Plasma Beta-thromboglobulin Research Articles

The effect of Naoxintong capsule treatment on carotid artery intima-media thickness, serum beta thromboglobulin, P-selectin and plasminogen activator inhibitor-1 in elderly type 2 diabetic patients with subclinical atherosclerotic vascular disease

Objective To investigate the effects of Naoxintong Capsule treatment on the carotid artery intima-media thickness(IMT), plasma beta thromboglobulin(beta-TG), P-selectin(CD62p)and plasminogen activator inhibitor-1(PAI-1)in elderly patients with type 2 diabetes mellitus and subclinical atherosclerotic vascular disease. Methods In retrospective study, 110 cases of elderly patients with type 2 diabetic vascular diseases were selected and admitted as study subjects from June 2014 to May 2015.They were randomized into observation group and control group(n=55, each). All patients were given routine treatment.The patients in the observation group were treated with Naoxintong Capsule.The levels of plasma β-TG, CD62p and PAI-1 were measured and compared between two groups. Results Before treatment, there were no significant differences in IMT, PAI-1, β-TG and CD62p levels between the two groups(P>0.05). After treatment, the observation group versus control group showed an improved four parameters of carotid artery IMT(1.31 ±0.26)mm vs.(1.44 ±0.26)mm, PAI-1(2.23 ±0.48)μg/L vs.(2.56 ±0.61)μg/L, β-TG(29.76 ± 10.24)μg/L vs.(35.98 ± 10.35)μg/L, CD62p(162.3 ± 21.5)ng/L vs.(176.96 ± 20.3)ng/L(t=4.058, 3.965, 11.293, 14.624 respectively, all P<0.05)with statistically significant differences. Conclusions Naoxintong Capsule treatment of type 2 diabetic patients with subclinical atherosclerotic vascular disease can reduce carotid intima-media thickness, decrease platelet releasing activity and lower the oxidative stress reaction.Thereby, it protects the vascular endothelium, and alleviates subclinical atherosclerotic vascular disease in the elderly type 2 diabetic patients. Key words: Diabetes mellitus, type 2; P-selectin; Plasminogen activator inhibitor 1

Effect of the FXa inhibitors Rivaroxaban and Apixaban on platelet activation in patients with atrial fibrillation

Rivaroxaban and Apixaban, increasingly used for stroke prevention in non-valvular atrial fibrillation (AF), might impact platelet reactivity directly or indirectly. By inhibition of Factor Xa (FXa) they preclude not only generation of relevant thrombin amounts but also block signalling of FXa via protease activated receptors. However, weather FXa-inhibition affects platelet haemostasis remains incompletely known. One hundred and twenty-eight patients with AF on chronic anticoagulation with either Rivaroxaban or Apixaban for at least 4 weeks were included in the study. In a time course group (25 on Rivaroxaban, 13 on Apixaban) venous blood samples were taken before NOAC medication intake in the morning as well as 2 and 6h afterwards. In 90 patients (Rivaroxaban n = 73, Apixaban n = 17) blood samples were drawn during left atrial RFA procedures before as well as 10 and 60min after the first heparin application (RFA group). Platelet reactivity analyzed by whole blood aggregometry (Multiplate Analyzer, Roche) in response to ADP, Collagen, TRAP and ASPI (arachidonic acid) was not altered by Rivaroxaban or Apixaban neither in the time course nor in the RFA group. Moreover, soluble P-selectin, Thrombospondin, von Willebrand Factor and beta thromboglobulin plasma levels, measured by ELISA, showed no statistically significant changes in both clinical settings for either FXa-inhibitor. The present study fails to demonstrate any significant changes on platelet reactivity in patients with AF under chronic Rivaroxaban or Apixaban medication, neither for trough or peak levels nor in case of a haemostatic activation in vivo as depicted by RFA procedures.

