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UDC 616.12-004.6-005.2
ATHEROSCLEROSIS OF THE CORONARY ARTERIES AND DISORDERS OF THE HEMOSTATIC SYSTEM
Altai State Medical University, Barnaul
V.A. Yelykomov, Ye.A. Nomokonova, A.A. Yefremushkina
For many decades coronary heart disease has retained the first place in the structure of mortality from cardiovascular diseases in Russia (49.9%). Disturbances in the hemostatic system form a permanent hypercoagulable state, which, against the background of atherosclerosis, can lead to thrombotic complications. This article presents the results of a study of the features of the hemostatic system, endothelial cell markers and the carriage of thrombogenic polymorphisms in patients with coronary heart disease at different levels of atherosclerotic lesion of the coronary arteries.
Key words: ischemic heart disease, hemostatic system, atherosclerosis.
Cardio-vascular diseases (CVD) are the most frequent mortality factor (in the RF - 49,9%, 2014), the first position among which has been for many years occupied by the ischemic heart disease (IHD) including its acute and chronic forms [5, 11]. It is known, that an important role in the development of atherosclerosis as the main cause of IHD is played by the disorders of the hemostatic system, moreover, the process involves all the components of the coagulation system [2, 16, 17]. There is formed the constant hypercoagula-tion state predisposing to the development of throm-botic complications associated with atherosclerosis. In these circumstances, the main risk is not atherosclerosis itself, but the artery thrombosis accumulated on it and leading to acute ischemia of vital organs and often having lethal outcome [10]. In patients with macrofocal myocardial infarction (MI), thrombosis of coronary arteries (CA) is registered in 95-97% of cases [3, 4, 8]. These processes can be determined both by genetic defects by congenital thrombophilia and by the result of the effect of external environment unfavorable factors and numerous diseases. Throm-bophilia itself increases the risk of thrombosis, and its significance can be considerably increased in combination with other risk factors [9, 15]. In recent ten years there have been not only identified the genetic roots of the majority of congenital pathologies, but there have been also found the candidates of the sweeping majority of acquired diseases including thrombogen-ic polymorphism and mutations determining the genetic predisposition to the intensive thrombogenesis [7, 12, 14, 18]. At the same time, some mutations, e.g. in the gene of VII, XIII factor, according to several authors, can reduce the risks of thrombosis (MI) even by expressed coronary atherosclerosis [1, 6, 13].
Objective: To study the parameters of the hemo-static system, markers of endotheliosis and throm-bogenic polymorphism in patients with IHD in comparison to the control group. To study the peculiarities of hemostatic system, markers of endotheliosis and thrombogenic polymorphism in patients with IHD by the different level of CA atherosclerotic disease.
Materials and methods
Using the method of random sampling, the main group included 130 men with coronary heart disease, average age - 50,8 ± 10,4. The control group included 39 healthy men, average age
- 47,5 ± 3,8 (p=0,06). In both groups, there were evaluated 16 parameters of the hemostatic system, 3 markers of endotheliosis and thrombogenic polymorphism by 12 parameters. The exclusion criteria for both groups: acute coronary syndrome (ACS) as the cause of the current hospital stay, oncology, concomitant pathology at the decompensation stage, inflammatory diseases, surgical interventions during the last 6 months. In both groups, there were evaluated 16 parameters of the hemostatic system, 3 markers of endotheliosis and thrombo-genic polymorphism by 12 parameters. Further, the main group was divided into subgroups depending on the level of the coronary arteries injury, which were compared to each other: I (n=35)
- single-vessel disease (myocardial infarction (MI) in the medical history - 71,4 %), II (n=32) - two-vessel disease (MI in the medical history - 78,1 %), III (n=58) - the multi- vessel disease of the coronary artery (CA) (MI in the medical history - 72,4 %), IV (n=5) - "clean" CA (MI in the medical history -100,0 %). The statistical processing of the material was performed by means of Statistica 6.0 programs. By the presence of normal distribution the statistical significance of the differences and the implemented sample data was determined by means of Student t-test. For each value possessing normal distribution there are given mean values (M) and standard deviation (SD). The comparison of qualitative characteristics was conducted by means of contingency tables 2x2, the hypothesis testing was performed according to the Pearson's chi-squared test x2. The differences were considered statistically significant by the probability of event p<0,05.
