View and Perspective

Migraine: Possible Role of Shear-Induced Platelet AggregationWith Serotonin Releasehead_2162 1..21

Piet Borgdorff, PhD; Geert Jan Tangelder, MD, PhD

Background.—Migraine patients are at an increased risk for stroke, as well as other thromboembolic events. This warrantsfurther study of the role of platelets in a proportion of migraine patients.

Objective.—To extend the “platelet hypothesis” using literature data and observations made in a rat model of shearstress-induced platelet aggregation. Such aggregation causes release of serotonin, leading to vasoconstriction during sufficientlystrong aggregation and to long-lasting vasodilation when aggregation diminishes. This vasodilation also depends on nitric oxideand prostaglandin formation.

Results.—A role for platelet aggregation in a number of migraineurs is indicated by reports of an increased platelet activityduring attacks and favorable effects of antiplatelet medication. We hypothesize that in those patients, a migraine attack with orwithout aura may both be caused by a rise in platelet-released plasma serotonin, albeit at different concentration. At highconcentrations, serotonin may cause vasoconstriction and, consequently, the neuronal signs of aura, whereas at low concentra-tions, it may already stimulate perivascular pain fibers and cause vasodilation via local formation of nitric oxide, prostaglandins,and neuropeptides. Platelet aggregation may be unilaterally evoked by elevated shear stress in a stenotic cervico-cranial artery,by reversible vasoconstriction or by other cardiovascular abnormality, eg, a symptomatic patent foramen ovale. This most likelyoccurs when a migraine trigger has further enhanced platelet aggregability; literature shows that many triggers either stimulateplatelets directly or reduce endogenous platelet antagonists like prostacyclin.

Conclusion.—New strategies for migraine medication and risk reduction of stroke are suggested.

Key words: migraine, platelet aggregation, shear stress, clopidogrel, serotonin, hypothesis

Abbreviations: ADP adenosine diphosphate, cAMP cyclic adenosine monophosphate, COX-2 cyclooxygenase-2, CSD corticalspreading depression, 5-HT 5-hydroxytryptamine (serotonin), LDL low-density lipoprotein, L-NMANG-methyl-L-arginine, MRI magnetic resonance imaging, NO nitric oxide, NSAID non-steroidal anti-inflammatory drug, PFO patent foramen ovale, PGI2 prostacyclin, vWf von Willebrand factor.

(Headache 2012;••:••-••)

Migraine attacks occur episodically and are char-acterized by a mostly unilateral long-lasting throb-bing headache (hours to days), often accompanied bynausea and photophobia or phonophobia. They can

be triggered by a variety of internal or externalfactors, such as female hormone levels, stress, foods, orweather conditions.1 The syndrome affects about 18%of women and 6% of men. In 20-30% of migraineurs,the attack starts with an aura lasting 20 to 30 minutes(scintillating scotoma, fortifications). The aura phaseis attended by oligemia and vasoconstriction in theFrom the Institute for Cardiovascular Research, VU University

Medical Center, Amsterdam, The Netherlands.

Address all correspondence to P. Borgdorff, Laboratory forPhysiology, VUMC, Van der Boechorststraat 7, 1081 BTAmsterdam, The Netherlands, email: p.borgdorff@vumc.nl

Accepted for publication March 21, 2012.

Conflict of Interest: The authors report no conflict of interest.

There was no financial support other than from our university.

ISSN 0017-8748doi: 10.1111/j.1526-4610.2012.02162.xPublished by Wiley Periodicals, Inc.

Headache© 2012 American Headache Society

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occipital regions, while during the headache phase,vasodilation may occur. At present, the prevailinghypothesis is that aura signs and the concomitantvasoconstriction are caused by a spreading depres-sion of cortical activity (CSD). The headache phase,however, has so far not been explained by CSD.Another aspect is that migraine is an established riskfactor for stroke and subclinical ischemic brainlesions, especially in patients with aura or frequentattacks (>1/month) (for review, see2). Stroke maycause CSDs,3 but the reverse has not been reported.Because in migraine-related stroke, both hypoperfu-sion and thromboembolism seem to be causallyinvolved,4 better understanding of the possible con-tribution of blood platelets in migraine might be ofvalue for treatment and preventive measures in atleast a subgroup of patients.

In this paper, we present an extension of theplatelet hypothesis of Hanington,5 integrating datafrom previously published literature with observa-tions made in a rat model of shear stress-inducedplatelet aggregation.6-9 Our hypothesis suggests thatin a number of patients, especially those with hyper-aggregable platelets, the neural and vascular symp-toms of migraine are independently initiated byserotonin (5-hydroxytryptamine, 5-HT) releasedfrom aggregating platelets.Aggregation might be elic-ited by increased shear stress at sites of vessel abnor-malities, especially when in these patients a migrainetrigger has further enhanced platelet aggregability,for example via reduction in circulating plateletantagonists like prostacyclin (PGI2).10,11

INCREASED PLATELET ACTIVITYIN MIGRAINE

Activation and aggregation of platelets may bestarted by several factors (eg, shear stress) whichincrease platelet intracellular calcium levels. Thisleads to a release of 5-HT and adenosine diphos-phate (ADP) from platelet-dense granules andvarious proteins from a-granules. ADP and 5-HTreinforce aggregation, and this is supported by pro-duction of thromboxane (thromboxane A2, TXA2)and platelet-activating factor. Aggregation that istoo strong is controlled by a variety of factors

including the intraplatelet formation of nitric oxide(NO) and by adenosine, the breakdown product ofADP.

