Combined use of haemostatic system indices for evaluation of upper respiratory tract cancer progression
Aim: To analyze whether comprehensive assessment of haemostatic system components, in particular, indices of coagulation and fibrinolytic systems along with functionally related proteins, could be indicative of upper respiratory tract (URT) cancer progression. Materials and Methods: Indices of coagu...
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Інститут експериментальної патології, онкології і радіобіології ім. Р.Є. Кавецького НАН України
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irk-123456789-1379832018-06-18T03:05:22Z Combined use of haemostatic system indices for evaluation of upper respiratory tract cancer progression Klys, Y.G. Gryn, N.V. Verevka, S.V. Original contributions Aim: To analyze whether comprehensive assessment of haemostatic system components, in particular, indices of coagulation and fibrinolytic systems along with functionally related proteins, could be indicative of upper respiratory tract (URT) cancer progression. Materials and Methods: Indices of coagulation and fibrinolytic systems along with functionally related proteins, in particular, trypsinlike amidolytic activity, trypsin-like proteolytic activity, thrombin-like amidolytic activity, elastase-like amidolytic activity, fibrinolytic activity, potential amidolytic plasmin activity, content of fibrinogen, antithrombin III, α1-proteinase inhibitor, and α₂-macroglobulin, and prothrombin time were evaluated in blood plasma of patients with URT cancer of II (n = 10) and III (n = 25) stages with the use of routine biochemical methods. Results: For both groups of patients with URT cancer there have been shown notable differences for the majority of the studied indices, especially the indexes of proteolytic activities, from these of healthy donors, and in the case of URT cancer of III stage they reached statistical significance. In contrary, the changes in the content of antithrombin III, α₁-proteinase inhibitor, and α₂-macroglobulin were insignificant. In both groups of patients significant increase of fibrinogen content has been registered, while the content of soluble fibrinogen didn’t change. Also, in both groups of patients there a significant increase of potential activity of plasminogen was documented, while clot lysis time was significantly increased only in patients with III stage URT cancer. Multifactorial analysis of haemostatic system indices evidenced for efficacy of their combined use for evaluation of URT cancer progression risk. Conclusion: Combined use of fibrinogen and α₂-macroglobulin content and the level of amidolytic thrombinlike activity could serve as an indicator of URT cancer progression. 2016 Article Combined use of haemostatic system indices for evaluation of upper respiratory tract cancer progression / Y.G. Klys, N.V. Gryn, S.V. Verevka // Experimental Oncology. — 2016 — Т. 38, № 1. — С. 36–39. — Бібліогр.: 30 назв. — англ. 1812-9269 http://dspace.nbuv.gov.ua/handle/123456789/137983 en Experimental Oncology Інститут експериментальної патології, онкології і радіобіології ім. Р.Є. Кавецького НАН України |
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Original contributions Original contributions |
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Original contributions Original contributions Klys, Y.G. Gryn, N.V. Verevka, S.V. Combined use of haemostatic system indices for evaluation of upper respiratory tract cancer progression Experimental Oncology |
| description |
Aim: To analyze whether comprehensive assessment of haemostatic system components, in particular, indices of coagulation and fibrinolytic systems along with functionally related proteins, could be indicative of upper respiratory tract (URT) cancer progression. Materials and Methods: Indices of coagulation and fibrinolytic systems along with functionally related proteins, in particular, trypsinlike amidolytic activity, trypsin-like proteolytic activity, thrombin-like amidolytic activity, elastase-like amidolytic activity, fibrinolytic activity, potential amidolytic plasmin activity, content of fibrinogen, antithrombin III, α1-proteinase inhibitor, and α₂-macroglobulin, and prothrombin time were evaluated in blood plasma of patients with URT cancer of II (n = 10) and III (n = 25) stages with the use of routine biochemical methods. Results: For both groups of patients with URT cancer there have been shown notable differences for the majority of the studied indices, especially the indexes of proteolytic activities, from these of healthy donors, and in the case of URT cancer of III stage they reached statistical significance. In contrary, the changes in the content of antithrombin III, α₁-proteinase inhibitor, and α₂-macroglobulin were insignificant. In both groups of patients significant increase of fibrinogen content has been registered, while the content of soluble fibrinogen didn’t change. Also, in both groups of patients there a significant increase of potential activity of plasminogen was documented, while clot lysis time was significantly increased only in patients with III stage URT cancer. Multifactorial analysis of haemostatic system indices evidenced for efficacy of their combined use for evaluation of URT cancer progression risk. Conclusion: Combined use of fibrinogen and α₂-macroglobulin content and the level of amidolytic thrombinlike activity could serve as an indicator of URT cancer progression. |
