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Positive Correlation Between Platelet Parameters And Genetic Markers of Thrombophilia Panel in Recurrent Pregnancy Loss
Tekrarlayan Gebelik Kaybı Öyküsü Olan Hastalarda Genetik Trombofili Paneli ve Platelet Parametreleri Arasındaki Pozitif Korelasyon
Haktan Bagis Erdem, Ahmet Cevdet Ceylan, Abdulkadir Kaya, Taha Bahsi, Zeynep Sever Erdem, Ibrahim Sahin, Abdulgani Tatar

 

How to cite / Atıf için: Erdem HB, Ceylan AC, Kaya A, Bahsi T, Sever Erdem Z, Sahin İ, Tatar A. Positive Correlation Between Platelet Parameters And Genetic Markers of Thrombophilia Panel in Recurrent Pregnancy Loss. Euras J Fam Med 2018;7(1):19-28

 

Original Research / Orijinal Araştırma


ABSTRACT

Aim: Recurrent pregnancy loss (RPL) defined as 3 or more miscarriages before 20 weeks of gestation by the World Health Organization, and is a common complication during pregnancy, especially for early gestation and affects about 1–5 % of pregnant. In this study, we analyzed mean platelet volume (MPV), platelet count (PLT) values, Factor II g.20210G>A, Factor V Leiden, MTHFR (C677T, A1298C), PAI-1, β-fibrinogen, Factor XIIIA (V34L) and glycoprotein IIIa (L33P) polymorphisms of patients who have RPL history and searched the relationship between genetic thrombophilia markers and platelet parameters in RPL. 

Methods: A retrospective, clinical trial was performed by reviewing the recurrent pregnancy loss history of 229 patients, and 200 controls. The results of the genetic thrombophilia panel were used to classify the study and control group into low, intermediate and high risk for thrombophilia groups. 

Results: Factor II g.20210G>A (p=0.035), Factor V Leiden mutations (p=0.027) and PAI-1 (4G/5G) (p<0.001), β-fibrinogen homozygous polymorphisms (p=0.004) and Factor XIIIA (V34L) homozygous polymorphisms (p=0.001) are significant for recurrent pregnancy loss. According to platelet parameters; additively, there was significant difference between MPV and PLT values of RPL and control group, thrombophilia mutations and polymorphisms also have a significant effect on MPV and PLT values in RPL, according to severity of thrombophilia mutations or polymorphisms (p<0.001). 

Conclusion: Severities of genetic thrombophilia markers have a significant effect on MPV and PLT values in RPL.

Keywords: miscarriage, thrombophilia, platelet

ÖZET

Amaç: Tekrarlayan gebelik kaybı, Dünya Sağlık Örgütü tarafından gebeliğin 20. haftasından önce gerçekleşmiş 3 veya daha fazla gebelik kaybı olarak tanımlanmakta olup, gebelerin %1-5’ini etkileyen yaygın bir komplikasyondur. Çalışmamızda, tekrarlayan gebelik kaybı öyküsü olan hastaların, ortalama platelet hacmi, platelet sayısı ve genetik trombofili paneli (Factor II g.20210G>A, Factor V Leiden, MTHFR (C677T, A1298C), PAI-1, β-fibrinogen, Factor XIIIA (V34L), Glycoprotein IIIa (L33P)) analiz edilerek, tekrarlayan gebelik kayıplarında platelet parametreleri ve genetik parametreler arasındaki ilişki araştırılmıştır. 

Yöntem: Çalışma için, tekrarlayan gebelik kaybı öyküsü olan 229 hasta ve 200 kontrol üzerinde retrospektif klinik çalışma planlanmıştır. Genetik trombofili panelinin sonuçlarına göre hasta grubu yüksek, orta ve düşük riskli olmak üzere 3 gruba ayrılmıştır. 