Sticky Platelet Syndrome and the Role of Glycoprotein Receptors: A Review of Literature

Thrombotic events are mainly caused by defects in circulating plasma proteins and platelets. Normally, the formers include hereditary clotting defects [e.g. deficiencies in protein-S (PS), in protein-C (PC), in antithrombin (AT) genes, or factor V Leiden, and Prothrombin (PT) G20210A substitution] and autoimmune diseases [(anti-phospholipid-antibodies syndrome (APA)]. Although these conditions are well-described in literature, prothrombotic platelet disorders are less well understood. The sticky platelet syndrome (SPS) is a congenital, autosomal dominant disorder, associated with both arterial and venous thromboembolic events. In pregnant women, complications such as fetal growth retardation and fetal loss have been reported. It is characterized by in vitro platelets hyperaggregability (platelet-rich plasma; PRP) triggered by different agonists responsible for its subclassifcation: adenosine diphosphate (ADP) plus epinephrine (type I), epinephrine alone (type II, the most frequent), or ADP alone (type III). Clinically, patients may present with acute myocardial infarction (AMI), transient cerebral ischemic attacks (TIA), angina pectoris, stroke, peripheral arterial thrombosis, retinal thrombosis, and venous thrombosis (VT) even during oral anticoagulant therapy. Conversely, low-dose aspirin treatment ameliorates the clinical symptoms and normalizes hyperaggregability. Clinical symptoms, especially arterial, often present following emotional stress. Combinations of SPS with other congenital prothrombotic defects have been described. Currently, a precise and definite etiology of this defect is not recognized, but receptors on the platelet surface are considered strongly involved candidates. Normal levels of platelet factor 4 (PF4) and betathromboglobulin (βTG) in plasma suggest that the platelets are not activated at all times; accordingly they appear to become hyperactive upon ADP or adrenaline release. In vivo clumping could temporarily or permanently occlude a vessel, leading to the described clinical manifestations. The syndrome appears to be prominent particularly in patients with unexplained arterial vascular occlusions. Despite studies investigating the role of platelet glycoprotein in SPS have been conducted, the precise defect(s) responsible for the syndrome remains unknown. This review discusses on the SPS and about the main receptors on the platelet surface, including some polymorphisms that appear to be involved in the pathology.

The transport of high amounts of vascular endothelial growth factor by blood platelets underlines their potential contribution in systemic sclerosis angiogenesis

Altered angiogenesis is a characteristic feature in SSc and remains ill-understood. VEGF is believed to play a central role. Serum VEGF is elevated in SSc patients but questions remain concerning the source of circulating VEGF. Here we investigated platelet activation and the role of platelets as a source of VEGF and other angiogenic mediators in this disease. A cohort of 40 patients with SSc was included. Age- and sex-matched healthy subjects and subjects presenting a primary RP were included as controls. Platelets were isolated, activated with thrombin and the secretion of VEGF, platelet derived growth factor, homodimeric form BB (PDGF-BB), TGF-beta1 and angiopoietins-1 and -2 measured. Plasma concentrations of these mediators and the functionality of platelet-derived VEGF were also studied. Platelet activation was assayed by measuring plasma beta-thromboglobulin and expression of P-selectin on platelets. The effect of iloprost on VEGF secretion by platelets was studied. Platelets from SSc patients, in contrast to controls, secreted large amounts of VEGF when activated, but not PDGF-BB, TGF-beta1 or angiopoietins. Increased expression of membrane P-selectin confirmed platelet activation in the patients. Iloprost inhibited VEGF secretion by platelets both in vivo and in vitro, through inhibition of platelet activation. Platelets transport high levels of VEGF in SSc. They may contribute to circulating VEGF because of ongoing activation in the course of the disease. If activated at the contact of injured endothelium, platelets may be important in the altered angiogenesis associated with the disease through the secretion of high levels of VEGF.

Intradialytic and postdialytic platelet activation, increased platelet phosphatidylserine exposure and ultrastructural changes in platelets in children with chronic uremia

The present research evaluated the intradialytic and postdialytic changes in platelet factor-4 and beta-thromboglobulin plasma levels by enzyme-linked immunoadsorbent assay method and platelet aggregation by ADP as well as flow cytometric percentage of annexin-V-positive platelets as a measure of phosphatidylserine externalization and ultrastructural examination of platelets in 37 uremic patients on regular hemodialysis and 25 age-matched and sex-matched controls. Platelet factor-4 plasma levels increased, remain consistently high during hemodialysis session (20.24 +/- 3.05 IU/ml after 30 min, P < 0.001 and 23.67 +/- 3.68 IU/ml after 240 min, P < 0.001) and returned to control values (6.10 +/- 1.54 IU/ml) only after 24 h following the end of the session. beta-Thromboglobulin showed a trend similar to that of platelet factor-4. Platelet aggregation by ADP showed reduced function in comparison with controls (69.32 +/- 12.37 versus 91.95 +/- 1.59%, P < 0.001). Flow cytometric percentage of annexin-V-positive platelet was significantly elevated (P < 0.001) in uremic patients when compared with normal controls. Ultrastructural studies of platelets 30 min after starting of dialysis showed degranulation of its granules and at 240 min showed complete degranulation, whereas in the postdialytic phase (12 h after the end of dialysis) refilled alpha-granules started to appear. Positive correlations were found between platelet concentration and platelet factor-4 and beta-thromboglobulin plasma levels during and after dialysis (P < 0.001) and with annexin-V-positive platelets percentage (P < 0.001). In conclusion, activated platelets were found in chronic hemodialysis patients, a finding that may explain why uremic patients often suffer from thrombotic accidents. The platelet activation is associated with exposure of phosphatidylserine on the platelet exterior. Platelet factor-4 and beta-thromboglobulin are released from platelets as a result of a defect in their granules membrane as shown by the electron microscopy, mainly as a consequence of the blood-membrane contact during dialysis, and they return only slowly to control values.

