Muscle contraction headache and migraine:Platelet activation and plasma norepinephrine during the cold pressor test

For clarification of possible platelet activation in migraine and chronic muscle contraction headache (MCH) under stress, plasma platelet factor 4 (PF4), norepinephrine (NE), and free fatty acids (FFA) were investigated during the cold pressor test. Both PF4 and NE increased significantly, whereas FFA showed no remarkable changes. The increases of PF4 in MCH and migraine during this test were significantly greater than in healthy controls. The increase of PF4, however, was independent of NE increase and FFA changes. On the other hand, we observed decreased NE levels in both MCH and migraine, which might suggest peripheral sympathetic hypofunction. The platelets of MCH or migraine patients seem to be impaired, and the impairment may be caused by continuous sympathetic hypofunction. The behaviour of the above three substances in MCH was similar to that in migraine throughout the present study.     

Platelet Activity in Migraine

SYNOPSIS
Migraine is a disease associated with increased platelet activity.
The aim of this paper was to study "in vivo" platelet activation by assessing platelet serotonin (5HT) content and beta-thromboglobulin (B-TG) and platelet factor four (PF4) plasma levels, in headache-free-periods and during migraine attacks.
In headache-free-periods, there was no differences in platelet 5HT values between migraine patients and control subjects. On the other hand, there were significant differences in B-TG and PF4 plasma levels. Furthermore, two groups of migraine patients were observed, one with normal B-TG plasma levels and the other with high B-TG plasma levels. PF4 plasma levels behave similarly.
During migraine attacks, platelet 5-HT fell, while B-TG and PF4 plasma levels rose, if compared to the values recorded immediately before attacks.
We suggest that migraine patients, particularly those ones with high basal values of B-TG and PF4 plasma levels, form a high risk group to cerebrovascular ischaemic diseases. For these patients a prophylaxis with antiplatelet drugs is indicated.     

Platelet alpha-granule release in chronic myeloproliferative disorders with thrombocytosis

Platelet alpha-granule release in 22 patients affected by chronic myeloproliferative disorders with thrombocytosis and seven subjects with thrombocytosis secondary to splenectomy were studied. We found elevated beta-thromboglobulin (BTG) and platelet factor 4 (PF4) plasma levels in all patients. Intraplatelet content of BTG and PF4 was decreased in patients with idiopathic thrombocythaemia (IT) and idiopathic myelofibrosis (IMF). The BTG and PF4 results were also expressed as the ratio plasma BTG and PF4: whole blood platelet count. In patients with IT, BTG: whole blood platelet count ratio was low, conversely, the same ratio was high in patients with IMF. In conclusion, our results suggest the presence of an abnormal, BTG-deficient clone in IT and a peripheral platelet activation in IMF.     

Platelet Substance P and 5-Hydroxytryptamine in Migraine and Tension-Type Headache

SYNOPSIS
Levels of substance P (SP) and 5-hydroxytryptamine (5-HT) in platelets were measured in 25 patients with migraine,31 patients with tension-type headache (TH) and 27 healthy controls. The mean concentration of SP in platelets was 355.3 pg/10 9 platelets in patients with migraine, 290.8 pg/10 9 platelets in patients with TH and 180.8 pg/10 9 platelets in the controls. The concentrations of platelet SP in the migrainous patients and in the TH patients were significantly higher than those in the controls. The mean concentration of 5-HT in platelets was 619.7 ng/10 9 platelets in patients with migraine, 579.3 ng/10 9 platelets in patients with TH and 811.9 ng/10 9 platelets in the controls. The concentration of platelet 5-HT in the patients with TH was significantly lower than that in the controls. The platelet SP/5-HT ratio in the migrainous patients and in the TH patients were significantly higher than that in the controls. There was significant negative correlation between the concentrations of platelet SP and those of platelet 5-HT. These results may support the hypothesis that SP released from the terminals of the trigeminal nerves causes migraine either through direct actions on the vessels or by releasing 5-HT from the platelets. The high levels of platelet SP in TH patients might reflect release of SP from the pain sensory system.     

