Thrombophilic Disorders in Migraine

Migraine is a widespread disorder thataffects about 18% of the people, in 2/3 ofcases women (1). The concept that migraine could berelated to some vascular diseases, such asmyocardial infarction or a stroke, havegrown over the years, mainly in migrainewith aura (2–6). In the last decades, severalstudies have been carried out to under-stand if and what the linkage could be.Among these studies, we have found manyresearches on thrombophilic disorders. Inthiscontext,thestudiesfocusonalterationsof coagulation factors, coagulation pro-teins,homocysteine with MTHFR variants,andauto-immunedisordersof coagulationsuch as anti-phospholipid antibodies. Theavailable data are sometimes difﬁcult tointerpret. The ﬁrst problem we meet is thatthrombophilic disorders usually have a lowprevalence, so we need larger sample stud-ies to reach signiﬁcant results. The secondproblem could be how to correctly selectthe proper study population,because somedeﬁcits could be inherited and some othersacquired,andresultscouldchangedepend-ing on contextual factors such as preg-nancyoranti-coagulantorestroprogestinictherapy. The third problem, mainly deal-ing with auto-immune coagulative disor-ders,couldbedifferentlaboratorymethodsand the different positivity criteria used.Another problem is that the prevalence ofthe coagulative deﬁcit could change withage, so we ﬁnd variable results in study-ing children or adults. Therefore, we needto calculate properly the sample size ofthe study population. Another chance tostudy the correlation between migraineand thrombophilic disorders could be byusing the data collected through spe-ciﬁc disease database. The main Interna-tional Disease Database is the EuropeanRegister on anti-phospholipid syndrome(APS). These data show that the ﬁrst andmost frequent symptom of the syndromeis a headache, probably a migraine con-sidering the reported descriptions (7, 8). Headaches are so important in APS tolead expert hematologists to recommendcarrying out tests for anti-phospholipidantibodies (aPL) in all patients present-ing severe headaches (9). The Italian Reg-istry of Rare Diseases is another impor-tant source of information. It was activatedby the National Health Institute (NHI)almost 10years ago, through the creationof Regional Registries. In the last Data-base Report of Rare Diseases’ 2013 data-base of the Piedmont Region, we ﬁnd howthe number of the diagnosis of a throm-bophilic disease performed in an headachecenter is equal or higher than the onerecorded by those centers taking care ofpatients who had experienced a throm-botic event (10). Articles published morerecently correlate migraine and throm-bophilic alterations, so we can presumethey could be co-morbid.Coagulative factors II, V, VII, VIII, IX,and von Willebrand have been studied inmigraineurs. The correlation between fac-tor II mutations and migraine has beenstudied throughout several smaller studies,always with negative results (11, 12). Onlyrecently,a population based study reporteda higher prevalence of factor II mutationin women suffering from migraine, but aselection bias could be suspected becausethis population had been selected amongwomen with a positive family history ofvenous and arterial thrombosis (13). Wecan ﬁnd a few reports of deﬁcit of fac-tor VII, which seems to be non-relevant(14, 15), and of factors von Willebrand,VIII e IX, and various platelet alloantigens(11, 16), topics that would be interestingto investigate further. Most authors studiedthe alterations of factor V in migraineurs,and also in these studies the sample sizeseem to be unrepresentative, and resultsare controversial (11, 15, 17–20). Further-more, some authors considered homozy-gous mutation alone, while others consid-ered both homozygous and heterozygousmutation. Among the coagulative factors,the V seems to be the most interestingone, but larger and better designed stud-ies are required, with more severe selectionof inclusion criteria.Still little is known on deﬁcit of coagu-lation proteins C and S. The main prob-lem of studying protein C deﬁcit is itslow prevalence, which is around 0.4%, thatrequires larger sample sizes to study anddetect any signiﬁcant difference in preva-lence between migraineurs and healthycontrols. The few available studies are toosmall to clearly understand this topic (11,18, 19). The prevalence of protein S deﬁcitis higher, but this type of deﬁcit is morecomplex to understand and diagnose. Firstof all, laboratory methods that are usedshould be clearly deﬁned, such as the sen-sitivity of the laboratory kit used andwhat type of protein S was dosed, and isit the total or only the free protein, allelements needed to make a proper diag-nosis of the type of defect (genetic oracquired). It would be better to distinguishinherited from acquired types of deﬁcit,because of the different clinical relevanceand etiopathogenesis. Inherited deﬁcits areeasiertodetectandthelevelofproteinScanbe stable over time, on the contrary of theacquired deﬁcits. It is also very importantto consider and exclude iatrogenic deﬁcits,such as those due to anti-coagulant orestroprogestinic therapy,or the physiologic