Association of plasma retinol-binding protein-4, adiponectin, and high molecular weight adiponectin with metabolic adversities in patients with schizophrenia

Objective

Metabolic adversities are prevalent in patients with schizophrenia. Retinol-binding protein 4 (RBP4) and high molecular weight (HMW) adiponectin have been recently found to be associated with metabolic features in non-psychiatric population. The study aimed to evaluate the associations between metabolic features and RBP4, total adiponectin, and HMW adiponectin in patients with schizophrenia.

Methods

We recruited 109 patients with schizophrenia treated with clozapine or haloperidol and evaluated their body mass index (BMI), waist circumference, blood pressure, and fasting triglyceride (TG), high-density lipoprotein cholesterol (HDL-C), fasting plasma glucose, insulin, RBP4, total adiponectin, and HMW adiponectin levels.

Results

We found that patients with metabolic syndrome (MS) had higher RBP4 level, and lower total adiponectin and HMW adiponectin levels than those without MS. There were no significant differences in metabolic features and adipocytokine levels between patients treated with clozapine and haloperidol. Most of the metabolic indexes were significantly correlated with the levels of adipocytokines. After adjusting the effects of age, gender, and BMI, marginal significant correlations existed between TG and RBP4 levels; HDL-C and total adiponectin and HMW adiponectin; insulin and HOMA-IR and HMW adiponectin. Receiver operating curve analysis showed that all of the three adipocytokines could differentiate patients with MS from those without MS. Meanwhile, total adiponectin and HMW adiponectin, but not RBP4, had the differentiating power for insulin resistance.

Conclusion

Higher RBP4 and lower total adiponectin and HMW adiponectin levels were observed in schizophrenic patients with MS. Only HMW adiponectin is marginally correlated with insulin sensitivity. The finding that metabolic profiles, but not the antipsychotic types, are associated with adipocytokine levels should be confirmed in longitudinal studies.     

Atorvastatin has antithrombotic effects in patients with type 1 diabetes and dyslipidemia

Introduction

Diabetes is a prothrombotic state involving a more thrombogenic fibrin network. In the present study we investigated the effects of lipid-lowering therapy with atorvastatin on fibrin network structure and platelet-derived microparticles in patients with type 1 diabetes and dyslipidemia.

Materials and Methods

Twenty patients were treated with atorvastatin (80 mg daily) or placebo during 2 months in a randomized, double-blind, cross-over study. Fibrin network permeability, expression of glycoprotein IIIa, P-selectin and tissue factor on platelet-derived microparticles, plasma endogenous thrombin potential, plasminogen activator inhibitor-1 and tissue plasminogen activator antigen levels were assessed. Additionally, levels of plasma fibrinogen, high-sensitivity C-reactive protein and glycated haemoglobin were measured.

Results

During treatment with atorvastatin, fibrin network permeability increased (p = 0.01), while endogenous thrombin potential and expression of glycoprotein IIIa, P-selectin and tissue factor decreased (p < 0.01). In vitro experiments indicated that platelet-derived microparticles influence the fibrin network formation as fibrin network permeability decreased significantly when platelet-derived microparticles were added to normal plasma. Baseline levels of plasminogen activator inhibitor-1 and tissue plasminogen activator antigen as well as plasma fibrinogen and high-sensitivity C-reactive protein were within reference values and not significantly changed during atorvastatin treatment, while glycated haemoglobin increased 0.3% (p < 0.001).

Conclusions

Novel treatment effects were found in patients with type 1 diabetes and dyslipidemia during atorvastatin therapy, i.e. a more porous fibrin network, to which reduced expression of glycoprotein IIIa, P-selectin and tissue factor on platelet-derived microparticles may contribute. The observed impairment of glycemic control during long-term statin treatment deserves attention.     

D-dimer relates positively with increased blood pressure in black South Africans: The SABPA study

Introduction

Hypertension is highly prevalent in black South Africans in which morbidity and mortality from stroke are on the increase. Elevated blood pressure and haemostatic markers can induce changes in blood rheology and endothelial function which could result in a procoagulant state that increases the risk for cerebrovascular disease. Information about the coagulation and fibrinolytic systems of people from African descent are limited. We therefore, investigated the haemostatic profile and its relationships with blood pressure in black South Africans.

Materials and methods

We measured ambulatory blood pressure and haemostatic markers of 201 black and 208 white school teachers. The haemostatic markers included measurements representing coagulation and fibrinolysis (von Willebrand factor, fibrinogen, plasminogen activator inhibitor-1, fibrin D-dimer and clot lysis time).

