Beta-thromboglobulin Concentration Research Articles

Prognostic significance of fibrinopeptide A in survivors of cerebral infarction.

We measured levels of fibrinopeptide A, beta-thromboglobulin, and fibrinogen in the plasma of 27 patients 2 months after their first stroke. Concentrations of fibrinopeptide A, a sensitive index of in vivo hypercoagulability, were significantly higher in the 18 ischemic stroke patients than in 40 age- and sex-matched controls and in the six patients who experienced recurrence within 5 years than in the 12 who remained asymptomatic. On the contrary, fibrinopeptide A levels had no prognostic significance among the nine patients with hemorrhagic stroke. Concentrations of beta-thromboglobulin, an index of platelet activation, were higher in the 27 stroke patients than in the 40 controls, but this index was not associated with stroke recurrence. Fibrinogen levels were not significantly higher in stroke patients than in controls. In a multivariate regression analysis of hemostatic and clinical variables, only fibrinopeptide A levels of greater than 4 ng/ml were significantly related to cerebral infarction. Our results support the role of hypercoagulability in the recurrence of ischemic stroke and may allow identification of subjects at high risk for it. If confirmed in more patients, our results could provide a rationale for clinical trials of anticoagulant therapy in such patients.

A new Low Molecular Weight Heparinoid Org 10172 as Anticoagulant in Hemodialysis

A low molecular weight heparinoid (Org 10172) was compared with unfractionated heparin in 36 patients on chronic hemodialysis in an open randomized cross-over study with three anti-coagulant treatment regimens for a single hemodialysis session. The anti-coagulant regimens were: a) standard heparin (3250-4750 I.U. heparin at start of hemodialysis followed by continuous infusion of 2000-2700 I.U. per hour); b) Org 10172 administered as a single intravenous bolus of 2400 anti-Xa units at start of dialysis; c) Org 10172 administered as a single bolus of 3200 anti-Xa units at start of dialysis. Plasma anti-Xa activity during hemodialysis was highest in regimen; d) and significantly lower when heparin was used. Mean beta-thromboglobulin concentrations changed to the same extent in the three groups. Plasma platelet factor 4 concentrations were higher after the use of heparin. The extracorporeal circuit was maintained patent in all groups; the volume of blood retained in the dialyzers did not differ markedly. Org 10172 proved safe and its anticoagulant effect was sufficient at the dose levels studied.

Awareness of High Blood Pressure Stimulates Platelet Release Reaction

The present study aimed at testing the hypothesis of a link between mental stress and blood platelet function. Twenty-nine 19-year-old men were recruited from the 98th percentile of mean blood pressure (116 mmHg) at a routine medical screening. They were not informed about their elevated blood pressures at the time of the screening. One year later they were randomized into two groups. Group 1 (n = 16) was exposed to mental stress by a letter informing them about their high blood pressure, while group 2 (n = 13) was sent a neutral letter. At an examination 2 weeks later, heart rate (p less than 0.05) and plasma adrenaline (p less than 0.05) responses to a cold pressor test were exaggerated in the informed group. The plasma beta-thromboglobulin (beta TG) concentration was elevated in the informed group (p less than 0.05) as was mean blood pressure (p less than 0.05). beta TG correlated positively with hematocrit (r = 0.59, p less than 0.005) and mean blood pressure (r = 0.43, p less than 0.05), and negatively with plasma HDL (r = -0.61, p = 0.001). The study shows that awareness of hypertension induces a hyperadrenergic state which is associated with the platelet release reaction. Under these circumstances platelet release seems to be correlated to established coronary heart disease risk factors.

Combination therapy with low-dose aspirin and ticlopidine in cerebral ischemia.

We compared combination therapy with low-dose aspirin plus ticlopidine to therapy with aspirin alone or ticlopidine alone in patients suffering transient ischemic attack or cerebral infarction. In 17, 24, and 23 patients, respectively, 300 mg/day aspirin, 200 mg/day ticlopidine, and 81 mg/day aspirin plus 100 mg/day ticlopidine were administered orally. Aspirin alone markedly inhibited platelet aggregation induced by arachidonic acid, partially inhibited platelet aggregation induced by adenosine diphosphate, and did not inhibit platelet aggregation induced by platelet activating factor. Ticlopidine alone inhibited platelet aggregation induced by adenosine diphosphate and platelet activating factor, but did not inhibit platelet aggregation induced by arachidonic acid. Combination therapy with aspirin plus ticlopidine markedly inhibited platelet aggregation induced by all three agonists. Plasma concentrations of beta-thromboglobulin and platelet factor 4 remained unchanged by aspirin alone, were slightly reduced by ticlopidine alone, and were markedly reduced by aspirin plus ticlopidine. Plasma concentration of thromboxane B2 was reduced by aspirin alone or with ticlopidine, but not by ticlopidine alone. The level of 6-ketoprostaglandin F1 alpha was reduced only by aspirin alone. Bleeding time was significantly prolonged by aspirin alone and by ticlopidine alone, although the greatest prolongation was produced by aspirin plus ticlopidine. Our results indicate that the combination of aspirin plus ticlopidine is a potent antiplatelet strategy, although the clinical importance of the changes observed need to be determined by a properly designed and controlled prospective study.