Impact of the therapy by renin–angiotensin system targeting antihypertensive agents perindopril versus telmisartan on prothrombotic state in essential hypertension

The aim of the study was to investigate the effect of therapy by perindopril or telmisartan on endothelial/platelet function and on coagulation/fibrinolysis in 20 and 16 hypertensive patients, respectively. The measurements were carried out before and after 1 month of therapy. Both systolic blood pressure and diastolic blood pressure were reduced (P<0.001) or normalized due to each therapy. Plasma thrombomodulin (TM) and von Willebrand factor (vWF) as indicators of endothelial dysfunction, plasma beta-thromboglobulin (betaTG), platelet factor 4 (PF4), soluble P-selectin (sPsel) and soluble glycoprotein V (sGpV) as indicators of in vivo platelet activation, plasminogen activator inhibitor type 1 (PAI-1) antigen and tissue type plasminogen activator (tPA) antigen as markers of fibrinolytic activity, soluble endothelial protein C receptor (sEPCR) as a new marker of hypercoagulation and fibrinogen level as a known risk factor for vascular changes were investigated. A decrease of plasma vWF, sPsel, sGpV, PAI-1 and tPA antigen level (P<0.05, respectively) after 1 month of therapy by perindopril was observed. On the other hand, a decrease of plasma sEPCR and fibrinogen level (P<0.05, respectively) after 1 month of therapy by telmisartan was found. We failed to find changes of plasma TM, betaTG and PF4 due to any therapy investigated. The additional beneficial 'antithrombotic' effects of the renin-angiotensin system targeting agents (vasculoprotective, anti-platelet and profibrinolytic effects of perindopril and anticoagulant/rheological effects of telmisartan) may be important in terms of the favourable role of antihypertensive drugs in cardiovascular morbidity.

3rd College of Physicians’ Lecture – Translational Research: From Bench to Bedside and From Bedside to Bench; Incorporating a Clinical Research Journey in IgA Nephritis (1976 to 2006)

Translational research (TR) can be defined as research where a discovery made in the laboratory (bench) can be applied in the diagnosis, treatment or prevention of a disease. Examples of medical discoveries contributing to translational medicine (TM) include the isolation of insulin by Banting (Nobel Laureate, 1923), the discovery of penicillin by Alexander Fleming (Nobel Laureate, 1945) and recently the discovery of the role of bacterium Helicobacter pylori in the causation of gastritis and peptic ulcer by Marshall and Warren (Nobel Laureates, 2005). Clinical research (CR) would be a more appropriate term for the bulk of research work undertaken by doctors. CR embraces both clinical based and laboratory-based research. The terminology "bedside to bench" applies more to CR as opposed to "bench to bedside" in the case of TR. But regardless of who does it, as long as the discovery can be translated to the bedside and results in improvement in patient care it can be considered a contribution to TM. Our work spans a 30-year period, involving laboratory-based research, clinical trials and genomics of IgA nephritis (Nx). This is a series of work to elucidate the pathogensis and therapy of IgANx. Plasma beta-thromboglobulin (BTG) an in-vivo index of platelet aggregation and anti-thrombin III increase due to a constant thrombogenecity resulting from platelet degranulation formed the basis for anti-platelet and low-dose warfarin therapy. A study of the natural history of IgANx revealed 2 courses, a slowly progressive course with end-stage renal failure (ESRF) at 7.7 years and a more rapid course at 3.3 years. Triple therapy (cyclophosphamide, persantin and low-dose warfarin) delayed progression to ESRF by about 8 years and for some patients up to 20 years. Documentation of abnormal suppressor T cell function provided the basis for immune therapy. Four patterns of proteinuria were present in IgANx and it is the quality and not so much the quantity of proteinuria which determined the prognosis. Low molecular weight proteinuria was a bad prognostic marker. A controlled therapeutic trial using ACEI/ATRA showed that therapy decreases proteinuria, improves renal function and converts non-selective to selective proteinuria. Subsequent work confirmed that it was the ATRA, not the ACEI which contributed to improved renal function. Individual anti proteinuria response to ATRA varies depending on ACE gene polymorphism. We found that the II genotype of the ACE gene was renoprotective and patients with this genotype had significantly reduced incidence of ESRF compared to those with the DD genotype. Patients responsive to ATRA therapy can retard progression to ESRF by up to 32 years. Mild renal failure can be reversed with possible regression of glomerulosclerosis because of glomerular remodelling by ATRA.

