THE SIGNIFICANCE OF DIAGNOSIS OF HEREDITARY THROMBOPHILIA IN COMBAT GUNSHOT INJURY

THE SIGNIFICANCE OF DIAGNOSIS OF HEREDITARY THROMBOPHILIA IN COMBAT GUNSHOT INJURY

Nikolaev K.N.1, Kapustin S.I.2, Zubritskiy V.F.3,4, Koltovich A.P., Vardanyan A.V.5, Ivchenko D.R.1
1Main Military Clinical Hospital of National Guard Troops of Russian Federation, Balashikha, Russia
2Russian Scientific Research Institute of Hematology and Transfusiology, Saint Petersburg, Russia
3Main Clinical Hospital of Ministry of Internal Affairs of Russian Federation,
4Institute of Medicosocial Technologies of Moscow State University of Food Production,
5Russian Medical Academy of Continuous Professional Education, Moscow, Russia

One of the priority directions of modern medicine is preclinical diagnostics and early prevention of venous thrombosis and pulmonary embolism. These diseases present a serious medical and social problem in the developed countries. Moreover, during the recent years one can observe the event of “younger” thrombosis with the continuous trend to manifestation in young and working age part of the population [1].
The Russian Federation demonstrates ones of the highest rates of mortality and disability from venous thromboembolic complications (VTEC). It testifies the need for correction of approaches to prevention and treatment of this pathology with consideration of the recent scientific achievements [2].
The etiology of venous thromboembolism is multifactorial. Together with the acquired risk factors (trauma, immobilization, surgical intervention etc.), the high significance relates to genetic predisposition determined by gene polymorphism in various components of the hemostasis system [3].
In 1995 the World Healthcare Organization introduced the term thrombophilia as a condition with unusual tendency to thrombosis at early age, with burden of family anamnesis, degree of thrombosis severity disproportionate to a known causal factor, and presence of recurrent thrombosis [4].
The Russian scientists consider thrombophilia as all inherent (primary, genetically determined) and acquired (secondary, symptomatic) hemostasis disorders with tendency to early manifestation and recurrence of thrombosis, thromboembolism, ischemia and organ infarctions [5]. Currently, the high number of genetic and acquired types of thrombophilia is known. They differ according to etiology, characteristics of disorders in the hemostasis system, complications and prognosis. The hemostatic disorders, which are caused by exogenous (infection, therapy with some pharmaceuticals, diet etc.) or endogenous factors of acquired origin (changes in immune and/or hormonal status after injuries, operations etc.) are usually transitory. Conversely, thrombophilia relating to defects in the genetic apparatus are associated with high risk of thrombosis during the whole life [1].
The most known prothrombotic hemostatic abnormalities are deficiency of natural anticoagulants (NA) – antithrombin III, proteins C and S, mutations in the genes of prothrombin (G20210A), factor V (G1691A, Leiden mutation), gamma-subunits of fibrinogen (FGG rs 2066865), resistance to activated protein C, dysfibrinogenemia and others. However the “classic” forms of genetic thrombophilia are only EA deficiency and mutations in the genes of the factors II and V [6].
Acquired thrombophilia is observed in injuries, operations, central vein catheterization, disseminated intravascular coagulation (DIC), long term bed rest, chronic infections, sepsis, smoking, dehydration, varicose disease of the lower extremities veins, thrombocytosis, malignant tumors, allergic diseases etc. [7, 8]. The relationship has been found between immune inflammation and prothrombotic changes in the hemostasis system in various diseases, particularly, in DIC [9].
For genetic thrombophilia diagnostics the important information is anamnesis findings from patients or their relatives. Such findings often include information about thrombosis, myocardial infarction, stroke, pulmonary embolism, early development of thrombophelebitis-complicated varicose disease, development of thrombosis and DIC after injuries and operations. Often these diseases show their signs at the age before 50.
The functionally significant genetic variations can be the cause of pathologic changes in the hemostasis system and determine the high predisposition to thrombosis. A provocative impact is important for initiation of a thrombotic event in presence of genetic predisposition (acquired or concurrent risk factors – operations, injuries, inflammation, bleeding etc.) [10].
Genetic defects of the hemostasis system are identified in not more than 40 % of patients with VTEC [11]. Postsurgical development of venous thrombosis in 57 % of surgical patients is associated with presence of genetic mutations in the components of the hemostasis system [12].
The pathogenesis of VTEC in wounded persons has some significant differences determined by the mechanism of gunshot injury, severity of condition, presence of extensive injuries to organs, tissues, vessels and nerves, acute massive blood loss and traumatic shock. The clinical recommendations “Prevention of thromboembolic syndromes” (GOST R 56377-2015) present the scale for individual estimation of risk of deep venous thrombosis according to Caprini. According to the scale, the patients with severe gunshot injuries have 8-12 points of risk factors and relate to the group with very high risk of VTEC [13]. The possibility of thrombosis demonstrates more than 10-fold increase in such patients [14].
The research of influence of various genetic and acquired forms of thrombophilia on development and features of thrombotic process course, as well as the search of efficient techniques for elimination of pathologic clotting are necessary for both improving the quality of life and decreasing costs of treatment, because development of VTEC within 3 months after surgical intervention gives more than 2-fold increase in general costs of treatment as compared to the uncomplicated postsurgical course and these costs remain at slightly higher level within the following months [15].
The objective was to study the effect of polymorphism in the genes of components of the hemostasis system on the development of venous thrombosis in the victims with combat gunshot trauma.

