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UDC 616.151.5:616-005.4:616.12-008
THROMBOTIC EVENTS AND CONDITION OF THROMBOTIC READINESS IN PATIENTS WITH ISCHEMIC HEART DISEASE
1 Altai State Medical University, Barnaul
2 Regional Clinical Hospital, Barnaul
V.A. Elykomovi, E.A. NomokonovaH A.A. Efremushkinai
Retrospectively, n = 130 men with ischemic heart disease (main group) and n = 39 men without ischemic heart disease (control group) were included for the analysis of thrombotic events in the anamnesis and the study of the parameters of the hemostasis system in order to assess the thrombotic readiness status. It was found that for patients with IHD, in comparison with the control group, an increased content of fibrinogen levels, RFMC, HC, ET-1, increased activity of factor VIII and FV, indicating the presence of thrombotic readiness, are typical. Patients with IHD and multi-vessel CA lesions had a more pronounced activation of blood clotting at the levels of RFMC, PV and factor VIII activity, and also ArgpT was significantly higher than in patients with less severe CA atherosclerosis. In these patients, more frequent occurrence of Hmzg and Htzg forms of folate cycle genes was found. In young patients who underwent MI with "pure" CA, gene polymorphisms were detected not only in the folate cycle, but also in PAI-1 and F XIII.
Key words: thrombotic events, thrombotic state, ischemic heart disease, coronary artery atherosclerosis.
An important role in the development of atherosclerosis as the main cause of the ischemic heart disease (IHD) is played by disorders in the hemostasis system [1, 2]. A permanent hypercoagulable state is formed, predisposing to the development of throm-botic complications in the setting of atherosclerosis. These processes can be caused both by genetic defects by congenital thrombophilia and a consequence of exposure to adverse environmental factors and numerous diseases [3, 4]. In the past ten years, not only the genetic roots of most congenital types of pathologies have been identified, but also candidate genes for the overwhelming number of acquired diseases, including thrombogenic polymorphisms and mutations that create an innate tendency to increased thrombus formation, have been found [5]. Studies devoted to thrombogenic polymorphisms in patients with IHD show that some mutations can be independent risk factors (RF) in the development of coronary atherosclerosis and complications associated with them. However, some mutations can reduce the risk of coronary artery thrombosis, even in patients with severe coronary atherosclerosis [6, 7, 8, 9]. The phenomenon of the development of thrombosis of the coronary vessels as a cause of myocardial infarction (MI) in the absence of atherosclerotic lesions of the coronary arteries (CA) in young patients remains poorly studied.
Materials and methods
The study was conducted in a group of patients n= 130 people, selected from the register of chronic isch-emic heart disease (HIBS) and examined at the Regional Clinical Hospital. These patients constituted the main group with an average age of 50.7 ± 10.4 years. The comparison group (control) was presented by 39 men who considered themselves healthy, without a personal and family thrombotic history, the av-
erage age was 47.5 ± 3.8 years. The groups were comparable in age and sex. In the regional hematological center of Z.S. Barkagan, in patients of both groups, there was carried out a laboratory study of blood using the methods of studying coagulation, anticoagulant, fibrinolytic units of the hemostasis system, vascular-platelet hemostasis, endotheliosis markers and molecular genetic testing using 12 parameters by the method of polymerase chain reaction. Statistical processing of the material was carried out using descriptive statistics, software packages STATISTICA 6.0. In the presence of a normal distribution, the statistical significance of the differences was determined using Student's t-test. For each of the values having a normal distribution, the mean (M), standard deviation (SD) are given. Upon detection of sample distributions other than normal, non-parametric data processing methods were used. Differences with the probability of an event p < 0.05 were considered statistically significant.
Results and discussion
The study of thrombotic history among patients with IHD showed that 77.7% of patients have a history of arterial thrombotic events (myocardial infarction, ischemic stroke), and their familial throm-botic events constituted 31.5%.
By the study of hemostasis parameters, it was found that for patients with IHD (main group) compared with the control group (Table 1), increased levels of fibrinogen and high-molecular components of the fibrinogen pool (SFC), increased activity of VIII and Willebrand (FV) factors, indicating a moderate activation of blood coagulation - a state of thrombotic readiness [10, 11], balanced by physiological anticoagulants, were typical. Thus, the level of SFC in patients with IHD was twice as high as its value in the control group, whereas the activity
of antithrombin (AT) III and protein C remained normal. In patients with coronary artery disease, the time of XII-a dependent fibrinolysis (XlI-a ZF), activated through the triggers of the contact phase
In addition, elevated levels of endothelin (ET) - 1 and homocysteine (HC) have been detected, indicating the presence of endothelial dysfunction [4, 12]. The difference in aggregation activity (platelet aggregation - AgrT) in the groups of patients with IHD and the control group, according to our data, was associated with the intake of antiplatelet agents.