Platelet activation in pregnancy-induced hypertension

Background Although excess platelet activation, as indicated by increased plasma beta thromboglobulin (β-TG), has been shown in pregnancy-induced hypertension (PIH), platelet adhesion, platelet morphology and a comparison of platelet and soluble (plasma) levels of the adhesion molecules P-selectin (pPsel and sPsel, respectively) have not been studied. Methods We conducted a cross-sectional study of 35 consecutive women with PIH (age 31±6 years), 31 consecutive women with normotensive pregnancies (age 29±5 years) and 30 normotensive non pregnant women (age 30±5 years). Platelet adhesion was studied in vitro by binding to fibrinogen-coated microwells, platelet morphology [mass and volume by flow cytometry], whole-platelet P-selectin (pPsel) by ELISA of the lysate of 2×10 8 cells, and the plasma markers soluble P-selectin (sP-sel) and β-TG, by ELISA. Results The women with PIH had significantly raised sPsel, pPsel and (as expected) β-TG (all p<0.05), when compared to the normotensive pregnant women and controls. However, in PIH platelet adhesion was similar to that in the normotensive pregnancy, but still higher than the normal controls ( p<0.001). There was no difference among the three groups with respect to platelet mass and volume. pPsel and platelet adhesion correlated with gestational age and with systolic and diastolic blood pressure (all p<0.05). Conclusions Increased platelet activation and adhesion develop during normal pregnancy, with some indices being further altered in PIH.

Platelet Function and Fibrinolytic Activity in Patients with Bronchial Asthma

Platelets have the capacity to release mediators with potent inflammatory or anaphylactic properties. Platelet factor-4 (PF4) and beta-thromboglobulin (BTG) are two of these mediators. On the other hand, plasminogen activator inhibitor-1 (PAI-1) and tissue plasminogen activator (tPA) are two important mediators of fibrinolysis. Both mediators are secreted mainly by vascular endothelium. Plasma levels of PF4, BTG, PAI-1, and tPA may show changes in chronic inflammatory diseases such as asthma. This study examined the role of thrombocytes and the function of the endothelium in asthmatic patients during an attack and during a stable phase. Eighteen patients with known allergic asthma who came to our emergency department with an asthma attack and 14 control subjects were included in the study. Blood samples were taken after starting therapy with salbutamol inhalation. Lung function tests were performed after receiving the first emergency therapy for asthma. Plasma levels of PF4, BTG, PAI-1, tPA were determined before starting steroid therapy and after receiving 1 week of steroid therapy. Plasma levels of PF4 among patients with an asthma attack were significantly higher than those of controls (150.5+/-8.92 IU/mL vs. 92.5+/-7.63 IU/mL, p<0.001). A further increase in plasma PF4 levels was detected after steroid therapy (163.5+/-9.16 IU/mL). Plasma BTG levels of patients on admission were not statistically different from those in the control group (140.4+/-6.34 IU/mL vs. 152.2+/-8.71 IU/mL). An increase was detected after therapy (171.6+/-7.27 IU/mL) and post-treatment plasma levels were statistically meaningful versus the controls. Plasma levels of tPA and PAI were statistically higher than those in controls in asthmatic patients on admission (6.01+/-2.72 vs. 5.4+/-2.3 ng/mL for tPA and 75.2+/-27.2 ng/mL vs. 32.7+/-14.3 ng/mL for PAI-1). Further increases were detected in two parameters after 1 week of therapy with steroids (tPA levels were 6.85+/-2.96 ng/mL and PAI-1 levels were 83.5+/-29.6 ng/mL). There seems to be an increased activity of platelets during an asthma attack. Elevated PAI-1 and tPA levels may also indicate the activated endothelium in asthma. Increases of plasma levels of PAI-1 and tPA after steroid therapy need further investigation because elevated PAI-1 levels enhance airway remodeling.