Results

Black participants displayed significantly higher blood pressure, von Willebrand factor, fibrinogen, plasminogen activator inhibitor-1 and D-dimer levels and longer clot lysis times (p ≤ 0.001). Single, partial and multiple regression analyses showed that systolic (p ≤ 0.011) and diastolic blood pressure (p = 0.010) correlated positively with D-dimer in black participants, while systolic (p ≤ 0.001) and daytime diastolic blood pressure (p = 0.011) correlated negatively with clot lysis time in white participants.

Conclusion

The black population had a more prothrombotic profile, with higher levels of coagulation markers and inhibited fibrinolysis, than the white study participants. The positive association between blood pressure and elevated D-dimer in the blacks may contribute to the high prevalence of hypertension and related increased cardiovascular and cerebrovascular risk in this group.     

Platelet-related fibrinolysis resistance in patients suffering from PV. Impact of clot retraction and isovolemic erythrocytapheresis

Using patients with polycythemia vera (PV) as an experimental model, we evaluated the impact of clot retraction (CR) and architecture of the clot on fibrinolysis. We studied the kinetics of clot retraction and the fibrinolysis rate in whole blood from 48 PV patients and 48 healthy controls. Measurements were performed before and after isovolemic eryhrocytapheresis (ECP). CR was measured by optical method. Clot lysis time (CLT) and maximum clot firmness (MCF) were measured by thromboelastometry in recalcified blood supplemented with t-PA and tissue factor.     

Endothelial function is impaired in patients with primary antiphospholipid syndrome

INTRODUCTION: The aim of this study was to evaluate endothelial function in patients with primary antiphospholipid syndrome (PAPS). PATIENTS AND METHODS: Flow mediated (FMD) and glyceryl trinitrate (GTN) induced dilation of the right brachial artery were studied in 25 patients with PAPS and 25 controls matched by age, sex and conventional risk factors for atherosclerosis. Fibrinogen, D-dimer, adhesion molecules, tissue plasminogen activator (t-PA) and plasminogen activator inhibitor-1 (PAI-1) antigens and activities were measured. RESULTS: Mean (SD) FMD was significantly lower in PAPS than in controls (8+/-5% vs. 15+/-6%, P<0.001); GTN-induced dilation did not differ between the groups. There was a correlation between the baseline diameter of the brachial artery and duration of the disease (-0.56, P<0.05) and between GTN induced dilation and duration of the disease (0.51, P<0.05). Concentrations of vascular cell adhesion molecule-1 (P<0.001), intracellular adhesion molecule-1 (P<0.001) and fibrinogen (P<0.05) were higher in patients than in controls but no differences were observed for D-dimer, t-PA and PAI-1 antigens and activities. There was correlation between concentration of vascular cell adhesion molecule-1 and FMD (-0.35, P<0.05) and between intracellular adhesion molecule-1 and FMD (-0.41, P<0.05). CONCLUSIONS: This study shows that endothelial function is impaired in patients with primary APS, possibly contributing to accelerated atherosclerosis and thromboembolic complications in these patients.     

The prevalence of metabolic syndrome in Korean patients with schizophrenia receiving a monotherapy with aripiprazole, olanzapine or risperidone

Second-generation antipsychotics (SGAs) increase the risk of metabolic syndrome (MetS). Although ethnicity also contributes to MetS risk, the majority of the studies on the relationship of SGAs to this syndrome come from Western countries, whereas few reports have come from Asian countries, especially regarding patients taking a single SGA. We reviewed the electronic medical records of patients with schizophrenia who received aripiprazole, olanzapine or risperidone monotherapies for at least three months. We evaluated the prevalence of MetS in our sample as well as the indirect standardized prevalence ratio (ISPR) using data from the 4th Korean National Health and Nutrition Examination Survey (KNHNES, 2007). The prevalence of MetS in our sample (n = 145) was 31.7%, and the ISPR was 2.09. Male patients had a higher prevalence of MetS than female patients (odds ratio [OR] = 4.18, 95% CI = 1.93-9.03). The ISPR of male patients was 2.67 and statistically significant, whereas the ISPR of female patients was not significant. In our sample, the frequency of abnormal MetS subcomponents occurred in descending order: increased waist circumference, increased triglyceride levels, decreased HDL-cholesterol levels, elevated blood pressure and elevated fasting blood glucose levels. Patients who received aripiprazole were significantly less likely to have MetS. However, a logistic regression showed that age and sex, but not the type of antipsychotic, its dose or the use of antidepressants, were significantly related to the presence of MetS. There were no statistically significant differences among SGAs in terms of MetS subcomponent abnormalities of after adjusting for age and sex. In conclusion, only male Korean patients with schizophrenia who received a monotherapy of aripiprazole, olanzapine or risperidone for more than three months were more likely to have MetS than the general population.     

