10.4081/btvb.2022.36
Circulating albumin and fibrinogen levels, commonly considered as inflammatory markers, have been shown to be associated with venous thromboembolism (VTE) risk. Circulating albumin-to-fibrinogen ratio (AFR) has been proposed as a novel inflammatory biomarker, but its association with VTE risk has not been investigated. We aimed to assess the prospective association of AFR with VTE risk. Circulating albumin and fibrinogen levels were measured at baseline in 2,284 men aged 42-61 years. Hazard ratios (HRs) with 95% confidence intervals (CIs) were estimated. During a median follow-up of 27.0 years, 156 VTE cases were recorded. In analysis adjusted for established risk factors, the HR (95% CI) for VTE comparing extreme tertiles of AFR was 1.53 (1.02-2.32), which remained similar on further adjustment for prevalent cancer, 1.52 (1.01-2.30). The associations of circulating albumin or fibrinogen with VTE risk were modest. Circulating AFR may be a stronger risk indicator for VTE compared with albumin or fibrinogen alone.
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Jari Laukkanen
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Bleeding, Thrombosis and Vascular Biology
Cohort study
Circulating albumin-to-fibrinogen ratio may be a risk indicator for venous thromboembolism: findings from a population-based prospective cohort study
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Original Articles
2022-07-14
2022-05-05
2022-05-23
2022-07-14
Bleed Thromb Vascul Biol
Jari Laukkanen
2022/07/14
10.4081/btvb.2022.36
Central Finland Health Care District Hospital District, Department of Medicine, Jyväskylä, Finland District, Jyväskylä, Finland; Institute of Public Health and Clinical Nutrition, University of Eastern Finland, Kuopio, Finland; Institute of Clinical Medicine, Department of Medicine, University of Eastern Finland, Kuopio
2785-5309
2
Cohort study
en
Lip GY, Lowe GD. Fibrin D-dimer: a useful clinical marker of thrombogenesis? Clin Sci (Lond) 1995;89:205-14.
Circulating albumin-to-fibrinogen ratio may be a risk indicator for venous thromboembolism: findings from a population-based prospective cohort study
https://www.btvb.org/btvb/article/download/36/32
1
                                                                                                             ORIGINAL ARTICLE

Circulating albumin-to-fibrinogen ratio may be a risk indicator for venous
thromboembolism: findings from a population-based prospective cohort study
Setor K. Kunutsor,1-3 Sudhir Kurl,4 Ari Voutilainen,4 Jari A. Laukkanen3-5
1
 National Institute for Health Research Bristol Biomedical Research Centre, University Hospitals Bristol and Weston NHS
Foundation Trust and the University of Bristol, Bristol, UK; 2Musculoskeletal Research Unit, Translational Health Sciences, Bristol
                                                                      Medical School, University of Bristol, Learning & Research
                                                                      Building, Southmead Hospital, Bristol, UK; 3Central Finland
                                                                      Health Care District Hospital District, Department of
                                                                      Medicine, Jyväskylä, Finland District, Jyväskylä, Finland;
                                                                      4
  Correspondence: Setor K. Kunutsor, Musculoskeletal Research           Institute of Public Health and Clinical Nutrition, University
  Unit, Translational Health Sciences, Bristol Medical School, Uni-   of Eastern Finland, Kuopio, Finland; 5Institute of Clinical
  versity of Bristol, Learning & Research Building (Level 1), South-  Medicine, Department of Medicine, University of Eastern
  mead Hospital, Bristol, BS10 5NB, UK.                               Finland, Kuopio, Finland
    Tel: +44-7539589186 - Fax: +44-1174147924.
    E-mail: skk31@cantab.net

    Key words: Albumin; Fibrinogen; Albumin-to-fibrinogen ratio; Ve-




                                                                                                ly
    nous thromboembolism; Cohort study.                                        ABSTRACT
                                                                                    Circulating albumin and fibrinogen levels, commonly con-




                                                                                         on
    Contributions: SKK: Study design, data analysis and interpretation,        sidered as inflammatory markers, have been shown to be asso-
    drafting manuscript, and revising manuscript content and approv-           ciated with venous thromboembolism (VTE) risk. Circulating
    ing final version of manuscript; SK: Study design and and revising         albumin-to-fibrinogen ratio (AFR) has been proposed as a novel