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Klys, Y.G. Gryn, N.V. Verevka, S.V. |
| author_facet |
Klys, Y.G. Gryn, N.V. Verevka, S.V. |
| author_sort |
Klys, Y.G. |
| title |
Combined use of haemostatic system indices for evaluation of upper respiratory tract cancer progression |
| title_short |
Combined use of haemostatic system indices for evaluation of upper respiratory tract cancer progression |
| title_full |
Combined use of haemostatic system indices for evaluation of upper respiratory tract cancer progression |
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Combined use of haemostatic system indices for evaluation of upper respiratory tract cancer progression |
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Combined use of haemostatic system indices for evaluation of upper respiratory tract cancer progression |
| title_sort |
combined use of haemostatic system indices for evaluation of upper respiratory tract cancer progression |
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Інститут експериментальної патології, онкології і радіобіології ім. Р.Є. Кавецького НАН України |
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2016 |
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Combined use of haemostatic system indices for evaluation of upper respiratory tract cancer progression / Y.G. Klys, N.V. Gryn, S.V. Verevka // Experimental Oncology. — 2016 — Т. 38, № 1. — С. 36–39. — Бібліогр.: 30 назв. — англ. |
| series |
Experimental Oncology |
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| first_indexed |
2025-07-10T02:42:04Z |
| last_indexed |
2025-07-10T02:42:04Z |
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1837226080874790912 |
| fulltext |
36 Experimental Oncology 38, 36–39, 2016 (March)
COMBINED USE OF HAEMOSTATIC SYSTEM INDICES
FOR EVALUATION OF UPPER RESPIRATORY TRACT CANCER
PROGRESSION
Y.G. Klys’, N.V. Gryn’, S.V. Verevka*
SI “O.S. Kolomiychenko Institute of Otolaryngology
of National Academy of Medical Sciences of Ukraine”, Kyiv 03057, Ukraine
Aim: To analyze whether comprehensive assessment of haemostatic system components, in particular, indices of coagulation and fi-
brinolytic systems along with functionally related proteins, could be indicative of upper respiratory tract (URT) cancer progression.
Materials and Methods: Indices of coagulation and fibrinolytic systems along with functionally related proteins, in particular, trypsin-
like amidolytic activity, trypsin-like proteolytic activity, thrombin-like amidolytic activity, elastase-like amidolytic activity, fibrino-
lytic activity, potential amidolytic plasmin activity, content of fibrinogen, antithrombin III, α1-proteinase inhibitor, and α2-macroglobulin,
and prothrombin time were evaluated in blood plasma of patients with URT cancer of II (n = 10) and III (n = 25) stages with the use
of routine biochemical methods. Results: For both groups of patients with URT cancer there have been shown notable differences for
the majority of the studied indices, especially the indexes of proteolytic activities, from these of healthy donors, and in the case of URT
cancer of III stage they reached statistical significance. In contrary, the changes in the content of antithrombin III, α1-proteinase
inhibitor, and α2-macroglobulin were insignificant. In both groups of patients significant increase of fibrinogen content has been
registered, while the content of soluble fibrinogen didn’t change. Also, in both groups of patients there a significant increase of poten-
tial activity of plasminogen was documented, while clot lysis time was significantly increased only in patients with III stage URT
cancer. Multifactorial analysis of haemostatic system indices evidenced for efficacy of their combined use for evaluation of URT
cancer progression risk. Conclusion: Combined use of fibrinogen and α2-macroglobulin content and the level of amidolytic thrombin-
like activity could serve as an indicator of URT cancer progression.
Key Words: upper respiratory tract cancer, prognosis, haemostatic system.
The raising cancer incidence is among the most
serious medical and social problems of our time.
According to the Cancer Register of Ukraine, the
annual mortality from malignant processes is close
to 100 thousands cases, and the annual morbidity
reaches 160 thousands cases (0.2 and 0.32% of the
country population, respectively). 7.5–8% of cancer
cases are related to the cancer of upper respiratory
tract (URT), which incidence has increased by 1.6 times
during last 10 years [1]. As it is commonly accepted,
the early detection of a disease is a key to its effective
therapy. However, cancer is usually detected by its late
clinical manifestations, and no universal index for early
cancer detection has been found so far [2]. However,
according to the data of some researchers, not a single
index but a combination of several cancer-related
biochemical alterations in components of haemostatic
system (HS), could be considered promising [3].