Patients of the main group were divided into three subgroups depending on the number of atherosclerosis affected CA: n = 35 - single-vessel, n = 32 - two-vessel, and n = 58 - multi-vessel lesion of CA. Five patients of the main group were not
of blood coagulation and the kallikrein-kinin system, was almost twice as long. At the same time, the amount of the substrate of the fibrinolytic system - plasminogen - was sufficient.
According to the frequency of carriage of throm-bogenic mutations and polymorphisms in the compared observation groups (Table 2), in patients with IHD, out of 12 studied genes, only the Hteg A66G genotype of the MTRR gene was found to predominate (p = 0.03).
included in any of these subgroups due to the absence of CA lesion according to the CAG data.
When comparing the parameters of the hemo-stasis system in patients with single- and multi-vessel lesions of CA, it turned out that a significant dif-
Table 1
Comparative characteristics of the studied parameters of the hemostasis system and endotheliosis markers in patients of the main and control groups
Parameter main group (IHD), n=130 (X±SD) Control group (healthy), n=39 (X±SD) P
Platelets,*109/l 229,80±55,87 249,66±49,03 0,3
PTT, c 33,83±4,96 35,02±2,03 0,1
Clotting time, c 13,42±2,16 13,36±1,26 0,8
Thrombin clotting time, c 20,02±3,51 18,84±1,20 0,04
Fibrinogen, g/l 4,09±1,41 2,98±0,74 <0,001
SFC, mg/100 ml 8,97±7,30 6,01±3,94 0,01
D-dimer, ng/ml 115,19±108,02 68,23±29,89 0,008
Antithrombin III activity, % 104,34±11,22 108,79±9,23 0,02
Screening for Disorders in the Protein C, HO System 1,01±0,18 1,09±0,14 0,007
XIIa-dependent fibrinolysis, min 25,82±13,99 14,35±9,26 <0,001
Plasminogen, % 118,86±21,63 114,48±15,82 0,2
Factor VIII activity, % 171,68±29,93 131,41±38,24 <0,001
AgrT - ADF, % 53,41±15,64 64,35±17,93 <0,001
AgrT - ristomycin, % 81,22±19,37 86,90±7,81 0,1
AgrT - adrenaline, % 34,94±23,56 36,64±28,20 0,7
AgrT - collagen, % 48,03±23,72 65,17±20,87 <0,001
WF, % 172,34±34,30 131,05±38,14 <0,001
HC, mkmol/l 13,64±5,87 9,86±2,22 0,04
ET-1, fmol/ml 0,79±0,90 0,26±0,02 <0,001
Table 2
Polymorphic variants of coagulation factor genes and folate cycle system genes in the studied groups
Locus Genotype Main group n=130, n (%) Control group n=39, n (%) P
MTRR A66G AA 31 (23,8) 12 (30,8) 0,4
AG 68 (52,4) 13 (33,3) 0,03
GG 31 (23,8) 14 (35,9) 0,1
ference was found in the level of SFC (p = 0.03), FV (p = 0.03) and factor VIII activity (p <0.001), which were higher by more severe lesion to CA (Table 3). In comparison with the control group, a significant difference was found in patients with respect to the level of fibrinogen, the activity of AT III, XII-a ZF along with an increased level of SFC, D-dimer and activity of VIII factor. Thus, the greatest shifts
The AgrT study on ADP, adrenaline and collagen showed a significant difference with greater aggregation in patients with multi-vessel lesions.
Comparison of subgroups showed that 52.9% of patients with the single-vessel lesion and 52.6% of patients with multi-vessel CA lesions received two-component antiplatelet therapy (p = 0.9). This fact indicates a lower efficacy of disaggregant therapy in patients with multi-vessel CA lesions.
When studying the parameters of the endo-thelium lesion, a significant difference was found in all subgroups compared with the control group for the level of WF, HC and ET-1. At the same time, the difference between the subgroups, as well as in the study of the hemostasis system, was found in patients with the multi-vessel lesion of the coronary artery, where there were more disorders than by the single-vessel process.
A comparative study of TP showed that in patients with the multi-vessel lesion, the Hteg genotype A1298C prevalence of the MTHFR gene is higher (53.5%) than in the control group (28.2%, p = 0.01) and in patients with the single(31, 4%, p = 0.04), two-vessel lesion of CA (31.2%, p = 0.04).
It should be noted that the Hmzg genotype G226A of the F XIII gene was less common in the subgroup with the multi-vessel CA lesion (3.5%), while this genotype was more common in the control group (15.4%, p = 0.03). This interesting fact may indicate the possible protective effect of the Hmzg carrier form of this gene in the development of MI. This hypothesis is supported by the messages
in SFC were revealed in the case of the multi-vessel lesion. At the same time, there was no difference in the anticoagulant level and fibrinolysis when comparing the subgroups between themselves and the control group, indicating a deterrent effect of the anticoagulants and the fibrinolysis system in response to moderate thrombinemia detected in patients with IHD.
of Andrienko E.Yu., Samokhodskfya L.M., Ba-latsky A. V., Makarevich P.I., Boytsov S.A. (2011) and Tsepokina A.V., Panasenko A.V. (2016) [6, 13].