Possible Mechanisms of Fibrin Deposition in the Hypereosinophilic Syndrome

Patients with the hypereosinophilic syndrome (HES) are at increased risk of thrombosis and have signs of fibrin deposition in the myocardial cavity; the pathogenesis of these complications is still unknown. We have studied a 51-year-old man affected by HES with heart, lung, skin, and gastrointestinal involvement. Routine laboratory parameters of the hemostatic system were normal with the exception of blood fibrinolytic activity. The latter was evaluated by both diluted blood clot lysis time and euglobulin lytic activity on fibrin plates before and after 10 min venous occlusion. The fibrinolytic activity measured on four occasions during a 3-month period, was impaired both in basal conditions and following venous occlusion. Platelet studies on two different occasions before and during therapy showed spontaneous platelet aggregation, lowered threshold concentrations of various aggregating agents, reduced platelet regeneration time and increased plasma beta-thromboglobulin concentration. The patient's polymorphonuclear cells (more than 75% eosinophils) were devoid of any procoagulant activity (PCA). Instead, patient's mononuclear cells studied before therapy generated significantly higher PCA on stimulation by endotoxin than cells from control subjects. The procoagulant response to endotoxin decreased markedly during therapy. The observed abnormalities could, at least partially, contribute to fibrin deposition in HES.

Abnormal haemostasis in small cell lung cancer.

Disorders of haemostasis and altered platelet activity have been documented in patients with malignant disease but their relation to response to treatment and prognosis are not known. Thrombin activity (fibrinopeptide A (FpA), plasmin mediated fibrinolysis (B beta 15-42) antigen), and platelet alpha granule release (beta thromboglobulin) were studied in 37 patients with small cell lung cancer to find out whether these indices show a relationship to chemoresponse. There was evidence of considerably increased thrombin activity, with a median fibrinopeptide A concentration of 13.2 (normal less than 4) pmol/ml, but only modestly increased fibrinolysis, with a median B beta 14-42 antigen concentration of 5.6 (normal less than 3) pmol/ml. Thus the ratio of fibrinopeptide A to B beta 15-42 concentration (FpA:B beta) was raised, with a median value of 2.2 (normal less than 1.33). In addition, 57% of patients had increased platelet alpha granule release, the median beta thromboglobulin concentration being 50 (normal less than 50) ng/ml. There was a significant association between increased thrombin generation and lack of response to chemotherapy. Furthermore, non-responders had higher FpA:B beta ratios. The same haemostatic markers were studied in nine patients who have been in complete remission for at least two years after chemotherapy for small cell lung cancer. There was a significant difference in thrombin activity and also in the ratio of thrombin activity to lysis between the pretreatment group and the group of two year survivors. Lack of response to chemotherapy appears to be related to increased thrombin activity. Such an association has not previously been reported in patients with malignant disease.

Raised concentrations of glucose and adrenaline and increased in vivo platelet activation after myocardial infarction.

Plasma concentration of beta thromboglobulin was used as an index of in vivo platelet activation in 36 patients after acute myocardial infarction. Twelve patients had diabetes, seven had pulmonary oedema or cardiogenic shock (pump failure) or both, and 17 had uncomplicated infarcts. On the first day of admission, concentrations of beta thromboglobulin were higher in the patients with diabetes and those with pump failure than in those with uncomplicated infarcts. Concentrations of beta thromboglobulin in the non-diabetic patients were studied by multiple regression analysis and were significantly associated with plasma concentrations of adrenaline, pump failure, and glucose but not with noradrenaline or infarct size. When all subjects were considered together, glucose, adrenaline, and pump failure were associated with the beta thromboglobulin concentration but diabetes was without significant effect. Hyperglycaemia and raised plasma adrenaline concentration after myocardial infarction may activate platelets, and this could contribute to poor outcome in such patients.

