on line editionInflammation – a common pathogenic factor of arterial atherosclerotic
ProfessIonal artIcle
id
Inflammation – a 
common pathogenic 
factor of arterial 
atherosclerotic
Department of Vascular 
Diseases, Division of 
Internal Medicine, 
University Medical Centre 
Ljubljana, Ljubljana
Correspondence:
Pavel Poredoš,  
e: pavel.poredos@kclj.si
Key words:
atherosclerosis; 
venous thrombosis; 
endothelial dysfunction; 
inflammatory markers; 
risk assessment
Cite as:
Zdrav Vestn. 2017;  
86:244–54.
received: 2. 12. 2016 
accepted: 7. 4. 2017
cardiovascular systemProfessional article Zdrav Vestn | May – June 2017 | Volume 86
Inflammation – a common pathogenic 
factor of arterial atherosclerotic and venous 
thromboembolic disease
Mateja Kaja Ježovnik, Pavel Poredoš
Abstract
Inflammation is one of the basic mechanisms of arterial atherosclerotic disease, most likely also in-
volved in the pathogenesis of venous thromboembolic disease. Various risk factors for atherosclerosis 
impair the vessel wall and elicit inflammatory changes resulting in the development of atherosclero-
sis. Subjects with advanced atherosclerosis, especially those with unstable atherosclerotic plaques re-
flecting profound inflammatory changes, have increased inflammatory blood markers, such ashigh-
sensitivity C-reactive protein (hs-CRP), which is a nonspecific systemic indicator of inflammation, 
and some interleukins (interleukin-6, interleukin-8), which are among the more specific markers 
of inflammation of the vessel wall. Therefore, the studies have focused on improving the prediction 
of cardiovascular events by determining the circulating markers of inflammation. However, due to 
low specificity of individual indicators of inflammation, different determination methods, and close 
relationship between the levels of inflammatory markers and conventional risk factors, these mark-
ers have not significantly contributed to the risk estimation for cardiovascular events. Currently, the 
determination of hs-CRP as the most recognizable risk factor is recommended only in subjects with 
a medium risk for cardiovascular events, or in patients who do not have conventional risk factors, 
and who are at risk for other reasons, such as familial predisposition for cardiovascular events.
Recently, inflammation has been found to be involved also in the pathogenesis of venous thrombosis. 
In case of damage to the venous wall, inflammation is most likely the response to the injury, whereas 
in idiopathic (unprovoked) venous thrombosis, where there are no known risk factors present, the 
inflammation of the vascular wall is the primary event followed by activation of coagulation. There is 
a close link between inflammation and coagulation; inflammation stimulates the procoagulant activ-
ity and inhibits the endogenous fibrinolysis. Therefore, patients with a history of venous thrombosis 
have increased systemic markers of inflammation, hs-CRP and interleukins in particular. It is not yet 
clear, whether the increased systemic indicators of inflammation are the cause or the consequence 
of venous thrombosis. The results of our studies show that they are more likely to be the cause of 
prothrombotic properties of blood stimulating the development of venous thrombosis. The patients 
who suffered venous thrombosis have constantly elevated inflammatory markers also in the stable 
period of the disease (3–5 years after the diagnosis).
An increased systemic inflammatory response in an arterial atherosclerotic and venous thromboem-
bolic disease indicates a close link between both diseases. Therefore, they may be two pathogenically 
similar diseases with different clinical features.
The recognition of an inflammatory basis for arterial and venous disease is important from the 
therapeutic point of view. Namely, until recently drugs with an anti-inflammatory effect were rather 
neglected in comparison to anticoagulant drugs. Aspirin has long been known to have not only anti-
on line edition Zdrav Vestn | May – June 2017 | Volume 86
cardIoVascular systeM
platelet, but also anti-inflammatory properties, therefore it appears that aspirin might be effective in 
the long-term prevention of recurrence and progression of venous thrombosis.
Cite as: Zdrav Vestn. 2017; 86:244–54.
