Affiliations
doi: 10.29271/jcpsppg.2025.01.132ABSTRACT
Objective: To determine the prognostic value of fibrinogen levels in predicting cardiovascular (CV) and other thrombotic events in haemodialysis-dependent chronic kidney disease (CKD) patients.
Study Design: Prospective cohort study.
Place and Duration of the Study: Department of Haematology, Combined Military Hospital, Lahore, Pakistan, from May 2024 to 2025.
Methodology: CKD patients on haemodialysis were included in this study, and their fibrinogen levels were measured. This cohort of patients was followed for a minimum of 12 months for thrombotic events, including CV events. The association between higher fibrinogen levels and thrombotic events was assessed using relative risk and regression analysis.
Results: A total of 163 CKD patients on haemodialysis were included, with a median age of 60.0 (42.0–64.0) years. The fibrinogen levels were comparatively higher with a median of 407.0 (338.0–458.0) mg/dL. CV events were observed in 56 (34.4%) patients, and 23 (14.1%) patients had other thrombotic events. Relative risk (RR) of CV events in the higher fibrinogen group was 3.14 (95% CI: 1.87-5.28). Patients with thrombotic events showed significantly higher fibrinogen levels (p <0.001). Fibrinogen levels independently predicted CV events, with each unit increase associated with a 1.4% higher risk (adjusted RR, Exp(B):1.014, 95% CI: 1.011-1.017, p <0.001). The receiver operating curve (ROC) analysis identified 355.50 mg/dl as an optimal cut-off value with an area under the curve of 0.829.
Conclusion: Fibrinogen levels in CKD patients on maintenance haemodialysis can predict CV events and serve as a valuable prognostic tool.
Key Words: Chronic kidney disease, Deep vein thrombosis, Fibrinogen, Cardiovascular events, Haemodialysis.
INTRODUCTION
Most patients with chronic kidney disease (CKD) show variable haemostatic manifestations with a tendency to bleeding, as well as life-threatening thrombotic episodes.1,2 Haemostatic mechanisms responsible for increased bleeding in patients with CKD include platelet dysfunction, abnormal Von Willebrand factor, complex platelet interactions, abnormalities of fibrinolysis, and degree of anaemia as well.1,3,4
Hypercoagulability in CKD manifests as cardiovascular (CV) events, deep vein thrombosis (DVT), pulmonary embolism, thrombosis of arteriovenous (AV) fistula, or haemodialysis access.5
There is a 2.5-fold increased risk of thrombosis in CKD stage 3 and 5.5-fold increased risk in CKD stage 4 and 5.6 Suggested mechanisms are uraemia, inflammation, and haemostatic derangements, such as hyperfibrinogenaemia as a physiological response of the body to increased bleeding tendency in CKD.7,8
Thrombotic episodes leading to CV disease are the leading cause of mortality and morbidity, accounting for 30–40% deaths in CKD.9 Risk factors such as diabetes mellitus and hypertension are usually studied in CKD; however, other haemostatic factors contributing to this hypercoagulability, such as increased fibrinogen levels, are not well studied as predictors of thrombotic events in the literature. In various studies, fibrinogen is established as an independent marker to predict CV disease in the general population.9 Few studies demonstrated it as an independent predictor of mortality in CKD patients.10
This study aimed to determine the prognostic significance of fibrinogen levels in predicting thrombotic events, especially CV events in CKD.
METHODOLOGY
This prospective observational cohort study was conducted at the dialysis unit of the Department of Haematology, Combined Military Hospital, Lahore, Pakistan, from May 2024 to 2025. The WHO sample size calculator was used to calculate sample size, keeping confidence level of 99%, margin of error 1%, relative precision of 50%, and the reported probability in the previous study of 46%. The estimated sample size came out to be 163. Approval for the study protocol was obtained from the Institutional Ethics Review Board of the hospital (Approval No: 660/2025). Informed consent was obtained from all participants.
