Thrombophilic Disorders in Migraine

Migraine is a widespread disorder that affects about 18% of the people, in 2/3 of cases women (1). The concept that migraine could be related to some vascular diseases, such as myocardial infarction or a stroke, have grown over the years, mainly in migraine with aura (2–6). In the last decades, several studies have been carried out to understand if and what the linkage could be. Among these studies, we have found many researches on thrombophilic disorders. In this context, the studies focus on alterations of coagulation factors, coagulation proteins, homocysteine with MTHFR variants, and auto-immune disorders of coagulation such as anti-phospholipid antibodies. The available data are sometimes difficult to interpret. The first problem we meet is that thrombophilic disorders usually have a low prevalence, so we need larger sample studies to reach significant results. The second problem could be how to correctly select the proper study population, because some deficits could be inherited and some others acquired, and results could change depending on contextual factors such as pregnancy or anti-coagulant or estroprogestinic therapy. The third problem, mainly dealing with auto-immune coagulative disorders, could be different laboratory methods and the different positivity criteria used. Another problem is that the prevalence of the coagulative deficit could change with age, so we find variable results in studying children or adults. Therefore, we need to calculate properly the sample size of the study population. Another chance to study the correlation between migraine and thrombophilic disorders could be by using the data collected through specific disease database. The main International Disease Database is the European Register on anti-phospholipid syndrome (APS). These data show that the first and most frequent symptom of the syndrome is a headache, probably a migraine considering the reported descriptions (7, 8). Headaches are so important in APS to lead expert hematologists to recommend carrying out tests for anti-phospholipid antibodies (aPL) in all patients presenting severe headaches (9). The Italian Registry of Rare Diseases is another important source of information. It was activated by the National Health Institute (NHI) almost 10 years ago, through the creation of Regional Registries. In the last Database Report of Rare Diseases’ 2013 database of the Piedmont Region, we find how the number of the diagnosis of a thrombophilic disease performed in an headache center is equal or higher than the one recorded by those centers taking care of patients who had experienced a thrombotic event (10). Articles published more recently correlate migraine and thrombophilic alterations, so we can presume they could be co-morbid. Coagulative factors II, V, VII, VIII, IX, and von Willebrand have been studied in migraineurs. The correlation between factor II mutations and migraine has been studied throughout several smaller studies, always with negative results (11, 12). Only recently, a population based study reported a higher prevalence of factor II mutation in women suffering from migraine, but a selection bias could be suspected because this population had been selected among women with a positive family history of venous and arterial thrombosis (13). We can find a few reports of deficit of factor 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 interesting to investigate further. Most authors studied the alterations of factor V in migraineurs, and also in these studies the sample size seem to be unrepresentative, and results are controversial (11, 15, 17–20). Furthermore, some authors considered homozygous mutation alone, while others considered both homozygous and heterozygous mutation. Among the coagulative factors, the V seems to be the most interesting one, but larger and better designed studies are required, with more severe selection of inclusion criteria. Still little is known on deficit of coagulation proteins C and S. The main problem of studying protein C deficit is its low prevalence, which is around 0.4%, that requires larger sample sizes to study and detect any significant difference in prevalence between migraineurs and healthy controls. The few available studies are too small to clearly understand this topic (11, 18, 19). The prevalence of protein S deficit is higher, but this type of deficit is more complex to understand and diagnose. First of all, laboratory methods that are used should be clearly defined, such as the sensitivity of the laboratory kit used and what type of protein S was dosed, and is it the total or only the free protein, all elements needed to make a proper diagnosis of the type of defect (genetic or acquired). It would be better to distinguish inherited from acquired types of deficit, because of the different clinical relevance and etiopathogenesis. Inherited deficits are easier to detect and the level of protein S can be stable over time, on the contrary of the acquired deficits. It is also very important to consider and exclude iatrogenic deficits, such as those due to anti-coagulant or estroprogestinic therapy, or the physiologic