                                                                                   e
    manuscript content and approving final version of manuscript; AV:
                                                                               inflammatory biomarker, but its association with VTE risk has
    Study design and revising manuscript content and approving final
    version of manuscript; JAL: Study design and conduct, responsi-
    bility for the patients and data collection, and revising manuscript
    content and approving final version of manuscript.
                                                                              us
                                                                               not been investigated. We aimed to assess the prospective asso-
                                                                               ciation of AFR with VTE risk. Circulating albumin and fibrino-
                                                                               gen levels were measured at baseline in 2,284 men aged 42-61
                                                                              al
                                                                               years. Hazard ratios (HRs) with 95% confidence intervals (CIs)
    Conflict of interest: The authors declare no potential conflict of in-     were estimated. During a median follow-up of 27.0 years, 156
                                                           ci

    terest.                                                                    VTE cases were recorded. In analysis adjusted for established
                                                         er


                                                                               risk factors, the HR (95% CI) for VTE comparing extreme ter-
    Funding: Prof. Laukkanen acknowledges support from The Finnish
                                                                               tiles of AFR was 1.53 (1.02-2.32), which remained similar on
    Foundation for Cardiovascular Research, Helsinki, Finland.
                                                        m



                                                                               further adjustment for prevalent cancer, 1.52 (1.01-2.30). The
    Acknowledgements: The Authors thank the staff of the Kuopio Re-            associations of circulating albumin or fibrinogen with VTE risk
                                            om




    search Institute of Exercise Medicine and the Research Institute of        were modest. Circulating AFR may be a stronger risk indicator
    Public Health and University of Eastern Finland, Kuopio, Finland           for VTE compared with albumin or fibrinogen alone.
    for the data collection in the study.
                                      -c




    Availability of data and material: There are no linked research data
    sets for this submission, because the authors do not have permis-
                             on




                                                                               INTRODUCTION
    sion to share data.
                                                                                   Venous thromboembolism (VTE) which includes both
                       N




    Ethics approval: The research protocol was approved by the insti-
    tutional review board of the University of Eastern Finland. All par-
                                                                               deep vein thrombosis (DVT) and pulmonary embolism
    ticipants provided written informed consent.                               (PE), is the third most common cardiovascular disease
                                                                               (CVD).1 Apart from being a leading and preventable
    Received for publication: 5 May 2022.
                                                                               cause of deaths, VTE is associated with substantial dis-
    Accepted for publication: 1 June 2022.
                                                                               ability and economic costs.2 Major risk factors implicated
    Publisher’s note: All claims expressed in this article are solely those    in VTE development include immobilisation, trauma, sur-
    of the authors and do not necessarily represent those of their affili-     gery, cancer, hormonal therapy, obesity, and hypercoagu-
    ated organizations, or those of the publisher, the editors and the re-
                                                                               lation disorders;3 however, it has been reported that its
    viewers. Any product that may be evaluated in this article or claim
    that may be made by its manufacturer is not guaranteed or endorsed         causes are unknown in 25-50% of cases.4 Identifying pu-
    by the publisher.                                                          tative risk factors that could be valuable in the develop-
    ©
                                                                               ment of more effective preventive strategies is essential.
     Copyright: the Author(s), 2022
    Licensee PAGEPress, Italy
                                                                               In addition to alterations in the coagulation cascade, ab-
    Bleeding, Thrombosis and Vascular Biology 2022; 1:36                       normalities in fibrin clot properties, endothelial dysfunc-
    doi:10.4081/btvb.2022.36                                                   tion, dyslipidemia and hypercoagulable states, an
                                                                               inflammatory hypothesis has been postulated in the patho-
    This work is licensed under a Creative Commons Attribution-
    NonCommercial 4.0 International License (CC BY-NC 4.0).                    physiology of VTE.5 Indeed, circulating inflammatory
                                                                               markers have been shown to be associated with the risk