A total of 163 adult patients of both genders, aged between 9 and 90 years, with end-stage renal disease (ESRD) on maintenance haemodialysis for at least 3 months were enrolled in the study using a non-probability consecutive sampling technique. Patients with history of any CV event and those on immunosuppressants were excluded from the study. Moreover, patients with conditions affecting fibrinogen levels, such as active infection, malignancy, known coagulation disorders, recent surgery (<3 months), or pregnant females were also excluded.
The demographic and comorbid conditions data, including hypertension and diabetes mellitus, as well as fibrinogen levels, were recorded at the time of enrolment. Blood samples were collected in a trisodium citrate anticoagulant tube in a 9:1 ratio of blood to anticoagulant. After collection, all samples were immediately transported to the laboratory and analysed within three hours to ensure accurate results and to rule out any pre-analytical errors. Each blood sample was centrifuged at 2500 g for 15 minutes, and plasma was separated from whole blood. An automated coagulation analyzer (Sysmex-660) was employed for fibrinogen estimation using 10 mL plasma from each sample. The normal range of fibrinogen was 200–400 mg/dL. Patients were followed for a period of 12 months to record the occurrence of any thrombotic events, including CV events, thrombosis of AV fistula, DVT, pulmonary embolism, catheter-related thrombosis, or renal vein thrombosis. CV events included coronary artery disease, myocardial infarction, unstable angina, or new-onset arrhythmias. The frequency of haemodialysis was also recorded for each patient. Event data were confirmed using clinical notes, imaging, and diagnostic reports.
Data analysis was performed using SPSS version 26:00. Normality of continuous variables was assessed using the Shapiro-Wilk test. Descriptive statistics were presented as median with interquartile range (IQR) for continuous variables, including age, frequency of haemodialysis, and fibrinogen levels. Categorical variables, including hypertension, diabetes mellitus, and thrombotic events, were reported as frequencies and percentages. Comparison between patients with thrombotic events and risk factors was performed using the Mann-Whitney U non-parametric test. The relative risk (RR) of CV events was calculated in patients with a higher fibrinogen group, divided on the basis of a median split, calculated using crosstabs with risk estimation. Regression analysis was performed using the Poisson regression with robust errors to calculate the adjusted RR for CV events. The receiver operating curve (ROC) analysis was performed to assess the optimal cut-off value of fibrinogen levels for predicting CV events in patients undergoing haemodialysis.
RESULTS
A total of 163 CKD patients on haemodialysis, with a median age of 60.0 (42.0-64.0) years, included 127 (77.9%) males and 36 (22.1%) females. Higher fibrinogen levels were recorded in these patients with a median of 407.0 (338.0 - 458.0) mg/dL. The median frequency of haemodialysis was 3.00 (2.00-3.00) per week. Baseline demographics are shown in Table I.
Out of a total of 163 patients, 102 (62.6%) had hypertension and 59 (36.2%) had diabetes mellitus. During follow-up of this cohort, 19 (11.7%) patients developed DVT, 56 (34.4%) developed a CV event, 3 (4.89%) had blockage of the AV fistula, and one (1.63%) had an episode of stroke. No episode of pulmonary embolism or any other thrombotic event was recorded. The CV events and DVT had a statistically significant association with fibrinogen levels (p <0.001); however, risk factors such as hypertension and diabetes mellitus did not have any association (p >0.05), as shown in Table II.
Patients with higher fibrinogen levels exhibited a significantly higher risk of CV events. The RR for CV events in the high fibrinogen group was 3.14 (95% CI: 1.87-5.28), as shown in Table III.
The fibrinogen level was established as a significant predictor of CV events, as each unit increase in fibrinogen level was associated with a 1.4% increased risk of CV events (adjusted RR Exp(B): 1.014, 95% CI: 1.011-1.017, p <0.001) as shown in Table IV. Hypertension, diabetes mellitus, and age showed no significant association with CV events in this model.
ROC analysis showed area under the curve (AUC) was 0.829 (95% CI: 0.768-0.890; p <0.001), indicating excellent discriminatory power as shown in Figure 1. An optimal cut-off value of 355.50 mg/dl was calculated with a sensitivity of 92.9% and a specificity of 49.5%. These results suggested that elevated fibrinogen level is a strong predictor of CV events (Figure 1).