It is well known that HS consists of two oppositely
directed enzymatic sub-systems, which provide the
formation of fibrin clot and its lysis. The majority of en-
zymatic HS components are trypsin-like proteinases
that are synthesized as inactive pro-enzymes with
their following processing into active forms via high-
selective enzymatic cleavage. In turn, these activated
proteinases are activators for other pro-enzymes, pro-
factors and are under strict control of high-selective
protein inhibitors [4, 5]. Disturbances of this highly
regulated systems lead to the disturbance of various
physiological processes that are aligned with nume-
rous diseases. Malfunction of proteolysis significantly
disturbs both fibrin clotting and fibrinolysis, comple-
ment and kinine systems [6, 7], and causes tissue
damage and uncontrolled tumor growth [8–12]. Can-
cer cells are known to produce proteolytic enzymes,
which affect haemostasis as well as promote tumor in-
vasion and metastasis [13, 14]. Non-functional proteo-
lysis plays a prominent role in post-operative compli-
cations, such as thrombosis and bleeding, recurrence
and metastasis [15–17]. It should be underlined that
a number of HS components is directly involved into
cancer development [18–20]. Therefore, in the pre sent
work we aimed to analyze whether comprehensive
assessment of HS components, in particular, indices
of coagulation and fibrinolytic systems along with
functionally related proteins, could be an informative
tool for prediction of disease progression in patients
with URT cancer.
MATERIALS AND METHODS
Patients. In the study, 10 patients with primary
laryngeal cancer of II stage and 25 patients with URT
cancer of III stage were enrolled. The patients were
cured in SI “O.S. Kolomiychenko Institute of Otola-
ryngology of National Academy of Medical Sciences
of Ukraine” in 2008–2010. The patients underwent
surgical treatment, those with URT cancer of III stage
Received: July 16, 2015.
*Correspondence: E-mail: sks-4072@mail.ru
Abbreviations used: α1IP — α1-proteinase inhibitor; α2M — α2-macro-
globulin; AT-III — antithrombin III; BAPNA — Nα-benzoyl-D,L-arginine
para-nitroanilide; FA — fibrinolytic activity; HS — haemostatic system;
p-NA — para-nitroaniline; PRA — trypsin-like proteolytic activity;
PT — prothrombin time; URT — upper respiratory tract.
Exp Oncol 2016
38, 1, 36–39
Experimental Oncology 38, 36–39, 2016 (March) 37
after surgery were treated by radiotherapy. Periphe-
ral blood was taken 1 day before the operation. The
control group consisted of 24 healthy donors. The
study has been performed in accordance with ethics
rules for biomedical research; all patients have given
an informed consent for the participation in the study.
Biochemical measurements. The samples
of platelet-delpeted citrate plasma were obtained
by centrifugation of blood at 1200 g for 20 min.
Trypsin-like amidolytic activity was determined
by extinction of para-nitroaniline (p-NA) formed
by splitting of chromogenic substrate — Nα-benzoyl-
D,L-arginine para-nitroanilide (BAPNA) using spec-
trophotometry at 383 nm and was expressed in nmol
of p-NA per 1 ml of plasma per 1 min [4].
Trypsin-like proteolytic activity (PRA) was deter-
mined by enzymatic cleavage of protamine with follow-
ing evaluation of arginine-containing peptides soluble
in 20% trichloroacetic acid and was expressed in nmol
of soluble arginine per 1 ml plasma per 1 min [4].
Thrombin-like amidolytic activity was determined
by extinction of p-NA formed by splitting of chro-
mogenic substrate — Tos-Gly-L-Pro-L-Arg-para-
nitroanilide (Chromozym TH) using spectrophotometry
at 405 nm and was expressed in nmol of p-NA per
1 ml of plasma per 1 min [21].
Elastase-like amidolytic activity was determined
by extinction of p-NA formed by splitting of chromo-
genic substrate — Suc-L-Ala3-para-nitroanilide using
spectrophotometry at 410 nm and was expressed
in nmol of p-NA per 1 ml of plasma per 1 min [22].