Bulgular: Factor II g.20210G>A (p=0,035) ve Factor V Leiden (p=0,027) mutasyonları, MTHFR (C677T, A1298C) polimorfizmleri (p<0,001), PAI-1 (4G/5G) polimorfizmi (p<0.001), β-fibrinogen’in homozigot polimorfizmi (p=0,004), Factor XIIIA (V34L)’nin homozigot polimorfizmi (p=0.001), tekrarlayan gebelik kayıpları açısından risk faktörü olarak değerlendirilmiştir. Ortalama trombosit hacmi (p<0,001) ve platelet sayısı (p=0,001) açısından hasta ve kontrol grubu arasında anlamlı fark vardır. Bunun yanında yüksek, orta ve düşük risk gruplarının ortalama platelet hacmi ve platelet sayısı arasında da anlamlı fark bulunmuştur (p<0,001). 

Sonuç: Tekrarlayan gebelik kayıplarında genetik trombofili parametrelerinin şiddeti ile MPV ve PLT değerleri arasında anlamlı bir ilişki mevcuttur.

Anahtar kelimeler: gebelik kaybı, trombofili, trombosit


Introduction

Recurrent pregnancy loss (RPL) defined as 3 or more miscarriages before 20 weeks of gestation by the World Health Organization (1), and is a common complication during pregnancy, especially for early gestation and affects about 1–5% of pregnant (2). The adverse effects of RPL causes both physical and psychological traumas for pregnant women. In addition to this, an event of miscarriage is related with an increased risk of miscarriage in a subsequent pregnancy (3). Because of these reasons, the underlying pathophysiological mechanism of RPL should be elucidated with large numbers of patients. Although the etiology of RPL is undefined in 50% of cases, several identifiable risk factors of RPL have been determined, such as genetic, anatomic, immune, endocrine and infectious defects, in up to 30–50% of cases (4). The causes of RPL still remain unexplained after comprehensive investigations.

According to genetic reasons of RPL, chromosomal abnormalities and thrombophilia are well known factors (5). Genetic thrombophilia markers comprises important part of thrombophilia. Some studies mentioned the strong association between the two most common gene mutations (FV c.1691G>A (Leiden), FII g.20210G>A) and RPL (6,7). Factor V is a large single-chain glycoprotein, used in coagulation cascade and controlled by activated protein C. The most common Factor V variation (c.1691G>A), which causes to a p.Arg506Gln amino acid exchange, leads to Factor V resistance to activated protein (8,9). Factor II converts fibrinogen into fibrin with its vitamin K-dependent glycoprotein structure. The most common variation of Factor II (g.20210G>A), leads to increased plasma prothrombin levels (10). In terms of MTHFR mutations, the hyperhomocysteinemia is a significant risk factor for RPL (11). Furthermore, MTHFR (C677T, A1298C) polymorphisms are also associated with neural tube defects (12). Although, the 4G/5G or 4G/4G polymorphisms of PAI-1 have been reported as risk factor of RPL in studies from different populations, some studies did not find significant difference from controls (11,13-15). Polymorphisms of the beta fibrinogen gene have been shown to affect plasma fibrinogen levels and the risk of RPL, as a result of placental thrombosis (16). A common G-to-T polymorphism in exon 2 causes the alteration of Val to Leu for FXIII Val34Leu polymorphism, which could impact the cross-linking activity and clot stability leading to abnormal blood clotting (17,18). Neverthe-less, the relationship between the FXIII Val34Leu polymorphism and RPL is still controversial. Some studies suggested that, the FXIII Val34Leu poly-morphism had a positive relationship with RPL and carriers of the Factor XIII polymorphism might be at an increased risk of RPL (19). On the contrary, the other studies showed that Factor XIII Val34Leu genetic variation was not associated with recurrent spontaneous abortion (20-23). Platelet glycoprotein IIb/IIa, a membrane receptor for fibrinogen and von Willebrand factor, has been implicated in the pathogenesis of thromboembolism but has not been determined as a risk factor for RPL, because of variable results from different publications (24-26).