Platelet and clotting activities after cold stress in diabetic patients

Platelet and clotting abnormalities have been described in diabetes, but little is known about their relationship to daily stresses. In order to evaluate whether states of abnormal carbohydrate metabolism modify the hemostatic response to stress, 12 subjects with type I diabetes mellitus, 9 with type II, with impaired glucose tolerance and 10 healthy controls were exposed to a cold pressor test. Plasma concentrations of beta-thromboglobulin (index of platelet activation) and of fibrinopeptide A (index of thrombin formation) were measured before and 15 minutes after forearm immersion in melting ice. Basal levels of both proteins were significantly elevated (p<0.02) in the combined group of patients with diabetes and impaired glucose tolerance. While in healthy controls cold exposure failed to modify plasma concentration of either protein, obvious changes occurred in the diabetic and impaired glucose tolerance groups. In the combined patients group, beta-thromboglobulin levels decreased from 1.37±0.44 nmol/1 to 1.03±0.39 (mean±SD,p<0.01), after the cold test, possibly in consequence of enhanced vascular permeabilityl while fibrinopeptide A levels increased from 1.52±1.03 nmol/l to 3.45±4.19 (p<0.02).The degree and pattern of abnormalities observed in basal as well as stimulated levels of fibrinopeptide A differed somewhat among the three groups of patients. These studies indicate that, in the basal state patients with diabetes or simple carbohydrate intolerance are more susceptible than controls to platelet activation and that after stress thrombin formation can occur although some variability exists among and within groups of patients. The consequences of such increased thrombotic activity may have a bearing on the pathogenesis of large vessel disease, a complication common to diabetes and impaired glucose tolerance.

A prospective study of platelets and plasma proteolytic systems during the early stages of Rocky Mountain spotted fever.

We prospectively examined early changes in platelets and plasma proteolytic systems in 12 vaccinated and 6 unvaccinated volunteers in whom Rocky Mountain spotted fever developed after challenge with Rickettsia rickettsii. The platelet counts declined while the plasma concentration of beta-thromboglobulin and the ratio of beta-thromboglobulin to platelet factor 4 increased, indicating in vivo activation of platelets. Plasma levels of antithrombin III decreased and levels of fibrinopeptide A increased, indicating in vivo activation of the coagulation system. Plasma fibrinogen levels peaked at 24 hours and gradually declined; this is consistent with the behavior of fibrinogen as an acute-phase reactant. Prolongation of the prothrombin time and a decrease in plasma levels of factor VII in the absence of evidence of liver injury suggested possible activation of the extrinsic pathway of coagulation. A decline in plasma prekallikrein levels with an increase in plasma C1-inhibitor-kallikrein complexes suggested activation of kallikrein, probably through the intrinsic coagulation system. Elevations in levels of plasma fibrin-degradation products and alpha 2-antiplasmin-plasmin complexes with declines in plasminogen and alpha 2-antiplasmin levels provided evidence of activation of the fibrinolytic system. Elevated plasma levels of tissue plasminogen activator and von Willebrand factor reflected endothelial stimulation. Thus, even early in the course of Rocky Mountain spotted fever that is treated promptly, there is activation of platelets, coagulation pathways, and the fibrinolytic system. These changes may be related to endothelial perturbation, a major pathogenetic mechanism in the disorder.

Beta-Thromboglobulin During Normal Pregnancy, LABOR, and Puerperium1

Platelet activation has been implicated in the pathogenesis of several obstetrical conditions such as preeclampsia and intrauterine growth retardation. Plasma beta-thromboglobulin (BTG) concentration is an index of in vivo platelet activation. The purpose of this study was to establish normal values of plasma BTG during pregnancy, labor and puerperium. Plasma BTG concentrations were determined from 121 uncomplicated pregnant women, 20 women in labor, 20 puerperal women, and a control group of 28 healthy non-pregnant volunteers. There was no significant difference in plasma BTG concentrations between non-pregnant and pregnant women. Gestational age, labor, and puerperium did not affect plasma BTG concentrations.

Caffeine stimulates in vivo platelet reactivity.

The effect of coffee drinking on platelet reactivity was studied in 12 healthy subjects. Plasma beta-thromboglobulin concentration was determined before and one hour after administration of 100 mg of caffeine, corresponding to one cup of coffee. Mean values were 47.0 +/- 19.3 and 179.3 +/- 85.5 ng/ml before and after caffeine administration respectively. The increase, 298 +/- 150%, is highly significant (p less than 0.001).