Table I: Baseline demographics and clinical details of patients (n = 163).|
Variables |
Values |
|
Total patients |
163 |
|
Median age, years |
60.0 (42.0–64.0) |
|
Gender Male, n (%) Female, n (%) |
127 (77.9%) 36 (22.1%) |
|
Median fibrinogen, mg/dl |
407.0 (338.0–458.0) |
|
Median dialysis frequency per week |
3.00 (2.00–3.00) |
|
Hypertension, n (%) |
102 (62.6%) |
|
Diabetes mellitus, n (%) |
59 (36.2%) |
Table II: Thrombotic events and risk factors in patients of CKD on HD (n = 163).
|
Thrombotic events/ |
Descriptive statistics |
Median fibrinogen |
p-values* |
|
|
CV events |
Yes |
56 (34.4) |
458.0 (419.0-488.0) |
<0.001 |
|
No |
107 (65.6) |
346 (313.0-431.0) |
||
|
DVT |
Yes |
19 (11.7) |
458.0 (431.0-488.0) |
<0.001 |
|
No |
144 (88.3) |
365 (329.0-454.0) |
||
|
HTN |
Yes |
102 (62.6) |
407.0 (346.0-458.0) |
0.413 |
|
No |
61 (37.4) |
419.0 (286.0-458.0) |
||
|
DM |
Yes |
59 (36.2) |
407.0 (346.0-458.0) |
0.191 |
|
No |
104 (63.8) |
419.0 (313.0-458.0) |
||
|
CV: Cardiovascular, DVT: Deep venous thrombosis, HTN: Hypertension, DM: Diabetes mellitus. *p-value was calculated by using the Mann-Whitney U test. |
||||
Table III: Association of fibrinogen levels with CV events in the CKD patients on haemodialysis.
|
Fibrinogen group |
CV events present (n, %) |
CV events absent (n, %) |
Total (n, %) |
Relative risk (95% CI) |
|
Low (≤ median) |
12 (21.40%) |
72 (67.30%) |
84 (51.50%) |
Reference |
|
High (> median) |
44 (78.60%) |
35 (32.70%) |
79 (48.50%) |
3.14 (1.87-5.28) |
|
CV: Cardiovascular. Fibrinogen groups were formed by median split. Relative risk (RR) was calculated using the crosstabs with risk estimation in SPSS. |
||||
Table IV: Fibrinogen levels and risk factors predicting CV events in CKD patients on haemodialysis.
|
Variables |
Regression analysis |
|
|
Exp(B) (95% CI) |
p-values |
|
|
Fibrinogen levels |
1.014 (1.011-1.017) |
<0.001 |
|
DVT events |
0.247 (0.088-0.699) |
0.008 |
|
Hypertension |
1.024 (0.730-1.438) |
0.909 |
|
Diabetes mellitus |
1.150 (0.822-1.068) |
0.392 |
|
Age |
1.008 (0.993-1.024) |
0.272 |
|
CV: Cardiovascular, DVT: Deep vein thrombosis, Exp(B): Adjusted relative risk (RR) of CV events, CI: Confidence interval. The p-values were determined using the Poisson regression with robust errors.
|
||
DISCUSSION
In this study, the authors investigated the prognostic value of fibrinogen level for predicting CV events in patients with CKD undergoing haemodialysis. The results demonstrated higher fibrinogen levels in CKD patients on haemodialysis with a median value of 407 mg/dL (IQR 338-458 mg/dL). Al Rahbi et al. reported similar results with 74.6% patients on haemo-dialysis having higher fibrinogen levels.11 Huang et al. and Lin et al. also reported higher fibrinogen levels in CKD patients as compared to healthy controls.12,13 Higher fibrinogen levels in CKD are primarily attributed to kidney dysfunction leading to uraemia, chronic inflammation, oxidative stress, decreased clearance, and increased production of fibrinogen.