Platelet parameters have an important role in the pathogenesis of vascular diseases (27). One of the most important platelet parameter, platelet count (PLT), was increased in RPL compared with healthy controls (28). Platelet volume (MPV) is a parameter of platelet function, and a positive indicator for platelet activity (29), which is determined by producing more thromboxane A2, platelet factor 4 and thromboglobulin (29,30). Platelet volume and density are formed by the bone marrow megakaryocyte, which is progenitor cell of platelet at thrombopoiesis. Size of platelets do not change in blood circulation (31,32).Relationship between increasing values of MPV, and RPL have been reported (33). Platelet volume has a relationship with increased platelet synthesis (34).

In this study, we analyzed MPV, PLT values, Factor II g.20210G>A, Factor V Leiden, MTHFR (C677T, A1298C), PAI-1, β-fibrinogen, Factor XIIIA (V34L) and glycoprotein IIIa (L33P) polymorphisms in patients who have RPL history and searched the relationship between genetic thrombophilia markers and platelet parameters in RPL.

Methods

Patient Selection

A clinical trial was performed by reviewing the RPL history of 229 patients, referred to Medical Genetics Department, from January 2014 to December 2015. Our control group included 200 age-matched healthy individuals who do not have coagulative disease history. All patients provided written informed consent before participating in the study. The choosing criteria of the study group were between 18-40 years, a history of 3 or more miscarriages before 20 weeks of gestationwith no other systemic or autoimmune diseases, the absence of any uterine anomaly, no sign of lower genitourinary infection, and the presence of hereditary thrombophilia. All of the patients were chosen after underwent a complete systemic examination and received chromosomal test to exclude balanced chromosome problem. MPV and PLT values of patient group, which were analyzed before RPL events, recorded from archive system. We chose the subjects, who did not use medications affecting platelet functions such as nonsteroidal anti-inflammatory drugs, oral contraceptives, hormonal medications, anti-platelet and anti-coagulant medications. For both RPL and control groups; biochemical thrombotic markers, such as activated protein C resistance, protein C and S deficiency, anticardiolipin antibodies or lupus anticoagulant negative individuals were selected. All patients provided written informed consent before participating in the study, which was approved by the Ethical Committee of the Ataturk University (decision number; 2016-1/13).

Genotyping Polymorphisms

Blood samples were collected into EDTA tubes. DNA of patients was extracted by QIAGEN®, EZ1® Advanced XL (Veltek Associates, Inc.) system. The PCR reactions were performed in 50 µl reaction mixture containing 18.5 µl PCR master mix (Qiagen GmbH, Hilden Germany), 2 µl of each primer, 2.5 µl Taq DNA polymerase, 17 µl H2O and 10 µl DNA in a thermal cycler (SensoQuest Labcycler, GmbH, Hilden, Germany) under the following conditions: 95 °C  for 15 min (initial denaturation) followed by 32 cycles at 94 °C for 1 min (denaturation), 56 °C for 1 min (annealing), 72 °C for 80 s (extension), and a final extension at 72 °C for 15 min. Factor II g.20210G>A, Factor V Leiden, MTHFR (C677T, A1298C), PAI-1, β-fibrinogen, Factor XIIIA (V34L) and glycoprotein IIIa (L33P) polymorphisms were analyzed by a pyrosequencing system (QIAGEN®, Pyromark Q24) with the specific primers. Results were evaluated with PyroMark Q24 Advanced Software (Fig 1).

Grouping Criteria

The results of the thrombophilia panel were used to classify the study group and control group into low, intermediate and high risk for thrombophilia groups. The high-risk group included patients homozygous/ heterozygous for Factor II g.20210G>A or Factor V Leiden mutations with/without any other polymorphism. The intermediate-risk group included patients homozygous or compound heterozygous for MTHFR (C677T, A1298C) with any other polymorphism, without Factor II g.20210G>A or Factor V Leiden mutations. The low-risk group included patients heterozygous for MTHFR (C677T, A1298C) and heterozygous or homozygous for PAI-1, β-fibrinogen, Factor XIIIA (V34L) and glycoprotein IIIa (L33P) polymorphisms without Factor II g.20210G>A or Factor V Leiden mutations.

Mutation Score

In low risk groups of patient and control groups, we accepted heterozygous polymorphisms as 1 point and homozygous polymorphisms for 2 points and calculate a total point in scoring. 