Plasma beta-thromboglobulin, platelet factor 4, fibrinopeptide A, and other hemostatic functions during improved, short-term glycemic control in diabetes mellitus

To determine the effect of improved, short-term glycemic control on various functions of hemostasis in insulin-dependent diabetes, we measured changes in plasma fibrinogen, fibrinopeptide A (FPA), functional antithrombin III (AT-III), factor VIII:ristocetin cofactor ( VIIIRCoF ), beta-thromboglobulin (BTG), platelet factor 4 (PF4), and platelet aggregation responses to ADP and collagen in 12 patients with low or undetectable stimulated (postprandial) serum C-peptide levels during 4-8 wk (median, 6 wk) of treatment with constant subcutaneous insulin infusion. Mean plasma fibrinogen, FPA, AT-III, VIIIRCoF , and BTG at baseline were elevated compared with normal. Three patients had heightened platelet responses to ADP that did not correlate to other indicators of a hypercoagulable state; the affected patients, in fact, had significantly lower plasma BTG (25.5 +/- 5.3 [SEM] versus 44.6 +/- 4.6 ng/ml, P less than 0.05) and FPA (1.1 +/- 0.1 versus 2.5 +/- 0.5 ng/ml, P less than 0.05) than the remaining patients. Patients with clinically evident vascular disease had higher baseline plasma BTG and FPA than those without vascular disease (44.6 +/- 5.4 versus 30.2 +/- 4.6, and 2.6 +/- 0.6 versus 1.3 +/- 0.2 ng/ml, P less than 0.05, respectively). During treatment, all patients had declining blood glucose (200 +/- 18 to 102 +/- 5 mg/dl, P less than 0.001) and HbA1 (11.8 +/- 0.6 to 10.2 +/- 0.4%, P less than 0.005). No statistically significant changes in hemostatic functions were noted. During treatment, one patient had an acute myocardial infarction.(ABSTRACT TRUNCATED AT 250 WORDS)     

Platelet alpha granule release in diabetes mellitus

We studied beta-thromboglobulin (BTG) and platelet factor 4 (PF4) plasma levels in 90 diabetic subjects; we found high plasma values of these proteins only in patients with complications. To provide further indications regarding the role of platelet activation in the pathogenesis of diabetic microangiopathy, we also tested mobilizable platelet content of BTG and PF4; we found these similar to those of normal subjects.     

Increased 11-dehydrothromboxane B 2 in Migraine: Platelet Hyperfunction in Patients with Migraine during Headache-free Period

SYNOPSIS
Several disturbances in platelet function have been reported in migraine and tension-type headache (TH). The plasma 11-dehydrothromboxane B ₂ (11-dTXB ₂ ) is free from artifactual increase during blood sampling, and it can be a reliable indicator of thromboxane A ₂ (TXA ₂ ) production in vivo. TXA ₂ is a very potent proaggregatory and vasoconstrictory metabolite formed in the platelets. We investigated plasma 11-dTXB ₂ and 5-hydroxytryptamine (5-HT) levels in patients with migraine during headache-free periods and in patients with chronic TH. The mean value of plasma 11 -dTXB ₂ levels in migrainous patients was significantly higher than those in TH patients and healthy controls. The mean value of plasma 5-HT levels in TH patients was significantly lower than those in migrainous patients and healthy controls. There was no correlation between plasma 11-dTXB ₂ levels and plasma 5-HT levels in any group. The results suggest the existence of continuous platelet activation in migrainous patients.     

Platelet activity in cluster headache

Platelets are known to be activated in common or classic migraine both during the attack and in headache-free periods. Platelet behavior is less well known in cluster headache. We have investigated beta-thromboglobulin (beta-TG) and platelet factor four (PF4) plasma levels, markers of in vivo platelet activation, in patients during remission and during bouts of cluster headache with and without pain. The results indicated that statistically significantly higher levels of beta-TG and PF4 occur in the patients during the remission period when compared with the control subjects. Such high levels seemed to persist between paroxysmal episodes in cluster periods. However, during the attacks of cluster headache beta-TG and PF4 plasma levels decreased by 42% and 50%, respectively, in comparison with plasma concentrations measured outside of attack. Thus, although platelet activation also occurs in patients with cluster headache, the attack as such seems to be characterized by a marked reduction in platelet activation.     