Fibrinolytic activity (FA) was evaluated by euglobu-
lin method and expressed as time (min) of fibrin clot
formation and dissolution [23].
Potential amidolytic plasmin activity was de-
termined by extinction of p-NA formed by splitting
of chromogenic substrate — H-D-Val-L-Leu-L-Lys-
para-nitroanilide (S-2251) using spectrophotometry
at 405 nm and was expressed in nmol of p-NA per
1 ml of plasma per 1 min [24].
The content of fibrinogen was determined by the
method of Belitser et al. [25].
Prothrombin time (PT) was evaluated by duration (s)
of plasma coagulation in the presence of thromboplas-
tin and calcium chloride [26].
The content of antithrombin III (AT-III) was deter-
mined by Abildgaarg method [21] and was expressed
as % of the norm.
The contents of α1-proteinase inhibitor (α1IP) and
α2-macroglobulin (α2M) were determined by inhibi-
tion of BAPNA lysis with or without soybean trypsin
inhibitor [4].
Statistical analysis of the data was performed
using Statistica program. The data were presented
as M ± m. The differences between the groups were
analyzed using Student’s t-criterion. The difference
was considered significant if p < 0.05.
RESULTS AND DISCUSSION
The main indices of plasma coagulation system
of the patients and healthy donors are presented
in Table 1. The most significant changes were re-
corded in the patients with URT cancer of III stage:
the contents of fibrinogen, AT-III, and level of ami-
dolytic thrombin-like activity increased by 1.8-, 1.2-
and 1.6-fold, respectively. Also, in this group PT was
significantly higher than in healthy donors. In the
patients with laryngeal cancer of II stage increased
PT and fibrinogen content are noted, whereas the level
of amidolytic thrombin-like activity was close to that
in control group. In both groups of the patients the
content of soluble forms of fibrin wasn’t different from
the normal level. We have conclude that pre-treatment
levels of fibrinogen, AT-III, and amidolytic thrombin-
like activity in the group of patients with III stage of ma-
lignancy were significantly higher than in patients with
II stage as well as in control group. These differences
may be evaluated as the evidence for the dependence
of these haemostatic indices of the stage of disease.
Таble 1. Indices of clotting system of blood plasma of patients with URT
cancer
Groups of pa-
tients
Content
of fibrino-
gen, g/l
Disso-
luble fi-
brin,
mg%
Prothrom-
bine
time, s
Content
of АТ-ІІІ, %
Amidolytic
thrombine-
like activity,
nmol p-NA/
(min∙ml)
Patients with
URT cancer
of ІІІ stage
(n = 25)
4.0 ± 0.3
p < 0.001 4.0 ± 0.3 29.0 ± 1.0
p < 0.001
119.0 ± 6.6
p < 0.02
16.0 ± 3.0
p < 0.05
Patients with
URT cancer
of ІІ stage
(n = 10)
3.1 ± 0.2
p < 0.001 4.0 ± 0.8 28.0 ± 1.4
p < 0.02 107.0 ± 5.0 10.2 ± 2.0
Healthy persons
(control group)
(n = 24)
2.2 ± 0.1 4.3 ± 0.4 23.5 ± 0.8 100.0 ± 2.7 9.6 ± 1.0
Note: statistically significant differences with control group are marked
by corresponding p value.
It is known that cancer cell secretion of proteolytic
enzymes causes the destruction of intercellular matrix
thus creating favorable conditions for tumor inva-
sion. The activity of proteases are dependent both
on the level of their production and of their blocking
by specific inhibitors [27, 28]. The levels of activity
of proteolytic enzymes and the content of protease
inhibitors (α2M and α1IP) in blood plasma of the pa-
tients are presented in Table 2. According to these
data, in the group of patients with UPT cancer of III
stage the levels of PRA and elastase-like amidolytic
activity are significantly higher than the correspon-
ding levels in healthy donors, while the content of α2M
is significantly reduced. PRA in patients with UTR
cancer of II stage was also significantly increased, but
lower than in the patients with stage III of the disease.
The elastase-like amidolytic activity in patients with
UTR cancer of II stage just tended to be increased
in comparison to the control group, while the content
of α2M was reduced in contrary to that in patients with
III stage. The level α1IP in patients with II stage of URT
cancer wasn’t different from its reference value.