1. Introduction
Cardiovascular disease is, especially 
in the developed world, still the lead-
ing cause of morbidity and mortality in 
the adult population. Advanced athero-
sclerosis and/or thromboembolic occlu-
sions of affected arteries and veins lead 
to cardiovascular events. Atherosclerotic 
changes develop in response to many 
known and less known risk factors. Ve-
nous thromboembolic events are the 
result of the so-called Virchow triad, 
which includes changes in the blood 
composition (resulting in increased 
coagulability), an injury to the blood 
vessel wall, and impaired blood flow 
(venous stasis). However, direct patho-
genic mechanisms of the vascular wall 
impairment in venous thrombosis have 
not been sufficiently elucidated yet. The 
disease process most likely begins with 
impairment of the inner layers of the ve-
nous or arterial wall caused by various 
factors: mechanical, chemical and meta-
bolic. Vessel wall injury is followed by an 
inflammatory response, which is prob-
ably the common denominator of harm-
ful effects of exo- and endogenous fac-
tors responsible for vessel wall damage. 
It is well known that chronic low-grade 
inflammation promotes atherosclerosis. 
In the last several years, evidence has 
emerged for a key role of inflammation 
in venous thrombosis and thromboem-
bolic complications. Inflammation tends 
to shift the hemostatic balance in favor 
of increased procoagulant activity of 
blood (1,2).
The results of studies showing a 
link between deep venous thrombosis 
(DVT), in particular idiopathic, and pre-
clinical and clinical atherosclerosis are 
in favor of an interrelationship between 
an arterial and venous disease that share 
inflammation as a common pathogenic 
factor (3,4).
2. Atherosclerosis 
and inflammation
Inflammation plays an important role 
in the formation, and the progression of 
the disease, and in atherosclerosis-relat-
ed cardiovascular complications  (5,6). 
Therefore, atherosclerosis is defined as a 
chronic inflammatory disease. The iden-
tification of inflammatory changes in 
the vessel wall, but also of circulating in-
flammatory markers in blood, is impor-
tant from the clinical, and in particular 
from the prognostic point of view.  Ali: is 
particularly important from the clinical, 
but also from the prognostic …
The accumulation of lipids in the 
arterial wall triggers an inflammatory 
response  (7). Increased lipid levels and 
mechanical stress lead to the accumu-
lation of cholesterol and other lipids in 
the arterial wall reducing endothelial 
protective properties and inhibiting the 
defense mechanisms that prevent the 
entry of inflammatory cells in the artery 
wall. An impaired endothelial function 
followed by morphological changes of 
endothelial cells, lead to the synthesis 
of adhesion molecules on the surface of 
endothelial cells. Adhesion molecules 
crosslink with different inflammatory 
cells and facilitate their entry into the ar-
Inflammation – a 
common pathogenic 
factor of arterial 
atherosclerotic
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ProfessIonal artIcle
tery wall. The result is the activation of 
the inflammatory response which causes 
a release of various mediators, in par-
ticular the cytokines that accelerate the 
transit of white blood cells from blood 
into the intimal layer of the vessel wall. 
Activated macrophages accumulate large 
quantities of lipids and eventually trans-
form into foam cells. Growth factors are 
released that encourage the reproduc-
tion and migration of vascular smooth 
muscle cells. Fibrinolytic enzymes, par-
ticularly metalloproteinase, degrade the 
connective tissue frame of the vessel wall 
and enable smooth muscle cells to pen-
etrate the elastic layer that separates the 
intima from the media. Cholesterol-rich 
macrophages break down and release 
cholesterol and other cellular compo-
nents in the intracellular space, which 
facilitates the inflammatory response. 
Further, inflammatory mediators and 
tissue factor are released, which is re-
sponsible for thromboembolic compli-
cations on the surface of the atheroscle-
roticaly changed vascular wall  (8) The 
inflammatory response in the vessel wall 
is additionally influenced by monocyte 
chemoattractant protein (MCP), MCP-1 
in particular (9). T-lymphocytes are ac-
tivated and T-cells promote the forma-
tion of pro-inflammatory cytokines and 
tumor necrosis factor beta (TNF-β). In 
this way, the inflammation not only pro-
motes the development of atheroma but 
is also responsible for acute thromboem-
bolic complications which may lead to a 
heart attack, stroke or ischemic events in 
other organ systems.