In a number of migraine patients, increased invivo platelet activity, as indicated by the parametersmentioned in Table 1, has been found during and, toa lesser degree, between attacks. Activation seemsmore marked in migraine with aura than in migrainewithout aura.12

A role for platelet aggregation in the pathogen-esis of migraine is further suggested by studiesshowing diminished prevalence or relief of migraineduring inhibition of platelet aggregation (Table 2).Note the substantial effect of measured correctionof platelet hyperaggregability in 23 consecutivepatients.13 Regarding ADP-receptor blockade withor without TXA2 reduction in patent foramen ovale(PFO) patients, it is known that closure of PFO mayrelieve migraine, but placement of an Amplatzeroccluder (AGA Medical Corporation, Plymouth,MN, USA) may also start or aggravate migraine in anumber of patients. We suppose that in thesepatients, platelets are activated by increased bloodshear stress as a consequence of incomplete closureor by blood–material contact. Successful studieswith high-dose aspirin (500-1300 mg/day)14-16 arenot mentioned in the table because in these doses,aspirin might reduce migraine pain by its analgesicaction as well.

POSSIBLE ROLE OF PLATELET-RELEASED SEROTONIN IN MIGRAINEHEADACHE

Blood serotonin is almost exclusively containedin platelets, with only a small active amount freelydissolved in plasma. It is likely that during the reduc-tions of intraplatelet serotonin, observed in bothcommon and classical migraine attacks,17-19 freeplasma serotonin will have risen to active levels.However, because circulating serotonin is rapidlycleared by endothelial cells, mainly in the lungs,20

measurement of changes in its concentration is diffi-cult. Nevertheless, a causative role for platelet-released 5-HT in a certain number of migraine casesis indicated by the fact that migraine may be induced

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by reserpine, chlorophenylpiperazine, and fenflu-ramine, agents that cause release of 5-HT.21,22 Further-more, migraine can be relieved by 5-HT-receptorantagonists like pizotifen.

Serotonin is an important regulator of pain sen-sation.23 Via vasa-vasorum, blood-borne 5-HT mayreach and activate perivascular pain fibers aroundextracranial arteries (intracranial arteries lack vasavasorum24) and cause sterile inflammation withplasma protein extravasation and edema.25 In addi-tion, serotonin sensitizes the 5-HT3 and 5-HT2A recep-tors on C-fibers in the densely innervated wall of pialand intracerebral arteries.23 The painful action ofserotonin is probably accompanied, and amplified orprolonged, by local formation of pain mediators likeNO, PGI2, and neuropeptides. During spontaneousmigraine, the levels of these substances in internaljugular-vein blood are elevated.26 In addition, head-ache may be induced by NO donors,27 or by PGI2,28

while it may be relieved by NO inhibitors,29 and bysuppression of prostaglandin formation with aid of

cyclooxygenase-2 (COX-2) inhibitors.30 Local vascu-lar31 and/or neural 32expressions of inducible NO syn-thase likely accounts for the often delayed and long-lasting effect of NO.

Serotonin exerts not only algesic but also analge-sic effects, depending on the receptor subtype and siteof action.23 Intravenous injection of 2 to 7.5 mg ofserotonin may even ease spontaneous or reserpine-induced migrainous headache.33 Sumatriptan, one ofthe most successful anti-migraine medicines, relievesmigraine pain probably not by its vasoconstrictiveeffect, but by blocking pain transmission via 5-HT1B/1D

receptors on trigeminal nerve endings.34 Sumatriptanalso scavenges superoxide, hydroxyl, and NOradicals,35 and blocks dural (neurogenic) plasmaextravasation.36

VASCULAR REACTIONS DURING THEAURA PHASE

Studies on regional cerebral blood flow duringaura have shown that an initial short-lasting hyper-

Table 1.—Studies Suggesting Increased Platelet Activity During or Between Migraine Attacks

Units During Attack Between Attacks In Controls Ref.

Serotonin (5-HT) inside platelets % ª70 (289) ª100 (289) 100 (9) 17

5-HT granules/100 platelets 48 (33) 469 (63) 448 (20) 18

ng/109 platelets 315 (14) 440 (14) 759 (14) 19

Plasma levels of a-granule proteinsb-TG ng/mL 84 (6) 39 (8) 31 (35) 91

ng/mL 128 (16) 69 (11) 61 (13) 150

ng/mL — 72 (33) 35 (19) 12

ng/mL — 151 (16) 80 (26) 151

Platelet factor 4 ng/mL — 22 (33) 6 (19) 12

ng/mL — 78 (16) 38 (26) 151

vWf antigen U/dL 130 (17) 72 (17) 72 (25) 89

% of normal — 126 (63) 106 (35) 152

P-selectin Arbitrary units — 1.41 (72) 1.29 (72) 153

PAF Not mentioned 886 (5) 565 (5) — 154

11-dehydro-thromboxane B2 pg/mL — 148 (29) 96 (27) 155

NO metabolites inside platelets nM/108 platelets 10.7 (47) 9.1 (28) 8.5 (28) 156

fM/min/mg protein 33.6 (25) 18.7 (25) 7.3 (30) 157

Circulating aggregated platelets % of all platelets — 22 (73) 5 (90) 158

23 (26) 6 (20) 159

32 (20) 10 (20) 160

Circulating platelet–leukocyte aggregates % of all platelets — 5.7 (72) 3.9 (72) 153

Mean values (number of subjects in parentheses). Patients were not diet restricted. Reference (Ref.)17 is a review of 12 studies. Ofnote: vWf, P-selectin, and PAF are not platelet specific but may also originate from endothelium or granulocytes.b-TG = b-thromboglobuline; NO = nitric oxide; PAF = platelet-activating factor; vWf = von Willebrand factor; — = not studied.