MATERIALS AND METHODS

The features of allelic polymorphism of 10 genes coding the various components of the hemostasis system have been examined in 46 patients with combat gunshot wounds. The patients received the treatment in Main Clinical Hospital of Ministry of Internal Affairs of Russian Federation and in Main Military Clinical Hospital of National Guard Troops of Russian Federation in 2013-2015. All patients were male at the mean age of 29.5 ± 5.1. Mine-explosive injuries were in 33 (71.7 %) patients, gunshot injuries – in 13 (28.3 %).
At the moment of admission, traumatic shock was diagnosed in 40 (86.9 %) patients. Shock of degree 1 was in 1 (2.5 %) patient, degree 2 – in 6 (15 %), degree 3 – in 32 (80 %), terminal state – in 1 (2.5 %). The severity of condition was 11.3 ± 1.7 according to Injury Severity Score (ISS) and 4.7 ± 0.9 according to Military Field Surgery-Injury (Gunshot Wound).
The stage of specialized medical care lasted for 68.3 ± 16.5 days.
The degree of VTEC risk was estimated on the basis of Russian clinical recommendations for diagnostics, treatment and prevention of VTEC [14]. All patients were referred to the group with high risk of VTEC development. They had 3-4 risk factors.
Depending on the presence of venous thrombosis, the patients were distributed into two groups. The main group included 13 patients (28.3 %) with venous thrombosis identified during the treatment. The control group included 33 (71.7 %) patients without signs of thrombosis.
The condition of the venous system and clots visualization were realized with ultrasonic angioscanning (USAS) with the expert class devices and the lineal transducers of 5-12 MHz. Also the mobile ultrasonic scanner MicroMaxx (Sonosite, USA) was used. USAS was conducted on the first day after admission to the hospital and 5-7 days subsequently, before surgery and during the postsurgical period. If any venous clots were identified, USAS was conducted 1 time within 2-3 days.
The investigation of allelic polymorphism of the genes relating to the clotting process was realized on the basis of polymerase chain reaction (PCR) and the analysis of polymorphism of lengths of PCR-product restriction fragments. The allelic polymorphism of the genes was studied. The genes were conventionally distributed into 3 groups:
The genes coding the components of the plasma link of hemostasis: clotting factors I, II, V, XII, plasminogen activator inhibitor (PAI-1);
The genes coding the components of thrombocytic receptors mediating the adhesion and aggregation processes in blood plates: GpIa, GpIbα, GpIIIa, P2Y12;
The genes of the components which are involved in endothelial dysfunction pathogenesis: MTHFR.  

All data was analyzed with the statistical methods with use of EXCEL-2010 and STATISTICA-7.0, BioStat for Windows. χ2 and Fisher’s exact two-tail test were used for estimating the strength of the relationship between the studied factors: φ (phi) and Cramer’s V; their values are presented in the table 1. The study was conducted in concordance with the requirements from the ethical committees of Main Military Clinical Hospital of National Guard Troops and Main Clinical Hospital of Ministry of Internal Affairs of Russian Federation.

Table 1. Interpretation of φ and Cramer's V tests according to recommendations by Rea & Parker [16]

Value of φ and Cramer's V tests

Relationship strength

< 0.1

Unessential

0.1 – <0.2

Weak

0.2 – <0.4

Middle

0.4 – <0.6

Relatively strong

0.6 – <0.8

Strong

0.8–1.0

Very strong

RESULTS

Before injury the examined military men had not any vascular diseases, thromboembolic complications, and the examination for thrombophilia was not conducted. During collecting the anamnesis data it was not possible to receive any exact findings relating to the presence of the disease in the patients’ relatives, because of severity of condition and low information capacity. Before military service most patients lived on the territory of the North Caucasian federal district.
All patients received from 1 to 33 surgical interventions. 19 (41.3 %) patients received transfusion of 330-3,000 ml of donor blood. The patients with gunshot fractures of the lower extremities (11 patients, 23.9 %) were treated with the external fixation devices. The mean timeframes for independent movement were 29.3 ± 11.7 days.
The analysis of the study showed the presence of prothrombotic genetic variants in 42 (91.3 %) patients. The table 2 shows the results of genotype distribution for the examined genes.