3. Risk factors for 
atherosclerosis and 
inflammation
Risk factors for atherosclerosis elicit 
their adverse effects probably through 
the promotion of inflammation in the 
vessel wall. It has long been known that 
lipids, especially LDL cholesterol, pro-
mote the inflammatory response, which 
is more intense if LDL cholesterol is oxi-
dized. Other lipoproteins such as VLDL, 
also promote inflammation and the de-
velopment of atherosclerosis (10).
Increased blood pressure causes a 
mechanical vessel wall damage, whereas 
pathogenic factors of arterial hyperten-
sion promote inflammation. Angioten-
sin II has vasoconstrictive effects and 
promotes inflammation of the intima. 
Increased blood pressure promotes the 
release of pro-inflammatory cytokines, 
in particular IL-6, and adhesion mole-
cules (VCAM-1) on the surface of endo-
thelial cells  (11). Hyperglycemia causes 
glycation of different molecules and 
also ingredients of the vessel wall, which 
stimulates the production of pro-inflam-
matory cytokines, increases oxidative 
stress and is the reason for the inflam-
matory response.
Excess body mass triggers inflam-
mation through the accompanying risk 
factors of atherosclerosis, such as the 
increased lipids, insulin resistance, and 
increased blood pressure. Moreover, 
adipose tissue can directly stimulate the 
production of cytokines, such as TNF-α 
and IL-6 (12).
4. Blood markers of 
inflammation
In persons with different atheroscle-
rotic diseases, it is possible to measure 
blood markers of inflammation, such 
as high-sensitivity C-reactive protein 
(hsCRP), fibrinogen, and serum amyloid-
A in the earliest stages of the atheroscle-
rotic process. These markers are present 
in small quantities in healthy subjects al-
ready but in case of atherosclerosis, their 
levels increase significantly. On the other 
Inflammation – a 
common pathogenic 
factor of arterial 
atherosclerotic
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cardIoVascular systeM
hand, in subjects at risk of atherosclero-
sis, we can already detect the inflamma-
tory blood markers which are otherwise 
not present in healthy subjects, such as 
the cytokine TNF-α and adhesion mol-
ecules. These inflammatory markers are 
quite reliable indicators of inflammation 
of the vessel wall, whereas the plasma 
concentrations of non-specific media-
tors may increase in various inflamma-
tory processes not only in inflamma-
tion of the vessel wall. Therefore, those 
markers are less specific indicators of the 
vascular wall impairment and accompa-
nying vascular diseases. Epidemiological 
studies have shown a close interrelation-
ship between the levels of inflammato-
ry markers in the blood and the risk of 
cardiovascular complications  (5,6). The 
results of these studies have stimulated 
an interest in monitoring the levels of in-
flammatory indicators and their predic-
tive value for cardiovascular events. Pro-
spective epidemiological studies have 
shown that increased levels of various 
inflammatory indicators, such as cyto-
kines (IL-6, TNF-α), adhesion molecules 
(ICAM-1, P-selectin, E-selectin) as well 
as the acute phase reactants, such as hs-
CRP, fibrinogen and serum amyloid A 
are important predictors of cardiovas-
cular events (13,14). The results of these 
studies indicate that increased levels of 
certain inflammatory markers (IL-6 and 
hs-CRP) are not only predictive of ath-
erosclerosis but also of insulin resistance 
and development of type 2 diabetes (15). 