                                                Bleeding, Thrombosis and Vascular Biology 2022; 1:36
36                                                    S.K. Kunutsor et al.




of VTE.6 Circulating albumin and fibrinogen, commonly              identified by computer linkage to the National Hospital
used markers for evaluating inflammatory conditions,               Discharge Registry data and a comprehensive review of
have also been shown to be associated with the risk of             available hospital records. Hazard ratios (HRs) with 95%
VTE.7,8 It has been reported that the addition of these            confidence intervals (CIs) were calculated using Cox pro-
markers to existing VTE risk assessment models could be            portional hazard models. All statistical analyses were con-
used to improve risk discrimination and reclassifica-              ducted using Stata version MP16 (Stata Corp, College
tion.9,10 Circulating albumin-to-fibrinogen (AFR), a novel         Station, Texas).
biomarker estimated from measurements of albumin and
fibrinogen, is potentially useful for evaluating and moni-
toring inflammatory conditions.11 Given that circulating           RESULTS
AFR reflects the activity of both albumin and fibrinogen
                                                                       The mean [standard deviation (SD)] for age, AFR and
in combination, we hypothesized that AFR may be a more
                                                                   circulating albumin levels of the 2284 men at baseline was
reliable risk indicator for inflammatory conditions com-
pared to albumin or fibrinogen alone. The association be-          53 (5) years, 14.5 (3.0) and 42.3 (3.5) g/l, respectively.
tween AFR and VTE has not been previously                          The median (interquartile range, IQR) for plasma fibrino-
investigated. Using a population-based cohort of 2284              gen was 2.96 (2.63-3.33) g/l (Table 1). Significant weak




                                                                                            ly
Caucasian men with no previous history of VTE, we                  and inverse correlations were observed between AFR and
                                                                   age, alcohol consumption, SES, body mass index, total




                                                                                    on
aimed to assess the prospective association of AFR with
VTE risk and evaluate separate associations of albumin             cholesterol, and triglycerides, whereas a significant weak
or fibrinogen with VTE risk.                                       and positive correlation was observed with high-density




                                                                               e
                                                                   lipoprotein cholesterol. Values of AFR were significantly
                                                                   lower in men who smoked compared with non-smokers
MATERIALS AND METHODS                                                    us
                                                                   and those with histories of type 2 diabetes or coronary
                                                                   heart disease compared with those without these comor-
                                                                  al
    Reporting of the study conformed to broad EQUA-                bidities (Table 1).
TOR guidelines,12 and was conducted according to                       During a median (IQR) follow-up of 27.0 (17.2-31.0)
                                                     ci

STROBE (STrengthening the Reporting of OBservational               years, a total of 156 VTE cases (annual rate 2.85/1000
                                                   er


studies in Epidemiology) guidelines for reporting obser-           person-years at risk; 95% CI: 2.44 to 3.34) were recorded.
vational studies in epidemiology (Supplementary Files).            Comparing the bottom versus top thirds of AFR, the HR
                                                  m



This analysis employed the Kuopio Ischemic Heart Dis-              (95% CI) for VTE in analysis adjusted for age, systolic
ease (KIHD) risk factor study, a general population-based          blood pressure, body mass index, total cholesterol, triglyc-
                                         om




prospective cohort study comprising men aged 42-61                 erides, smoking status, history of type 2 diabetes, preva-
years who were recruited from Kuopio and its surround-             lent coronary heart disease, lipid medication, alcohol
ings in eastern Finland. The KIHD cohort was originally
                                    -c




                                                                   consumption, total physical activity, socioeconomic sta-
designed to investigate risk factors for atherosclerotic           tus, total energy intake, and history of cancer was 1.52
                             on




CVD in middle-aged and older men, given the high preva-            (1.01-2.30) (Figure 1). Analysis in the same set of partic-
lence and incidence of coronary heart disease in this pop-         ipants showed no significant evidence of associations of
ulation group.13 The research protocol was approved by
                        N