Plasma and urine beta-thromboglobulin in severe preeclampsia.

Beta-thromboglobulin (BTG) has been shown to be a specific platelet protein and can be used as a marker of platelet activation in preeclampsia. Concomitant studies of BTG levels in plasma and urine were performed with eight primiparous severe preeclamptic patients and eight normal primiparous women matched for age. The mean plasma BTG in the severe preeclamptic patients was 186.62 +/- 29.93 ng/ml, and in the control group 45.38 +/- 31.84 ng/ml. The P-value for the difference was highly significant (P = 0.000). In contrast, the mean urine BTG in the study group was 8.42 +/- 4.61 ng/ml, while the mean value for the control group was similar, 5.00 +/- 3.20 ng/ml. The P-value for the difference was not significant (0.05 less than P less than 0.10). These results show that urinary BTG cannot be considered an indicator of platelet activation in severe preeclampsia. A low urinary BTG concentration in the presence of high plasma BTG levels may rather express renal impairment. Failure of BTG renal clearance would contribute to further raising the level of plasma BTG.

Platelet activation in muscle contraction headache and migraine.

In migraine, the role of platelets is regarded as an important factor. We investigated plasma beta-thromboglobulin (BTG), platelet factor 4 (PF4), and 5-hydroxytryptamine (5-HT) in migraine patients and muscle contraction headache (MCH) patients during headache-free periods. The mean values of the plasma BTG, PF4, and 5-HT concentrations in the migraine group and the MCH group were significantly higher than those in healthy controls. The mean value of the plasma BTG concentration was significantly higher in the migraine group than in the MCH group, but the differences in the mean plasma PF4 and 5-HT concentrations between the two groups were not significant. Continuous platelet activation exists in both MCH patients and migraine patients. From the biochemical point of view, we have provided evidence for a similarity between migraine and MCH.

Effect of vitamin E and ticlopidine on platelet aggregation in Fabry's disease.

Thromboembolism, increased platelet aggregation and high plasma concentration of beta-thromboglobulin were observed frequently in hemizygotes and heterozygotes of Fabry's disease. The administration of vitamin E and ticlopidine could improve the increased platelet aggregation in this disease. The platelet activation, probably induced by vascular endothelial damages, would accelerate atherosclerotic and thromboembolic vascular changes. Antiplatelet therapy will be effective for the prevention of these vascular complications in this disease.

Thrombin generation during collection of blood from donors taking oral contraceptives.

Thrombin generation, as evidenced by plasma fibrinopeptide A (FPA) concentrations, was studied during blood collection from donors taking oral contraceptives (OC). 450 ml blood were drawn into Fenwal PVC bags from 26 OC users and 28 nonusers. Blood samples for determination of FPA, beta-thromboglobulin (BTG), thrombotest (TT), prekallikrein (PKK), antithrombin-III (AT-III) and factor VIII procoagulant activity (FVIII:C) were drawn from the bags immediately after ending blood donation and following storage for 24 h at 4 degrees C. The FPA concentrations following donation were significantly higher in the OC than in the control group (p less than 0.05). The levels of PKK were also higher in blood obtained from OC users (p less than 0.001), as was the FVIII:C level, the latter difference, however, was not significant (p = 0.06). No cold-promoted activation of factor VII, as evidenced from TT, was detected following storage at 4 degrees C, neither was any change observed in the FPA, PKK and AT-III levels. The BTG concentrations increased significantly during storage, most pronounced in the control group (p less than 0.05). The decay of FVIII:C was similar in the two groups, averaging 24.7%. No correlation was observed between the FPA levels and the other parameters determined. We conclude that thrombin generation is more pronounced during routine blood collection from donors taking OC.

Study of in vivo platelet activation in uncomplicated essential hypertension

Beta-thromboglobulin (BTG) and platelet factor 4 (PF4), platelet alpha-granule specific proteins, and serotonin (5-HT) which is stored in dense granules are released when platelets are activated. To investigate in vivo platelet activation in uncomplicated essential hypertension, platelet 5-HT and PF4 contents, plasma BTG and PF4 concentrations, as well as urinary BTG levels were assessed in normotensive and hypertensive subjects. Plasma BTG and PF4 concentrations and urinary BTG levels were comparable in both groups. Mean platelet 5-HT content was significantly decreased in hypertensive subjects without modification of the intraplatelet PF4 content. These data suggest first of all that the decrease in platelet 5-HT content is due mainly to the inhibition of platelet 5-HT uptake previously described, and second of all that no significant in vivo telet activation occurs in essential hypertensive subjects devoid of cardiovascular complications.