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emia is followed by hypoperfusion of the occipitalbrain (for review, see37). These flow changes are pres-ently often interpreted as epiphenomena of CSD,which is thought to cause the aura signs like movingscotomata.

Another theory states that the hypoperfusionduring aura is caused by serotonergic vasoconstric-tion, because the reaction can be prevented bymethysergide, a 5-HT-antagonist. In this view, aurasigns could be caused by hypoxia in progressivelymore brain cells as blood flow decreases.38-41 It isnoteworthy that aura symptoms disappear afterinhalation of carbon dioxide, a strong cerebralvasodilator.42 Vascular and neuronal theories of aura

do not necessarily exclude each other, because CSDitself may be triggered by vasoconstricton-inducedhypoxia.40,43

A rise in circulating serotonin could also explainthe initial hyperemia, because at low concentration,serotonin causes vasodilation.8 Serotonin may bereleased by brainstem raphe neurons, by enterochro-maffin cells in the gut, and by aggregating blood plate-lets, but which of these mechanisms is actuallyinvolved is still unknown. In this paper, we will accen-tuate the latter possibility. Although there is no directevidence for the contribution of serotonin fromaggregating platelets to vasoconstriction in migraineaura, experiments in dogs show that intracisternal

Table 2.—Effect of Platelet Inhibition on Migraine

Platelet Antagonist (mg/day)No. of Migraine

Patients Result Ref.

TXA2 reductionAspirin (50) 525 Small decrease in frequency, severity, duration, and

migraine-related disability in 59.6% of 525 women (vs56.4% in the placebo group)

161

Aspirin (160) 0 Six percent of 11,037 US male doctors using aspirinreported migraine (vs 7.4 % in the group usingplacebo)

162

Aspirin (300) 135 In 30 % of patients, >50% reduction in migraine rate 163

Aspirin (325) + dipyridamole (25) 25 In 68 % of patients, significant improvement in headachefrequency, intensity, and limitation of activity(compared with placebo)

164

Picotamide (2 ¥ 300) 20 Decrease in mean frequency of migraine aura from 6.85to 2.85 per trimester

165

ADP-receptor blockade with or without TXA2 reductionClopidogrel (75) + aspirin (325) 5 Migraine due to transcatheter placement of an Amplatzer

occluder in PFO patients was completely relieved

88

Clopidogrel (75) + aspirin (150-300) 0 Prevalence of migraine after transcatheter placement ofan Amplatzer occluder in PFO patients was reduced(12 % in 89 cases vs 42 % in 71 cases with aspirinalone)

87

Ticlopidine (200) + aspirin (200) 1 Migraine due to transcatheter placement of an Amplatzeroccluder in a PFO patient was completely relieved

166

Ticlopidine (750) 1 Complete relief of migraine in a patient withthrombocythemia

167

Correction of platelet hyperaggregabilityTiclopidine (100) and/or aspirin (100-300) 23 Prevention of headache in all and of aura in 7 of 10

migraine patients with platelet hyperaggregability

13

In reference (Ref.)13, platelet hyperaggregability and its correction were measured with aggregometry. All these studies were open,patients knew their medication.ADP = adenosine diphosphate; ADP-receptor blockade by clopidogrel or ticlopidine; PFO = patent foramen ovale;TXA2 = thromboxane A2; TXA2 synthase inhibition by aspirin, picotamide, or dipyridamole.

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injection of platelet-rich plasma induces acute cere-bral vasospasm.44

VASCULAR REACTIONS DURING THEHEADACHE PHASE

Dilation of large and smaller cranial arteries hasconsistently been noted during the headache phase ofa spontaneous migraine attack (Table 3). Absence ofvasodilation in a study with nitroglycerin-evokedheadache45 may probably be ascribed to less sensitivemeasurement.46

Less equivocal results have been found forregional cerebral blood flow. Studies in whichmigraine was a consequence of intracarotid injec-tion of Xenon-133 showed hyperemia in nearlyall studied patients,47-52 while no hyperemia wasobserved in red wine-induced migraine.53 Duringspontaneous migraine, an increase, no change, oreven a decrease in cerebral blood flow was observed(Table 4). Methodological differences might beinvolved. Newer methods aim to localize flow abnor-malities more precisely in deeper brain layers. Inpositron emission tomography studies, for example,blood flow in large blood vessel regions is, to thisend, often removed from the analyzed areas of inter-est.54 It is therefore conceivable that such measure-ments are more sensitive to flow changes in thecerebral microcirculation and less sensitive to

changes in large and smaller arteries. As a conse-quence, absence of hyperemia in some studies withregional cerebral blood flow measurement does notexclude a possible dilation of large arteries in super-ficial brain structures, as is indicated by the data inTable 3. This contention would imply that migrain-ous vasodilation does not occur, or is less prominent,in cerebral microcirculation of deeper brain layers,but is confined to large extracranial and intracranialvessels.