38 Experimental Oncology 38, 36–39, 2016 (March)
Table 2. Characteristics of PRA, elastase-like amidolytic activity and con-
tents of their inhibitors in blood plasma of patients with URT cancer
Groups of patients
PRA,
nmol Arg/
(min∙ml)
Amidolytic
elastase-
like activ-
ity, nmol
p-NA/
(h∙ml)
Content
of α2М, g/l
Content
of α1IP, g/l
Patients with URT can-
cer of ІІІ stage (n = 25)
78.0 ± 4.0
p < 0,001
14.0 ± 1.7
p < 0.02
1.5 ± 0.1
p < 0.001
2.5 ± 0.2
p < 0.05
Patients with URT can-
cer of ІІ stage (n = 10)
72.5 ± 5.1
p < 0.01 10.3 ± 1.5 1.6 ± 0.2 1.8 ± 0.2
Healthy persons (con-
trol group) (n = 24) 55.5 ± 3.2 9.2 ± 1.0 2.00 ± 0.08 2.00 ± 0.08
Note: statistically significant differences with control group are marked
by corresponding p value.
Both total FA and potential activity of plasminogen
are exclusively important indicators of the state of fibri-
nolytic system. The process of plasminogen activation
into plasmin plays a key role in fibrin clot lysis, but could
be involved in tumor development by non-functional
activation of matrix proteinases with following direct
or mediated destruction of extracellular matrix [29,
30]. As one may see (Table 3), there is a significant
slowdown of FA in patients with URT cancer of III stage.
In both groups of patients a statistically significant
increase in the potential activity of plasminogen was
noted.
Таble 3. Indices of fibrinolytic system of blood plasma of patients with
URT cancer
Groups of patients Clot lysis time,
min
Potential plasmin-like
amidolytic activity,
nmol p-NA/(min∙ml)
Patients with URT cancer of ІІІ stage
(n = 25)
263.0 ± 12.0
p < 0.02
0.76 ± 0.06
p < 0.001
Patients with URT cancer of ІІ stage
(n = 10) 238.0 ± 6.0 0.74 ± 0.10
p < 0.05
Healthy persons (control group)
(n = 24) 237 ± 5 0.57 ± 0.02
Note: statistically significant differences with control group are marked
by corresponding p value.
According to the data of postoperative clinical
observation of the patients with UTR of III stage,
in 3–12 months after surgical removal of primary
tumor, 10 patients developed relapse or lymph node
metastases, and 15 patients were in remission. Pre-
treatment indices of haemostasis system of these
patients are represented in Table 4. We can see that
pre-treatment levels of PRA, thrombin-like amidolytic
and elastase-like amidolytic activities, the contents
of fibrinogen and α1IP were significantly higher in both
groups of patients compared to the group of healthy
persons. Contrary, the level α2M as well as FA were
considerably lower.
Could all these data be considered useful for the
evaluation of UTR cancer progression? Combined
use of the studied indices allowed create an effec-
tive approach based on evaluation of pre-treatment
level of amidolytic thrombin-like activity, the content
of fibrinogen and α2M. At the same time, the levels
of amidolytic elastase-like and PRA remain valuable
indicators of the general condition of the patients,
but they were less informative in regard of prognosis
of disease course in post-treatment period. That’s why
it seems reasonable to use an additional index ac-
counting the differences between the thrombin-like
activity and contents of fibrinogen and α2M of each
patient from their normal levels ([Fg], [Thr] and [α2M]).
The formula for calculation of such index (let’s name
it “index H”) is as follows:
H = [Fg][Thr] / [α2M].
By calculation of individual parameters of the
patients with URT cancer using this formula with follo-
wing use of the methods of variation statistics for both
groups of patients, the average value of H index for
the group of patients with complications was 6.35 ±
1.67 vs 2.65 ± 0.53 for group patients in remission
(p < 0.05).
In conclusion, the results of combined use of pre-
treatment indices of HS and functionally related pro-
teins of blood plasma in patients with II and III stages
of URT cancer evidence on association of these indices
with the disease progression. The level of thrombin-
like amidolytic activity, α2M and fibrinogen contents
in blood plasma of the patients with URT cancer
of III stage could be used as valuable index for cancer
recurrence and metastasis at post-treatment period.
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Таble 4. Pre-treatment indices of the groups of patients with URT cancer of III stage with post-operative complications and patients in remission
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Experimental Oncology 38, 36–39, 2016 (March) 39
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