Appendix: Association between hemostatic profile and migraine: a Mendelian randomization analysis

<p><b>Objective:  </b><span>To assess support for a causal relationship between </span>hemostatic measures and migraine susceptibility using genetic instrumental analysis.</p> <p><b>Methods:  </b>Two-sample Mendelian randomization (MR) instrumental leveraging available genome-wide association study (GWAS) summary statistics was applied to hemostatic measures as potential causal for migraine and its subtypes, migraine with aura (MA) and migraine without aura (MO).  Twelve blood-based measures of hemostasis were examined, including plasma level or activity of eight hemostatic factors and two <span>fibrinopeptides together with </span>two hemostasis clinical tests<span>.</span></p> <p><b>Results:  </b>There were significant instrumental effects between increased coagulation factor VIII activity (FVIII, odds ratio[95% confidence interval]=1.05[1.03, 1.08]/standard deviation (SD), <i>P</i>=6.08×10^-05), von Willebrand factor level (VWF, 1.05[1.03, 1.08]/SD, <i>P</i>=2.25×10^-06), and phosphorylated <span>fibrinopeptide A level</span> (1.13[1.07, 1.19]/SD, <i>P</i>=5.44×10^-06) with migraine susceptibility. When extended to migraine subtypes, FVIII, VWF, and phosphorylated <span>fibrinopeptide A</span> showed slightly stronger effects with MA than overall migraine. Fibrinogen level was inversely linked with MA (0.76[0.64, 0.91]/SD, <i>P</i>=2.32×10^-03) but not overall migraine. None of the hemostatic factors was linked with MO.  In sensitivity analysis, effects for fibrinogen and phosphorylated <span>fibrinopeptide A</span> were robust, while independent effects of FVIII and VWF could not be distinguished, and FVIIII associations were potentially affected by pleiotropy at the <i>ABO</i> locus. Causal effects from migraine to the hemostatic measures were not supported in reverse MR.  However, MA was not included due to lack of instruments.</p> <p><b>Conclusions:</b> The current study supports potential causality of increased FVIII, VWF, and phosphorylated <span>fibrinopeptide A,</span> and decreased fibrinogen in migraine susceptibility, especially for MA, and may provide insights into the etiology underlying the relationship between <span>hemostasis</span> and migraine.</p>