Table 2. Distribution of genotypes of studied genes in patients 

Gene,
polymorphism

Genotype

Patients
with thrombosis

Patients
without
thrombosis

Total

р

φ
and Cramer's
V

FV, G1691A

GA

1

0

1

0.283

0.2 – <0.4

GG

12

33

45

FII, G20210A

GA

3

0

3

0.019

0.4 – <0.6

GG

10

33

43

GpIbα,

T434C

TC

8

8

16

0.014

0.2 – <0.4

CC

1

0

1

0.167

0.4 – <0.6

TT

4

25

29

FI-B,

-455 G/A

AA

5

1

6

0.005

0.4 – <0.6

GA

2

13

15

0.686

0.1 – <0.2

GG

6

19

25

GpIa,

C807T

TT

3

1

4

0.062

0.2 – <0.4

CT

7

18

25

CC

3

14

17

PAI-1,

-675 4G/5G

4G/4G

5

8

13

0.469

0.1 – <0.2

4G/5G

5

14

19

5G/5G

3

11

14

P2Y12, H1/H2

H2/H2

1

1

2

0.443

0.1 – <0.2

H1/H2

4

6

10

0.422

0.1 – <0.2

H1/H1

8

26

34

FXII,

C46T

TT

2

2

4

0.566

0.1 – <0.2

CT

4

15

19

CC

7

16

23

GpIIIa,

T1565C

TC

3

5

8

0.669

<0.1

TT

10

28

38

MTHFR,

C677T

TT

1

2

3

1.000

<0.1

CT

3

10

13

CC

9

21

30

Note:  gray color means the prothrombotic variants of genotype.


The results of the examination of the genotypes of the factors I, II, V, GpIbα and GpIa are the most interesting.
FV Leiden mutation was found in 1 patient in the group of the patients with thrombosis, whereas the control group did not show any carriers of this marker of genetic thrombophilia. The identified differences were not statistically significant owing to rare incidence of this mutation in the examined group. However the “mean” (0.2 - < 0.4) strength of the relationship between the presence of FV Leiden mutation and the possibility of thrombosis indicates the necessity for determination of this genetic marker in predicting the risk of VTEC.
The analysis of prothrombin gene polymorphism showed the genotype FII 20210GA in 3 (23.1 %) of the patients with diagnosed thrombosis, whereas none of the control patients was not a carrier of this prothrombotic variant (p = 0.019). For the above-mentioned genotype the evident risk of thrombosis (OR = 22.3; 95 % CI: 1.1-468.7; р = 0.019) was identified, as well as a “relatively strong” (0.4 - < 0.6) correlation relationship between the presence of mutation FII G20210A and the possibility of thrombosis development.
The analysis of the genotypes GpIbα showed the variant 434C in 9 (69.2 %) patients in the main group, i.e. almost three times higher than in the control group – 24.2 % (OR = 7.0; 95 % CI: 1.7-29.2; p = 0.007). For the genotype 434 TC the evident risk of thrombosis development was identified (OR = 6.3; 95 % CI: 1.5-26.4; p = 0.014) and the “mean” (0.2 - < 0.4) strength of the relationship between the presence of this variant and possible development of thrombosis was found. For the genotype 434 CC the result was not statistically significant (p > 0.05) owing to its rareness. But a “relatively strong” (0.4 - < 0.6) relationship between the presence of the genetic variant (GpIbα 434 СC) and the possibility of thrombosis development was found.
For the genotype -455 AA the analysis of gene polymorphism of fibrinogen β-subunit showed the statistically significant risk of VTEC and a “relatively strong” (0.4 - < 0.6) relationship between the presence of this variant and the possibility of thrombosis development. -455A allele homozygotes were observed almost 13 times higher than in the comparison group (38.5 % vs. 3.0 % correspondingly; OR = 20.0; 95 % CI: 2.0-196.1; p = 0.005). The heterozygote genotype FI-B -455 GA was identified in 15.4 % of the patients with thrombosis and in 39.4 % of the control patients. It did not influence significantly on the risk of VTEC. A “low” (0.1 - < 0.2) strength of the relationship between these signs was found for this genotype.
The analysis of GpIa gene polymorphism showed almost 8-fold increase in the incidence of 807TT genotype in the main group as compared to the patients without thrombosis (23.1 % vs. 3.0 % correspondingly; OR = 9.6; 95 % CI: 0.9-103.0; p = 0.062). A “mean” (0.2 - < 0.4) relationship between the indicated genotype and the possibility of thrombosis development was found.
The analysis of genotype distribution for other genes did not find any significant differences between the examined groups of the patients.