The monitoring of inflammatory makers 
permits the evaluation of the effective-
ness of the preventive measures, and the 
treatment of risk factors in the preven-
tion of atherosclerotic complications.
hs-CRP is one of the most investi-
gated inflammatory markers and pre-
dictors of cardiovascular events. hs-CRP 
has a connecting role in the formation 
and activation of other inflammatory 
indicators, in particular the cytokines. 
hs-CRP stimulates the production of 
adhesion molecules and promotes the 
entry of LDL cholesterol and monocytes 
into the vessel wall (6). Recently, hs-CRP 
has received much attention because of 
its ability to improve the prediction of 
cardiovascular events in subjects who do 
not have classic risk factors for athero-
sclerosis, and has been used to measure 
the effectiveness of various preventive 
measures of atherosclerosis, in particular 
the effectiveness of statins (16). Numer-
ous studies have demonstrated a link be-
tween hs-CRP and cardiovascular events. 
The MRFIT study (Multiple Risk Factor 
Intervention Trial) has demonstrated a 
close link between the level of hs-CRP 
and cardiovascular mortality in adult 
men  (17). In the Women Heart Study, 
which included around 28,000 healthy 
women who were followed for 8 years, 
hs-CRP was an independent predictor of 
cardiovascular events. Its predictive val-
ue was greater than that of LDL choles-
terol (18). In spite of numerous research 
findings in the field of primary preven-
tion of atherosclerosis, the question aris-
es as to whether the determination of 
hs-CRP adds the predictive value to the 
risk assessments based on the presence 
of classical risk factors. The Emerging 
Risk Factors Collaboration found only a 
limited clinical utility of hs-CRP deter-
mination due to its low specificity  (19). 
The analysis of 52 cohort studies that 
included 246,669 people showed that 
hs-CRP or fibrinogen determination in 
subjects without a known cardiovascular 
disease and medium-high risk of cardio-
vascular disease could prevent only one 
cardiovascular event in the 10-year pe-
riod in 400–500 persons screened. The 
predictive value of hs-CRP is limited be-
cause it is the acute phase reactant, and is 
increased in different inflammatory and 
infectious diseases. Long-term changes 
Inflammation – a 
common pathogenic 
factor of arterial 
atherosclerotic
on line editionInflammation – a common pathogenic factor of arterial atherosclerotic
ProfessIonal artIcle
in basal hs-CRP values have the highest 
discriminatory value in the identifica-
tion of those individuals who, in spite 
of the absence of classical risk factors of 
atherosclerosis are at an increased risk 
of atherosclerotic cardiovascular com-
plications. Increased hs-CRP levels have 
a better predictive value in subjects who 
are younger than 75 years, men, and in-
dividuals who have normal values of sys-
tolic blood pressure. The predictive value 
of hs-CRP is reduced in the presence of 
other risk factors of atherosclerosis. The 
risk assessed in Reynolds Risk Score, 
which in addition to the traditional risk 
factors also includes a family history of 
cardiovascular disease and hs-CRP lev-
els shows that the hs-CRP determination 
only slightly contributes to the risk as-
sessment determined solely on the basis 
of conventional risk factors (20). Despite 
the positive results of some studies and 
even meta-analyses about the value of 
hs-CRP when assessing the risk of car-
diovascular events there are also numer-
ous studies showing negative results. The 
results of meta-analyses of the value of 
cardiovascular  biomarkers, which were 
not included in the Framingham score, 
showed that often the study results fa-
vored certain biomarkers and abused 
statistical tools to obtain positive re-
sults  (21). For this reason, the hs-CRP 
determination in risk individuals has 
only a limited impact on cardiovascular 
risk assessment, and determination of 
hs-CRP in routine clinical practice is not 
recommended. Nevertheless, in healthy 
subjects who are at a medium-high risk 
of cardiovascular events the hs-CRP 
value between 1.0 and 3.0 mg/L repre-
sents a medium risk, and if the hs-CRP 
level is greater than 3.0 mg/L, these indi-
viduals are at high risk of cardiovascular 
events (22). On the other hand, there are 
different opinions regarding the indica-
tions for hs-CRP determination in this 
latter patient population, thus the latest 
European guidelines on the prevention 
of cardiovascular disease do not recom-
mend hs-CRP determination (23).
hs-CRP has proven to be a reliable 
indicator of the effectiveness of the pre-
ventive and therapeutic measures that 
aim to reduce the risk of cardiovascular 
events. The JUPITER study (Justification 
for the Use of Statins in Primary Preven-
tion: an Intervention Trial Evaluating 
Rosuvastatin) showed a concomitant 
proportional decrease in LDL cholester-
ol and hs-CRP levels. In addition, even 
in subjects with normal LDL cholesterol 
and increased hs-CRP values, statins sig-
nificantly reduced the risk of cardiovas-
cular events, which was directly propor-
tional to the reductions of hs-CRP (24).