偏头痛患者精神状态异常与血浆5-HT水平的关系

目的:探讨偏头痛患者精神状态异常与血浆5-羟色胺(5-HT)浓度之间的关系。方法:40例偏头痛患者和30例正常人(对照组)均进行抑郁和焦虑自评量表(SDS、SAS)、90项症状自评量表(SCL-90)及血浆5-HT浓度的差异,分析偏头痛组患者精神状态异常与血浆5-HT浓度之间的相关性。结果:与对照组比较,偏头痛组SCL-90总分、阳性项目数、阳性项目均分显著升高,其各因子分中躯体化、抑郁、焦虑、敌对、恐惧评分显著升高;SAS和SDS标准分亦显著升高(均P0.01)。血浆5-HT浓度,偏头痛组显著高于对照组(P0.01)。偏头痛组血浆5-HT浓度与SCL-90总分及躯体化、焦虑、抑郁、敌对和恐惧等因子分呈明显正相关(R=0.344～0.458);与SDS和SAS标准分呈明显正相关(R=0.323、0.271)。结论:偏头痛患者存在精神状态异常和血浆5-HT浓度的升高,且精神状态异常与血浆5-HT浓度的升高存在一定的相关性。     

Platelet Serotonin (5-HT) and 5-HT Releasing Factor in Plasma of Migrainous Patients

SYNOPSIS
The mean platelet 5-HT concentration in 24 migrainous patients during headache-free intervals (580 ± 53.3 ng10⁹ platelets, M ± SEM) was similar to that found in 25 healthy persons (550 ± 48.1). A significant fall in platelet 5-HT level (about 15% p<0.05) was found during migraine attacks as compared with headache-free intervals. When platelets from blood collected during headache-free intervals were incubated with platelet-poor plasma taken from another migrainous patient in attack, the 5-HT content diminished by 22%. On the other hand, plasma taken in the headache-free period did not produce a considerable release of platelet 5-HT. Moreover, plasma from migrainous sufferers in the attack did not elicit 5-HT release from platelets of healthy persons. These results lend support to the hypothesis that a 5-HT releasing factor appears in plasma during the migraine attack, and that some platelet abnormality is present in these patients.     

顽固性偏头痛患者血清血管活性物质水平检测及临床意义分析

目的探讨顽固性偏头痛患者血清5-羟色胺(5-HT)、血管活性肠肽(VIP)、β-内啡肽(β-EP)及肿瘤坏死因子-α(TNF-α)检测水平特征及临床意义。方法选取顽固性偏头痛患者106例作为顽固性偏头痛组,110例健康成年人作为健康组,采用ELISA法检测2组人群血清5-HT、VIP、β-EP及TNF-α水平。并对顽固性偏头痛患者5-HT、VIP、β-EP及TNF-α水平进行相关性分析和多元线性回归分析。结果顽固性偏头痛患者血清5-HT、VIP、β-EP水平均低于健康组,TNF-α水平均高于健康组(P<0.05),头痛发作期患者血清5-HT、VIP、β-EP水平均低于间歇期,TNF-α水平均高于间歇期(P<0.05)。相关性分析结果显示顽固性偏头痛患者的5-HT、VIP、β-EP水平两两间呈正相关,与TNF-α水平均呈负相关(P<0.05)。多元线性回归分析显示头痛评分(分)=0.754+0.337×5-HT(μg/L)+0.216×VIP(ng/L)+0.034×β-EP(ng/L)+0.097×TNF-α(pg/mL),决定系数R 2=0.543。结论血清5-HT、VIP、β-EP及TNF-α与偏头痛存在关联,可能与顽固性偏头痛的发生与发展有关,可作为判断患者病情严重程度的潜在参考依据,但还需要今后进行更为深入的临床研究来证实。     