Investigation of Platelet Functions in Chronic Myeloproliferative Disorders by Optical and Luminesance Method.

Background: Bleeding and thrombosis are common causes of morbidity and mortality in patients with myeloproliferative disorders (MPD). Qualitative platelet abnormalities are frequently found in these patients and range from platelet hypofunction as demonstrated by defective invitro platelet aggregation, acquired storage pool disease and/or platelet membrane defects, in addition to enhanced platelet aggregation, increased plasma beta thromboglobulin levels or shortened platelet survival. In this study we aimed to perform platelet aggregation studies by optical method (on platelet rich plasma=PRP) and luminesance method (on whole blood) in chronic myeloproliferative disorders.Methods:A total of twenty-five patients with MPD (17 chronic myeloid leukemia, 6 polycythemia vera, 2 essential thrombocytosis) were enrolled. Median age was 54,4 (29–76). Platelet aggregation was measured using the optic and luminesance method. The agonists used were adenosine diphosphate (ADP), arachidonic acid (AA) ristocetin and collagen. Platelets were considered to be hyperactive if at least one result (i.e. aggregation or ATP release with one agonist) was above the reference range, and hypoactive if at least one result (i.e. aggregation or ATP release) was below the reference range. Mixed hypo- and hyperactive platelets were considered present when at least one result (i.e. aggregation or ATP release) was below and above the reference range respectively.Results:Platelet aggregation test results by two methods in myeloproliferative disorders were shown in Table 1. The percent for detection of platelet function abnormality by luminesance method was found to be higher than the optic method and a significant difference was shown between two methods (p<0,05).Conclusion Our findings suggest that;1. Luminesance platelet aggregation study is more valuable than optic platelet aggregation study for invitro assessment of platelet function in patients with MPD. 2. The use of luminesance platelet aggregation study appears useful to select patients for antiplatelet therapy.Platelet aggregation test results in myeloproliferative disorders (n=25)NormalHypofunctionHyperfunctionMixTotal abnormalityLuminesance method1(%4)4(%16)8(%32)11(%44)24(%96)Optic method9(%36)11(%44)2(%8)3(%12)16(%64)

Blood platelet count and reactivity are associated with restenosis 6 months after coronary angioplasty

Objectives—Restenosis occurs in 40–50% of patients treated with percutaneous transluminal coronary angioplasty (PTCA). Some data indicate that platelet derived growth factor (PDGF) plays a pathogenetic role. The aims of the present study were to measure the plasma levels of PDGF across the coronary circulation during PTCA and relate them to the development of restenosis.Design and results—Blood samples from the aortic root and coronary sinus were drawn simultaneously before, and after completed PTCA in 26 patients. Plasma levels of PDGF and beta‐thromboglobulin (BTG), as well as platelet counts were measured. Restenosis was evaluated by quantitative coronary angiography after 6 months. Significant increases both in PDGF and BTG were encountered in the aortic root after PTCA in patients who developed restenosis as compared to patients without restenosis. Patients who developed restenosis also had significantly higher platelet counts compared to those without.Conclusion—Increases in plasma PDGF and BTG in the aortic root after PTCA seem to be markers for restenosis 6 months after PTCA. This finding may strengthen the hypothesis that platelets contribute to the process of restenosis.

Heart surgery with extracorporeal circulation leads to platelet activation at the time of hospital discharge.

Heart surgery with extracorporeal circulation has a marked effect on platelet function and coagulation accounting for abnormal blood loss and allegedly a low incidence of thromboembolic complications. Little is known about platelet function at the time of hospital discharge of routine patients. Blood samples from 91 patients undergoing elective heart surgery were drawn before surgery and prior to discharge. Thirty-seven patients underwent coronary artery surgery and 54 an aortic valve implantation. The mean age of patients was 69+/-9 years. Fifty patients were male and 41 female. Platelet function was evaluated using plasma beta-thromboglobulin quantification in enzyme-linked immunosorbent assay. In addition, flow cytometric analysis of platelet-monocyte conjugates and platelet-neutrophil conjugates was performed. The platelet count before discharge was significantly increased (265+/-86 vs. 212+/-61 x 10(9)/l preoperatively). beta-Thromboglobulin was significantly increased (176+/-127 vs. 79+/-70 ng/ml preoperatively) and flow cytometry proved a significant increase in monocyte-platelet aggregates (8.3+/-5.4% vs. 5.3+/-2.6% preoperatively) indicating platelet activation at the time of hospital discharge. There were no significant differences among the three subgroups coronary surgery, mechanical valve insertion and biological valve insertion. Heart surgery with extracorporeal circulation leads to significant platelet activation and a reactive increase in platelet count before discharge. This is in contrast to the reduced platelet function immediately postoperatively.

