Genetic heterogeneity of platelet glycoproteins Ia and IIIa is associated with in vitro fertilisation implantation failure

Vlachadis, Nikolaos; Tsamadias, Vasileios; Kouskouni, Evaggelia; Vitoratos, N.; Hatziveis, K.; Economou, Emmanuel

doi:10.3109/01443615.2015.1004528

Cited by 8 publications

(5 citation statements)

References 17 publications

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“…There is accumulating evidence that recurrent miscarriages, as well as IVF-ET failures, share extensive common pathogenetic mechanisms. We have previously reported that genetic heterogeneity of platelet glycoproteins Ia and IIIa associated with platelet-derived thrombophilia is a risk factor for recurrent IVF-ET failures [ 23 ], and subsequently, this finding was also confirmed for spontaneous miscarriages [ 24 ]. Similarly, the associations of proinflammatory PECAM-1 (Leu125Val) and P-Selectin (Thr715Pro) gene polymorphisms with unexplained spontaneous miscarriages as well as IVF-ET failures have been reported [ 25 , 26 ].…”

Section: Discussionmentioning

confidence: 92%

Human Leukocyte Antigen Alleles Compatibility and Immunophenotypic Profile Associations in Infertile Couples

Oikonomou¹,

Vlachadis²,

Tsamadias³

et al. 2023

Cureus

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Introduction: The maternal immune system has a major role in the successful embryo implantation and maintenance of the pregnancy. This study aimed to investigate the maternal immunophenotyping profile (percentage of Natural Killer [NK] cells and the CD4/CD8 [cluster designation] ratio in peripheral blood lymphocytes) and the HLA (Human Leukocyte Antigen)-DQA1 alleles sharing in infertile couples. Methods: This cross-sectional study included 78 women who had experienced at least two spontaneous miscarriages and 110 women with a history of recurrent implantation failures after in vitro fertilization (IVF) or intracytoplasmic sperm injection (ICSI) and embryo transfer (ET) (IVF-ET failures). The NK cell percentage and the CD4/CD8 ratio were determined by flow cytometry. Genotyping of the HLA-DQA1 alleles was carried out for all women and their partners, and couple HLA-DQA1 compatibility was expressed as the percentage of common HLA-DQA1 alleles (totaling 35 alleles) shared between spouses to the sum of the unique alleles observed. Results: In women with recurrent miscarriages, high values (%) of the NK population with a median (interquartile range [IQR]) of 10.3% (7.7% to 12.5%) and CD4/CD8 ratio (1.7) (1.5 to 2.1) were found. In women with IVF-ET failures, the (%) NK population (10.5%) (8.6% to 12.5%) and CD4/CD8 ratio (1.8) (1.5 to 2.1) were similarly increased (p=0.390, and p=0.490, respectively). The proportion of women with >10% NK cells was 53.8% and 58.2% in women with miscarriages and IVF-ET failures, respectively (p=0.554). The prevalence of HLA-DQA1*5 allele carriage was elevated in women with miscarriages as well as those with IVF-ET failures (52.6% and 61.8%, respectively; p=0.206). The proportion of couples with high (>50%) HLA-DQA1 sharing was 65.4% in the group with miscarriages and 73.6% in the group with IVF-ET failures, respectively (p=0.222). The CD4/CD8 ratio was statistically significantly positively correlated with the (%) NK population in women with IVF-ET failures (rho = 0.297, p=0.002) and with the (%) HLA-DQA1 sharing in the group with miscarriages (rho = 0.266, p=0.019). The couples in which both spouses were carriers of the HLA-DQA1*5 allele had an increased probability of high (>50%) HLA-DQA1 compatibility compared with the couples in which neither of the spouses carried the allele in the miscarriage group (OR = 24.3, 95% CI: 3.0 to 198.9, p<0.001), and the IVF-ET failure group (OR = 10.5, 95% CI: 2.2 to 49.8, p<0.001). Conclusion: The peripheral NK (%) population and CD4/CD8 ratio, as well as the prevalence of the HLA-DQA1*5 allele, were elevated in women with recurrent miscarriages and IVF-ET failures. Furthermore, these couples with negative reproductive outcomes had a high percentage of HLA-DQA1 allele similarity. The presence of the HLA-DQA1*5 allele in spouses was strongly associated with overall couple HLA-DQA1 compatibility, implying that it could be used as a surrogate marker for assessing overall immunological compatibility in infertile co...