Measurement of MPV and PLT Values

For patient group (before RPL events) and control group two MPV and PLT had been recorded by three months, from archive system; than average of two values were calculated for two groups. The platelet parameters (MPV, PLT) were determined using automated hematology analyzer (LXP50; Beckman Coulter, Brea, CA). Patients were instructed not to take alcohol or cigarette or engage in heavy exercise for 24 hours.

Statistical Analysis

All analyses were performed using the Statistical Package for Social Sciences (SPSS version 15.0) and the statistical significance level was defined as pCategorical data, such as average and standard deviation were given as numerically and percentages. Chi-square test, Mann-Whitney U test and Student t test were used as hypothesis test.

Figure 1. Pyrosequence images of thrombophilia mutations and polymorphisms

Results

229 patients, who have RPL history and genetic thrombophilia factors was compared with 200 participants in control group who had not experienced thromboembolic event. The median age of patient group was 29.2 (29.29±5.93), and the median age of control group was 33.5 (29.37±5.90). 

Thrombophilia risk groups have separated to high, intermediate and low risk groups according to Cunningham et al., Robertson et al., Rosendaal et al., with mean MPV and mean PLT values in Table 1 (35-37). Of the 229 patients and 200 controls; 39 (17%) of patients and, 15 (7.5%) of controls who were determined as a high risk group, had Factor II g.20210G>A or Factor V Leiden homozygous/ heterozygous mutations with/without any other polymorphism. 86 (37.6%) of patients and, 52 (26%) of controls, who were determined as intermediate risk group, had homozygous or compound heterozygous polymorphisms of MTHFR (C677T, A1298C) with any other polymorphism, without Factor II g.20210G>A or Factor V Leiden mutations. 104 (45.4%) of patients and, 133 (66.5%) of controls, who were determined as low risk group, had heterozygous polymorphisms of MTHFR (C677T, A1298C) and heterozygous or homozygous polymorphisms of PAI-1, β-fibrinogen, Factor XIIIA (V34L) and glycoprotein IIIa (L33P), without Factor II g.20210G>A or Factor V Leiden mutations.

Table 1. Summary of descriptive statistics for the groups

According to results, there were a significant difference in Factor II g.20210G>A (p=0.035) and Factor V Leiden (p=0.027) mutation rates, MTHFR (C677T, A1298C) polymorphism rates (p<0.001), PAI-1 (4G/5G) polymorphism rates (p<0.001), β-fibrinogen polymorphism rates (p=0.004) and Factor XIIIA (V34L) polymorphism rates (p=0.001) between patient group and control group. There was not a significant difference in glycoprotein IIIa (L33P) polymorphism rates between patient group and control group (p=0.184) (Table 2). There was a significant difference between total polymorphism scores of control group and patient group (p<0.001) (Table 1).

Table 2. Summary of descriptive statistics for the polymorphism

In addition, there was significant difference between MPV (p<0.001) and PLT (p=0.001) values of RPL and control group values; there was also significant difference between low, intermediate and high risk group patients, in terms of MPV (p<0.001) and PLT (p<0.001) values (Table 1).

Discussion

By reason of hemostatic disturbances in pregnancy, the thrombophilia risk, which is increased in pregnancy with hemostatic disturbances, causes obstetric complications such as miscarriages, intrauterine fetal death in early gestational age, and abruptio placentae or preeclampsia in the second or third trimester. The decrease in antithrombotic factors and increase in prothrombotic factors result in modification of the hemostatic equilibrium in placental vessels, causing inadequate fetomaternal circulation and placental perfusion (38). The most common polymorphism studied for association with RPL is Factor V Leiden (36). Rosendaal et al. reported that, the risk of venous thrombosis is increased 7-10 times with heterozygous mutation of Factor V Leiden, and about 100 times higher risk with homozygous mutation of Factor V Leiden (37). It is also reported that, the risk of venous thrombosis is increased 2-19 times with heterozygous mutation of Factor II g.20210G>A, and about 26 times higher risk with homozygous mutation of Factor II g.20210G>A (35,36). According to MTHFR gene, the risk of venous thrombosis is increased 1-3 times with homozygous or compound heterozygous mutations of MTHFR (C677T, A1298C) mutations (35,36). Effect of Factor II g.20210G>A, Factor V Leiden and MTHFR (C677T, A1298C) mutations on venous thromboembolism is widely accepted, but effect of the other polymorphisms (PAI-1, β-fibrinogen, Factor XIIIA (V34L), glycoprotein IIIa (L33P)), which are performed in the present study, are still controversial, and not well explained. Factor V Leiden mutation prevalence was reported between 5-8% in United States (39), its prevalence in Turkey is approximately 10% (40). In the present study we found prevalence of Factor V Leiden mutation 12.2% in RPL group and 6% in control group. Although, prevalence rate of Factor II g.20210G>A mutation in Turkey is 2.6% (41), we found prevalence of Factor II g.20210G>A mutation 4.8% in RPL group and 1.5% in control group. These results showed us Factor II g.20210G>A and Factor V Leiden mutations are important risk factors for RPL.

