An Exploratory Pilot Study of Coagulation- and Fibrinolysis-Related Proteins in Unexplained Infertility

Unexplained infertility (UI) accounts for an estimated 15-30% of infertility but its biological basis remains poorly defined. Plasma haemostatic abnormalities have been implicated in recurrent pregnancy loss; however, whether the circulating coagulation-fibrinolysis axis differs between women with UI and those with infertility attributable to other causes has not been characterised. The aim of this study was to compare 20 coagulation- and fibrinolysis-related proteins between women with UI and women with male-factor infertility (MFI) as control. In this exploratory case-control study, plasma from 11 women with UI and 14 women with MFI were analysed using SOMAscan proteomics. Group means were compared using Welch's two-sample t-test, Cohen's d with 95% confidence intervals, and a two-sided permutation test on the mean difference (20,000 random label permutations). False discovery rate (FDR) was used for multiple comparisons. Pairwise Pearson and Spearman correlations were performed. Three proteins differed between groups (p < 0.05), all lower in UI than in MFI: vitamin K-dependent protein S (Cohen's d = -1.11, 95% CI -1.95 to -0.26; Welch p = 0.016; permutation p = 0.015), antithrombin-III (d = -1.00, 95% CI -1.84 to -0.16; p = 0.024; permutation p = 0.020) and α2-antiplasmin (d = -0.82, 95% CI -1.64 to 0.00; p = 0.051; permutation p = 0.054). No protein survived FDR correction. Within UI, the three proteins co-varied positively, with significant pairwise correlations between protein S and antithrombin-III (r = 0.67, p = 0.024) and between antithrombin-III and α2-antiplasmin (r = 0.71, p = 0.015). Within MFI, antithrombin-III and α2-antiplasmin remained tightly correlated (r = 0.70, p = 0.006) but protein S decoupled from both (r = 0.20 and 0.10, both non-significant). In this hypothesis-generating study, women with UI showed reduction in three plasma regulators of anticoagulant and antifibrinolytic capacity, protein S, antithrombin-III and α2-antiplasmin relative to women with MFI, raising the possibility that UI may be in part a subtle immunothrombotic/endothelial implantation disorder.