Summary: Four coagulation measures were associated with migraine with aura. These hemostatic factors may have a causal role in migraine with aura.
Source: Brigham and Women’s Hospital
Nearly 15 percent of the U.S. population experiences migraine. One subtype of migraine that is not well understood is migraine with aura (MA). Individuals who experience MA often see flashing lights, blind spots, or jagged lines in their visual field prior to onset of their migraine headaches.
Individuals who experience MA also face a heightened risk of stroke and cardiovascular disease, although scientists continue to explore why this correlation exists.
In a new study from Brigham and Women’s Hospital, researchers used a technique in genetic analysis termed Mendelian randomization to examine 12 coagulation measures, uncovering four that are associated with migraine susceptibility.
Interestingly, scientists only observed these associations in individuals who experience MA and did not observe such associations among individuals who experience migraine without aura (MO).
Their research suggests that these hemostatic factors could potentially have a causal role in MA.
Their results are published in Neurology.
“We’ve always wanted to know why people with MA have this higher risk of stroke and other cardiovascular diseases,” said corresponding author Daniel Chasman, PhD, of the Division of Preventive Medicine at the Brigham. “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.”
There has been speculation in the field about relationships between coagulation and migraine susceptibility for some time, but previous research has been largely inconclusive. Most individuals first experience migraine at a young age for example, during childhood or young adulthood.
Because previous study designs included only middle-aged and older adults, investigators have questioned whether coagulation causes migraine or if causality exists between these two elements at all.
In this study, leveraging Mendelian randomization, which can support or refute potential causal effects on a health outcome, scientists for the first time found evidence that hemostatic factors may contribute to risk of MA.
“Even if we see an association between migraine and these coagulation factors when we measure both factors in a population at the same time, we still wonder: Which one came first?” said co-author Pamela Rist, ScD, of the Division of Preventive Medicine at the Brigham. “One of the interesting parts of Mendelian randomization is that it allows you to examine potential causality.”
Researchers used summary statistics from decades of previously collected data from individuals who experience migraine and individuals who do not experience migraine. Because the diagnostic criteria are different for MA versus MO, they could examine these two conditions separately.
Investigators found a strong association between four coagulation factors and migraine susceptibility.
They observed that genetically increased levels of three blood clotting factors: coagulation factor VIII, von Willebrand factor, and phosphorylated fibrinopeptide A, and genetically decreased levels of fibrinogen (a protein important in the late stages of the blood clotting process) were all associated, in part, with migraine susceptibility.
Interestingly, scientists did not find this association among individuals who experience migraine without aura (MO), indicating a specific relationship between these hemostatic factors and MA.
Scientists note that Mendelian randomization has its limitations. In the future, researchers could examine if the causal associations implied by genetics can be observed in clinical practice.
“It is very exciting that by using Mendelian randomization we were able to show that hemostatic factors are associated with MA,” said first author Yanjun Guo, MD, PhD of the Division of Preventative Medicine at the Brigham. “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.”
Funding: Funding for this work was provided by the U.S. National Institutes of Health and U.S. National Institute of Neurological Disorders and Stroke (R21NS09296 and R21NS104398), the National Heart, Lung and Blood Institute (R01HL134894, R01HL139553, and , K01 HL128791), the American Heart Association (grant 18CDA34110116), a Miguel Servet contract from the ISCIII Spanish Health Institute (CP17/00142) and co-financed by the European Social Fund. The WGHS is supported by the National Heart, Lung, and Blood Institute (HL043851 and HL080467) and the National Cancer Institute (CA047988 and UM1CA182913) with funding for genotyping provided by Amgen.
Disclosures: A co-author reports to have provided methodological expertise to Amgen and CoLucid, for which the Charité Universitätsmedizin Berlin has received financial compensation and further received honoraria from Novartis and Daiichi Sankyo for a scientific presentation and from Lilly, Newsenselab, and Total for methodological advice. The remaining authors have nothing to disclose.
Association Between Hemostatic Profile and Migraine: A Mendelian Randomization Analysis
To assess support for a causal relationship between hemostatic measures and migraine susceptibility using genetic instrumental analysis.
Two-sample Mendelian randomization instrumental analyses leveraging available genome-wide association study (GWAS) summary statistics were applied to hemostatic measures as potentially 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 8 hemostatic factors and 2 fibrinopeptides together with 2 hemostasis clinical tests.
There were significant instrumental effects between increased coagulation factor VIII activity (FVIII; odds ratio [95% confidence interval] 1.05 [1.03, 1.08]/SD, p = 6.08 × 10−05), von Willebrand factor level (vWF; 1.05 [1.03, 1.08]/SD, p = 2.25 × 10−06), and phosphorylated fibrinopeptide A level (1.13 [1.07, 1.19]/SD, p = 5.44 × 10−06) with migraine susceptibility. When extended to migraine subtypes, FVIII, vWF, and phosphorylated fibrinopeptide A showed slightly stronger effects with MA than overall migraine. Fibrinogen level was inversely linked with MA (0.76 [0.64, 0.91]/SD, p = 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 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. Causal effects from migraine to the hemostatic measures were not supported in reverse Mendelian randomization. However, MA was not included due to lack of instruments.
The findings support potential causality of increased FVIII, vWF, and phosphorylated fibrinopeptide A and decreased fibrinogen in migraine susceptibility, especially for MA, potentially revealing etiologic relationships between hemostasis and migraine.