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56
UDC 616-005.6/7:575.224:613.99:618.2
APC-RESISTANCE ON THE BACKGROUND OF COMORBID STATES AS A POSSIBLE VTEC PREDICTOR IN THE CARRIERS OF FACTOR V LEIDEN MUTATION DURING PREGNANCY
1 Altai State Medical University, Barnaul
2 National Medical Research Center of Hematology, Barnaul
M.G. Nikolaevai, A.P. Momot2, A.V. Molchanovi
The aim of the study is to determine the role of factor Va resistance to activated protein C and comorbidity in carriers of the FVL (1691) GA mutation in the realization of venous thromboembolic complications (VTEC) during pregnancy. A prospective clinical cohort study of 1100 women of reproductive age was conducted, the course and outcomes of 2,707 pregnancies were analyzed. Two cohorts were identified: the main group - 500 patients with genotype FVL (1691) GA and control group - 600 women, with the genotype FVL (1691) GG. The carriage of the FVL (1691) GA mutation in pregnancy is statistically significantly associated with the development of VTEC compared with the genotype FVL (1691) GG (RR4.7, p <0.0001). In all cases, in the time period preceding the thrombosis episode, the APC resistance index for the normalized ratio (NR) was <0.49, while for APC resistance with NR >0.5, episodes of VTEC were not determined. When VTEC occurs during gestation, carriers of the FVL (1691) GA mutation are significantly more likely to suffer from comorbid conditions (RR4.5, p <0.0001). It was found that venous thromboses during gestation are realized under the condition of pronounced APC-resistance caused by the carriage of the FVL (1691) GA mutation and comorbidity. The indicator of APC-resistance can serve as an objective laboratory marker determining the feasibility of conducting antenatal thromboprophylaxis. Key words: factor V Leiden mutation, genotype FVL (1691) GA, thromboembolic complications, pregnancy, comorbidity, APC-resistance.
The discussion of issues related to the study of risk factors for thromboembolic events during pregnancy has invaluable practical significance. Accumulated knowledge suggests that today it is not possible to consider VTEC in isolation, in the context of either just a genetic predisposition or taking into account only certain proven risk factors. A thrombotic event represents the tip of the iceberg, the clinical implementation of the totality of the whole spectrum of congenital and acquired risk factors with their combined influence.
The gestation period is associated with a significant procoagulant shift in the balance of the he-mostasis system, as well as with other metabolic changes [1-2]. The relative risk (standardized incidence rate) of VTEC [3-4] in pregnant women or women after childbirth ranges from 4 to 4.5. The first 6 weeks after birth are associated with a 22-fold increase in risk, with a peak observed in the first 3 weeks [5-6].
The carriage of mutations of factor V Leiden (FVL(1961)GA) is traditionally considered as a genetic, unmodifiable risk factor for the development of VTEC [7-9]. Moreover, the risk stratification is based on the zygosity of the mutation: FVL(1961) AA carriage is defined as high risk, and FVL(1961) GA carriage is moderate [10-12]. The implementation of VTEC in both carrier variants is most often associated with a provoking factor, such as surgery, trauma, postpartum period, immobilization, hormone therapy or chemotherapy, or the coexistence of other risk factors, such as pregnancy, age
and comorbid conditions [13-16]. Examples of co-morbidities that are associated with an increased risk of thrombosis in pregnant women include urinary tract infections [12], cardiovascular diseases [14], pregnancy-induced hypertension/pre-ec-lampsia [13,16], obesity [18-19], varicose veins [17].
Multiple risk factors increase the risk of thrombosis [20], however, to date, the available evidence does not allow an accurate assessment of the risk of developing VTEC based on a combination of various factors [9].
Thus, it is not always possible to predict the degree of probability of the implementation of VTEC with carriage of FVL(1691)GA mutation, based on the already proposed risk stratification. Considering the available data, it is not quite clear why, when predicting the development of clinically significant events, the laboratory phenotype of the FVL(1691)AA/GA mutation does not take into account the resistance of factor Vа to activated protein C (APC-resistance), the magnitude of which, in fact, determines the tendency to intravascular thrombosis.
The ambiguous opinion of researchers about the significance of the heterozygous carriage of the FVL(1961)GA mutation, both independently and in combination with the known temporary risk factors for the development of VTEC, lack of data on the role of the laboratory phenotype in the form of APC-resistance and comorbidity in the implementation of thrombotic events determined the goal of our research.
Research objective: to determine the role of factor Va resistance to activated protein C and comorbidity in carriers of FVL(1691)GA mutation for the realization of venous thromboembolic complications.