Interleukins play a key role in inflam-
matory response to stimuli and promote 
the synthesis of hs-CRP and fibrinogen 
in the liver. Among the most known and 
studied anti-inflammatory interleukins 
there are IL-6 and IL-8, whereas IL-10 
possesses an anti-inflammatory activity 
and reduces the inflammatory response. 
Interleukins and their receptors have 
been found in atherosclerotic plaques. It 
has been demonstrated that the concen-
tration of various cytokines in plasma is 
positively correlated with the risk of car-
diovascular events, in particular of sud-
den coronary artery occlusions. Similar-
ly, IL-6 values are increased in patients 
with peripheral arterial occlusive disease 
and their concentration increases with 
the progression of the disease. Several 
prospective studies have shown that in-
creased IL-6 levels are associated with 
2–3 times higher risk of cardiovascular 
events compared to subjects with nor-
mal IL-6 values (25). The determination 
of plasma levels of certain interleukins is 
important because interleukins are more 
specific indicators of inflammation of 
the vessel wall than other inflammatory 
Inflammation – a 
common pathogenic 
factor of arterial 
atherosclerotic
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cardIoVascular systeM
markers. Their concentration in plasma 
is closely related to the progression of 
atherosclerosis and the presence of un-
stable atherosclerotic lesions, which are 
a source of cardiovascular events. Un-
fortunately, due to unreliable labora-
tory methods and many factors affecting 
the level of the interleukin in plasma, 
the determination of interleukin con-
centrations has not been established as 
a method for the assessment of risk of 
cardiovascular events in everyday clini-
cal practice.
5. Inflammation and venous 
thromboembolic disease
Recent data indicates that inflamma-
tion is involved also in the formation of 
venous thrombosis (VT). The damaged 
vessel wall is most likely the key factor 
that triggers the inflammatory response 
in VT. On the other hand, in idiopathic 
(unprovoked) VT inflammation is prob-
ably the primary event which triggers the 
activation of the coagulation system and 
blood clot formation. There is a close link 
between inflammation and hemostasis, 
which includes proinflammatory cyto-
kines, chemokines, adhesion molecules, 
tissue factor, platelet and endothelial cell 
activation, and formation of micropar-
ticles. Inflammation increases the syn-
thesis of the factors that accelerate co-
agulation, and inhibits the endogenous 
fibrinolytic activity thus encouraging the 
thrombotic process and blood clot for-
mation. Besides, inflammation damages 
the defense mechanisms of endothelial 
cells; attenuates their anticoagulant and 
antiplatelet properties, and inhibits the 
vasodilator properties (26). At the same 
time, the activation of the coagulation 
system promotes inflammation. Throm-
bin stimulates the synthesis and excre-
tion of proinflammatory cytokines and 
growth factors. Furthermore, platelets 
which are activated in the context of co-
agulation, also promote the inflamma-
tory response. In one of our studies, we 
found that the patients with idiopathic 
VT had increased levels of inflamma-
tory markers compared with healthy 
subjects (27). Long-term follow-up after 
5 years showed that in the patients with 
idiopathic deep VT inflammatory mark-
ers such as hs-CRP, TNF-α, and IL-6 were 
still elevated, while the anti-inflammato-
ry IL-10 was significantly reduced. Ad-
ditionally, we found increased markers 
of endothelial damage (von Willebrand 
factor, P-selectin)  (27). These findings 
indicate that increased levels of inflam-
matory markers in VT patients are not a 
consequence of VT, but are probably the 
cause of thrombosis formation avtorja, 
preverita pomen. Therefore, the values of 
inflammatory markers in these subjects 
remain continuously increased. Accord-
ingly, inflammatory markers were stud-
ied as predictors of and as diagnostic 
criteria for the diagnosis of VT (28,29).