Although the large cerebral arteries are pain sen-sitive,55 migraine does not seem to be caused byvasodilation itself. For example, no migraine pain isfelt when vasodilation is elicited by vasoactive intes-tinal peptide56 (ie, a NO-independent vasodilator).Moreover, hyperemia is not time locked to ictal painduring spontaneous migraine,51,57 and the throbbingof the headache is not phase locked to the arterialpulse.58 Both pain and hyperemia during the head-ache phase are more likely caused independently by acommon factor. Circulating serotonin is a good can-didate, because it is a pain mediator and, in low con-centration, a vasodilator. Absence of pain sensationduring the aura phase, in which serotonin concentra-tion is supposed to be high, might be due to thehypoxic suppression of neuronal activity; thereafterpain might be felt as soon as cerebral hypoxia hasdiminished to a level that enables pain sensation.

Table 3.—Large Cranial Artery Diameter and Flow in the Headache Phase of Migraine

Method Change No. of Patients Ref. Year

Spontaneous attacksDiameter of

Temporal artery and conjunctival vessels Visual ↑ Common bedside observation 55 1955MCA and PCA MRA ↑ 1 168 2008MCA Doppler + SPECT ↑ 7 169 1991

Frontotemporal cutaneous blood flow Tissue clearance of NaCl ↑ 18 24,170 1964Red ear syndrome in children Visual ↑ In 7 of 8 171 2002

↑ In 40 of 172 172 2011Evoked by CGRP

MMA and MCA MRA circumference ↑ 15 46 2010Evoked by NTG

MMA and MCA MRA diameter = 20 45 2008

CGRP = calcitonin gene-related peptide; MCA = middle cerebral artery; MMA = middle meningeal artery; MRA = magnetic reso-nance angiography; NTG = nitroglycerin; PCA = posterior cerebral artery; SPECT = single photon emission computed tomography.

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SIMILARITY BETWEEN VASCULARREACTIONS IN MIGRAINE AND THOSEELICITED BY SHEAR-INDUCEDPLATELET AGGREGATION INA RAT MODEL

The earlier 2 sections of this report on vascularreactions indicate that during migraine with aura, atriphasic reaction may occur: an initial short-lastingvasodilation, followed by a longer-lasting (20 minutesto some hours) vasoconstriction, and – in a number ofpatients – a subsequent long-lasting (hours to days)dilation of superficial cranial arteries. In commonmigraine, that is without aura, only vasodilation willoccur. It must be noted that within an animal model,such a triphasic vascular reaction can be evoked byplatelet aggregation, initiated by shear stress.

To study vascular effects due to platelet aggrega-tion in vivo, it is of crucial importance to avoid the useof platelet agonists that are vasoactive by themselves.In previous work on pentobarbital-anesthetizedrats, we have elicited platelet aggregation with aid ofelevated shear stress in a carotid-to-femoral extracor-

poreal loop of polyvinylchloride (PVC) tubing.8

Shear-induced platelet aggregation may occur at sitesof accelerated flow, as for example in patients withsevere internal carotid artery stenosis.59 It is agonistindependent and mediated by conformational changeof large multimers of plasma von Willebrand factor(vWf). When changing from a globular state into anextended chain,vWf presents itsA1 domain that bindsto platelet glycoprotein Ib receptors.60,61 This bindingtriggers intraplatelet calcium mobilization with sub-sequent release of dense body constituents (ADP,serotonin) and aggregation. In our rat experiments,compression of the extracorporeal tubing causedplatelet aggregation and dilation of the femoral bedthat were both prevented by blocking the binding ofvWf to the platelet glycoprotein Ib receptors withaurintricarboxylic acid.6 More intense platelet aggre-gation, induced with aid of a roller pump on the tubing,elicited a triphasic vascular reaction as depicted inFigure 1:an initial vasodilation followed by temporaryvasoconstriction and a long-lasting (hours) vasodila-tion. Of note, measurement of free hemoglobin in

Table 4.—Regional Cerebral Blood Flow in the Headache Phase of Spontaneous Migraine

MethodDirection of Change

(in Number of Patients)No. of Studied

PatientsType of

Migraine Ref. Year

Xenon-133 inhalation ↓ followed by ↑ (10) 10 MA 173 1971↑ (12) 13 MA+MWA 174 1978↑ (29) 42 MA+MWA 175 1986

SPECT ↑ (7) 7 MA 176 1988↓ (13) followed by ↑ (6) 25 MA 51 1990= (12) 12 MWA 57 1984↓ (8) = (3) 11 MA 57 1984

MRIPerfusion weighted ↑ (1) 1 MA 168 2008

= (mean of 14) 14 MWA 177 1999Arterial spin-labeled ↑ (1) 1 MWA 178 2010

↑ (3) 3 MA 179 2008PET

15C-O2 inhalation ↑ (mean of 9) 9 MWA 180 1995H2

15O iv injection ↑ (mean of 5) 5 MA+MWA 181 2005H2

15O iv injection ↓ (1) 1 MWA 182 1994H2

15O iv injection ↓ (5) 7 MWA 183† 2008H2

15O iv injection ↓ (8) ↑ (1) 9 MWA 54‡ 1998

†Hypoperfusion was bilateral in patients with unilateral headache.‡Large blood vessel regions excluded.iv = intravenous; MA = migraine with aura; MRI = magnetic resonance imaging; MWA = migraine without aura; PET = positronemission tomography; SPECT = single photon emission computed tomography.