Materials and methods
According to the goal, a prospective clinical cohort study of 1,100 women of reproductive age was conducted on the basis of clinical units of the Altai State Medical University of the Ministry of Health of the Russian Federation from 2009 to 2017, and the course and outcomes of 2707 pregnancies were analyzed. Two cohorts were identified: the main group — 500 patients with FVL(1691)GA genotype (mean age 30,2±4,7 years, total number of completed pregnancies — 1085) and the control group — 600 women, normozy-gous for the FVL(1691)GG mutation (mean age 30,3±3,9 years, total number of completed pregnancies - 1622). The groups were comparable in age (p> 0.05) and ethnicity: the main group was 91.2% Russian, the control group - 89.9% (p> 0.05).
Criteria for inclusion in the main group:
- female gender;
- carriage of FVL(1691)GA mutation;
- age from 18 to 45 years;
- confirmed uterine pregnancy with a period of 7-8 weeks, occurred in the natural cycle.
The criteria for inclusion in the control group were the same as in the main group, but the patients did not carry FVL(1691)GA /AA gene.
Exclusion criteria from study groups:
- multiple pregnancies;
- pregnancy occurring in assisted reproductive technology programs;
- somatic diseases in the stage of decompensation;
- autoimmune diseases, including antiphos-pholipid syndrome;
- presence of chromosomal aberrations.
The study was approved by the local ethical
committee of the Altai State Medical University of the Ministry of Health of the Russian Federation (Records No. 5 of 06/25/2009).
Along with the standard methods of examination, regulated by the Order of the Ministry of Health of the Russian Federation dated November 1, 2012 No. 572n "On approval of the procedure for providing medical care in the profile "obstetrics and gynecology (except for using assisted reproductive technologies)", and determining of factor V Leiden mutation, all patients were studied for APC-resistance. Eight points were selected to assess APC-resistance, taking into account tro-phoblast invasion waves and reflecting the "critical" periods of pregnancy: 7-8 weeks, 12-13 weeks, 18-19 weeks, 22-23 weeks, 27-28 weeks, 32-33 weeks, 36-37 weeks and 2-3 days after delivery. It should be noted that this laboratory analysis was carried out in the absence of heparin prophylaxis.
APC-resistance was determined using the "Factor V-PC-test" reagent kit (Technology-Standard LLC, Russia) by the value of the normalized ratio (NR).
Statistical data processing was performed using the MedCalc Version 17.9.7 statistical software package (license BU556-P12YT-BBS55-YAH5M-UBE51). Verification of variation series for normality was performed using the Shapiro-Wilcoxon test. Data of laboratory parameters are presented in the form of a median (Me), 95% confidence interval (95% CI) and interquartile range [25th and 75th percentiles]. Series comparison was performed using non-parametric methods. For indicators characterizing qualitative signs, the absolute value and the relative value in percent were indicated, the verification of statistical hypotheses about the coincidence of the observed and expected frequencies was performed using the x2 criterion and Fisher's exact test. For binary signs, the relative risk (RR) and 95% confidence interval (95% CI) were calculated. The critical level of significance of differences (p) is defined as p <0.05. To analyze the relationship between one qualitative sign (VTEC/absence of VTEC), acting as a dependent, resulting indicator, and a subset of quantitative and qualitative signs, we used a logistic regression model with a step-by-step predictor inclusion algorithm. The results of the evaluation of the logistic regression equations are represented by a set of regression coefficients, the achieved significance levels for each coefficient, as well as an assessment of the agreement index (Concordant) of the actual membership of the patient in one group or another.
Results and discussion
In the present study, out of 500 female carriers of FVL(1691)GA mutation, thrombotic events were recorded in 70 women (14.0% of 500) versus 9 (1.5% of 600) compared with the normozygous FVL(1691)GG genotype (control group), which possesses statistical significance [RR9,3; 95%Cl:4,7-18,5; p<0,0001].
In all nine cases of thrombosis, patients of the control group were diagnosed with DVT. In six of the patients, thrombosis was determined outside of pregnancy and was induced in five cases by taking combined hormonal contraceptives, in one case - by blocking intramedullary osteosyn-thesis for diaphyseal fracture of the tibia (second day of the postoperative period). In three cases, DVT was registered during pregnancy: one episode in the first trimester, two in the postpartum period (the third and sixth days).