Impaired glucose metabolism and type 2 diabetes are associated with hypercoagulability: potential role of central adiposity and low-grade inflammation--the Hoorn Study

Introduction

Type 2 diabetes (DM2) is associated with greater risk for cardiovascular disease (CVD), which may, at least partially, be explained by prothrombotic alterations. We therefore investigated; first, the extent to which individuals with impaired glucose metabolism (IGM) and/or DM2 had greater levels of thrombin generation than those with normal glucose metabolism (NGM); and second, whether any differences were independent of other cardiovascular risk factors, such as smoking, hypertension, dyslipidaemia, (micro)albuminuria, glycemic control and (central) adiposity, and/or were potentially ‘mediated’ by low-grade inflammation (high-sensitivity C-reactive protein (hsCRP)).

Materials and methods

We studied 744 individuals from the Hoorn Study (275 NGM, 176 IGM and 293 DM2, mean age 68.6 ± 7.1 years). Thrombin generation in platelet-poor plasma was measured using the Calibrated Automated Thrombogram and three parameters were derived: lag time, peak height and endogenous thrombin potential (ETP). Data were analyzed with multiple linear regression analyses.

Results

After adjustment for age, sex, prior CVD and smoking status, individuals with IGM or DM2 had a longer lag time [ß = 0.14 min (95% CI: 0.02; 0.26)], higher peak height [ß = 7.29 nM (− 1.33; 15.91)] and ETP [ß = 35.65nM*min (0.97; 70.34)] than those with NGM. These differences were attenuated to ß = 0.06 min (− 0.07; 0.19), 3.82 nM (− 5.46; 13.10) and 16.34 nM*min (− 20.92; 53.59), respectively, when further adjusted for waist circumference and hsCRP.

Conclusion

Individuals with IGM or DM2 had up to 4% higher thrombin generation compared with NGM, which may be explained, to a great extent, by the greater levels of central adiposity and related low-grade inflammation characterizing these individuals.     

Postprandial changes in the phospholipid composition of circulating microparticles are not associated with coagulation activation

Introduction

Evidence is present that the phospholipid composition of circulating cell-derived microparticles (MP) affects coagulation in vivo, and that postprandial metabolic alterations may be associated with hypercoagulable state. Our objective was to investigate whether postprandial metabolic responses affect the phospholipid composition of MP, and whether such changes are associated with coagulation activation.

Materials and Methods

Twelve healthy males were studied twice and randomly received two consecutive meals or remained fasted. Blood was collected before and at 2, 4, 6 and 8 h following breakfast. Plasma concentrations of prothrombin-F_1 + 2 and thrombin-antithrombin-complexes were measured. Numbers and cellular origin of MP were determined by flowcytometry. The phospholipid composition of MP was determined by hpTLC. In vitro procoagulant activity of MP was studied by fibrin generation.

Results

During the meal visit, plasma glucose, triglyceride and insulin levels increased, compared to baseline and the fasting visit (all P < 0.05). Postprandially, the total numbers of MP increased in time compared to the fasting visit (P < 0.05). Erythrocyte-derived MP increased (6-fold) during the meal visit, but remained constant on the fasting day (P < 0.001). On the meal versus fasting day circulating MP contained increased phosphatidylcholine (P < 0.05) and decreased sphingomyelin (P < 0.05) amounts. The amount of phosphatidylserine did not change. Concentrations of plasma F_1 + 2 and thrombin-antithrombin were similar on both days, as was the ability of MP to generate fibrin in vitro.

Conclusion

Although numbers, cellular origin and phospholipid composition of MP alter during exposure to two consecutive meals in healthy subjects, this does not lead to changes in the coagulation activation in vivo.     

Endothelial haemostatic markers in members of families with familial combined hyperlipidemia

Introduction

The aim of this study was to evaluate the plasma levels of endothelial haemostatic markers - von Willebrand factor (vWF), plasminogen activator inhibitor-1 (PAI-1), tissue plasminogen activator (t-PA) and soluble thrombomodulin (sTM) — in asymptomatic, nonsmoking members of families with familial combined hyperlipidemia (FCH). We investigated the association between these factors and the intima-media thickness (IMT) of the common carotid artery, selected risk factors of atherosclerosis and markers of insulin resistance.

Methods

82 members of 29 FCH families were divided into two groups: HL (probands and hyperlipidemic first-degree relatives, n = 47) and NL (normolipidemic first-degree relatives, n = 35). The control groups C-HL (n = 20) and C-NL (n = 20) consisted of sex- and age-matched healthy individuals. IMT was measured by ultrasound at a far wall of both common carotid arteries.