NO-induced migraine attack: strong increase in plasma calcitonin gene-related peptide (CGRP) concentration and negative correlation with platelet serotonin release

The aim of the present study was to investigate changes in the plasma calcitonin gene-related peptide (CGRP) concentration and platelet serotonin (5-hydroxytriptamine, 5-HT) content during the immediate headache and the delayed genuine migraine attack provoked by nitroglycerin. Fifteen female migraineurs (without aura) and eight controls participated in the study. Sublingual nitroglycerin (0.5 mg) was administered. Blood was collected from the antecubital vein four times: 60 min before and after the nitroglycerin application, and 60 and 120 min after the beginning of the migraine attack (mean 344 and 404 min; 12 subjects). In those subjects who had no migraine attack (11 subjects) a similar time schedule was used. Plasma CGRP concentration increased significantly (P<0.01) during the migraine attack and returned to baseline after the cessation of the migraine. In addition, both change and peak, showed significant positive correlations with migraine headache intensity (P<0.001). However, plasma CGRP concentrations failed to change during immediate headache and in the subjects with no migraine attack. Basal CGRP concentration was significantly higher and platelet 5-HT content tended to be lower in subjects who experienced a migraine attack. Platelet serotonin content decreased significantly (P<0.01) after nitroglycerin in subjects with no migraine attack but no consistent change was observed in patients with migraine attack. In conclusion, the fact that plasma CGRP concentration correlates with the timing and severity of a migraine headache suggests a direct relationship between CGRP and migraine. In contrast, serotonin release from platelets does not provoke migraine, it may even counteract the headache and the concomitant CGRP release in this model.     

The Platelet Release Reaction During Migraine Attacks

SYNOPSIS
An investigation is reported of serum levels of Beta Thromboglobulin (BTG), a platelet release reaction specific protein, and the stable metabolites of thromboxane B2 and prostacyclin during and between migraine attacks, and in age and sex matched controls.
The level of BTG in plasma from controls was 61.3 ngml (± 26.15), in patients during migraine attacks 127.69 ngml (± 82.8) whilst between attacks the level was 69.06 ngml.
No changes were observed in the levels of the stable metabolite of thromboxane B2 and prostacyclin.
The significant rise in BTG (p = < .02) during migraine attacks indicates that the platelet release reaction occurs during the headache phase.     

常见心脑血管疾病的血液流变性和血小板功能变化

本文应用多种血小板功能试验配合血液流变学试验对高血压、心胶痛、急性心梗、 糖尿病、脑梗塞、脑出血等血栓性疾病的患者进行检测，发现有规律性变化，最敏感的试验 是β－ＴＧ和血小板粘附性、次为ＰＦ４和ＴＸＢ２、再次为血小板聚集性和６－酮－ＰＧＦ１２。大多数患 者的全血粘度和血浆粘度也同时显著升高。     

Decreased Serum Interleukin-2 Level in Patients With Chronic Headache

Some cellular immune functions are impaired in cluster headache patients. Interleukin-2 (IL-2) is a polypeptide secreted by antigen or mitogen-actuated T lymphocytes that functions as a growth factor for T cells. To investigate cellular immune functions in patients with chronic headache, we measured the IL-2 concentration of sera in patients with migraine and in patients with tension-type headache. Thirteen subjects suffering from migraine without aura (5 males and 8 females, mean age: 32.8 years) and 46 subjects (20 males and 26 females, mean age: 39.7 years) with tension-type headache (TH) were selected for this study. Forty-three normal healthy volunteers composed the control group (15 males and 28 females, average age 41.6 years). The IL-2 levels of sera were determined using enzyme-linked immunosorbent assay (ELISA) techniques. The IL-2 levels of sera were 3.18 +/- 1.8 U/ml (mean +/- SD) in the healthy controls, 2.29 +/- 2.6 U/ml in the patients with migraine and 1.59 +/- 1.0 U/ml in the patients with TH. The serum level of IL-2 in the patients with migraine was significantly lower than in the controls. The serum level of IL-2 in the patients with TH was significantly lower than in the controls. The central nervous system (CNS) has been considered to be involved in the development of the immune phenomena. In the patients with TH or migraine, reduction in platelet 5-hydroxytryptamine (5-HT) levels and sympathetic hypofunction have been observed. These phenomena might reflect decrease in 5-HT levels in CNS in the patients with TH or migraine. The decreased serum IL-2 level, observed in this study, might reflect a reduction in 5-HT or catecholamine levels in CNS in the patients with migraine or TH.     