American College of Obstetricians and Gynecologists (ACOG) suggests screening Factor V Leiden, Factor II g.20210G>A, protein C, protein S, and antithrombin III for RPL (42) Most physicians order these tests; but some of physicians also order MTHFR (C677T, A1298C), PAI-1, β-fibrinogen, Factor XIIIA (V34L), glycoprotein IIIa (L33P) polymorphisms, although not recommended according to the ACOG. In our study, we also performedMTHFR (C677T, A1298C), PAI-1, β-fibrinogen, Factor XIIIA (V34L), glycoprotein IIIa (L33P) polymorphisms.

Association of the low risk group polymorphisms in the present study (PAI-1, β-fibrinogen, Factor XIIIA (V34L) and glycoprotein IIIa (L33P)) with RPL is not as clear as Factor II g.20210G>A and Factor V Leiden or MTHFR (C677T, A1298C) (35-37). Therefore, in the present study, these polymorphisms were scored for each low risk group patients, to understand the effect of them in RPL. Homozygous polymorphisms were scored as 2 points; each case. As a result, there was a significant difference between polymorphism score of control group and RPL group. When these polymorphisms compared one by one between RPL group and patient group; there was a significant difference in PAI-1 (4G/5G), β-fibrinogen and Factor XIIIA (V34L) polymorphisms in our study. In spite of our results, these polymorphisms (PAI-1, β-fibrinogen, Factor XIIIA (V34L) and glycoprotein IIIa (L33P)) are still controversial in terms of RPL due to a lot of published studies with different results.

The present study also emphasizes the association between RPL and MPV, PLT levels, which are thought to function as inflammatory markers for various diseases. MPV is an important platelet parameter, because larger platelets are more reactive and more prone to aggregation than the smaller platelets (43). Previous studies showed that PLT value, which is the other platelet parameter of present study, reduced in RPL compared with healthy controls (44). We also demonstrated that the MPV and PLT levels of RPL were higher than normal controls in our study.

Previously, relationship with platelet parameters and thrombophilia mutations (Factor II g.20210G>A, Factor V Leiden and MTHFR (C677T, A1298C))were investigated in recurrent pregnancy loss [28]. Aynıoglu et al. reported that, MPV and PLT values were higher than the control group; but the more important result was, MPV and PLT values of the patients, who have thrombophilia mutations were higher than the patients, who do not have thrombophilia mutations. This relationship was also investigated in ischemic stroke group as an arterial thrombotic event by our research group, but there was not a significant difference (45). In the present study, MPV and PLT values of thrombotic risk groups (low-intermediate-high) were compared in each other and also with control group, for understanding the relationship between platelet parameters and thrombotic risk groups in RPL.

Conclusion

In conclusion, there was a significant difference between MPV and PLT values of RPL and control group, thrombophilia mutations and polymorphisms also have a significant effect on MPV and PLT values in RPL, changing according to severity of thrombophilia mutations or polymorphisms. 

Acknowledgement

This study was presented as an oral presentation at the 12thNational Medical Genetics Congress, 5-9 October 2016 İzmir Turkey.No conflict of interest was declared by the authors.

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