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blood behind the pump showed no signs of hemolysis.As is typical for shear-induced aggregation,62 plateletactivation and vascular reactions were only weaklyattenuated by low-dose aspirin.10 Blockade of plateletP2Y12 ADP receptors with clopidogrel stronglyreduced aggregation and vasoconstriction but was in-sufficient to prevent vasodilation in the femoral bed.9

Vascular reactions similar to those presented inFigure 1 were also found for the carotid bed with anextracorporeal ipsilateral carotid-to-carotid arteryloop (Unpublished data, experiments approved bythe Committee for Animal Experiments at our uni-versity). Total carotid flow and laser-Doppler flux of

the dura mater decreased during strong aggregationand increased during mild aggregation. The latenciesbetween the start of platelet aggregation and changeof flux demonstrated that the vascular responses weremediated by a blood-borne factor. From flow-velocitymeasurements, it could be calculated that this factorwas released at the site of platelet aggregation.

ROLE OF 5-HT, NO, AND PROSTAGLANDINFORMATION IN OUR RAT MODEL

During strong platelet aggregation, plasma sero-tonin levels in the tubing after the pump rose 6-foldand leveled off when aggregation diminished.8 The

Fig 1.—Triphasic vascular reaction to shear stress-induced platelet aggregation in the rat. Spontaneous flow through an extracor-poreal tube from carotid to femoral artery was converted to pump perfusion by tightening the pump rollers with a calibrated screwjust until flow stopped and by then starting the pump at a speed that restored flow to its original level (see arrow and “shear stress”).This causes an increase in shear forces. The ensuing platelet aggregation led to a triphasic change in resistance of the femoralvascular bed (Rfem): an initial short-lasting (c. 1 minute) decrease (vasodilation, designated as [1]) is followed by a temporaryincrease (vasoconstriction, [2]) during strong aggregation, and a subsequent long-lasting (hours) decrease (vasodilation, [3]) whenaggregation diminishes. Femoral resistance was continuously derived as the ratio of mean femoral artery pressure (not shown) overflow, as measured with an in-line flow probe (1N, Transonic Systems Inc, Ithaca, NY, USA). Adapted from Circulation.2002;106:2588-2593. Paortic = aortic pressure.

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vasoconstriction was prevented and the vasodila-tion reduced by blockade of 5-HT2-receptors withritanserin or pizotifen and could be mimicked by infu-sion of a high, respectively low dose of serotonin intothe extracorporeal tubing. These results are in linewith what is known about the vasoactive effects ofserotonin: in high dose, it causes vasoconstriction bystimulating 5-HT2A receptors on smooth muscle andperivascular nerve endings44 (or 5-HT1db receptors inthe cranial vasculature of man63), while in lower con-centration, it mainly stimulates endothelial 5-HT2B

receptors which cause vasodilation by local release ofNO.64 and prostaglandins.65 The vasodilation in ourexperiments could indeed also be reduced by sup-pression of prostaglandin formation with aid of pare-coxib,10 and completely be prevented, or evenreversed, by inhibiting the production of NO with aidof NG-methyl-L-arginine (L-NMA).8 The fact thatthe long-lasting vasodilation could, after more than 2hours, be reversed by NO blockade indicates that thevasodilation, initiated by serotonin, was sustained bycontinuously enhanced production of NO.

Figure 1 additionally shows that strong plateletaggregation was accompanied by a marked decline inmean aortic pressure. This decline was prevented byclopidogrel9 or L-NMA8 and reminds to the diastolic

hypotension (pressure below 60 mmHg) observed ina number of patients during migraine attacks.66 It isconceivable that the hypotension in migraine contrib-utes to, or may be part of, the autonomic dysfunctionthat causes nausea and emesis. Such dysfunctionmight result from increased plasma levels of seroto-nin that stimulate 5-HT3 receptors on the parasympa-thetic nuclei in the area postrema, located outside theblood–brain barrier.An increase of vagal motor activ-ity will, on its turn, stimulate release of serotonin fromenterochromaffin cells, further exciting vagal activityin a positive serotonergic–parasympathetic feedbackloop.67

ANALOGIES BETWEEN EVENTS INMIGRAINE AND HEMODYNAMICCHANGES CAUSED BY SHEAR-INDUCEDPLATELET AGGREGATION IN RATS

These analogies are summarized in Table 5. Theysuggest that in a certain number of migraine attacks,platelet aggregation induced by shear stress or othermeans, with concomitant release of serotonin, mayplay a role. The headache phase and aura are, in thisview, not independent phenomena but caused byvarying intensities of the same event, ie, a rise in freeplasma serotonin concentration. The longer duration

Table 5.—Analogies Between Human Migraine and Hemodynamic Changes Caused by Shear-Induced Platelet Aggregationin Rats

