Japanese Journal of Veterinary Research 66(2): 119-123, 2018
SHORT COMMUNICATION Clinical Case Report
Age-related change of the plasma fibrinogen 
concentration in dogs
 
Abstract
The aim of the present study was to investigate whether canine plasma fibrinogen concentration 
changes with age. We also investigated sex differences in the plasma fibrinogen concentration. As a 
result, the plasma fibrinogen concentration was found to moderately increase with age (Spearman’s 
r ＝ 0.55, P ＜ 0.001), whereas that of the male and female dogs did not differ to a statistically significant 
extent. This finding suggests the need to consider aging as a factor that affects the plasma fibrinogen 
concentration.
 
Key Words: Age; Dog; Fibrinogen
Kazuhito Segawa1,＊), Chika Takahashi2), Makoto Takahashi2),  
Tetsuro Ito3), Sakurako Neo1), Masaharu Hisasue1) and Ryo Tsuchiya1)
1) The Laboratory of Small Animal Internal Medicine, School of Veterinary Medicine, Azabu University, Kanagawa 252-5201, 
Japan
2) Higashihashimoto Animal Hospital, Kanagawa 252-0144, Japan
3) The Laboratory of Small Animal Clinics, Veterinary Teaching Hospital, Azabu University, Kanagawa 252-5201, Japan
Received for publication, June 7, 2017; accepted, December 20, 2017
*Corresponding author: Kazuhito Segawa, The Laboratory of Small Animal Internal Medicine, School of Veterinary 
Medicine, Azabu University, 1-17-71 Fuchinobe, Chuou-ku, Sagamihara-shi, Kanagawa 252-5201, Japan
Fax: +81-42-769-1636. E-mail: segawa@azabu-u.ac.jp
doi: 10.14943/jjvr.66.2.119
　　Fibrinogen is a plasma glycoprotein which is 
synthesized in the liver. It plays an essential role 
in the secondary hemostatic process. Decreased 
plasma fibrinogen concentrations are therefore 
associated with life threatening bleeding. The 
common causes of hypofibrinogenemia are 
production insufficiency due to liver dysfunction, 
increased consumption during local hemostasis or 
systemic disseminated intravascular coagulation, 
hemodilution, and genetic problems that affect 
fibrinogen production.1) On the other hand, the 
plasma fibrinogen concentration is increased 
during the inflammatory response because 
fibrinogen is an acute-phase protein.11)
　　Aside from pathological states, the mean 
plasma fibrinogen concentrations of healthy 
humans are reported to differ according to age, 
sex, body mass index, and smoking status.8,9,12) At 
present, there is no evidence regarding such 
differences in dogs. However, we occasionally 
encounter healthy adolescent dogs with a plasma 
fibrinogen concentration that is below the lowest 
limit of the reference interval (RI) and have 
hypothesized that the plasma fibrinogen 
concentration is correlated with age in dogs. 
Thus, the aim of this study is to investigate the 
age-related change in the plasma fibrinogen 
concentration in dogs. Sex differences in plasma 
fibrinogen concentrations were also investigated.
　　The present study included 159 client-owned 
Correlation between fibrinogen and age120
dogs that were undergoing neuter surgery or 
deciduous tooth extraction between January 2009 
and May 2015 at a primary care veterinary clinic 
(Higashihashimoto Animal Hospital, Kanagawa, 
Japan). The research protocols were approved by 
the Animal Experiment Committee of Azabu 
University. Prior to the operations, the dogs were 
confirmed to be healthy based on interviews, 
physical examinations, and blood tests. The blood 
tests included complete blood counts, liver and 
kidney biochemistry, and blood coagulation tests, 
including assessments of the prothrombin time 
and the activated partial thromboplastin time, 
while also determining the plasma fibrinogen 
concentration.
　　Blood samples were obtained from the jugular 
or cephalic vein of dogs after overnight fasting, 
and transferred to a 3.2% sodium citrate tube for 
the blood coagulation tests. The blood samples in 
the sodium citrate tubes were centrifuged for 15 
minutes at 1,000 ×g to separate the plasma 
immediately after collection. The citrate plasma 
was visually checked for hemolysis.
　　The plasma fibrinogen concentrations were 
measured by the Clauss method9) using a WAKO 
Coag 2V system (Wako Corp., Osaka, Japan). 
This machine assesses clot formation time in an 
oscillating magnetic field, and calculates fibrinogen 
concentrations using the reference laboratory 
method.10) The assay validation in dogs were 
reported by Kitoh et al.7); the domestic marketing 
of the canine system is permitted by the Japanese 
Ministry of Agriculture, Forestry, and Fisheries.
　　According to the Clinical and Laboratory 
Standards Institute guidelines adopted for 
veterinary species, the sample size was sufficient 
to determine the RI of plasma fibrinogen 
concentration.3) Normal distribution was confirmed 
with the Anderson-Darling test. Outliers were 
examined with Dixon’s Q test. The Reference 
Value Advisor software program (version 2.1) 
was used to calculate the RI based on 
non-parametric methods.5) The 90% confidence 
interval (CI) was determined using the bootstrap 
method for a subgroup (sex). The relationship 
between the plasma fibrinogen concentration and 
age was analyzed by Spearman’s rank correlation 
coefficient. The difference in the plasma fibrinogen 
concentration between the subgroups was also 
analyzed using the unpaired Student’s t-test. The 
Prism software program (version 5.0, GraphPad 
Software Inc., San Diego, CA) was used to perform 
the Spearman’s rank correlation coefficient 
analyses and t-test.
