Platelet Glycoprotein Receptor Ia-C807T and IIIa-PlA1/PlA2 Genetic Polymorphisms Are Associated With Enhanced Platelet Function in Women With Recurrent Miscarriages.

INTRODUCTION: Thrombophilic genetic polymorphisms of the platelet glycoproteins Ia (GpIa) and IIIa (GpIIIa) have been associated with an increased risk of recurrent miscarriages. The aim of this study was to investigate the association of genetic polymorphisms GpIa-C807T and GpIIIa-T1565C-PlA1/PlA2 with platelet function in women with unexplained spontaneous recurrent miscarriages. METHODS: This cross-sectional study comprised 196 unrelated nulliparous Greek women with a history of unexplained recurrent miscarriages. Patients were genotyped for the presence of the GpIa-C807T (rs1126643) and GpIIIa-T1565C-PlA1/PlA2 (rs5918) genetic polymorphisms by pyrosequencing, and the collagen/epinephrine closure time (COL/EPI CT) of the subjects was assessed using the platelet function analyzer (PFA)-100. RESULTS:  In the total population of women with recurrent miscarriages, the COL/EPI CT ranged from 70 to 160 seconds (median: 122 seconds, interquartile range (IQR): 102.3-138 seconds). In comparison with the double homozygotes CC/PlA1PlA1 that had the most prolonged CT (mean: 131.9 ± 17.5 seconds), the COL/EPI CT was statistically significantly shorter for the GpIa-807T single carriers (mean: 120.3 ± 20.9 seconds) (p=0.011) (absolute difference: 11.6 seconds, 95% confidence interval (CI): 21.2 to -2.0 seconds; relative difference: -9%, 95% CI: -16% to -2%), and the GpIIIa-PlA2 single carriers also displayed a trend for shorter COL/EPI CT (mean: 121.3 ± 23.7 seconds) (p=0.141) (absolute difference: -10.6 seconds, relative difference: -8%), whereas the combined carriers of the GpIa-807T and the GpIIIa-PlA2 alleles exhibited the shortest COL/EPI CT (mean: 104.1 ± 19.7 seconds) (absolute difference: -27.7 seconds, 95% CI: -39.1 to -16.3 seconds; relative difference: -21%, 95% CI: -30% to -12%) (p<0.001). In comparing genotype frequencies in the lower half with those in the upper half of the COL/EPI CT range, the GpIa-807T and the GpIIIa-PlA2 single carriers were associated with higher odds of COL/EPI CT < 122 seconds (odds ratio (OR)=3.4, 95% CI: 1.5 to 7.5, p=0.002, and OR=2.6, 95% CI: 1.0 to 7.2, p=0.053, respectively). The association was strongest for the combined carriers with OR of 15.0 (95% CI: 5.2 to 43.2, p<0.001) for COL/EPI CT below the median and OR of 35.5 (95% CI: 4.4 to 284.5, p<0.001) for COL/EPI CT < 100 seconds. CONCLUSION: The GpIa-C807T and GpIIIa-PlA1/PlA2 polymorphisms and more pronouncedly the combined carriers of the risk variants are associated with enhanced platelet reactivity expressed via shorter COL/EPI CT. These findings provide further evidence for the role of platelet-associated genetic thrombophilia in the pathogenesis of recurrent miscarriages and promote the analysis of platelet function as a diagnostic tool in the evaluation of this disorder.

Baseline Values and Kinetics of IL-6, Procalcitonin, and TNF-α in Landrace-Large White Swine Anesthetized with Propofol-Based Total Intravenous Anesthesia.

The baseline levels of various inflammatory mediators and their changes during anesthesia in swine are not known. The aim of this animal study was to measure the baseline values and kinetics of interleukin-6, procalcitonin, and tumor necrosis factor-alpha in healthy Landrace-Large White swine anesthetized with propofol-based total intravenous anesthesia. We included 8 healthy male pigs with an average weight of 19 ± 2 kg (aged 10-15 weeks) that were subjected to propofol-based total intravenous anesthesia for 8 hours. Complete blood count, serum chemistry, and serum levels of interleukin-6, procalcitonin, and tumor necrosis factor-alpha were analyzed, and serum levels were quantified hourly. Blood was also collected for bacterial culturing. Baseline values of interleukin-6 and procalcitonin were 18 pg/ml and 21 ng/ml, respectively, while tumor necrosis factor-alpha was not detectable during collection of baseline samples. A statistically significant difference was observed in interleukin-6 levels between time points (p < 0.0001). Procalcitonin increased with time, but there were no significant differences between time points (p = 0.152). Tumor necrosis factor-alpha increased until the 3rd hour of propofol-based total intravenous anesthesia, while after the 4th hour, it gradually decreased, reaching its baseline undetectable values by the 7th hour (p < 0.001). Our results can serve as the basis for further translational research.