Results and discussion
Patients with IHD (main group) in comparison with the control group showed the increase of the fibrinogen level (p<0,001) and high molecular components of the fibrinogen pool (SFC)
(p=0,01), the growth of activity of VIII factors (p<0,001) and Willebrand factors (p<0,001). Totally, it testifies the moderate activation of blood coagulation balanced by physiological anticoagulants. Thus, the SFC level in patients with chronic IHD was two times higher than its value in the control group, while the activity of anti-thrombin and C protein stayed normal. In patients with CIHD the time of XlI-a dependent fibrinolysis activated through the triggers of the contact stage of blood coagulation and kinin-kallikrein system also turned out to be two times longer (p<0,001). Herewith, the amount of the fibrinolytic system substrate - plasminogen - turned out to be sufficient. Additionally, the endothelial dysfunction was present: elevated level of homocysteine (HC, p=0,04) and endothelin-1 (ET-1, p<0,01). According to our data, the difference of the aggregation activity of thrombocytes - adenosine diphosphate (ADP) and collagen (p<0,001) in the group of patients with IHD and the control group was connected with the intake of disaggregants. The study of frequency of thrombogenic mutations and polymorphism carriage in the compared groups showed, that in patients with IHD there is a significant prevalence of only Hteg genotype of A66G gene MTRR (p=0,03). The comparison of the hemostatic system parameters in patients of the subgroups with single- and multi-vessel CA disease demonstrated, that the significant difference is determined by SFC level (p=0,03), Willebrand factor (p=0,03) and the activity of VIII factor (p<0,001), which were higher by more severe CA disease (Table 1). By the comparison of the subgroups with each other and with the control group, the anticoagulant element and fibrinolysis did not show any differences, which evidences the retaining effect of anticoagulants and the fibrinolytic system in response to moderate thrombinemia registered in patients with IHD. The examination of thrombocyte aggregation in response to ADP, adrenalin and collagen showed, that the significant difference is observed between the subgroups of patients with single-and multi-vessel CA disease (p<0,01). The comparison of the subgroups showed, that the two-component antiaggregant therapy was received by 52,8% of patients with single-vessel disease and 52,6% of patients with multi-vessel CA disease (p=0,9). By multi-vessel CA disease the aggregation of thrombocytes was the highest, while its studied parameters did not differ from the parameters of the control group despite the intake of disag-gregants at appropriate dose. The stated fact can indicate the lower effectiveness of disaggregant therapy in patients with multi-vessel CA disease. The comparative study of thrombogenic polymorphisms showed, that in patients with multi-vessel CA disease the prevalence of Hteg A1298C genotype of MTHFR gene is higher (53,5%) than in the control group (28,2 %, p=0,01) and in patients with single-vessel (31,4 %, p=0,04), two-vessel CA disease (31,2 %, p=0,04).
It should be noted, that Hmzg genotype of G226A gene F XIII was rarer registered exactly in the subgroup with multi-vessel CA disease (3,5 %), while in the control group this genotype was met more often (15,4 %,p=0,03). This interesting fact can indicate the possible protective effect of Hmzg form carriage of this gene in the development of MI [1, 13]. As the current research has shown, out of 130 patients with IHD only 5 (3,8 %) lack the atherosclerotic CA disease. These 5 patients had undergone laboratory and instrumentally confirmed MI at a young age. The average age of patients with "clean" CA constituted 36,6±2,6 years.