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Section: Discussionmentioning

confidence: 92%

Human Leukocyte Antigen Alleles Compatibility and Immunophenotypic Profile Associations in Infertile Couples

Oikonomou¹,

Vlachadis²,

Tsamadias³

et al. 2023

Cureus

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“…In a recent pilot study of 60 strictly selected women with unexplained recurrent IVF-ET failures excluding all cases with other known risk factors, we reported an increased occurrence of carriers of the Gpllla-PIA2 allele, in comparison with a control group of 60 fertile women with no history of pregnancy or vascular complications, resulting in an odd ratio of 2.9 and a stronger association for the younger participants [10]. Furthermore, in a previous study in Bulgaria, Ivanov et al [8] also found a 2.6-fold increased risk during the comparison of 67 women with IVF-ET failures with 96 fertile controls [11].…”

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confidence: 75%

“…The Gpllla-PIA2 factor especially in synergy with the 807T allele of the glycoprotein la gene as we have shown recently [10] underlines the importance of the platelet-associated thrombophilia and could have a remarkable clinical impact on potential medical intervention with an individualized approach of the aspirin therapy to improve unexplained poor IVF implantation outcome [14].…”

mentioning

confidence: 91%

The PlA2 variant of the platelet glycoprotein IIIa as a genetic risk factor for IVF implantation failure: accumulating evidence

Vlachadis

Vrachnis

Economou

2016

J Assist Reprod Genet

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We read with great interest the recent article of Patounakis et al. [1] who examined the potential role of nine genetic thrombophilic factors in in vitro fertilization (IVF) outcome. Even though the authors came to the conclusion that the thrombophilic single nucleotide polymorphisms (SNPs) which were evaluated, individually or cumulatively, do not have any significant effect, an important clinical finding, the correlation of the genetic polymorphism PIA1/PIA2 (T1565C-Leu33Pro) (rs5918) of the platelet glycoprotein llla (Gpllla) gene with implantation failure after IVF embryotransfer (IVF-ET failure), was overlooked.Expanding the findings of many studies concerning miscarriages, a number of researchers reported that thrombophilic factors affect the success of implantation or the accomplishment of clinical pregnancy in IVF treatment. A large majority of these studies examined the role of anti-phospholipid antibodies in the IVF outcome, and Di Nisio et al. [2] in their meta-analysis of 20 case-control studies including 3542 patients calculated a 3.3-fold increased risk, although this was not confirmed in the respective analysis of cohort studies. On the contrary, since the first published study by Grandone et al. [3] which found that the prevalence of the factor V Leiden (FVL) and prothrombin 20210A allele carriers cumulatively was significantly higher in a small group of 18 women with ≥3 IVF-ET failures (implantation failures or fetal loss), as compared with 216 fertile women with uneventful pregnancies after spontaneous conception, a small number of relative studies that followed have not given conclusive results while certain correlations of genetic thrombophilic factors with IVF-ET failure have ensued with an additive nonspecial approach. Moreover, from the genetic variants that are relative to the coagulation factor gain of function (factors I, II, V, XII), anticoagulant deficiency (plasminogen activator inhibitor-1, PAI-1) or hyperhomocysteinemia (methylene tetrahydrofolate reductase, MTHFR) which were assessed in the study of Patounakis et al., only FVL [4, 5] and MTHFR-677TT [4, 5] and MTHFR-1298CC [6] homozygosities have been singly associated with a negative IVF outcome so far, while noncorrelation was also found in the meta-analysis of Di Nisio et al. with the exception of FVL [2].We consider that the most significant finding of the study of Patounakis et al. is the indication of additional suggestive evidence (although non-significant under strict statistical consideration) that the presence of the GpIIIa-PIA2 allele increases the risk of IVF-ET failure. Clinical pregnancy rate was approximately 17 % higher for the Gpllla-PIA1 homozygotes than that in the Gpllla-PIA2 carriers (56 versus 48 %, p = 0.010). This correlation probably has not been able to reach strict statistical significance due to the use of an unselected group of participants undergoing their first IVF cycle, despite their large number, and the simultaneous comparison of nine SNPs which decreased the power of the study due to the necessa...

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“…Furthermore, P-Selectin receptors participate in the interactions leading to Th1 lymphocyte migration into the decidua which is involved in the rejection of trophoblast cells [ 20 ]. It has been suggested that genetic alterations of platelet membrane factors, including PECAM-1 and P-Selectin, are synergistically involved in the pathogenesis of miscarriages [ 10 ] and implantation failure [ 9 , 21 , 22 ]. In a relative study, Dendana et al [ 23 ] found a statistically significant association between the presence of the G allele of another P-Selectin gene polymorphism (P-Selectin-C2123G, rs6127) and recurrent pregnancy loss.…”

Section: Discussionmentioning

confidence: 99%

Association of the PECAM-1 (Leu125Val) and P-Selectin (Thr715Pro) Gene Polymorphisms With Unexplained Spontaneous Miscarriages

Vlachadis¹,

Tsamadias²,

Siori³

et al. 2022

Cureus

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Genetic heterogeneity of platelet glycoproteins Ia and IIIa is associated with in vitro fertilisation implantation failure

Cited by 8 publications

References 17 publications

Human Leukocyte Antigen Alleles Compatibility and Immunophenotypic Profile Associations in Infertile Couples

Human Leukocyte Antigen Alleles Compatibility and Immunophenotypic Profile Associations in Infertile Couples

The PlA2 variant of the platelet glycoprotein IIIa as a genetic risk factor for IVF implantation failure: accumulating evidence

Association of the PECAM-1 (Leu125Val) and P-Selectin (Thr715Pro) Gene Polymorphisms With Unexplained Spontaneous Miscarriages

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