Human Migraine Shear Stress in Rats

Circulating platelet aggregates Increased IncreasedPlasma levels of 5-HT Likely increased IncreasedTriphasic vascular reaction Short hyperemia, followed by

oligemia in aura and long-lastingvasodilation in pain phase

Short-lasting dilation, followed by longerlasting constriction and long-lastingdilation

5-HT2B-receptor blockade with pizotifen Prophylaxis Reduces long-lasting vasodilationPlasma von Willebrand factor Increased Blocking its platelet receptor prevents

aggregation and vascular effectsPlatelet ADP P2Y12-receptor blockade May prevent migraine Prevents aggregation, vasoconstriction, and

systemic hypotensionLow-dose aspirin Only weak attenuation Only weak attenuation of aggregation and

vascular effectsNO inhibition Relieve Prevention or reversion of vasodilationCOX-2 (prostaglandin) inhibition Relieve Attenuates vasodilationAortic pressure Decrease Decrease

COX-2 = cyclooxygenase-2; 5-HT = serotonin; NO = nitric oxide.

8

of vasoconstriction in human migraine aura, com-pared with that in our rats, might be explained by alonger duration of sufficient serotonin release, due toa larger amount of circulating platelets.

POSSIBLE SITES OF ELEVATED SHEARSTRESS IN MIGRAINE

Head-Neck Region.—Blood shear stress might beelevated at a stenosis or at other sites of vessel abnor-malities with increased blood flow velocities. Both theinternal carotid and vertebral arteries are tortuous andhave to pass a small foramen in entering the skull.Common sites of stenosis in man are the origin andintracranial part of the vertebral artery and the inter-nal carotid artery at the bifurcation.68 In addition, in apopulation-based study on 150 healthy volunteers ahigh prevalence (58%) of incomplete posterior circleof Willis has been found.69 The relevance of such ananatomical characteristic for migraine might be that atemporal obstruction of contralateral carotid flow (eg,in the case of head rotation70) may lead to increasedflow velocity and shear stress both in the underdevel-oped branch of the circle of Willis and in the narrowedcarotid artery.71 Migraine has indeed repeatedly beenassociated with stenoses or dissection of the ipsilateralinternal carotid or vertebral artery, and also withreversible cerebral arterial vasoconstriction, and withcerebral arteriovenous malformations (Table 6). Alsounderdevelopment of collaterals in the circle of Willis

seems to be more prevalent in migraine than in con-trols,72 be it that the prevalence in controls was unex-pectly low (18%) in that study.

As known from the localization of speech func-tion by intracarotid injection of sodium amytal,carotid and vertebral blood flow are mainly directedto the ipsilateral hemisphere. Hence, a local increaseof shear stress at a vascular abnormality as a source ofmigraine would comply with the unilaterality of mostattacks.

Complete recovery from severe migraine hasbeen reported after thromboend arterectomy in apatient with carotid artery stenosis,73 and afterobliteration of an arteriovenous malformation.74-76

Because vessels may be narrowed by local muscularspasms or by unnatural body position, involvementof vessel stenosis in migraine is also suggestedby favorable consequences of 2 months chiropracticspinal therapy (>90% attack reduction in 22% andsignificant improvement in 49% of 83 patients).77

It may, furthermore, explain why migraine patients,in contrast to patients with tension-type headachewho massage their scalp, often try to relieve theirpain by changing their posture,78 as if they attemptto reduce the degree of vascular stenosis or shearstress.

Thoracic Region.—Evidence for an increasedprevalence of migraine with aura in patients withsymptomatic PFO, or other pulmonary or cardial

Table 6.—Studies in Which Migraine Might Have Been Caused by Elevated Blood Shear Stress in Head-Neck Region

Possible Site of Increased Shear Stress Prevalence Ref.

Internal carotid artery stenosis In 7 of 15 ischemic migraine attacks 184

In 16 case reports of migraine 73,185-187

Internal carotid artery spasm In 4 case reports of migraine 188,189

Middle cerebral artery narrowing In 37% of 62 migrainous children 190

Middle cerebral artery spasm In 6.5% of 62 migrainous children 190

Incomplete circle of Willis In 49% of 47 migraineurs (vs 18% in controls) 72

Vertebral artery hypoplasia In 36% of 59 and in 28% of 92 migraineurs 191,192

Cerebral arteriovenous malformation (AVM) Migraine in 47% of 51, 19% of 36, and 31% of 48patients with AVM

76,193,194

Case report of migraine in patient with AVM 74

Cervical artery dissection (CAD) In 8 case reports of migraine 195-198

Migraine in 34% of 62 CAD patients 199

Odds ratio for migraine: 2.06 and 3.6 200,201

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shunts, is circumstantial.79-81 Migraine complaints in apatient with aortic coarctation were abolished byballoon dilatation.82