Results

Compared with healthy controls, hyperlipidemic subjects had significantly higher levels of vWF (146.4 ± 73.2% versus 112.2 ± 29.4%, p < 0.05), of PAI-1 (102.4[83.0-117.0] ng/ml versus 63.5[31.8-87.3] ng/ml, p < 0.01) and of t-PA (5.1[2.5-7.9] ng/ml versus 3.4[1.4-5.8] ng/ml, p < 0.05). They had increased IMT, which correlated with vWF (r = 0.29, p < 0.05). Their normolipidemic relatives had significantly higher levels of vWF (137.2 ± 42.8% versus 106.6 ± 24.0%, p < 0.01) and of PAI-1 (75.3[53.2-92.0] ng/ml versus 48.6[37.4-85.9] ng/ml, p < 0.05). Levels of vWF, PAI-l and t-PA were independently associated with several markers of insulin resistance.

Conclusions

Asymptomatic members of FCH families have increased endothelial haemostatic factors— vWF, PAI-1, t-PA, which are associated with insulin resistance. VWF correlates with morphological vascular changes, detected by the increase of IMT, presented in only hyperlipidemic subjects.     

Association of the ADRA1A gene and the severity of metabolic abnormalities in patients with schizophrenia

Patients with schizophrenia have a higher risk of developing metabolic abnormalities and their associated diseases. Some studies found that the accumulative number of metabolic syndrome components was associated with the severity of metabolic abnormalities. The purpose of this study was to examine the roles of the ADRA1A, ADRA2A, ADRB3, and 5HT2A genes in the risk of having more severe metabolic abnormalities among patients with schizophrenia. We studied a sample of 232 chronic inpatients with schizophrenia (120 males and 112 females) to explore the associations between the four candidate genes and the severity of metabolic syndrome by accumulative number of the components. Four single nucleotide polymorphisms in the candidate genes were genotyped, including the Arg347Cys in ADRA1A, the C1291G in ADRA2A, the Try64Arg in ADRB3, and the T102C in 5HT2A. An association between the accumulative number of metabolic syndrome components and the ADRA1A gene was found after adjusting age, sex, and other related variables (p-value = 0.036). Presence of the Arg347 allele in the ADRA1A gene is a risk factor for having more severe metabolic abnormalities. These findings suggest a medical attention of closely monitoring metabolic risks for schizophrenia patients with high-risk genotypes.     

Reduced plasma fibrin clot permeability and susceptibility to fibrinolysis are associated with increased intima-media thickness in patients with primary antiphospholipid syndrome

Introduction

Formation of denser fibrin networks displaying impaired lysability has been reported in subjects at an increased risk of atherosclerosis. Given recent data on prothrombotic fibrin clot phenotype reported in patients with antiphospholipid syndrome (APS), we tested the hypothesis that altered fibrin clot properties are associated with increased intima-media thickness (IMT) observed in PAPS.

Materials and methods

We studied 30 consecutive patients with PAPS and 30 controls matched for age, sex and the type of previous thromboembolism. We assessed plasma fibrin clot permeability (K_s) and clot lysis time (CLT) with their potential determinants. The IMT was measured in 3 segments of the carotid arteries.

Results

Patients with APS had 15.2% lower K_s (p = 0.002) and 9.7% prolonged CLT (p = 0.039) compared with controls. The IMT in the APS group was greater in the common carotid artery (5.7%; p = 0.002), at the bifurcation (17.46%; p < 0.001), and the internal artery (9.26%; p = 0.015). Patients with triple positivity in the antiphospholipid antibody profile (n = 9; 30%) had lower K_s and greater IMT (both, p < 0.05), compared with those with single positivity (n = 13; 43.3%). Multivariate analysis adjusted for potential confounders showed that in APS patients, oxidized low-density lipoproteins (p = 0.019) were the only independent predictor of K_s, while thrombin activatable fibrinolysis inhibitor activity (p < 0.001) predicted CLT. Plasminogen activator inhibitor-1 (PAI-1) was found to be the independent predictor of the IMT in the common carotid artery (p = 0.004), and in the internal carotid artery (p < 0.001).

Conclusions

Reduced K_s and susceptibility to lysis are associated with greater IMT in PAPS, which might contribute to the early atherosclerosis in this disease.     

Global haemostasis assays, from bench to bedside

Bleeding and thrombosis are the ultimate clinical outcomes of aberrations in the haemostatic process. Haemostasis prevents excessive blood loss due to the effort of various compartments like the vasculature, blood cells, coagulation and fibrinolysis. The complexity of all processes involved makes the diagnosis of aberrations difficult, cumbersome and expensive. A single assay to detect any factor disturbing this haemostatic balance with high sensitivity and specificity would be of great value, especially if the outcome of this assay correlates well with clinical outcome. Despite years of research, such an assay is not yet available; however, some interesting candidates are under development and combine the effects of various compartments. This review describes the development of global haemostasis assays and summarizes the current state of the art of these haemostasis assays covering thrombin and plasmin generation, turbidity and thromboelastography/thromboelastometry. Finally, we discuss the applicability of global assays in clinical practice and we provide a future perspective on the ongoing development of automation and miniaturisation as it is our belief that these developments will benefit the standardization of global haemostasis assays.