In 70 patients-carriers of FVL(1961)GA mutation, 98 episodes of thrombotic events were recorded at various periods of life: in 45 women (64.3% of 70) - a single episode of VTEC; retrombosis (2 or more) in 25 (35.7% of 70) women. In total, thrombotic events occurred outside of pregnancy in 58 (11.6% of 500) women and accounted for 65
episodes, the incidence of retromboses was determined in 12.1% (7 out of 65) of cases. During pregnancy, heterozygous carriage of the FVL(1961)GA mutation was realized by thrombotic events in 33 patients, and in 2/3 (21 out of 33), these were episodes of retromboses.
In the next part of the work, in order to study the somatic status, more than 30 nosological forms were analyzed according to the International Classification of Diseases (ICD), X issue. Diagnosis of the selected conditions was carried out by re-
lated experts in accordance with the directive documents using laboratory, functional and clinical research methods. Analysis of the data showed that patients with a personal history of thrombosis with FVL(1691)GA mutation were statistically significantly more likely to have lower limb varicose veins (LLVV) (ICD code X - I83.9), hypertensive disorders (ICD code X - I11.9), overweight (ICD code X - E66) and chronic inflammatory diseases of the respiratory system (Table 1).
iaDiei Somatic status of patients with a personal history of thrombosis with carriage of FVL(1691)GA mutation
Nosological form Personal history of thromboses n=70 Personal history of thromboses lacks n=430 Statistics
a6c % a6c % P RR 95%CL
Hypertensive heart disease 29 41,4 76 17,7 <0,0001 2,3 1,6-3,3
Obesity and other types of redundancy (BMI >25) 38 54,3 135 31,4 0,0001 1,7 1,3-2,2
Chronic inflammatory diseases of the respiratory system 38 54,3 142 33,0 0,0001 1,6 1,2-2,1
LLVV 39 55,7 155 36,0 0,0005 1,5 1,2-1,9
Further, the relation of comorbidity of the isolated (Table 1) states with the development of VTEC in carriers of FVL(1691)GA mutation was studied. Somatically healthy women with episodes of VTEC in a personal history were not identified
in the study. Comorbid conditions by carriage of FVL(169l)GA mutations were detected in 95.7% (67 of 70) patients with thrombosis in their personal history and 24.4% (92 of 430) in the absence of those [RR 4,5; 95%Cl:3,7-5,4; p<0,0001] (Figure 1).
Figure 1 - Comorbidity in patients - carriers of FVL(1691)GA mutation, depending on the clinical implementation
in the form of thrombotic events.
A more detailed analysis showed that by the implementation of a thrombotic event, hypertensive disorders in 27.6% of cases were combined with overweight, in 41.4% - with LLVV; varicose disease, in turn, was registered in 28.5% of cases against the background of overweight and in 25.6% against
the background of chronic inflammatory diseases of the respiratory organs. The structure of co-morbid conditions is shown in Figure 2. A study of comorbidity by the carriage of FVL(1691)GA mutation showed that a combination of the two nosologies considered increases the risk of thrombosis
during gestation by 4.6 times [RR4,6; 95%Cl:3,7-5,7; p<0,0001], and comorbidity, represented by three
nosological forms, by 3.7 times [RR3,7; 95%Cl:1.5-9.2; p=0,039].
Note: HHD - hypertensive heart disease, CIRD - chronic inflammatory respiratory diseases. Figure 2 - The structure of comorbidity in patients - carriers of FVL(1691)GA mutation by clinical implementation
in the form of thrombotic events.
It should be noted that, despite the presence of an associative, statistically significant association between the carrier of FVL(1691)GA mutation in combination with the identified temporary risk factors, it is unlikely to predict the likelihood of thrombotic events. Given this circumstance, we attempted to consider the importance of the manifested laboratory phenotype of FVL(1691)GA mutation in the form of APC-resistance for the development of thrombotic complications. Since activated protein C is one of the main physiological anticoagulants that break down activated coagulation factors Va and VIIIa, by APC resistance, Va and VIIIa factors become insensitive to the inactivating effect of C protein, which leads to excessive thrombin formation and inhibition of fibrinolysis. The value of APC-resistance, as noted above, in fact, determines the propensity for intravascular thrombus formation [21-22].
In accordance with the data obtained, an explicit connection of APC-resistance in carriers of FVL(1691)GA mutation with the development of VTEC has been determined. Thus, the median NR indicator, reflecting the degree of APC-resistance, preceding the episode of phlebothrombosis in the first trimester (7-8 weeks), constituted 0,49 [95%Cl:0,43-0,49]; in the third trimester (32 weeks) - 0. 48 [95%Cl:0,46-0,49]; on 2nd-3rd day after delivery - 0.44 [95%Cl:0,43-0,48], and was statistically significantly lower than in the group of women with a favorable course of pregnancy (Figure 3).