PFO.—This remnant of fetal anatomy is a slit-like interatrial shunt, which is present in approxi-mately 25 % of the adult population. Interestingly,migraine is associated with PFO when PFO is symp-tomatic,79,80 ie, in the presence of recurrent cryptoge-nic stroke or transient ischemic attacks, but hardly ornot at all with asymptomatic PFO.83,84 In the first case,shear-induced platelet aggregation may occur withinthe shunt, especially during Valsalva maneuvers (eg,straining during defecation). Closure of PFO mayreduce migraine.79,85 This was significant even in theMigraine Intervention With STARFlex Technologytrial, after correction for 2 outliers.86 A temporaryenhancement of migraine after PFO closure couldpoint to increased local shear stress as a result ofincomplete closure. This possibility is supported bythe fact that migraine in such patients was betterreduced by clopidogrel than by aspirin.87,88 From invitro studies, it is known that shear-induced plateletaggregation and thrombus formation are inhibited byclopidogrel, but not by aspirin.62 An explanationmight be that at high shear stress, aggregationdepends more on release of vWf from a-granules,which is not inhibited by aspirin, than on formation ofTXA2.10,11

POSSIBLE INITIATION OF MIGRAINEATTACKS BY TRIGGERS THAT ENHANCEPLATELET AGGREGABILITY

Although a number of migraine patients showincreased platelet aggregabilty,13,89-94 and their plate-lets may even continuously be activated (Table 1),aggregation might frequently be too weak to causesufficient release of platelet serotonin for a migraineattack. Because many migraine triggers are known fortheir ability to potently enhance platelet aggregability(Table 7), we propose that a proportion of migraineattacks might be triggered by a temporary furtherincrease of platelet aggregation, as depicted sche-matically in Figure 2.A further enhancement of plate-let aggregability during attacks has indeed beendocumented in several studies.90-93

The migraine triggers in Table 7 may have adirect stimulating effect on platelets or may increaseplatelet aggregability by decreasing the level of cir-culating endogenous PGI2, which is a plateletantagonist (see later). Triggers like emotional orphysical stress, or awakening in the morning, areexamples of the first; they stimulate platelet activityby a rise in plasma catecholamine levels.95,96 Estro-gens and their platelet effects will be dealt withlater. Other triggers, like, eg, alcohol and nitrites, notmentioned in Table 7, might cause migraine by directrelease of serotonin from platelets97 or by release ofNO from vascular endothelium.

PGI2 and Platelet Aggregability.—In migrainepatients, lowered levels of plasma PGI2 have beenfound.98-100 This endogenous platelet antagonist ismainly produced by endothelial COX-2. PGI2

reduces intracellular free calcium levels via stimula-tion of platelet adenylate cyclase which elevates cyclicadenosine monophosphate.101 We have recently dem-onstrated that the circulating level of PGI2 in healthymale volunteers is sufficiently high to control plateletaggregability in basal conditions, and that its reduc-tion by COX-2 inhibitors enhances platelet aggrega-bility.11 The endothelial production and half-life ofPGI2 can be temporarily suppressed by exogenousestrogens (see later), smoking,102 several foods,103

exercise,104 infections,105 low-density lipoproteins(LDL),100,106 and non-steroidal anti-inflammatorydrugs that inhibit COX-2.

Table 7.—Migraine Provoking Triggers That Increase PlateletAggregability

Estrogens:Fall in premenstrual levels;110,202,203 oral anticonceptives;204,205

hormonal replacement therapy121

Catecholamines:Emotional and physical stress;206,207 awakening in themorning;95 cold weather;208 low blood sugar; and fasting209

Additives in food and beverages:Salt;210,211 saturated fatty acids;210 glutamate (tasteenhancer);212 tyramine (preservative)213

Numbers in the table refer to references indicating increasedplatelet aggregability. For enumeration of migraine triggers, seereference.1

10

Estrogens and Platelet Aggregability.—In the daysbefore menstruation, platelet activation increases107

during the drop in circulating 17 beta-estradiol.108

Physiological levels of this hormone have cardio-vascular and neural functions (for review, see109),one being suppression of platelet aggregation.110-114

Migraine attacks are less prevalent in pregnancy,when estrogen levels increase, but return after deliv-ery when estrogen levels sharply decline.115 Abruptestrogen withdrawal by other causes is associatedwith severe migraine.116 Hence, premenstrualmigraine, the most common type of this disease, mightbe partly caused by increased platelet aggregability.However, estrogen supplementation does not alwaysprevent migraine,117 and use of estrogen containingoral contraceptives in premenopausal woman, orhormone replacement therapy in postmenopausal

woman, even increases the frequency of attacks.118,119

These adverse effects may be related to the fact thatexogenous estrogens are often given in supraphysi-ologic doses,120 which increase platelet aggregabil-ity,121 possibly by a decrease of PGI2 production.122 Ithas recently been shown that use of estrogen-free oralcontraceptives significantly reduces the number ofmigraine attacks.123

RELATION BETWEEN MIGRAINEAND STROKE

We propose that the enhanced prevalence ofstroke and posterior infarcts in migraine patients iscaused by platelet aggregates, that are, among others,induced by elevated shear stress.2 Platelet thrombimay travel to the distal cerebral vasculature during(“migrainous infarction”) or in the days after a

Fig 2.—Schematic view of possible role of shear-induced platelet aggregation with release of serotonin (5-HT) in the origin ofmigraine. In a subgroup of migraine patients, platelets might become activated by elevated shear stress in a stenotic or narrowcervico-cranial artery, at sites of reversible constriction or other vascular abnormality. Between attacks, platelet aggregation at thesesites may be negligible or modest, and not cause migraine. An attack might be triggered by conditions that enhance plateletaggregability, causing platelet aggregation with release of serotonin (5-HT). High 5-HT concentrations can evoke vasoconstrictionwith aura symptoms, whereas less marked 5-HT release may cause vasodilation, among others by stimulating the production ofnitric oxide (NO) and prostaglandins (PGs). 5-HT, NO, and PGs may at the same time mediate the pain in the headache phase.