                                                                   albumin or fibrinogen with the risk of VTE (Table 1).
the institutional review board of the University of Eastern
Finland and all study procedures were conducted accord-
ing to the Declaration of Helsinki. Details of the study de-       DISCUSSION
sign, recruitment methods and assessment of risk markers
have been reported previously.6 The baseline cohort com-               In this population-based prospective cohort involving
prised 2682 men who had baseline assessments performed             middle-aged and older Caucasian men, baseline AFR was
between March 1984 and December 1989. In the current               most weakly and inversely correlated with several risk
analysis, complete information on serum AFR, relevant              markers for VTE. We observed a significant association
covariates, and VTE outcomes was available for 2284                between lower levels of circulating AFR and an increased
men. Serum albumin concentrations were measured using              risk of VTE. The association was independent of several
Coulter’s bromcresol purple (BCP) colorimetric assay               established risk factors (such as age, body mass index,
(Kone Specific, Kone Corporation, Espoo, Finland).7,14             smoking status, history of type 2 diabetes, prevalent coro-
Plasma fibrinogen concentrations were determined in                nary heart disease, and history of cancer) and other po-
fresh plasma samples with excess thrombin using the Co-            tential confounders. Further evaluation in the same group
agulometer KC4 device (Heinrich Amelung GmbH,                      of participants showed that AFR was a stronger risk indi-
Lemgo, Germany). We included all first VTE events that             cator for VTE compared with circulating albumin or fib-
occurred from study entry through to 2018. These were              rinogen alone.

                                     Bleeding, Thrombosis and Vascular Biology 2022; 1:36
                         Circulating albumin-to-fibrinogen ratio may be a risk indicator for venous thromboembolism                                    37



    The current findings cannot be compared to any pre-                          Fibrinogen is a biomarker of chronic inflammation, has
vious work given that this is the first evaluation of the                        coagulative properties and is an important determinant
prospective association between circulating AFR and                              of blood viscosity and platelet aggregation;18 hence, el-
VTE risk. However, a number of observational cohort                              evated fibrinogen levels may increase the risk of throm-
studies have reported evidence of associations of low al-                        bus formation.19 The current findings suggest that
bumin and high fibrinogen levels with increased VTE                              circulating AFR may be a more useful risk indicator for
risk.7,8 Whereas serum albumin has been suggested to be                          VTE risk than albumin or fibrinogen alone and it can
causally related to VTE,15 the relationship between cir-                         simply be estimated by dividing albumin measurements
culating fibrinogen and VTE has not been demonstrated                            by that of fibrinogen. The potential clinical relevance of
to be causal.8 Possible factors underlying any association                       using AFR in VTE prevention and management deserves
between low albumin and increased VTE risk may in-                               further evaluation.
clude inflammatory or hypercoagulable states,16 under-                               The strengths of the current evaluation include the
lying poor general health,16 cancer, and atherosclerotic                         novelty, use of a large-scale population-based prospec-
CVD,17 which are all linked to the development of VTE.5                          tive cohort comprising a homogeneous sample of men




                                                                                                        ly
                                                                                              on
Table 1. Baseline characteristics of study participants and cross-sectional correlates of circulating albumin-to-fibrinogen ratio.
Characteristics                               Mean (SD) or                     Pearson correlation Percentage difference (95% CI) in values of
                                              median (IQR)                          r (95% CI)a            percentage of AFR per 1 SD higher or




                                                                                      e
                                                                                                        compared to reference category of correlateb
Albumin-to-fibrinogen ratio
Serum albumin, g/l
                                                 14.5 (3.0)
                                                 42.3 (3.5)
                                                                              us          -
                                                                                          -
                                                                                                                              -
                                                                                                                              -
                                                                       al
Plasma fibrinogen, g/l                       2.96 (2.63-3.33)                             -                                   -
                                                            Questionnaire/Prevalent conditions
                                                      ci

Age (years)                                        53 (5)                     -0.15 (-0.19, -0.11)***             -0.47% (-0.60, -0.35)***
                                                    er


Alcohol consumption (g/week)                  31.9 (6.4-91.9)                 -0.11 (-0.15, -0.06)***             -0.33% (-0.46, -0.20)***
Socioeconomic status                            8.42 (4.22)                   -0.14 (-0.18, -0.10)***             -0.42% (-0.55, -0.30)***
                                                   m




