Hemostatic Factors May Play a Causal Role in Migraine With Aura

Researchers identified 4 coagulation factors that may contribute to patients’ susceptibility to migraine with aura (MA). Findings of the Mendelian randomization (MR) analysis were published in Neurology.

Although migraineurs who suffer from MA—or flashing lights, blind spots, or jagged lines in their visual field prior to an attack—face heightened risk of ischemic stroke and cardiovascular disease, the underlying mechanisms of this relationship are not well understood.

“Based on prior studies, it is controversial whether enhanced atherosclerosis among individuals with MA is likely to explain the migraine association with stroke, suggesting the existence of alternative mechanisms, including endothelial activation or a potential role of hypercoagulability and microemboli,” researchers wrote.

Previous studies also only included middle-aged and older migraineurs, precluding an answer as to whether coagulation causes migraine or if causality exists between these 2 factors at all. Most individuals experience their first migraine at a young age.

To address this knowledge gap, the investigators assessed a potential causal relationship between hemostatic profiles and migraine by leveraging large-scale genome-wide association study (GWAS) statistics.

The latest GWAS summary data for migraine included 59,674 migraineurs and 316,078 controls. Of those patients, subgroups included one with 4837 MA patients and 49,174 controls and another consisted of 4833 patients with migraine without aura (MO) and 106,834 controls. Data were gleaned from the International Headache Genetics Consortium.

Summary statistics for fibrinogen levels, D-dimer levels, and other factors were provided by the Cohorts for Heart and Aging Research in Genomic Epidemiology Consortium Hemostasis Working Group.

All participants had European ancestry, and “bidirectional MR analyses were conducted between each hemostatic biomarker and migraine or migraine subtypes (MA and MO),” the authors wrote. In addition, 12 blood-based measures of hemostasis were assessed.

Analyses revealed:

• Significant instrumental effects between increased coagulation factor VIII activity (FVIII) (odds ratio [OR], 1.04; 95% CI, 1.03-1.08/SD; P = 6.08 × 10⁻⁰⁵), von Willebrand factor level (vWF; OR, 1.05; 95% CI, 1.03-1.08/SD; P = 2.25 × 10⁻⁰⁶), and phosphorylated fibrinopeptide A level (OR, 1.13; 95% CI, 1.07-1.19/SD; P = 5.44 × 10⁻⁰⁶) with migraine susceptibility
• FVIII, vWF, and phosphorylated fibrinopeptide A showed slightly stronger effects with MA than overall migraine
• Fibrinogen level was inversely linked with MA (OR, 0.76; 95% CI, 0.64-0.91/SD; P = 2.32 × 10⁻⁰³) but not overall migraine
• No hemostatic factors were linked with MO
• In sensitivity analyses, effects for fibrinogen and phosphorylated fibrinopeptide A were robust, whereas independent effects of FVIII and vWF could not be distinguished, and FVIII associations were potentially affected by pleiotropy at the ABO locus
• Reverse MR results showed no significant effects of migraine or MO on any of the hemostatic factors (all P > .05) although MA was not included in this analysis due to lack of genetic instruments

“This study offers promising leads specific to MA. Finding a possible cause for migraine with aura has been an outstanding question in the field for a long time,” said study author Daniel Chasman, PhD.

Overall, the insights support coagulation and thrombosis as a potential etiology for migraine susceptibility, the researchers wrote, as genetically increased FVIII, vWF, and phosphorylated fibrinopeptide, in addition to genetically decreased fibrinogen, all have potential causal effects on increased susceptibility.

Research indicates vWF is related to increased platelet aggregation, inflammation, and oxidative stress and other factors, all relevant to endothelial dysfunction thought to be important for migraine pathophysiology. But because the multivariable MR found effects of FVIII and vWF are not independent of one another, “current data are not able to prioritize the effects of FVIII and vWF on migraine and its subtypes,” the authors said.

As participants were only of European ancestry, the findings may not be generalizable, and the researchers could not evaluate the potential of unmeasured confounding due to the nature of the study.

“It is very exciting that by using Mendelian randomization we were able to show that hemostatic factors are associated with MA," said study author Yanjun Guo, MD, PhD. "And because in the observational studies we saw that MA patients have a higher risk of stroke, these findings may reveal a potential connection between MA and stroke."

Authors concluded future research into the roles of hypercoagulation and endothelial dysfunction and their targeting for therapeutic strategies in migraine susceptibility is warranted.

Reference

Guo Y, Rist PM, Sabater-Lleal M, et al. Association between hemostatic profile and migraine: a Mendelian randomization analysis. Neurology. Published online April 1, 2021. doi:10.1212/WNL.0000000000011931