Withdrawal of statin treatment abrogates stroke protection in mice.

Statins (3-hydroxy-3-methylglutaryl-coenzyme A [HMG-CoA] reductase inhibitors) reduce stroke damage independent of lipid lowering by upregulation of endothelial nitric oxide synthase (eNOS). Acute withdrawal of statin treatment may suppress endothelial NO production and impair vascular function. To test this hypothesis, we treated 129/SV mice with atorvastatin (10 mg/kg) for 14 days and then withdrew treatment. Treatment with atorvastatin conferred stroke protection by 40% after filamentous occlusion of the middle cerebral artery followed by reperfusion. Withdrawal of statin treatment, however, resulted in the loss of stroke protection after 2 and 4 days. In mouse aortas and brain vasculature, statins upregulated eNOS message 2.3- and 1.7-fold, respectively, as measured by reverse transcription-polymerase chain reaction. Withdrawal of statins resulted in 5- and 2.7-fold downregulation of eNOS in aorta and brain, respectively, after 2 days. Statin treatment decreased RhoA GTPase membrane expression to 48%, while withdrawal of statins resulted in 4-fold increase of RhoA in the membrane. Moreover, platelet factor 4 and beta-thromboglobulin in plasma were significantly downregulated by statin treatment, but withdrawal of statins resulted in a 2.9- and 3.1-fold upregulation after 2 days, respectively. Thrombus formation induced by ligature of the inferior vena cava was significantly reduced by statin treatment. When statin treatment was withdrawn, however, protection was lost between 2 and 4 days. Acute termination of statin treatment results in a rapid loss of protection in mouse models of cerebral ischemia and thrombus formation independent of lipid lowering. In patients with acute or impending stroke, withdrawal of statins may impair outcome.

A study of platelet activation in atrial fibrillation and the effects of antithrombotic therapy.

Platelet function may be abnormal in patients with atrial fibrillation (AF) and could be related to abnormal thrombogenesis. The aim of this cross-sectional study was to investigate new aspects of platelet biology in AF, predominantly focusing on platelet activation and the effects of concomitant antiplatelet and anticoagulant therapy. The study group of 238 patients were (i). 93 patients on no antithrombotic therapy, (ii). 60 patients taking 75-325 mg aspirin/day, and (iii). 85 patients on dose-adjusted warfarin (International Normalised Ratio [INR] range 2.0-3.0). Results were compared with those from 50 age- and sex-matched normal subjects. Platelet markers (plasma beta-thromboglobulin, soluble glycoprotein V [both ELISA]), coagulation markers (fibrin D-dimer [ELISA] and fibrinogen [Clauss]), and platelet aggregation in response to standard platelet agonists were studied. beta-thromboglobulin (P=0.01), soluble glycoprotein V (P<0.001) and fibrin D-dimer (P=0.002) were higher in untreated AF patients compared to healthy controls. AF patients on warfarin had lower fibrin D-dimer (P<0.001) when compared to AF patients on no therapy. Plasma fibrinogen and platelet aggregation was no different between patients with AF and healthy controls. Aspirin use was associated with reduced platelet aggregation response to epinephrine (P=0.01), whilst patients established on warfarin had significantly lower plasma fibrin D-dimer levels. AF patients exhibit changes in plasma markers of platelet function but no significant abnormalities of platelet aggregation. However, treatment with warfarin or aspirin failed to demonstrate any significant benefit on platelet activation, although warfarin use was associated with reduced thrombogenesis (fibrin D-dimer). We suggest that platelet activation may not play an important role in the pathogenesis of thromboembolism in AF.