DISCUSSION

The available medical literature includes only rare materials about researching genetic thrombophilia in patients with combat gunshot injuries [17, 18]. This category of patients presents the interest owing to:
Patients are young men (age of 20-35) with previous medical examination and good health for military service, without previous events of thrombosis;
The thrombotic process is observed in all patients and is a protective response to a gunshot injury; however many cases are associated with pathologic clotting that causes thrombosis and pulmonary embolism;
The modern weapon makes the powerful destructive influence on the human organs and tissues and causes extensive injuries not only in the point of impact, but also over significant distance from the injury site;
Hemostasis disorders appear after an injury; the intensity of such disorders highly depends on the amount of the injuries, degree of acute massive blood loss and severity of traumatic shock;
The determinants of treatment outcome can be the presence of latent risk factors of complications in severe gunshot injuries.
 Currently, the complex estimation of the prothrombotic potential of the genotype can be performed with the analysis of allelic polymorphism of several tens of the genes which code the component of the thrombotic and plasma links of hemostasis and various metabolic systems influencing on the integrity and functional activity of vascular endothelium, i.e. these genes determine the risk of VTEC to the high degree. The increase in the objectivity and the information capacity of the results was achieved with the statistical methods for significant amounts of genetic data with possibility to conduct the analysis of so called gene-gene interactions and to identify the unfavorable combinations of allelic variants of various genes [6].
A region of residence plays a significant role for predicting the thrombotic danger of a human genotype. The differences in the genetic risk factors of thrombosis in patients from the Western and Eastern countries have been identified [19]. So, the variant FV Leiden (FV R506Q) relating to resistance to activated CRP [20, 21] and mutation G20210A in the prothrombin gene are the most common genetic factors of VTEC risk in the Western populations, but are absent or extremely rare in residents of the Eastern countries [23-28]. At the same time, inherent deficiency of the main natural anticoagulants (antithrombin III, protein C and protein S) is quite rare in the Western countries, but presents serious danger in the Asian countries [29-33]. Also black patients show 40 % higher incidence of VTEC as compared to white [34]. Taking into account the significant territory of Russia, military patients suffering from gunshot injuries in local war conflicts can show the significant differences in presence of any genetic risk factors depending on their place of residence.
Our study showed that the presence of mutation FII G20210A, variants GpIbα 434C and FI-B -455AA were associated with the evident increasing risk of VTEC in the patients. FV Leiden mutation and GpIa 807TT genotype were observed in the group of the patients with thrombosis, but the differences were not statistically significant in comparison with the control group.
Thrombophilia is determined as predisposition to thrombosis and should be considered within the context of other risk factors of thrombosis relating to the course of diseases, influences of medical agents and appearance of some conditions (injuries) [7].
In this study the highest amount of the patients without any signs of thrombosis was related to the presence of the patients with mild injuries and mean ISS (11.3 ± 1.7). It was found that the injury severity with ISS of 23-31 caused the intermittent increasing probability of venous thrombosis in 52.9 % of cases [35].
The high predisposition to VTEC in patients with genetic thrombophilia actualizes the issue of preventive measures. Some authors offer to consider a genotype, when prescribing the treatment for such patients [11]. At the same time, the time of examination of the homozygote and heterozygote variants of FV factor mutation and their influence on the course of venous thrombosis did not identify any statistically significant differences between the studied variants. It allowed recommending the implementation of similar preventive measures for patients with various types of genetic polymorphism [36].
The analysis of the medical literature showed the absence of the uniform opinion concerning VTEC prevention for patients with genetic thrombophilia. The necessity for higher (medical) preventive dosages of anticoagulants is a significant difference during prevention of venous thrombosis in some groups of patients with genetic mutation in the hemostasis system as compared to patients without genetic mutations [14].
The problem of prevention of thrombotic complications in patients with genetic thrombophilia is being reviewed, but it has been not solved yet. The results of the study show the necessity for goal-oriented prevention of VTEC with consideration of the risk of possible bleeding after an extensive gunshot wound.

CONCLUSION

This study is the first Russian work dedicated to research of the incidence of allelic variants of the genes of the hemostasis system components and their role in venous thrombosis pathogenesis in patients with combat gunshot injuries. The analysis of the results showed that not all genetic risk factors were related to thrombosis development, despite of high incidence (genetic mutations were found in 91.3 % of military personnel). The potentiation effect allows supposing that the highest possibility of appearance of clinical manifestations of thrombosis should be expected in patients with combinations of several genetic mutations.
It was found that the most significant risk factors of VTEC were FII G20210A mutation, carriage of GpIbα 434C allele and FI-B -455AA genotype. The subsequent studies will possibly identify the unfavorable combinations of prothrombotic variants of various genes increasing the risk of thrombosis development in wounded persons.
The data of presence of military men in the genotype and predisposition to thrombosis can be the basis for identification of risk groups and development of recommendations for prevention and treatment of VTEC in carriers of prothrombotic genotypes.

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