Headache 11

migraine attack. Because platelet activation is par-ticularly strong in migraineurs with aura,12,124 the riskfor stroke will be highest in these migraine patients.

Migraine has also been linked to myocardial in-farction and other ischemic vascular disorders.125

Remarkably, both the prevalence of migraine andrisk for myocardial infarction are lower in Japanesepopulations compared with the Western popula-tions.126,127 A genetic susceptibility has been foundfor both migraine and vascular disorders, suggestingcommon pathogenic mechanisms.128 In the lipidprofile of migraineurs, increased levels of LDL arefound.129 LDL shortens the half-life of PGI2,106

thereby increasing platelet aggregability. Migrainepatients therefore seem to be at a general throm-botic risk.

PROPHYLACTIC ACTION OF CALCIUMAND b-BLOCKERS

The favorable anti-migraine effect of most b-blockers and calcium antagonists is not well under-stood.130 Because some of them are hydrophilic anddo not cross the blood–brain barrier,131,132 a directeffect on central neural mechanisms seems unlikely.Many b-blockers decrease platelet aggregability (pro-pranolol,133 metoprolol,134 pindolol,134 practolol,135

esmolol,136 carvedilol,137 alprenolol,138 atenolol133),probably by increased PGI2 formation in the arterialwall.135 Also, the prophylactic effect of calciumantagonists might be associated with their well-known antiplatelet effect.139 The same may hold forangiotensin-converting enzyme inhibitors,140 ribofla-vin,141 dark chocolate,142 and goshuyuto, a famous tra-ditional Oriental migraine medicine.143

IMPLICATIONS OF THEPLATELET-SEROTONIN-RELEASEHYPOTHESIS FOR MIGRAINE THERAPY

Although the percentage of migraine patientsthat show increased platelet aggregability has notbeen determined in a population-based study,several investigations suggest that this percentagemay be noteworthy.13,89-94 In 1 study on 23 consecu-tive patients with severe migraine, hyperaggregabil-ity was demonstrated in all of them.13 To testmigraine patients on hyperaggregability, several

devices are available.144 Platelet sensitivity toincreased shear stress may best be measured bythe Platelet Function Analyzer (PFA 100, DadeBehring, Newark, DE, USA), which aspirates cit-rated whole blood over an ADP-coated surface. Toget information about platelet aggregability in vivo,it is important to perform the tests immediatelyafter (venous) blood collection.11 A promisingeasy method to measure shear-induced aggregationwithin 90 seconds using non-anticoagulated bloodfrom a finger stick has recently been proposed.145

We suggest that in patients with hyperaggregabil-ity, attacks might be prevented by inhibiting shearstress-induced platelet aggregation. This could mostspecifically be accomplished by blockade of vWfbinding to platelet glycoprotein 1b receptors. A can-didate may be the recently developed ARC1779 thatinhibits this binding, while it gives less increase inbleeding than conventional antiplatelet agents. In arandomized trial on 36 patients, it markedly reducedcerebral embolization after carotid endarterec-tomy.146 Alternatively, shear-induced platelet aggrega-tion in humans could be suppressed by in vivoinhibition of fibrinogen binding to GPIIB/IIIA recep-tors,147 or by clopidogrel, which blocks platelet ADPP2Y12 receptors.145 A favorable effect of clopidogrel inpreventing migraine has already been mentioned insome studies (Table 2), and its efficacy is presentlytested in 2 randomized, placebo-controlled trials(“CANOA” study at Laval University, Quebec,Canada, and “Clopidogrel as prophylactic treatmentfor migraine “study by J. Chambers, London). Aneven more practical solution might be the use ofticagrelor, which, in contrast to clopidogrel, whichrequires hepatic conversion, is a direct-acting revers-ible inhibitor of platelet ADP P2Y12 receptors,148

enabling a patient to take such medication at theonset, or prodrome, of a migraine attack.

Patients in which migraine is successfully pre-vented or aborted by agents that inhibit shear-induced platelet aggregation could be successivelyscanned for the presence of a cardial or pulmonaryshunt, a stenosis or dissection of a cervico-cranialartery, or reversible cerebral arterial constriction.149

Proper treatment of these anomalies will also reducetheir important risk for cerebral stroke.

12

CONCLUSIONOur extension of the platelet hypothesis of

migraine, as depicted schematically in Figure 2, sug-gests that in a number of patients, a migraine attackwith or without aura may be caused by the sameevent, but at different intensity, namely a rise inplasma serotonin which is released from aggregatingplatelets. Aggregation may be initiated by elevatedshear stress in a stenotic cervico-cranial artery or atsites of reversible vasoconstriction or other cardio-vascular abnormality, especially when platelet aggre-gability is temporarily enhanced by a migrainetrigger. A clinical implication of the present theory isthe testing of migraineurs for increased plateletaggregability and treating them with one of therecently developed short-acting inhibitors of shear-induced platelet aggregation. Patients respondingfavorably could be scanned for cardiovascularanomalies in the thorax-head region, treatment ofwhich will reduce their risk for cerebral stroke.

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