A statistically significant association was seen between fibrino-gen levels and thrombotic events, especially CV events and DVT (p <0.001). Yu et al. reported similar results, estab-lishing that higher fibrinogen levels have a significant association with increased risk of CV events. The average fibrinogen level reported was 412 ± 138 mg/dL. Out of 29.6% CKD patients who died in this study during follow-up, 49.6% died due to CV events.10 Lim et al. also reported fibrinogen level as one of the key predictors of CV and thrombotic events in a cohort of CKD patients followed for a minimum of 12 months.14 Xie et al. reported fibrinogen levels to be associated with higher CV mortality in patients with ESRD.15 Janus et al. also included fibrinogen level in the panel of biomarkers to discriminate risk of heart failure in mild-to-moderate CKD.16
Furthermore, it was found in this study that fibrinogen level is a prognostic marker for CV risk in patients on haemodialysis. Patients with higher fibrinogen levels showed a significantly higher risk of CV events. The RR of CV events in the higher fibrinogen group was 3.14, indicating that patients of the higher fibrinogen group were 3.14 times more likely to experience CV events as compared to the lower fibrinogen group when divided on the basis of median split. Fibrinogen levels independently predicted CV events, with each 1 mg/dL increase associated with a 1.4% higher risk (adjusted RR Exp(B): 1.014). ROC analysis showed AUC to be 0.829. An optimal cut-off point of fibrinogen was identified at 355.50 mg/dL. Yan et al. established fibrinogen-to-albumin ratio as an independent predictor, and the AUC in patients with CKD on peritoneal dialysis was 0.572 (95% CI: 0.500–0.643).17 Other studies used fibrinogen/albumin ratio instead of fibrinogen only and studied its predictive value for CV events as well as the severity of coronary artery disease in CKD.18,19 This further supports the prognostic role of fibrinogen levels, especially in a hypercoagulable state leading to CV disease, which is the leading cause of mortality and morbidity in CKD.20,21 Limited or no studies were found in which only fibrinogen is used for prognostication in CKD for CV events.
From a clinical standpoint, incorporating fibrinogen level assessment into routine monitoring of haemodialysis patients may help identify those at higher risk of CV complications. Early interventions, such as intensified CV surveillance, anti-inflammatory strategies, or individualised dialysis protocols, could be considered for patients with elevated fibrinogen levels.
Limitations of this study include its observational nature, limited sample size, and short follow-up period, which may affect the generalisability of these findings. Additionally, the logistic model reached the maximum number of iterations, which may reflect data complexity or multicollinearity. Future studies should validate these findings in larger, multicentre cohorts, also considering factors such as duration of disease, to assess the incremental value of fibrinogen when added to established risk prediction models.
CONCLUSION
This study demonstrates that elevated fibrinogen level is an independent predictor of CV events in CKD patients on haemodialysis. The RR and the high AUC support its potential utility as a screening tool for CV risk stratification. These findings suggest that fibrinogen may serve as a valuable biomarker for early identification of high-risk patients, potentially guiding more tailored therapeutic interventions. Further studies are warranted to validate and refine its clinical application.
ETHICAL APPROVAL:
Ethical approval was obtained from the Institutional Ethical Review Board of the Combined Military Hospital, Lahore, Pakistan (Certificate No. 660/2025).
PATIENTS’ CONSENT:
Written informed consent was obtained from all patients who participated in this study, and the confidentiality of data was maintained.
COMPETING INTEREST:
The authors declared no conflict of interest.
AUTHORS’ CONTRIBUTION:
AC: Data collection, data analysis, drafting, and critical revision.
HMR: Study design, conception, proofreading, and critical revision.
AR: Conception, data analysis, proofreading, and critical revision.
MI: Design, drafting, proofreading, and critical revision.
MI: Data collection, drafting, and data analysis.
AW: Conception, data collection, and critical revision.
All authors approved the final version of the manuscript to be published.
REFERENCES
Figure 1: Cut-off value estimation of fibrinogen level in predicting CV events.