In patients with "clean" CA in comparison to the patients with different CA disease there was observed the tendency to a higher concentration of the components of the fibrinogen pool (SFC) — 13,30±6,22 mg/100ml; the increase of the time of XII-a dependent fibrinolysis - 29,80±14,65 min and HC concentration - 14,52±4,41 mcmol/l (Table 1). All 5 patients showed the carriage of throm-bogenic polymorphisms of the same gene - combination of Hmzg and Hteg forms of PAI 1 genes and genes of the folate cycle (MTR, MTRR, MTH-FR). Also, despite the presence of MI in the medical history, in all cases there is registered the presence of Hmtg and Hteg forms of F XIII gene, which indicates the lack of protective effect from MI of this gene in patients with "clean" CA.In our opinion, the obtained results differ from the data of literature, probably, because of the fact, that in our work "clean" CA by IHD are discovered only in young patients, but not in patients with systemic atherosclerosis and require further research. This is partially confirmed by the significantly lower frequency of Hmzg form of F XIII gene carriage in patients with multi-vascular coronary disease. All this invites the assumption, that at a young age MI is developed not as a consequence, but in contradiction to CA atherosclerotic disease.
In the current case, all five patients had coagulation disorders in the form of thrombinemia, disorders of the internal mechanism of fibrino-lysis and high level of HC and ET-1. At the same time, these patients had an adequate response to the disaggregant therapy. According to the literature sources [3, 9], thrombophilia is characterized by: young age, thrombotic family history, changes in the hemostatic system in combination with the carriage of Hmzg or Hteg forms of throm-bogenic genes. Consequently, the development of MI in patients with 'clean" CA is determined by thrombophilia.
Conclusion
In patients with IHD there were discovered the signs of moderate thrombinemia and endothe-lial dysfunction, which are more expressed in patients with multi-vessel CA disease. In patients with multi-vessel CA disease the thrombocyte aggregation in response to ADP, adrenalin and collagen was much higher than in patients with one-vessel
Table 1
Comparative characteristics of the studied parameters of the hemostatic system and endothelial dysfiinction in patients with IHD depending on the level ofCA disease
Parameter Main group (M±SD) Control group n=39, (M±SD) pi-2/1-3/1-4/2-3/ 2-4/3-4 pi-5/2-5/3-5/4-5
«clean» CA n=5 single-vessel disease n=35 two-vessel disease n=32 multi-vessel disease n=58
1 2 3 4 5
Thrombocytes,*109/k 250,00±59,78 233,89±61,80 241,82±48,68 218,75±55,38 249,66±49,03 0,5/0,7/0,2/0,6/0,2/0,06 0,9/0,5/0,7/0,1
APTT, s 33,60±3,50 33,41±3,81 33,35±4,62 34,15±5,81 35,02±2,03 0,8/0,9/0,8/0,9/0,5/0,5 0,03/0,02/0,04/0,4
Prothrombin time, s 12,40±1,23 13,38±2,36 13,96±3,18 13,27±1,29 13,36±1,26 0,1/0,3/0,4/0,4/0,7/0,1 0,1/0,9/0,3/0,7
Thrombin time, s 20,60±2,0 7 20,29±5,27 19,48±2,06 20,28±2,92 18,84±1,20 0,7/0,3/0,7/0,4/0,9/0,1 0,007/0,09/0,1/0,004
Fibrinogen, g/1 3,98±1,51 3,80±1,34 3,77±1,02 4,30±1,47 2,98±0,74 0,8/0,8/0,4/0,9/0,1/0,07 <0,001
