Abstract
Migraine with aura has been shown to be an independent risk factor for stroke. Although the precise mechanism of migraine-related stroke is not known, risk factors for hypercoagulability have been found in migraineurs. Prothrombin factor 1.2 (F1.2) is a cleavage product of prothrombin. Elevated plasma F1.2 has been shown to be a sensitive and a specific marker of ongoing thrombin generation, and thus may serve as an indicator of hypercoagulability. In this study we determined plasma F1.2 levels in 35 patients with migraine (22 with aura and 13 without aura) and in 24 healthy age- and sex-matched volunteers. Elevated F1.2 levels were found in 11 of 22 (50%) patients with migraine with aura (1.25–3.5 nmol/l). None of the patients with migraine without aura nor any of the healthy volunteers had elevated plasma F1.2 levels (normal < 1.1 nmol/l). We conclude that prothrombin F1.2 levels are elevated in a significant number of patients with migraine with aura but not in patients with migraine without aura. This finding suggests that there is activation of the clotting system in certain patients with migraine with aura.
Introduction
Migraine has been reported to be a risk factor for ischaemic stroke in men (1, 2) and pre-menopausal women (2–6). Two studies have shown that migraine with aura poses a higher risk for stroke than migraine without aura (4, 7). Migraine may also acutely precipitate stroke, as some patients have a stroke during a migraine attack, an event known as a migrainous stroke (8–10). Possible mechanisms predisposing young migraineurs to ischaemic stroke may be vascular, neuronal, or related to coagulation abnormalities (8). Some workers consider migraine to be a blood disorder due to the increased platelet activation detected both during and between attacks (11–15). Plasma coagulability, although much less studied, is also enhanced during migraine attacks (16). Coagulation alterations, in particular the presence of antiphospholipid antibodies, have been reported in some studies, particularly in migraine with aura and in patients with migrainous stroke (17–22). Recently, newly discovered inherited clotting defects which might play a role in hypercoagulable states, such as resistance to activated protein C (APCR) due to Factor V Leiden mutation (R506Q), factor II 20210 mutation, antithrombin, protein C, and protein S deficiencies, elevated factor VIII levels and hyperhomocysteinemia, have been described. An increased incidence of some of these genetic alterations in migraine patients has been observed by some, but could not be confirmed in other, studies (23–27).
Prothrombin factor 1.2 (F1.2) is a cleavage product of prothrombin. Plasma F1.2 levels are a sensitive and a specific marker of ongoing thrombin generation, and thus may serve as an indicator of activation of the clotting cascade and are elevated in patients with hypercoagulable states. In this study we determined the plasma F1.2 concentrations in a cohort of patients with migraine with aura and migraine without aura in an attempt to determine whether activation of coagulation is detectable in these patients.
Patients and methods
Thirty-five migraine patients, 31 females and four males, ranging from 19 to 64 years of age, were recruited from the outpatient headache unit at our hospital. Twenty-two had migraine with aura and 13 had migraine without aura. The diagnosis of migraine was according to the International Headache Society (IHS) classification, 1988 (28). Twenty-four healthy age- and sex-matched volunteers comprised the control group. None was taking birth control pills or had a family history of stroke.
All blood samples were taken at least 1 week after the last migraine attack. Briefly, 4 mL of blood was drawn into tubes containing 3.8% sodium citrate (Vacutainer®, Becton Dickinson, Plymouth, UK). Plasma was obtained by centrifugation at 1500
Statistical analysis was performed using SPSS version 6.0 software. The three subject groups (migraine with aura, migraine without aura and control) were compared using a one-way analysis of variance (
Results
The mean age of the subjects was 34.8 years (range 23–52), and the mean duration of migraine was 27.9 years (range 9–34). Twenty-two patients had migraine with aura and 13 had migraine without aura. Demographic data for the patient and control groups are summarized in Table 1. All subjects' physical and neurological evaluations and cerebral CTs were normal. None of the patients nor controls had protein C, protein S or antithrombin deficiency, activated protein C resistance or anticardiolipin antibodies.
Demographic and laboratory data regarding the study subjects
There was no significant difference between the three groups regarding age or sex distribution by
Eleven of the 22 patients (50%) with migraine with aura had an elevated F1.2 level (1.25–3.5 nmol/l). All patients with migraine without aura, as well as all healthy volunteers, had normal F1.2 blood levels (< 1.1 nmol/l) (Fig. 1). The mean (± standard deviation,
Mean and standard deviation F1.2 levels in the three study groups.
Age, sex or duration of migraine did not influence F1.2 levels when analysed by regression analysis.
Discussion
The distinction between migraine with aura and migraine without aura is often difficult, since until now no biological marker has been found possessing specificity for a particular type of migraine. In this study we show that a marker of ongoing thrombin generation, prothrombin fragment F1.2, may be useful in differentiating between these two subsets of patients with migraine. In our cohort of patients with migraine with aura, F1.2 levels were elevated in 50% of subjects, while all of the patients suffering from migraine without aura and control subjects had normal F1.2 levels.
The fact that only half of the patients with migraine with aura had elevated F1.2 levels may be explained by the observation that migraine with aura is not a single entity but that subsets of patients with migraine with aura may be defined. Such subgroups include familial hemiplegic migraine (FHM) and a disorder known as CADASIL (cerebrovascular accidents, aura, dementia, autosomal dominant, subcortical leukoencephalopathy). These syndromes are linked to chromosome 19 but most patients with migraine with aura do not carry this chromosomal abnormality. It is likely that further subtypes of migraine with aura will be characterized in the future and the degree of activation of the clotting pathway should be studied in these subgroups.
It is noteworthy that F1.2 levels were elevated in patients with migraine with aura between attacks. This points to an ongoing thrombotic process even while patients are asymptomatic. This persistent hypercoagulability might explain the tendency for patients with migraine with aura to develop thromboembolic cerebrovascular events, especially when they are exposed to an additional procoagulant stress such as oral contraceptive ingestion. This finding also suggests that enhancement of a thrombotic tendency may be causally linked to migraine with aura, rather than intravascular coagulation leading to the development of headache.
Our findings suggest that persistent thrombin generation occurs in a significant proportion of migraineurs with aura and thus the haemostatic pathway may be a potential therapeutic target for both the treatment and prevention of headache in migraineurs with aura. To establish the efficacy of such an approach, clinical studies of antiplatelet and anticoagulant agents in these patients will need to be performed.