Serum and follicular fluid irisin levels in women with polycystic ovaries undergoing ovarian stimulation: correlation with insulin resistance and lipoprotein lipid profiles.

Irisin, a novel exercise-induced myokine, has been implicated in different aspects of human metabolism and could be connected to polycystic ovary syndrome (PCOS). This study aimed to investigate serum and follicular fluid (FF) irisin levels in PCOS and normal women undergoing controlled ovarian stimulation and correlate them to the lipid and lipoprotein levels as well as with other metabolic parameters. Serum and FF irisin, together with serum lipid and lipoprotein levels were assessed in 70 women with diagnosed PCOS and 70 non-PCOS controls, under in vitro fertilization (IVF) treatment. Regardless of BMI, PCOS women had a significantly increased number of oocytes retrieved, fertilized oocytes and transferred embryos, although the number of women achieving pregnancies did not differ between groups. No correlation between FF irisin levels and pregnancy could be established. Serum and FF irisin levels were significantly higher in PCOS and overweight women and were positively associated with BMI and dyslipidemia. FF irisin levels correlated positively to and were lower than serum irisin levels. Further research would be helpful to analyze irisin's role in female reproduction, if any, as well as in human metabolism and the pathophysiology of PCOS.

Adropin levels in women with polycystic ovaries undergoing ovarian stimulation: correlation with lipoprotein lipid profiles.

This study aimed to investigate serum and follicular fluid (FF) adropin levels in polycystic ovary syndrome (PCOS) and normal women undergoing controlled ovarian stimulation and correlate them with the lipid and lipoprotein levels. We included 60 women (30 lean and 30 overweight) with diagnosed PCOS, and 60 age and weight-matched non-PCOS controls (30 lean and 30 overweight), under in vitro fertilization (IVF) treatment. Serum lipid and lipoprotein levels were assessed by the Abbott Architect c8000 autoanalyzer while adropin levels were determined by enzyme immunoassay. Serum and FF adropin levels were significantly lower in PCOS women compared with controls and FF adropin levels were lower than serum levels. Significantly higher serum levels of total cholesterol, LDL-C, triglycerides, apolipoprotein B, lipoprotein(a) and homocysteine were encountered in PCOS subjects, while HDL-C and apolipoprotein A1 were significantly lower compared with controls. According to univariate and multivariate analysis, serum and FF adropin levels were positively correlated with BMI and HDL-C levels and negatively correlated with LDL-C levels. Women with polycystic ovaries exhibit lipid lipoprotein alterations increasing the risk of cardiovascular diseases later in life. Our findings suggest a probable involvement of adropin both in human metabolism and in the pathophysiology of PCOS.

Matrix metalloproteinase-3 gene promoter polymorphisms: A potential risk factor for pelvic organ prolapse.

Pelvic organ prolapse (POP) is a common multifactorial condition. Matrix metalloproteinases (MMPs) are enzymes capable of breaking down various connective tissue elements. Single-nucleotide polymorphisms (SNPs) in regulatory areas of MMP-encoding genes can alter their transcription rate, and therefore the possible effect on pelvic floor supporting structures. The insertion of an adenine (A) base in the promoter of the MMP-3 gene at position -1612/-1617 produces a sequence of six adenines (6A), whereas the other allele has five (5A). The aim of the present study was to investigate the possible association of MMP-3 gene promoter SNPs with the risk of POP. The patient group comprised 80 women with clinically significant POP [Stage II, III or IV; POP quantification (POP-Q) system]. The control group consisted of 80 females without any or important pelvic floor support defects (Stages 0 or I; POP-Q system). All the participants underwent the same preoperative evaluation. SNP detection was determined with whole blood sample DNA analysis by quantitative polymerase chain reaction (PCR) in LightCycler® PCR platforms, using the technique of sequence-specific hybridization probe-binding assays and melting temperature curve analysis. The results showed there was no statistically significant difference between 5A/5A, 5A/6A and 6A/6A MMP-3 gene promoter variants in the two study groups (P=0.4758). Therefore, MMP-3 gene promoter SNPs alone is insufficient to increase the genetic susceptibility to POP development.