The existence of associations between low FXII activity levels and thrombotic outcomes has been under debate for more than a decade. We previously reported that the miscarriage rate of patients with low FXII activity (less than 39%) was significantly higher than that of patients with normal FXII activity[16]. CT and TT genotypes and the FXII activity were also compared between the patients and controls. Subsequent miscarriage rates among the CC, CT, TT genotypes and according to the FXII activity was examined. MP-A08 LA was associated with reduced FXII activity. The CT, but not the TT, genotype was confirmed to be a risk factor MP-A08 for RPL in the cross-sectional study using multivariate logistic regression analysis (OR, 2.8; 95% CI, 1.375.85). The plasma FXII activity in the patients was similar to that in the controls. Neither low FXII activity nor the SIRT4 CT genotype predicted the subsequent pregnancy outcome in the cohort study. On the other hand, and intermediate FXII activity level of 85101% was predictive of subsequent miscarriage. == Conclusions MP-A08 == Low FXII activity was not associated with RPL. The FXII gene was found to be one of the significant susceptibility genes for RPL, similar to the FV Leiden mutation. However, the clinical influence of the CT genotype might be relatively small, because the presence/absence of this genotype did not have any predictive value for the subsequent pregnancy outcome. This was the first study indicating the influence ofFXII 46C/Ton further pregnancy outcomes. == Introduction == Recurrent miscarriage (RM) is classically defined as three or more consecutive miscarriage[1]. However, many researchers have now revised the definition to two or more pregnancy losses, namely recurrent pregnancy loss (RPL), because of the recent increase in the prevalence of childless couples. The estimated incidence of RM and RPL are 1% and 5%, respectively[1]. Established causes of RPL include antiphospholipid syndrome (APS), uterine anomalies, and chromosomal abnormalities, particularly translocations, in either partner[1][4]. However, according to reports, in about a half of the cases seen at research centers, the cause remains unexplained despite conventional examinations conducted to identify the cause[5],[6]. Recently, we found that an abnormal embryonic karyotype was the most frequent cause of 2 or more RPL, accounting for as high as 41% of all the cases[7]. APS, acquired thrombophilia, is the only one treatable cause of RPL, and combined low-dose aspirin and heparin treatment having been shown to improve the MP-A08 live birth rate in patients with APS[8],[9]. Heritable thrombophilia has been reported to be associated with RM[10],[11]. Coagulation factor XII (FXII) is an 80-kDa serine protease that is involved in the initiation of the intrinsic pathway of the coagulation cascade. It is converted to its active form (activated factor XII, XIIa) by limited proteolysis[12], either by autoactivation on the surface of negatively charged compounds or by kallikrein[13]. Although FXII deficiency is associated with a prolonged activated partial thromboplastin time (aPTT), it is not associated with increased bleeding[14]. A C/T polymorphism has been identified in the promoter region of theFXIIgene at nt46. The 46C/T polymorphism creates a new initiation codon (ATG) for transcription of the mRNA and a frameshift that produces a truncated protein. The T allele destroys the Kozak’s consensus sequence (GCCAGCCATGG) for translation initiation signaling and prevents proper recognition of the translation initiation site. The T allele is therefore well-known to be associated with low plasma levels of factor XII[15]. The existence of associations between low FXII activity levels and thrombotic outcomes has been under debate for more than a decade. We previously reported that the miscarriage rate of patients with low FXII activity (less than 39%) was significantly higher than that of patients with normal FXII activity[16]. We also found that the frequency of the T allele did not differ between the women with a history of RPL and control fertile women[17]. However, the association between the C/T polymorphism or FXII activity and RPL could not be clearly elucidated, because the sample size was relatively small. Thus, we conducted this cross-sectional and cohort study to determine the clinical significance of C/T polymorphism and FXII activity. We examined the association between 46C/T polymorphism and RPL, and between FXII activity and RPL in the cross-sectional study. We examined whether 46C/T polymorphism or FXII activity influenced the subsequent miscarriage rate in the cohort study. This was the first study to investigate the influence ofFXIISNP on the subsequent pregnancy outcome. == Materials and Methods == == Patients and controls == All patients were seen at Nagoya City University Hospital between September 2008 and July 2012. The study group consisted of 279 Japanese women with two or more consecutive pregnancy losses. All patients underwent systematic examination, including hysterosalpingography, chromosome analysis of both partners, determination of aPL, including lupus anticoagulant (LA), by 5x-diluted aPTT, diluted Russel’s viper venom time (RVVT) and 2 glycoprotein I-dependent anticardiolipin antibody determination (2GPI-aCL),.