Effects of alcohol ingestion post-exercise on platelet aggregation

The present study examined the influence of ingesting a moderate dose of alcohol on platelet count and platelet aggregation during recovery following exercise. Nineteen subjects (11 male and 8 female) were studied immediately after a standardised cycle ergometer test and during the 24-h period of recovery. In random order, alcohol (0.7 g/kg body mass) was given 1 h after exercise on one test occasion, while an equal volume of alcohol-free solution was administered on the other. Venous blood samples were obtained at baseline, post-exercise, and at 1, 5, and 22 h post-alcohol ingestion. Blood alcohol level increased significantly 1 h after the ingestion of alcohol, but decreased and returned to the resting baseline level at 5 h during recovery. Males and females subjects exhibited similar mean values of platelet count, platelet aggregation, and beta-thromboglobulin concentration at rest and following exercise and recovery. A significant increase in platelet count and a decrease in platelet aggregation using adenosine diphosphate (ADP) was found following exercise. Although plasma beta-thromboglobulin level (pooled data for males and females) showed an increase by 26.0% (from a mean pre-exercise value of 22.3–28.1 IU/ml), this rise was not significant ( P>.05). The post-exercise increase in platelet count was mainly due to exercise-induced plasma volume loss. During recovery, while the increase in platelet count post-exercise returned to the baseline level in control and alcohol trials, the optical density of platelet aggregation remained significantly depressed at 5-h during recovery in the alcohol trial but not in the normal control condition. It is concluded that exercise induces significant reduction in platelet aggregation and the consumption of alcohol after physical exercise delays the normal return of platelet aggregation to the resting baseline levels during recovery.

Mean platelet volume: a useful marker of inflammatory bowel disease activity.

We investigated whether the mean platelet volume would be a useful marker in the evaluation of inflammatory bowel disease activity. Complete blood count, C-reactive protein, erythrocyte sedimentation rate, serum thrombopoietin and erythropoietin, plasma beta-thromboglobulin, and platelet factor 4 were measured in 93 patients with ulcerative colitis, 66 patients with Crohn's disease, and 38 healthy blood donors. Disease activity was assessed by the Clinical Colitis Activity Index in patients with ulcerative colitis and by the Crohn's Disease Activity Index in patients with Crohn's disease. Mean platelet count was increased in patients with active compared to inactive ulcerative colitis (p < 0.05), and in patients with active compared to inactive Crohn's disease (p = 0.0002) or healthy controls (p < 0.0001). On the other hand, mean platelet volume was significantly decreased in patients with active compared to inactive ulcerative colitis (p = 0.02) or healthy controls (p < 0.0001), and in patients with active compared to inactive Crohn's disease (p = 0.0005) or healthy controls (p < 0.0001). Mean platelet volume was inversely correlated with the white blood cell count (r = -0.17, p = 0.02), C-reactive protein (r = -0.46, p = 0.009) and erythrocyte sedimentation rate (r = -0.28, p = 0.008). No significant correlations were found between mean platelet volume and serum thrombopoietin or erythropoietin levels; however, a strong negative correlation between mean platelet volume and beta-thromboglobulin (r = -0.34, p < 0.0001) and platelet factor 4 (r = -0.30, p = 0.0002) was observed. Mean platelet volume is significantly reduced in active inflammatory bowel disease and is negatively correlated with the known inflammatory bowel disease activity markers and the platelet activation products. We propose that mean platelet volume provides a useful marker of activity in inflammatory bowel disease.

Platelet Pl(A2) allele and incidence of coronary heart disease: results from the Atherosclerosis Risk In Communities (ARIC) Study.

The major platelet integrin glycoprotein IIb-IIIa plays a primary role in platelet aggregation and acute thrombus formation at the site of vascular injury. A genetic polymorphism of glycoprotein IIb-IIIa (Pl(A)) has recently been proposed as a potential genetic factor linking to platelet hyperaggregability and increased risk of myocardial infarction. Despite numerous, mostly nonprospective studies, the role of this polymorphism as a clinically relevant, inherited risk factor for coronary heart disease (CHD) is still controversial. The purpose of this study was to determine whether Pl(A2) is a risk factor for incident CHD and whether it is correlated with increased platelet activation in a case-cohort study nested within a prospective epidemiologic investigation. Blood samples were collected and processed from the Atherosclerosis Risk in Communities Study cohort at the baseline examination (1987 to 1989). They were stored at -80 degrees C. Pl(A1/A2) genotype and plasma beta-thromboglobulin levels were determined in 439 incident CHD cases and a reference cohort sample of 544 (of whom 18 were also CHD cases). The prevalence of the Pl(A2) allele was not different in cases versus noncases. No significant correlation between CHD risk factors and the Pl(A2) allele was noted either. Platelet activation, as measured by plasma beta-thromboglobulin levels, was not enhanced in individuals with the Pl(A2) allele. This prospective study indicates that healthy individuals carrying the Pl(A2) allele do not have an increased risk of CHD.