Thrombin Generation During Collection of Blood from Donors Taking Oral Contraceptives

Thrombin generation, as evidenced by plasma fibrinopeptide A (FPA) concentrations, was studied during blood collection from donors taking oral contraceptives (OC). 450 ml blood were drawn into Fenwal PVC bags from 26 OC users and 28 nonusers. Blood samples for determination of FPA, beta-thromboglobulin (BTG), thrombotest (TT), prekallikrein (PKK), antithrombin-III (AT-III) and factor VIII procoagulant activity (FVIII:C) were drawn from the bags immediately after ending blood donation and following storage for 24 h at 4°C. The FPA concentrations following donation were significantly higher in the OC than in the control group (p<0.05). The levels of PKK were also higher in blood obtained from OC users (p<0.001), as was the FVIII:C level, the latter difference, however, was not significant (p=0.06). No cold-promoted activation of factor VII, as evidenced from TT, was detected following storage at 4°C, neither was any change observed in the FPA, PKK and AT-III levels. The BTG concentrations increased significantly during storage, most pronounced in the control group (p<0.05). The decay of FVIIIiC was similar in the two groups, averaging 24.7%. No correlation was observed between the FPA levels and the other parameters determined. We conclude that thrombin generation is more pronounced during routine blood collection from donors taking OC.

Activation of platelet function in Fabry's disease.

Increased platelet aggregation and high plasma concentration of beta-thromboglobulin were observed in hemizygotes and heterozygotes of Fabry's disease. Carbamazepine and phenytoin administered for the treatment of pains in these patients showed no significant effect on platelet aggregation. No activation of platelets was observed after the addition of ceramide trihexoside, the storage lipid of this disease. Mitral valve prolapse was found in eight of 12 patients. Although the pathogenesis of platelet activation and mitral valve prolapse are not known, the platelet activation could be an early indicator and an accelerating factor of thromboembolic vascular change in this disease.

Blood platelet release correlates with serum lipids in 50 year old men with essential hypertension.

50 year old men with moderate, essential hypertension (n = 39) were compared to normotensive males of similar age (n = 31). The hypertensive men were heavier (10 kg in average, p less than 0.01), and had a higher pulse rate (5 beats per minute (p less than 0.05). Plasma beta-thromboglobulin, a marker of platelet release reaction, was 49% higher in the hypertensive group (p less than 0.01). Total cholesterol, LDL + VLDL cholesterol and serum triglycerides were not significantly different between the groups. In the hypertensive group, plasma beta-thromboglobulin concentration correlated significantly with total cholesterol (r = 0.47, p less than 0.01) as well as with LDL + VLDL cholesterol (r = 0.50, p less than 0.01). In the normotensive group no such correlation was found. The results suggest activation of platelets in hypertension, and suggest that in hypertension, even a normal cholesterol concentration may influence platelet function.

Urine Beta-Thromboglobulin Concentration or Beta-Thromboglobulin/Creatinine Ratio in Single Voided Urine Samples Cannot Be Reliably Used to Estimate Quantitative Beta-Thromboglobulin Excretion

Different procedures are currently used in the urine beta-thromboglobulin (BTG) assay. We investigated the reliability of limited urine collections and of different expressions of urine BTG results (concentration, urine BTG/creatinine ratio) for the measurement of hourly or daily BTG excretion rates. BTG was measured by a sensitive RIA method in various urine collections of normal subjects (n.80) and patients (n.120) with miscellaneous diseases where an enhanced in-vivo platelet activation could be expected. The BTG concentration in a 6-hour urine collection appeared to change in relation to the urine flow rate (r = -0.53 in normals, r = 0.27 in patients, p less than 0.01) and urine osmolality (r = 0.46 in normals, r = 0.31 in patients, p less than 0.01). In both normals and patients not a very good correlation was observed between the urine BTG/creatinine ratio and the BTG excretion rate (r = 0.54 and r = 0.48; p less than 0.001, respectively). Variable coefficients of correlation (r = 0.83-0.34) were observed between the BTG excretion rate of single voidings of the morning, afternoon-evening and night and the daily BTG excretion both in normals and patients. Reliable measurements of the BTG in urine should be expressed as the hourly excretion rate in a given period of the day for limited urine collections or as the daily excretion for 24-hour urine collections.