A multiple logistic regression analysis was performed to rank the selected predictors of FVL(1691)GA mutation according to the degree of association with the implementation of VTEC during pregnancy. Several models were ob-
tained in various clinical situations determined according to the recommended methodology for stratifying the risk of VTEC during pregnancy and in the postpartum period [9]: 1) Asymptomatic patients (who do not have thrombosis episodes); 2) One-time VTEC in history, associated with transient risk factors; 3) Multiple episodes of VTEC in history.
The models were formed through the gradual inclusion of predictor variables, in which five risk factors were selected, significantly more common in pregnant women with FVL(1691)GA mutations with a personal history of thrombosis: hypertensive states, lower limb varicose veins, BMI>25, chronic inflammatory respiratory diseases and "APC-resistance with NR <0.49", preceding a thrombotic event. The categorical response variable is a VTEC fact (presented as a binary value: 1 - yes; 0 - no). Table 2 presents models that have concordant values of more than 80%.
The inclusion of somatic conditions as predictor variables in logit analysis of pregnant carriers of FVL(1691)GA mutation showed that a statistically significant additional risk factor for the development of VTEC is comorbidity, which is determined by the association of hypertensive disorders and LLVV. Thus, with the association of isolated nosologies, the implementation of thrombosis in asymptomatic carriers of FVL(1691)GA mutation mutation is predicted in 71% of cases, and when the predictive variable "phlebothrombosis in history" is added to the model, the implementation of VTEC during the period of gestation is predicted in 89% of observations.
0,7
0,6
0,5
u о
Й
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3
0,4
0,3 -
oo
Carriers of the FVL(1691)GA mutation
(ИГО
oo
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7-8 weeks
32-33 weeks
2nd-3rd day after delivery
- favorable pregnancy course
Д--Д -
pregnancy with VTEC episodes
Notes: median - marker; "box" - inter-quarter span between 25% and 75%; lines - values corresponding to 2.5 and 97.5
percentiles; free elements - emissions. Figure 3 - Values of APC-resistance at control points preceding venous thrombosis by carriage of FVL(1691)GA mutation
It is noteworthy that, according to the predictive models obtained in pregnant women, when the variable "APC-resistance <0.49" preceding the thrombotic event was included, background somatic states lost their statistical significance. In these cases, the manifestation of the laboratory phenotype of FVL(1961)GA mutation was the decisive risk factor for the implementation of VTEC, and thrombosis is already predicted in 85% of asymptomatic women and in 93% of cases with an episode of VTEC in history.
This study showed that carriage of FVL(1961) GA mutation during pregnancy is associated with VTEC and is due to exposure to additional risk factors and/or background somatic pathology.
In accordance with the data obtained, along with the main factor inducing the implementation of thrombotic events (APC-resistance) in carriers of FVL(1961)GA, an important role belongs to background somatic pathology. At the same time, the dominant factors of thrombogenic risk during gestation are the comorbid conditions considered in the study in various combinations.
There are numerous papers in the scientific literature reflecting that the risk of VTEC developing is higher in patients with a non-infectious therapeutic profile, including: cancer, diseases of the cardiovascular system, chronic diseases of the upper respiratory tract and obesity [23-25], which is consistent with our study . However, we have not met any work that determines the risk of thrombosis when one patient combines two or more chronic diseases pathogenetically interrelated or coinciding in time, regardless of the activity of each of them, that is, by comorbid conditions [26].
Comorbid conditions of the cardiovascular system in the form of arterial hypertension and LLVV dominate in the present work, which, probably, along with pronounced APC-resistance, forms the Virchow's triad [27], which determines thrombus formation: endothelial damage (arterial hypertension), decrease in blood flow velocity varicose veins of the lower limbs and increased blood clotting (APC-resistance).
The obtained data on the structure of somatic pathology with comorbidity, in our opinion, are of practical interest from the point of view of the possibility of modifying these risk factors. For example, overweight, a proven risk factor for VTEC [28-29] is a controlled factor, weight correction can not only reduce the risk of developing VTEC [30], but also affect blood pressure indicators [31-34], thereby further reducing the risk of implementation of thrombotic events.
Interestingly, in previously published papers on the subject, APC-resistance and its severity by FVL(1961)GA carriage was not considered as a prognostic factor in the development of clinical events.