Platelet activation during angiotensin II infusion in healthy volunteers

The present study was undertaken to evaluate the effects of an intravenous infusion of angiotensin II (10 ng/kg per min) on platelet function and coagulation in vivo in 18 healthy males. The infusion increased mean arterial pressure by 23+/-2 mm Hg. Plasma beta-thromboglobulin levels, reflecting platelet secretion, increased by 66+/-24% during the infusion, as did also platelet surface expression of P-selectin as measured by flow cytometry. Platelet fibrinogen binding increased, whereas platelet aggregability, assessed by ex vivo filtragometry, was unaltered. Angiotensin II caused mild activation of the coagulation cascade with increases in plasma levels of thrombin-antithrombin complex and prothrombin fragment F1 + 2. In conclusion, angiotensin II has mild platelet-activating effects in vivo and also enhances coagulation. Markers of platelet secretion are significantly increased, whereas markers of platelet aggregability are less affected. The clinical relevance of these findings remains to be clarified.

BLOOD LEVELS OF TGF??1 IN LIVER TRANSPLANT RECIPIENTS RECEIVING EITHER TACROLIMUS OR MICRO-EMULSIFIED CYCLOSPORINE

Transforming growth factor beta-1 (TGFbeta1) is pro-fibrotic in addition to being a potent immunosuppressive cytokine. Cyclosporine (cyclosporin A[CsA]) has been found to increase circulating TGFbeta1 levels in patients (1, 2). To determine whether tacrolimus (FK506) similarly increases TGFbeta1 we have measured TGFbeta levels in blood samples from liver graft recipients who were of known TGFbeta1-responder status. Sequential serum and plasma samples were obtained from liver transplant recipients in the UK trial of tacrolimus versus microemulsified CsA, with a follow up period of between 50 and 265 days. Twelve patients received CsA and 13 received tacrolimus. Active and total TGFbeta1 protein were measured and plasma beta thromboglobulin (betaTG) levels were used as an indirect indication of platelet-derived TGFbeta contamination of samples. We found no correlation between trough drug levels and active TGFbeta1 levels in serum of either set of patients. Plasma beta thromboglobulin was detected in platelet-depleted plasma samples, indicative of platelet damage before plasma separation. Neither CsA nor tacrolimus induced active TGFbeta1 blood levels in liver transplant recipients during a follow up period of < or = 265 days.

Effects of a Novel Calcium Antagonist, Benidipine Hydrochloride, on Platelet Responsiveness to Mental Stress in Patients with Essential Hypertension

The effects of a novel calcium antagonist, benidipine hydrochloride, on responses of platelets to mental stress were evaluated in nine patients with essential hypertension. Before and 12 weeks after the monotherapy with benidipine (2-4 mg/day), platelet aggregability and plasma beta-thromboglobulin were determined during rest and after a 10-min arithmetic stress. Before the treatment, arithmetic stress significantly increased platelet aggregability in response to adenosine diphosphate (ADP) and plasma beta-thromboglobulin level. Blood pressure, pulse rate, and plasma catecholamines also increased during arithmetic stress. The treatment with benidipine did not affect resting values of platelet functions, but attenuated significantly stress-induced alterations in primary aggregation to 1.0 microM ADP (34 +/- 4% to 40 +/- 3% before treatment vs. 32 +/- 2% to 34 +/- 3% after benidipine), ADP threshold for biphasic aggregation (2.2 +/- 0.4 to 1.8 +/- 0.3 microM before treatment vs. 2.2 +/- 0.3 to 2.2 +/- 0.4 microM after benidipine) and plasma beta-thromboglobulin level (74 +/- 16 to 104 +/- 15 ng/ml before treatment vs. 60 +/- 10 to 52 +/- 8 ng/ml after benidipine; p < 0.05 for Stress x Treatment interactions in all values). The pretreatment elevations in blood pressure and sympathetic activity with stress were not modified by benidipine treatment. In conclusion, the monotherapy with benidipine did not affect platelet function during the resting condition, but significantly suppressed the platelet activation induced by arithmetic stress in patients with essential hypertension.