Platelet serotonin measures in migraine

OBJECTIVE AND BACKGROUND: Serotonergic mechanisms play an important role in the pathogenesis of headache. To search for potential indicators of altered serotonin homeostasis in migraine, we have investigated three parameters of the platelet serotonin (5HT) system, platelet serotonin level (PSL), platelet serotonin uptake (PSU), and monoamine oxidase (MAO-B) activity, in a group of 55 patients with migraine and in 81 healthy controls. METHODS: After platelet separation, PSL was determined fluorimetrically; PSU was measured by incubating aliquots of platelet-rich plasma with six concentrations of 14C-5-HT for 60 seconds at 37 degrees C, followed by vacuum filtration; platelet MAO-B activity (toward kynuramine as a substrate) was determined fluorimetrically. RESULTS: Values of the investigated measures, in patients versus controls, amounted to (mean +/- SD) 608 +/- 166 vs. 591 +/- 184 ng/10(9) platelets for PSL, 139 +/- 25 vs. 142 +/- 25 pmol 5HT/10(8) platelets/minute for Vmax of PSU, 376 +/- 62 vs. 404 +/- 72 nM for Km of PSU, and 15.8 +/- 5.1 vs. 14.3 +/- 5.7 nmol product/10(8) platelets/60 minutes for velocity of MAO-B. Mentioned parameters did not show statistical differences between patients and controls, with exception of a small difference in Km of PSU, reaching significance (P<0.01). After subgrouping of patients according to diagnosis (migraine with aura, migraine without aura, and migraine attack) and gender, no differences retained significance. CONCLUSIONS: Our results indicate the absence of a measurable disturbance in 5HT homeostasis in migraine, as shown by platelet 5HT parameters, and they question the suitability of the use of mentioned blood elements in this regard.     

Concentration and uptake of 5-hydroxytryptamine in platelets from cluster headache and migraine patients

Concentrations of 5-hydroxytryptamine (5-HT) in platelets were determined in 33 cluster headache patients (17 males) and in 34 migraine patients (16 males) outside attacks. The 5-HT uptake into platelets was measured and the kinetic constants V_max and K_m determined in 26 cluster patients (14 males) and in 30 migraine patients (13 males). Significantly lower 5-HT concentrations in whole blood were found in cluster headache and migraine patients than in 50 healthy controls (19 males). The V_max and K_m values of the 5-HT uptake were significantly lower in cluster headache and migraine patients compared with 22 healthy controls (9 males). The 5-HT concentrations and the kinetics of the 5-HT uptake did not differ between cluster headache and migraine. In healthy controls a significant positive correlation was found between the 5-HT uptake rate at 0.25 μM and K_m but not in cluster headache and migraine patients. The 5-HT concentrations in whole blood correlated positively with V_max and K_m, respectively, in cluster headache and with K_m in healthy controls but not with V_max nor with K_m in migraine. There was no obvious relation between the kinetics of platelet monoamine oxidase (MAO) and the 5-HT uptake except for an increased incidence of low V_max of MAO and low K_m of the 5-HT uptake in cluster headache. The kinetics of the 5-HT uptake was apparently not related to the state of migraine. The results indicate a possible constitutional trait in cluster headache and migraine expressed as low 5-HT concentrations in whole blood and low V_max and K_m of the 5-HT uptake into platelets.     

