Startseite Frequency of Thrombophilic Gene Mutations in Patients with Deep Vein Thrombosis and in Women with Recurrent Pregnancy Loss
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Frequency of Thrombophilic Gene Mutations in Patients with Deep Vein Thrombosis and in Women with Recurrent Pregnancy Loss

  • Mahmoud Mohamed Elgari EMAIL logo , Nadir Ahmed Ibrahim , Abdel Rahim Mahmoud Muddathir , Faris Mergheni Eltoom und Ibrahim M Ibrahim
Veröffentlicht/Copyright: 10. Mai 2017
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Open Life Sciences
Aus der Zeitschrift Open Life Sciences Band 12 Heft 1

Abstract

Thrombophilia may be anticipated by single or combined hereditary defects in encoding genes factor V, Prothrombin, and MTHFR. The aim of this study was to determine the prevalence and associated risks of V Leiden (G1691A), Prothrombin (G20210A), and MTHFR (C677T) mutations in Saudi women with Deep Vein Thrombosis (DVT) and women with recurrent pregnancy loss (RPL). Protein C and protein S activity were measured to determine combined effects, if any. We examined 60 women with a history of DVT and 60 with RPL, extracted DNA from EDTA blood and determined three mutations by using multiplex PCR reactions followed by Strip Assay KIT. Pro C Global assay was used to determine the cutoff value [PCATNR = 0.80]. Protein C/S chromogenic assay was used to estimate protein C and S percentages. Frequency of Factor V Leiden G/A genotype in patients with DVT 7 (11.6%) had a significant association for DVT χ2 (OR = 5.1, P = 0.03). In women with RPL the three mutations did not show any significant association, levels of Protein C, protein S and PCAT-NR in patient groups not different from controls (P > 0.05). In conclusion, we recommend expanding on these data to provide larger-scale studies.

Keywords: DVT; Factor V (G1691A); Prothrombin (G20210A); MTHFR (C677T); RPL; PCA-NR

1 Introduction

Deep vein thrombosis (DVT) usually affects the deep leg veins, and although men have increased risk of recurrent thrombosis, both males and females are equally affected by a first thrombosis, [1]. The incidence rate of DVT is low in children. While pregnancies have a higher risk of venous thrombosis than non-pregnant women of matched age [2]. The incidence appears to be increased in the postpartum period [3]. The possible increased risk of recurrent pregnancy loss or deep vein thrombosis can be classified as acquired or genetic risk factors, when genetic defects are combined with one or more acquired risk factors it results in a risk of DVT that exceeds the separate effects of a single factor [4]. Hereditary factors including Factor V Leiden, Prothrombin, and Methylenetetrahydrofolate reductase gene mutations are valuable molecular markers used in evaluation of venous thrombosis predisposition. [5]. Factor V Leiden is a common mutation among Caucasians and Middle-Easterners, and with a moderate prevalence is found in Hispanic Americans, Indians, and African. Interest in the genetic basis of thrombosis was accelerated with the discovery of the factor V Leiden (FVL) mutation G1691A, which is considered to be the most common genetic risk factor. This mutation is characterized by a single point mutation adenine for guanine (A>G) at nucleotide position at 1691 in the gene coding for factor V [6]. This condition results in (FVL) that cannot be as easily degraded by aPC (activated Protein C), leading to longer persistence of activated factor V in blood circulation, increasing the risk of developing venous thrombosis [7]. The activated protein C resistance (APCR) defect resulting from factor V Leiden is the most common genetic defect associated with deep vein thrombosis, occurring in the normal population and in patients with documented thrombophilia [8]. Protein S, protein C and anti-thrombin accounted for 12-15% thrombophilia [9].

