations

Not applicable.

This retrospective study was approved by the Institutional Review Board of Ethics Committee of Lianyungang First People's Hospital. Given the retrospective nature of the study and the use of de-identified patient data, the requirement for informed consent was waived by the IRB. The study was conducted in accordance with the ethical standards of the Declaration of Helsinki and its later amendments.

Submission of work requires that the piece to be reviewed has not been previously published. Upon acceptance, the Author assigns to the right to publish and distribute the manuscript in part or in its entirety. The Author's name will always be included with the publication of the manuscript.

The Author has the following nonexclusive rights: (1) to use the manuscript in the Author's teaching activities; (2) to publish the manuscript, or permit its publication, as part of any book the Author may write; (3) to include the manuscript in the Author's own personal or departmental (but not institutional) database or on-line site; and (4) to license reprints of the manuscript to third persons for educational photocopying. The Author also agrees to properly credit the Thrombosis Journal as the original place of publication.

The Author hereby grants the Thrombosis Journal full and exclusive rights to the manuscript, all revisions, and the full copyright. The Thrombosis Journal rights include but are not limited to the following: (1) to reproduce, publish, sell, and distribute copies of the manuscript, selections of the manuscript, and translations and other derivative works based upon the manuscript, in print, audio-visual, electronic, or by any and all media now or hereafter known or devised; (2) to license reprints of the manuscript to third persons for educational photocopying; (3) to license others to create abstracts of the manuscript and to index the manuscript; (4) to license secondary publishers to reproduce the manuscript in print, microform, or any computer-readable form, including electronic on-line databases; and (5) to license the manuscript for document delivery. These exclusive rights run the full term of the copyright, and all renewals and extensions thereof.

Credit author statement

Chen Yan: Mainly responsible for the conceptualization and design of research, as well as the preliminary analysis of data. Important revisions and improvements have been made to the overall structure and content of the thesis. Qian Wang: Mainly responsible for most of the data collection and organization work. Assist in data analysis and interpretation of results. The method and experimental parts of the thesis were written, and the full text was carefully proofread. Xin Li: Participated in the design of the research and the data collection process.

Ethical statement

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. The study was approved by the Ethics Committee of Lianyungang First People's Hospital.

This study was performed in line with the principles of the Declaration of Helsinki. Approval was granted by Ethics Committee of Lianyungang First People's Hospital.

Approval was obtained from the ethics committee of Ethics Committee of Lianyungang First People's Hospital. The procedures used in this study adhere to the tenets of the Declaration of Helsinki.

Funding

None.