Platelet met-enkephalin immunoreactivity and 5-hydroxytryptamine concentrations in migraine patients: effects of 5-hydroxytryptophan, amitriptyline and chlorimipramine treatment

In thirty patients with common migraine the platelet concentrations of met-enkephalin immunoreactivity (ME) (76 ± 9 pg/mg protein) were similar to those in 23 healthy volunteers (77 ± 5), suggesting that there is no alteration in the ME pool in this biochemical compartment in migraine. Chronic treatment (4 weeks) with drugs that interfere with 5-hydroxytryptamine (5-HT) synthesis or uptake induced the expected changes in platelet 5-HT levels, i.e. a rise following administration of the 5-HT precursor 5-hydroxytryptophan (daily dose: 300–500 mg, n = 9) and a decrease after amine uptake inhibition by amitryptyline (30–75 mg, n = 7) and even more by chlorimipramine (30–50 mg, n = 9). Platelet ME concentrations rose by up to ∼90% over the basal values after either 5-hydroxytryptophan (significantly from week 2) or amitriptyline (at week 2) and were unchanged after chlorimipramine, indicating that 5-HT and ME concentrations in platelets can vary independently. The high platelet ME levels following 5-hydroxytryptophan and amitriptyline cannot be explained at present. They might be due either to increased ME synthesis, possibly in the megakaryocyte, or to decreased utilization by platelets or both.     

Increased plasma concentrations of soluble CD40 ligand in acute coronary syndrome depend on in vitro platelet activation

BACKGROUND: Soluble CD40 ligand (sCD40L) was suggested as a novel biomarker of cardiovascular risk. We examined the effect of preanalytical variation on the measurement of sCD40L concentration. METHODS: From healthy control individuals (n = 20) and patients with acute coronary syndrome (ACS) (n = 20) or sepsis (n = 20), we obtained blood drawn into 5 tubes containing citrate or a mixture of citrate, theophylline, adenosine, and dipyridamole (CTAD). The tubes were incubated for 30 min at room temperature or 0 degrees C before a single or double centrifugation (15 min, 2500 g) at room temperature or 4 degrees C, respectively. sCD40L, beta-thromboglobulin (betaTG), and platelet factor 4 (PF4) concentrations were measured using immunoassays. RESULTS: Concentrations of sCD40L were very low in all CTAD and citrated samples maintained at 0 degrees C (median < or = 0.076 microg/L). Although increased betaTG and PF4 confirmed disease-related in vivo platelet activation, sCD40L was not higher in patients than in controls. In contrast, if the samples were processed at room temperature, sCD40L was significantly higher in ACS patients than in controls (P <0.02 in CTAD and citrated plasma at room temperature). Moreover, the betaTG:PF4 ratio decreased in patient but not control CTAD samples, suggesting a greater susceptibility of patient platelets to in vitro activation. CONCLUSIONS: Increased sCD40L concentrations resulted from in vitro platelet activation during sample preparation. Disease-related in vivo activation did not contribute to sCD40L concentrations in plasma. Therefore, published studies of sCD40L demand cautious interpretation, because their preanalytical conditions were not standardized.     

Cardiovascular Sympathetic Hypofunction in Muscle Contraction Headache and Migraine

There have been some recent reports proposing that muscle contraction headache (MCH) and migraine are similar and may have a common etiology. It has been hypothesized that derangement of the autonomic nervous system (ANS) plays an important role in the pathogenesis of migraine. However, reports on the ANS function in MCH have rarely been submitted. Therefore, in this report, MCH patients were investigated as well as migraine patients. The cardiovascular reflex responses by orthostatic test, isometric work test and the pulse rate (R-R interval) variation in fifteen MCH patients and fifteen migraine patients were recorded during headache-free intervals. The plasma norepinephrine (NE) levels were also measured throughout the orthostatic tests. Fifteen healthy subjects served as the age-matched control group. In the MCH group and the migraine group, blood pressure immediately after going from the supine to the erect position decreased more significantly than in the control group. The basal NE level was significantly low in both the MCH group and the migraine group, in comparison with the control group. MCH patients as well as migraine patients showed cardiovascular sympathetic hypofunction.