As reported previously Prothrombin gene mutation G20210A with increased prothrombin production, considered as hereditary risk factor for deep vein thrombosis after the factor V Leiden mutation [10]. Roosendaal et al, 1998 found high prevalence of heterozygous prothrombin G20210A gene mutation, which is reported as common risk in European population and found to be as the most cause of heritable deep vein thrombophilia [11, 12]. The MTHFR mutations described as heterozygous C677T or homozygous C677TT, found that about ten percent of the North American population are homozygous for this polymorphism. MTHFR gene mutation reduces the enzyme activity and increases hyperhomocysteinemia could be risk factor and associated with a coronary artery disease or deep vein thrombosis [13].

2 Materials and Methods

2.1 Study subjects

A total of 120 Saudi hospitalized female patients was diagnosed at Madina Maternity & Children Hospital, Saudi Arabia from Aug 2014 to Aug 2015. 60 had DVT and 60 had (RPL) of ≥ 2 consecutive fetal losses before 20 weeks of gestation, all patients were Saudi individuals. The mean age was 38 ± 12 years. Eighty apparently healthy age-matched females without any personal or family history of venous thrombosis or recurrent pregnancy loss were included as control subjects.

Ethical approval: The research related to human use has been complied with all the relevant national regulations, institutional policies and in accordance the tenets of the Helsinki Declaration, and has been approved by the Research Ethical Committee of Madina Maternity & Children Hospital, Saudi Arabia (IRB No: 12).

Informed consent: Informed consent has been obtained from all individuals included in this study.

2.2 Detection of the three mutations

Five ml EDTA blood and 2 ml citrate blood samples were collected from each individual in the hematology section. DNA was extracted from EDTA blood by using a column based extraction kit (NLM code AA1001). PCR of target mutant fragments FV G1691A (Leiden), prothrombin G20210A and MTHFRC677T was amplified by the multiplex PCR reaction, three mutations were determined by using Cardiovascular Disease (CVD) StripAssay (Vienna Lab, Austria) as described by the manufacturer. The thermocycler program consisted of an initial step denatured followed by 35 cycles for CVD assay at 95°C for 30 seconds and at 95°C for 15 seconds, annealing at 60°C for 30 seconds, and extension at 72°C for 45 seconds and at 72°C for 2 minutes. Each biotinylated amplified PCR product hybridized to the test strip with allele-specific oligonucleotide probes for wild type or mutant alleles. Bound biotinylated sequences were determined in addition to streptavidin - alkaline phosphatase and color substrates. Wild and mutant type bands for each mutation were visualized on the membrane of the strip. For each mutation, one of the following patterns should be obtained: normal genotype (only wild type one line), heterozygous genotype (wild type and mutant 2 lines), homozygous genotype (only mutant one line).

2.3 Pro C Global assay(Behring Diagnostics)

A new screening test for the protein C system such as the presented Pro C Global is highly sensitive to activated protein C resistance/FV Leiden, protein C deficiency and sensitive to protein S deficiency. Principally it is activated through a partial thromboplastin time (APTT) based assay in which Protac snake venom is used for activation of the endogenous protein C in the plasma sample. The protein C activation time in the presence of the activator (PCAT) and in the absence of activator PCAT/0 was estimated by the COBAS coagulation analyzer to obtain patient protein C activation time normalized ratio ( PCAT - NR ). The normal range of the Pro C Global Assay with an appropriate cutoff [PCAT-NR = 0.80] can detect all patients with the Factor V Leiden mutation.

2.4 Protein C/S Chromogenic assay

Principally the method of protein C/S system US 5726028A was used, in which the test citrate plasma is treated with a venom-derived activator and the concentration of Protein C is determined from the rate of color change in the test sample due to cleavage of a chromogenic substrate. The amount of functional protein C produced is measured spectrophotometrically. Results are reported as % protein C activities. Reference range: 70 - 130%. Chromogenic assay for determination of Protein S based on that Factor Xa was used as an indicator for measurement of Protein S concentration. This technique utilizes activated Protein C on Protein S in order to inactivate a known portion of Factor VIII. Residual Factor VIII is then activated and acts with Factor IXa to activate Factor X. The chromogenic substrate is then cleaved by Factor Xa and the rate of conversion of the indicator molecule is proportional to Protein S concentration. Reference range: 60 - 140%.