According to our studies, out of 130 patients with IHD, only five (3.8%) did not have atherosclerotic CA leisons. These five patients had MI at the young age, confirmed laboratory and instru-mentally (ECG, EchoCG). The average age of patients with "clean" CA was 36.6 ± 2.6 years.
In patients with "clean" CA, compared with patients with various types of CA, a tendency to a higher content of the components of the fibrin-ogen pool (SFC) was found - 13.30 ± 6.22 mg/100 ml (p <0.05); to an increase in time of XII-a dependent fibrinolysis - 29.80 ± 14.65 minutes and HC content - 14.52 ± 4.41 |jmol/l. All five patients showed a carrier of the same type of thrombogenic polymorphisms - a combination of Hmzg and Hteg forms of PAI 1 genes and folate cycle genes (MTR, MTRR, MTHFR). And also, despite the history of MI, in all cases, the presence of the Hmzg or Hteg form of the F XIII gene is noted, which disproves the theory of the protective effect of this gene in patients with "clean" CA.
The phenomenon of "clean" coronary arteries and the presence of myocardial infarction in the history of young patients turned out to be interesting. This is partially confirmed by the discovery of a significantly lower Hmzg carrier frequency of the form of the F XIII gene in patients with the multi-vessel coronary lesion.
iaDie a Comparative characteristics of the studied parameters of the hemostasis system and endothelial dysfunction in patients with IHD, depending on the degree of CA lesion
Main group n=130, (X±SD)
Parameter Single-vessel lesion n=35 Two-vessel lesion n=32 Multi-vessel lesion n=58 р1-2/1-3/2-3
1 2 3
SFC, mg/100 ml 8,27±5,19 8,57±4,83 11,05±6,33 0,8/0,03/0,06
Factor VIII activity,% 159,33±37,65 166,58±30,25 181,40±21,75 0,4/<0,001/0,009
AgrT - ADF, % 48,03±8,36 51,83±16,04 58,61±17,18 0,2/0,001/0,07
AgrT - adrenaline, % 29,32±19,11 32,38±24,34 43,02±24,73 0,6/0,01/0,1
AgrT - collagen, % 40,12±24,65 44,00±26,39 55,15±19,62 0,6/0,02/0,07
WF, % 159,90±38,83 176,00±27,80 176,12±33,14 0,06/0,03/0,9
According to the accepted concepts, thrombo-philia is characterized by: young age, familial TA, changes in the hemostasis system in combination with Hmzg or Hteg carrier forms of thrombogenic genes [13, 14, 15]. Consequently, the development of myocardial infarction in patients with "clean" CA, in our opinion, is due to thrombophilia.
Conclusions
1. Retrospectively, TS among patients with IHD was 77.7%, and familial TS - 31.5%.
2. In patients with IHD, a state of thrombotic readiness was detected, which is more pronounced in laboratory patients with multi-vessel lesions of CA. Against the background of the same disag-gregant therapy, patients with the multi-vessel CA lesion, AgrT on ADP, adrenaline and collagen were higher than in patients with the single-vessel CA lesion.
3. The facts of the prevalence of the Hteg genotype A1298C of the MTHFR gene with a simultaneously low frequency of Hmzg G226A genotype of the F XIII gene by multivascular CA were found.
4. Among patients with "clean" CA and MI in history, in all cases, a carrier of Hmzg or Hteg forms of PAI 1, F XIII genes and folate cycle (MTR, MTRR, MTHFR) was found.
5. MI at a young age in patients with "clean" CA is associated with thrombophilia.
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Contacts
Corresponding author: Elykomov Valery Anatoly-evich, Doctor of Medical Sciences, Professor, Head of the Department of therapy and general medical practice with the course FVE of the Altai State Medical University, Barnaul. 656038, Barnaul, Len-ina Prospekt, 40. Tel.: (3852) 689673. E-mail: [email protected]
Author Information
Nomokonova Evgenia Alexandrovna, Candidate of Medical Sciences, Assistant of the Department of therapy and general medical practice with the course FVE of the Altai State Medical University, Head of the admission department, cardiologist of the Regional Clinical Hospital, Barnaul. 656000, Barnaul, ul. Lyapidevskogo, 1. Tel.: (3852) 689852. E-mail: [email protected] Efremushkina Anna Alexandrovna, Doctor of Medical Sciences, Professor of the Department of therapy and general medical practice with the course FVE of the Altai State Medical University, Barnaul. 656038, Barnaul, Lenina Prospekt, 40. Tel.: (3852) 689673. E-mail: [email protected]