Total energy intake (KJ/day)                   9856 (2605)                       0.01 (-0.03, 0.05)                 0.03% (-0.10, 0.15)
                                         om




Physical activity (KJ/day)                   1215 (636-2005)
History of type 2 diabetes (%)
No                                              2196 (96.2)                               -                                 ref
                                  -c




Yes                                               88 (3.9)                                -                        -0.86% (-1.50, -0.21)*
Current smoking (%)
                           on




No                                              1588 (69.5)                               -                                 ref
Yes                                              696 (30.5)                               -                       -1.83% (-2.09, -1.57)***
                     N




History of CHD (%)
No                                              1724 (75.5)                               -                                 ref
Yes                                              560 (24.5)                               -                       -0.71% (-1.01, -0.42)***
Lipid lowering medication (%)
No                                              2272 (99.5)                               -                                 ref
Yes                                               12 (0.5)                                -                         -1.29% (-2.99, 0.42)
                                                                 Physical measurements
            2
BMI (kg/m )                                      26.9 (3.5)                    -0.08 (-0.12, -0.04)**              -0.24% (-0.36, -0.11)**
SBP (mmHg)                                       134 (17)                        0.02 (-0.03, 0.06)                  0.05 (-0.08, 0.17)
DBP (mmHg)                                        89 (10)                        0.01 (-0.03, 0.05)                  0.04 (-0.09, 0.16)
                                                                    Blood biomarkers
Total cholesterol (mmol/l)                      5.90 (1.07)                   -0.13 (-0.17, -0.08)***              -0.38 (-0.50, -0.26)***
Triglycerides (mmol/l)                       1.11 (0.81-1.58)                   -0.04 (-0.08, -0.00)*               -0.13 (-0.25, -0.00)*
HDL-C (mmol/l)                                  1.29 (0.30)                     0.11 (0.07, 0.15)***                0.32 (0.20, 0.44)***
AFR, albumin-to-fibrinogen ratio; BMI, body mass index; CHD, coronary heart disease; DBP, diastolic blood pressure; HDL-C, high-density lipoprotein
cholesterol; IQR, interquartile range; ref, reference; SD, standard deviation; SBP, systolic blood pressure. aPearson correlation coefficients between
circulating AFR and the row variables; bPercentage change in values of circulating AFR per 1-SD increase in the row variable (or for categorical
variables, the percentage difference in mean values of circulating AFR for the category versus the reference). Asterisks indicate the level of statistical
significance: *p<0.05; **p<0.01; ***p<0.001.


                                            Bleeding, Thrombosis and Vascular Biology 2022; 1:36
38                                                     S.K. Kunutsor et al.




                                                                                                          ly
                                                                                               on
                                                                                       e
                                                                            us
                                                                     AFR, albumin-to-fibrinogen ratio; CI, confidence interval; HR, hazard ratio; ref, reference;
                                                                     T, tertile.
                                                                   al
                                                                     Model 1: Adjusted for age. Model 2: Model 1 plus systolic blood pressure, body mass
                                                                     index, total cholesterol, triglycerides, smoking status, history of type 2 diabetes, prevalent
                                                                     coronary heart disease, lipid medication, alcohol consumption, total physical activity,
                                                      ci

                                                                     socioeconomic status, and total energy intake. Model 3: Model 2 plus prevalent cancer.
                                                    er


Figure 1. Associations of serum albumin-to-fibrinogen ratio, albumin, and fibrinogen with risk of venous thromboembolism.
                                                   m
                                          om




who were nationally representative, the long-term fol-
low-up of the cohort which was adequate for the ascer-              CONCLUSIONS
tainment of VTE events, and adjustment for a                           In middle-aged and older Caucasian men, circulating
                                    -c




comprehensive panel of VTE risk factors. The limita-                AFR appears to be a stronger risk indicator for VTE com-
                             on




tions included the inability to generalize the findings to          pared with albumin or fibrinogen levels alone.
women and other populations, lack of data on VTE sub-
types, the relatively low VTE rate, and potential biases
                         N




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                                         Bleeding, Thrombosis and Vascular Biology 2022; 1:36