2.5 Statistical Analysis

Data were analyzed using SPSS software, Version 20. Chi-square or student’s t test were used to compare between variables. Data are reported as mean ±SD for continuous variables or as percentages. Statistical significance was set at < 0.05.

3 Results

The frequency and prevalence of the heterozygous Factor V Leiden G/A mutant genotype in patients with DVT was 7 (11.6%), and showed significant association with deep vein thrombosis compared to controls χ2, P = 0.03, OR = 5.1. In contrast, the frequency and prevalence of heterozygous prothrombin G/A mutant genotype in patients with DVT was 3 (5%), which was not significant χ2, P = 1.0, OR= 0.789. The frequency and prevalence of the heterozygous MTHFR C/T mutant genotype in patients with DVT was 6 (10 %), which was not significantly different from controls χ2, P= 0.558, OR= 1.6 (Table1).

Table 1

The frequency and association of FV Leiden G1691A, Prothrombin G20210A and MTHFR C677T mutations in patients with DVT (n = 60)

MutationGenotypeControlsPatientsORP
FV LeidenG/G7853
G/A2(2.5%)7(11.6%)5.10.03
Proth. G20210AG/G7557
G/A5(6.2%)3(5%)0.7891.0
MTHFR C677TC/C7354
C/T7(8.7%)6 (10%)1.60.558

Our results of the prevalence of heterozygous Factor V Leiden mutation genotype G/A in patients with RPL was 4 (6.6%), which was not significantly associated with RPL: χ2= 0.91, P= 0.8, OR= 0.75. While heterozygous prothrombin mutant genotype G/A in patients with RPL was 2 (3.3%) compared to controls, which difference was not statistically significant: χ2= 0.966, P= 0.4, OR= 0.4. The prevalence of heterozygous MTHFR mutant genotype C/T among patients with RPL 3 (5%), which was notstatistically significant : χ2= 0.28, P = 1.0, OR= 1.1 (Table2).

Table 2

The frequency and association of FV Leiden G1691A. Prothrombin G20210A and MTHFR C677T mutations in patients with RPL (n = 60)

MutationGenotypeControlsPatientsORP
FV LeidenG/G7456
G/A6(7.5%)4(6.6%)0.80.75
Proth. G20210AG/G7558
G/A5(6.2%)2(3.3%)0.40.4
MTHFRC677TC/C7757
C/T3(3.7%)3(5%)1.11.0

Levels of Protein C, protein S and PCAT-NR in patient groups did not differ significantly from controls ( P > 0.05) (Table3).

Table 3

Levels of Protein C, protein S and PCAT-NR in DVT (n=60) and RPL (n=60) patients compared to controls (n=80)

ParameterSubjectMean ± SDP.V.
Protein C%DVT107.0 ± 25.5
Controls108.5 ± 28.50.758
Protein S%DVT86.0 ± 30.4
Controls87.3 ± 30.60.812
PCAT-NRDVT0.97 ± 0.21
Controls1.99 ± 0.180.548
Protein C%RPL105 ± 39
Controls106 ± 290.596
Protein S%RPL90 ± 28
Controls87 ± 310.626
PCAT-NRRPL0.98 ± 0.13
Controls1.0 ± 0.190.906