SFC, mg/100 ml 13,30±6,22 8,27±5,19 8,57±4,83 11,05±6,33 6,01±3,94 0,06/0,06/0,4/0,8/0,03/0,06 <0,001/0,06/0,03/<0,001
D-dimer, ng/ml 113,20±109,40 104,73±86,45 124,22±99,90 122,75±99,42 68,23±29,89 0,7/0,6/0,7/0,4/0,4/0,9 0,04/0,01/0,001/0,001
in antithrombin activity, % 108,20±8,89 106,94±10,89 109,00±10,60 99,91±10,66 108,79±9,23 0,6/0,8/0,09/0,4/0,003/<0,001 0,9/0,4/0,9/<0,001
Screening of disorders in the system of C, HO proteins 1,02±0,31 0,96±0,17 1,05±0,14 1,02±0,19 1,09±0,14 0,5/0,7/0,9/0,03/0,1/0,4 /<0,001/0,1/0,03
XH-a dependent fibrinolysis, min 29,80±14,65 25,00±14,54 22,25±10,83 26,52±13,99 14,35±9,26 0,2/0,1/0,3/0,4/0,6/0,1 <0,001
Plasminogen, % 132,20±29,50 119,45±20,04 117,09±121,36 117,80±22,17 114,48±15,82 0,2/0,2/0,2/0,6/0,7/0,8 0,04/0,2/0,5/0,4
Vin factor activity, % 168,20±27,95 159,33±37,65 166,58±30,25 181,40±21,75 131,41±38,24 0,6/0,9/0,2/0,4/<0,001/0,009 <0,001
Thrombocyte aggregation -ADP, % 47,80±18,63 48,03±8,36 51,83±16,04 58,61±17,18 64,35±17,93 0,9/0,6/0,2/0,2/0,001/0,0 7 <0,001/<0,001/0,003/0,1
Thrombocyte aggregation -ristomycin, % 82,66±10,69 82,00±14,28 74,77±26,44 82,73±19,64 86,90±7,81 0,9/0,4/0,9/0,4/0,9/0,3 0,3/0,2/0,02/0,3
Thrombocyte aggregation -adrenalin, % 18,50±11,67 29,32±19,11 32,38±24,34 43,02±24,73 36,64±28,20 0,3/0,3/0,06/0,6/0,01/0,1 0,2/0,2/0,5/0,3
Thrombocyte aggregation -collagen, % 46,00±28,43 40,12±24,65 44,00±26,39 55,15±19,62 65,17±20,87 0,5/0,7/0,1/0,6/0,02/0,07 0,l/<0,001/0,002/0,03
Willebrand factor, % 172,20±47,48 159,90±38,83 176,00±27,80 176,12±33,14 131,05±38,14 0,5/0,8/0,8/0,06/0,03/0,9 <0,001/0,002/<0,001/<0,001
Homocysteine, mkmol/1 14,52±4,41 13,37±7,01 13,76±5,62 13,60±5,63 9,86±2,22 0,7/0,8/0,7/0,8/0,8/0,9 <0,001
Endothelin-1, fmol/ml 0,48±0,12 0,71±0,68 0,81±0,71 0,86±1,13 0,26±0,02 0,5/0,3/0,4/0,5/0,5/0,8 <0,001
03
hi H
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hi 2
ho O
disease, despite the identical disaggregation therapy. The prevalence of Hteg genotype of the A1298C gene MTHFR in patients with multi-vessel coronary disease is higher (53,5%) than in the control group (28,2 %) and in patients with single-vessel (31,4 %) and two-vessel disease (31,2 %). Patients with "clean" CA constituted 3,8 % and had: MI onset at a young age, coagulation disorders in the form of thrombinemia, disorders of the internal mechanism of fibrinolysis and high level of HC and ET-1. In these patients there was registered the same type of thrombogenic polymorphism - the combination of Hmzg and Hteg gene forms PAI-1 and genes of the folate cycle (MTR, MTRR, MTHFR), which in complex with coagulation disorders and the absence of CA atherosclerotic lesions are the markers of thrombophilia.
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Contacts:
Corresponding author - Yefremushkina Anna Aleksandrovna, Doctor of Medical Sciences, Professor of the Department of therapy and general medical practice with the course of further vocational education of the FSBEI HE Altai State Medical University of the Ministry of Health of the Russian Federation, Barnaul. 656038, Lenina Prospekt, 40. Tel.: (3852) 566858. Email: sunsun3@yandex.ru