Opinions about the role of hs-CRP 
and VT formation are divided. Two large 
studies investigated the role of hs-CRP 
in the pathogenesis of VT. In the Physi-
cians Health Study, including more than 
22,000 American physicians, plasma 
hs-CRP levels were not significantly as-
sociated with the incidence of venous 
thromboembolism (VTE). The cause for 
the absence of statistical significance be-
tween hs-CRP levels and the occurrence 
of VT was most likely due to the low 
incidence of VT. During a 14-year fol-
low-up, only 101 subjects developed VT. 
Similarly, in the Cardiovascular Health 
Study no relationship between hs-CRP 
levels and the development of deep VT 
was found (28). Neither was there a dif-
ference after the incidence of VTE in re-
lation to the quartile of hs-CRP was ad-
justed by age, race, and gender. However, 
Inflammation – a 
common pathogenic 
factor of arterial 
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ProfessIonal artIcle
hs-CRP has proved to be a useful test in 
the diagnosis of VT.
The role of hs-CRP in the diagnosis of 
VTE in individuals with suspected VTE 
has been investigated in several studies. 
Thomas and co-workers aimed at find-
ing whether increased hs-CRP values 
would be useful in the identification of 
VTE (hs-CRP was defined as increased 
if the values were greater than 10 mg/L). 
The sensitivity of the increased hs-CRP 
value was 100 %, and specificity only 
52 %, the positive predictive value was 
56 %, and the negative predictive value 
100 %. Their results indicated that low 
or normal hs-CRP values could be used 
for the exclusion of VTE in patients 
with suspected VTE, however, this was 
not confirmed in subsequent studies by 
Wong and co-workers (29). Hence, it has 
been concluded that hs-CRP values do 
not allow to confirm or to exclude the 
diagnosis of VTE in patients with clini-
cal suspicion of this disease.
Inflammatory markers in VT include 
cytokines (interleukins, lymphokines, 
monokines), TNF-α, growth factors and 
alpha interferons. Interleukins, especial-
ly IL-6, followed by IL-8, and IL-10, were 
the most frequently studied in patients 
with VT.. Most of the research was done 
in patients with an acute VT. Van Aken 
noted that patients who had at least two 
episodes of VT had significantly higher 
values of IL-6 and IL-8  (30). The same 
group of researchers came to similar 
findings in the Leiden Thrombophilia 
Study (LTS). This study included 474 
patients with VT and the same number 
of healthy subjects. It was found that 
patients had significantly higher IL-8 
values, and that 90 % higher values of 
interleukin as compared to healthy sub-
jects were related to 1.9 times higher risk, 
whereas a 99 % increase in IL-8 compared 
to control subjects was associated with a 
6-fold higher risk of developing VT (31). 
The additional analysis of the LTS study 
confirmed IL-6, IL-8, and TNF-α to be 
ranked among the independent risk fac-
tors for VT (32). On the contrary, IL-10 
was shown to have a protective role: in-
dividuals with higher IL-10 values were 
at a lower risk of VT compared to in-
dividuals with lower IL-10 values  (2). 
Prehod A group of Dutch researchers 
observed interleukin values in the acute 
phase of VT, at the time of the first diag-
nosis and five days later. At the time of 
diagnosis, they found increased levels of 
IL-6, IL-8, and hs-CRP, whereas five days 
later the IL-6 and hs-CRP values were 
already significantly reduced, therefore 
they have concluded that inflammation 
is a consequence and not a cause of VT. 
The authors considered the reduction of 
clinical symptoms to be accompanied by 
a reduction of inflammatory markers. 