Given that in all cases in the period preceding an episode of thrombosis, the NR index was <0,49 [95%Cl:0,41^-0,49], we can note the leading role of APC-resistance, which, together with clinical data, determines the appropriateness heparin prophylaxis.
Logit models with risk factors for the implementation of VTEC by carriage of FVL(1691)GA mutations in various clinical situations lapie z.
... Coefficient Standard Variable ,, > (b) error , Adjusted odds 95% confidence interval p -v ratio (OR) (95% Cl)
Asymptomatic carriers of FVL (1691) GA during pregnancy
Constant term -4,0538
LLVV 1,12792 0,40290 0,0050 3,0892 1,4025- 6,8047
Hypertensive states 1,16268 0,38223 0,0024 3,1985 1,5121- 6,7656
Percentage of concordance 91,40 %
Chi-squared - 29,307; P < 0,0001; AUC=0,71; 95%Cl 0,69-0,73
Asymptomatic carriers of FVL(1691)GA during pregnancy with laboratory phenotype APC-resistance <0.49
Constant term -5,3221
LLVV 0,72249 0,51437 0,1601 2,0596 0,7515 - 5,6444
Hypertensive states 0,60268 0,52296 0,2491 1,8270 0,6555 - 5,0921
APC-resistance <0,49 3,31762 1,04563 0,0015 27,5945 3,554 - 214,231
Percentage of concordance 93,60 %
Chi-squared - 33,415; P < 0,0001; AUC=0,85; 95%Cl 0,80-0,90
Pregnant carriers of FVL(1691)GA with episodes of thrombosis in history
Constant term -4,0054
Hypertensive states 0,93798 0,42215 0,0263 2,5548 1,1169- 5,8439
LLVV 1,02765 0,43265 0,0175 2,7945 1,1968 - 6,5251
Episode of VTEC in 2,50308 0,41229 history <0,0001 12,2201 5,4467 - 27,417
Percentage of concordance 95,60 %
Chi-squared - 29,307; P < 0,0001; AUC=0,89; 95%Cl 0,87-0,93
Pregnant carriers of FVL(1691)GA with episodes of thrombosis in history with laboratory phenotype APC- by NR <0.49
Constant term -6,0866
Hypertensive states 0,61156 0,57227 0,2852 1,8433 0,6004 - 5,6588
LLVV 0,64990 0,56564 0,2506 1,9153 0,6321 - 5,8040
Episode of VTEC in 2,26496 0,57556 history 0,0001 9,6307 3,117 - 29,7568
APC-resistance <0,49 3,45147 1,06639 0,0012 31,5468 3,901 - 255,085
Percentage of concordance 96,80 %
Chi-squared - 49,516; P < 0,0001; AUC=0,93; 95%Cl 0,89-0,98
Conclusion In modern clinical medicine, various diseases lose their mononosological nature, acquiring the status of comorbidity. The data obtained allow the formation of thrombosis-associated co-morbidity, including arterial hypertension, LLVV, overweight (BMI> 25), chronic inflammatory respi- ratory diseases and the carriage of FVL(1961)GA mutation. Obviously, the objective laboratory criterion that determines the risk of implementation of VTEC in this group is the indicator of APC-resistance. Patients so stratified require lifelong clinical examination and allowable modification of controlled factors. The high degree of comorbidity
determines the need for a comprehensive individual approach to the management of each patient, the development of diagnostic criteria, prevention and treatment.
In terms of the preventive nature of personalized medicine, it is necessary to take into account that the heterozygous carriage of FVL(1691)GA mutation against the background of comorbid conditions is:
- risk factor for the development of VTEC in asymptomatic women during pregnancy [RR4,7; 95%Cl:1,5-14,7; р=0,0069];
- indications for determining the severity of APC-resistance.
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Contacts
Corresponding author: Nikolaeva Maria Gennad-yevna, Candidate of Medical Sciences, Associate Professor of the Department of Obstetrics and Gy-necology with the course of FVE of the Altai State Medical University, Barnaul. 656038, Barnaul, Lenina Prospekt, 40. Tel.: (3852) 566869. E-mail: nikolmg@yandex.ru
Author information
Momot Andrei Pavlovich, Doctor of Medical Sciences, Professor, Director of the Altai branch of the National Medical Research Center of Hema-tology, Barnaul.
656000, Barnaul. ul. Lyapidevskogo, 1. Tel.: (3852) 689800 E-mail: xyzan@yandex.ru
Molchanov Aleksandr Vasilyevich, 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: science@agmu.ru