4 Discussion

Thrombosis occurs as a result of a defect in the blood clotting system. Therefore, it is crucial to determine the frequencies and risks of the most common mutant genes causing deep vein thrombosis or recurrent pregnancy loss. In the present study we determined the frequencies of the FV Leiden G1691A, Prothrombin A20210G and MTHFR C677T mutant genotypes in Saudi female patients with deep vein thrombosis and in women suffering recurrent pregnancy loss. We found the frequencies and the prevalence of the three gene mutations in patients with deep vein thrombosis were FV Leiden G/A 7 (11.6%), Prothrombin A/G 3 (5%) and MTHFR C/T 6 (10%) respectively. We found that the FV Leiden G/A genotype was significantly associated with DVT; these findings are in agreement with studies that concluded that Factor V Leiden G/A genotype is associated with deep vein thrombosis [14]. Likewise, other investigators determined the high prevalence of FVL G1691A mutation and indicated as risk factors of venous thrombosis, some researchers stated that the prevalence of this mutation increased among patients with deep venous thrombosis[15]. New reports determined the frequency of factor V Leiden mutation in the European population as about 5% and about 20% in patients with venous thrombosis [16]. While the prevalence of heterozygous prothrombin G20210A genotype among Saudi patients with DVT was 3 (5%) in agreement with those who suggested an insignificant association between prothrombin G20210A and DVT [17]. Heterozygous MTHFR C677T genotype among Saudi female patients with DVT was 6 (10%) and did not reach the significance level (P = 0.558), in agreement with a previous report stating that there is no association between MTHFR C677T and DVT [18]. Several studies revealed that the association between MTHFR C677T and the increased risk of VTE is still controversial [19].

Others suggest that the risk of this mutation is weak, increasing in older patients and with co- inheritance with other mutations. We found the frequencies and the prevalence of the heterozygous FVL, Prothrombin G20210A, and MTHFRC677T genotypes in Saudi patients with RPL were 4 (6.6%), 2 (3.3%), and 3 (5%), respectively. We observed that the heterozygous mutant Factor V Leiden G1691A genotype in patients suffering recurrent pregnancy loss (RPL) was not significantly different from controls (P = 0.75) and did not reveal an association with RPL, which is inconsistent with a study by Ahmad et a l2013 [20]. By contrast, Kobashi et al., 2005 did not find the FV Leiden mutation in Japanese women with RPL [21]. We found the frequency of heterozygous prothrombin G20210A mutant genotype among recurrent pregnancy loss patients was not different from controls (P = 0.4), in agreement with data reported by several investigators showing a non-significant association between patients and controls [23,24]. The prevalence of MTHFR C677T was 3 (5%), which was not statistically significant (P = 1.0), in which is in agreement with a genetic study that did not find any correlation between the prevalence of heterozygous MTHFR C677T genotype in female patients with RPL and healthy women [23]. We did not find any significant differences in protein C, Protein S activity and PCAT-NR in patient groups compared to control groups, except in 7 patients(11.6%) with deep vein thrombosis who were positive for FV Leiden G1691A and showed that PCAT-NR < 0.80 below the cutoff level.

5 Conclusion

High frequency of heterozygous factor V Leiden mutation G/A genotype is significantly associated with DVT. Prothrombin G20210A and MTHFR C677T mutations had a lower impact on the risk of DVT and RPL. Levels of Protein C, Protein S and PCAT-NR did not show significant differences in patient groups compared to controls.

Acknowledgements

The Authors thank the Deanship of Scientific Research Taibah University, for funding this project (Grant 1435/6181); a lot of thanks to Miss. Bayan Saleem Al-hazmi for her support in samples collection. Wealso thank Dr. Atef Albooq.

  1. Conflict of interest: Authors state no conflict of interest

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Received: 2017-1-14
Accepted: 2017-3-17
Published Online: 2017-5-10

© 2017 Mahmoud Mohamed Elgari et al.

This work is licensed under the Creative Commons Attribution-NonCommercial-NoDerivatives 3.0 License.

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https://doi.org/10.1515/biol-2017-0019
Schlagwörter für diesen Artikel
DVT; Factor V (G1691A); Prothrombin (G20210A); MTHFR (C677T); RPL; PCA-NR
Creative Commons
BY-NC-ND 3.0

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Heruntergeladen am 18.9.2025 von https://www.degruyterbrill.com/document/doi/10.1515/biol-2017-0019/html
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