However, the reduction of inflammatory 
markers within five days after the onset 
of acute VT could also result from hepa-
rin treatment. Namely, heparin has been 
shown to possess an anti-inflammatory 
activity (33).
The prognostic importance of in-
flammatory markers, of interleukins in 
particular, was studied in a Norwegian 
prospective study (HUNT 2 – The Nord-
Trøndelag Health Study). + ref Blood 
samples for inflammatory markers were 
taken from 66,140 healthy subjects; it 
was found that the levels of inflamma-
tory markers (IL-1b, IL-6, IL-8, IL-10, 
and IL-12) did not differ from the sub-
jects who developed VT during a three-
year follow-up period when compared 
with the samples taken from people 
who were similar to the cases but had no 
thrombosis. On the basis of these results 
the authors have concluded that there is 
no evidence to support the hypothesis 
that increased inflammatory markers 
would be a risk factor of developing VT 
and that the alteration in the inflamma-
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common pathogenic 
factor of arterial 
atherosclerotic
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cardIoVascular systeM
tory profile after VT is more likely to be 
the result and not the cause of VT (34). 
However, the flow of the study was the 
lack of data on inflammatory markers 
immediately (days or weeks) before the 
occurrence of thrombosis.
In our study, we found that the pa-
tients with idiopathic deep VT had in-
creased levels of IL-6, and IL-8, and 
TNF- α also five years after the initial 
event. This indicates an increased in-
flammatory response present in a stable 
period (up to 5 years), suggesting that 
VT is not only an episodic event but a 
chronic condition which is accompanied 
by long-term systemic inflammatory 
changes. Although we did not have data 
about the levels of inflammatory mark-
ers immediately before the development 
of VT, the results of our study and data 
from other studies imply that this long-
term increased inflammatory response 
is the cause of VT, and not caused by VT. 
A chronic inflammatory response could 
be explained by the processes taking 
place in the thrombosed vein directly af-
ter an acute event. The acute occlusion is 
certainly accompanied by inflammation, 
followed by a breakdown of a blood clot 
and/or connective tissue organization. 
Inflammatory cells are present in both 
later processes and are probably respon-
sible for maintaining the inflammatory 
process in the venous wall. VT is only 
rarely followed by a complete healing of 
the vessel wall and a total restitution of 
physiological conditions through a pre-
viously thrombosed vein. This is prob-
ably also one of the reasons why individ-
uals with VT have long-term increased 
markers of inflammation.
Inflammation plays an important, 
perhaps even a decisive role, in recanali-
zation of venous thrombotic occlusions. 
The relationship between the elevated 
systemic markers of inflammation (IL-
6) and resolution of the blood clot that 
is associated with the occurrence of 
the postthrombotic syndrome, was de-
scribed by Dutch authors (35).
6. A connecting role 
of inflammation in the 
pathogenesis of arterial and 
venous vascular disorders
The association between arterial ath-
erosclerotic and venous thromboembol-
ic disease was first suggested by studies 
where inflammation was recognized as 
one of the basic pathogenic mechanisms. 
Several studies found a link between VT 
and preclinical atherosclerosis, such as 
asymptomatic atherosclerotic plaques in 
carotid arteries and endothelial dysfunc-
tion observed in both diseases  (4,36). 
Moreover, atherosclerosis as well as 
VTE, share many common risk factors 
for which inflammation represents the 
common denominator of its harmful ac-
tion on the vessel wall (37).
The risk factors for atherosclerosis 
and VTE are both classical and non-
conventional. For example, increasing 
age increases the risk of both diseases, 
increased body weight is related to in-
creased risk of VTE and atherosclero-
sis. Recent data have shown that hy-
percholesterolemia as one of the most 
important risk factors for atherosclero-
sis increases the risk of VTE, and also 
increased blood pressure and hyperho-
mocysteinemia are positively correlated 
with VTE  (38). Significantly related to 
VTE are mainly metabolic risk fac-
tors for atherosclerosis, such as obe-
sity, hypertriglyceridemia and reduced 
HDL-cholesterol  (39). A significant risk 
factor for both diseases is also the meta-
bolic syndrome which is involved in the 
pathogenesis of atherosclerosis and VTE 
via inflammation and increased levels of 
plasminogen-activator inhibitor (40).