　　A single outlier (590 mg/dl), which was 
detected among the adult male dogs was excluded 
from the analysis. As a result, there were 81 
males and 77 females.
　　The breeds included Toy Poodle (n ＝ 32), 
Chihuahua (n ＝ 31), Miniature Dachshund (n ＝ 
17) and others (n＝78; mixed breed dogs [n ＝ 
21], Maltese [n ＝ 5], Welsh Corgi [n ＝ 5], and 
purebred dogs from 21 other breeds [n ＝ 47]). 
The median body weight of all dogs was 4.2 kg 
(range: 1.7-45.0 kg).
　　The overall RI of plasma fibrinogen 
concentration was 113-402 mg/dl (90% CI for the 
lower limit: 102-117; 90% CI for the upper limit: 
344-590). The plasma fibrinogen concentration 
was moderately correlated with age (Fig. 1; 
Spearman’s r ＝ 0.55, P ＜ 0.001). The data 
according to the major breeds and other breeds 
were also indicated in Fig. 2. The plasma 
Fig. 1. The relationships between plasma 
fibrinogen concentration and age in all dogs.  The 
shaded area indicated the manufacturer provided RI of 
the plasma fibrinogen concentration (150-450 mg/dl). ***: 
The plasma fibrinogen concentration was significantly 
correlated with age (P ＜ 0.001).
Kazuhito Segawa et al. 121
fibrinogen concentration of Toy Poodles and 
Miniature Dachshunds were strongly correlated 
with age (Toy Poodles: Spearman’s r ＝ 0.69, 
P ＜ 0.0001, Chihuahuas: Spearman’s r ＝ 0.45, 
P ＝ 0.011, Miniature Dachshunds: Spearman’s 
r ＝ 0.68, P ＝ 0.005, Others: Spearman’s r ＝ 0.48, 
P ＜ 0.0001).
　　The plasma fibrinogen concentrations of the 
male and female dogs did not differ to a 
statistically significant extent (Fig. 3). The RIs 
for plasma fibrinogen concentration in male and 
female dogs were 114-400 mg/dl (90% CI for the 
lower limit: 102-120; 90% CI for the upper limit: 
341-420) and 109-394 mg/dl (90% CI for the 
lower limit: 102-119; 90% CI for the upper limit: 
332-427), respectively.
　　In this report, although there were some 
differences between breeds, the plasma fibrinogen 
concentrations were relatively correlated with 
age. A similar correlation is also reported in 
human medicine, and the higher plasma 
fibrinogen concentration in older people is 
thought to be a risk factor for the development of 
ischemic cardiovascular disease.8) We did not 
identify the reasons why older dogs tended to 
have higher plasma fibrinogen concentrations; 
however, occult acute phase reactions, subclinical 
activations of coagulation, and a lower turnover 
rate of fibrinogen have been reported as reasons 
in older people.4,6)
　　Younger dogs tended to have lower plasma 
fibrinogen concentrations. If we used the 
Fig. 2. The relationships between plasma fibrinogen concentration and age in Toy Poodle (A), Chihuahua 
(B), Miniature Dachshund (C) and others (D).  The shaded area indicated the manufacturer provided RI of the 
plasma fibrinogen concentration (150-450 mg/dl). *, **, ****: The plasma fibrinogen concentrations were 
significantly correlated with age (P ＜ 0.05, 0.01, 0.0001).
Correlation between fibrinogen and age122
manufacturer-provided RI of the plasma 
fibrinogen concentration (150-450 mg/dl), 37 dogs 
would have been below the RI; 33 of these dogs 
were 12 months of age or younger. However, 
the low plasma fibrinogen concentration of the 
younger dogs in this study was not associated 
with life threatening bleeding. Thus, if we 
encounter younger dogs with a plasma fibrinogen 
concentration below the lowest limit of the RI 
without bleeding events, a re-examination after 
an interval of several months might show that 
the concentration has increased into the reference 
range because of age-related change.
　　We did not observe a sex difference in the 
plasma fibrinogen concentration. In human 
medicine, the plasma fibrinogen concentrations 
of females are higher than those of males.8,9,12) In 
particular, the plasma fibrinogen concentration 
in pregnant individuals would be higher than 
that in non-pregnant individuals, and pregnant 
females are at a high risk of developing 
thrombosis.2) Although we did not include 
pregnant dogs in this study, we might need to 
investigate the plasma fibrinogen concentration 
of pregnant dogs and the risk of thrombosis.
　　The present study is associated with some 
limitations. The body condition score and the 
owner’s smoking status, which have been reported 
as potentially modifiable determinants of the 
fibrinogen concentration in healthy humans, 
were not investigated in this study. Also, because 
small breeds are popular in Japan, this report 
only included a few large breeds. The correlation 
between plasma fibrinogen concentration and age 
in large breeds might need to be investigated 
separately.
　　The results of this study imply that the 
plasma fibrinogen concentrations increase 
significantly with age in dogs. The cause of this 
phenomenon remains to be studied.
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Fig. 3. The plasma fibrinogen concentrations of 
male and female dogs.  For box graphs, the line within 
the box represents the median value, the limits of the 
box represent the 25th and 75th percentile values, and 
the whiskers represent the range. The single outlier 
(male, 590 mg/dl) is not included in these graphs.
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