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7. Inflammation as a challenge 
for new therapeutic approaches 
in cardiovascular diseases
Although it has long been known that 
atherosclerosis is a chronic inflamma-
tory disease, little attention was given to 
the anti-inflammatory treatment of ath-
erosclerosis. Low-dose aspirin and cer-
tain other antiplatelet agents prescribed 
to patients at risk for atherosclerosis for 
several decades, but the main focus for 
the prescription of these drugs has been 
their antiplatelet and antithrombotic ac-
tivity and not their anti-inflammatory 
effects. Recently, anti-inflammatory ef-
fects have been recognized in some 
drugs that primarily do not possess 
an anti-inflammatory activity, such as 
statins. The JUPITER trial (Justification 
for the Use of Statins in Primary Preven-
tion: An Intervention Trial Evaluating 
Rosuvastatin trial) has shown that the 
preventive effects of statins are linearly 
associated with their anti-inflammatory 
effects, therefore, they are effective in 
subjects who have normal LDL choles-
terol levels but increased hs-CRP levels. 
Their anti-inflammatory effect has been 
associated with a reduction in the levels 
of inflammatory mediators, hs-CRP in 
particular, regardless of the changes in 
the cholesterol level  (41). This indicates 
that in the prevention and treatment of 
atherosclerosis more attention should be 
paid to anti-inflammatory actions and 
the selection of drugs that have a more 
pronounced anti-inflammatory effect.
For the acute treatment of deep vein 
thrombosis (DVT), anticoagulant drugs 
have proved to be more effective than as-
pirin. On the other hand, several studies 
have reported that aspirin and perhaps 
other drugs with anti-inflammatory ef-
fects as well, if prescribed to patients 
with a history of DVT for the long-term 
prevention of DVT, may reduce DVT 
recurrence  (42). In a randomized, pla-
cebo-controlled study it has been shown 
that the treatment with 100 mg aspirin 
daily after the discontinuation of anti-
coagulant therapy (6 to 8 months after 
the DVT diagnosis) reduces the risk of 
DVT recurrence for up to 40 %. There is 
also evidence that statins, the basic an-
tiatherosclerotic drugs, may also reduce 
the risk of VTE. Their preventive effect 
on the risk of DVT has been supposed 
based on the cholesterol-independent, 
parallel (pleiotropic) effect of statins, 
particularly the anti-inflammatory ef-
fects  (43). Similarly, the results of two 
meta-analyses have pointed to the ef-
fectiveness of statins in the prevention 
of VTE, specifically in subjects with high 
hs-CRP and normal lipid values (44,45). 
Likewise, the INSPIRE collaboration (In-
ternational Collaboration of Aspirin Tri-
als for Recurrent Venous Thromboem-
bolism) has concluded that aspirin after 
anticoagulation treatment reduces the 
overall risk of VTE recurrence by more 
than one third in a broad cross-section 
of patients with a first unprovoked VTE, 
without significantly increasing the risk 
of bleeding (46).
Based on these facts the question 
arises whether a combination of antico-
agulant and anti-inflammatory drugs in 
the acute phase of DVT treatment might 
be more effective than anticoagulant 
drugs alone. The administration of aspi-
rin, which has anti-inflammatory effects, 
together with anticoagulant drugs in the 
acute phase of DVT might improve the 
recanalization of thrombotic venous oc-
clusions and thereby prevent the devel-
opment of postthrombotic syndrome, 
which is known to be more common in 
case of chronically occluded veins, and 
dramatically reduces patients quality of 
life.
Inflammation – a 
common pathogenic 
factor of arterial 
atherosclerotic
on line edition Zdrav Vestn | May – June 2017 | Volume 86
cardIoVascular systeM
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Inflammation – a 
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on line edition Zdrav Vestn | May – June 2017 | Volume 86
cardIoVascular systeM