Tissue Plasminogen Activator Antigen Research Articles

Determination of tissue plasminogen activator (t-PA) antigen in seminal plasma by modified enzyme-linked immunosorbant assay (ELISA).

The determination of tissue plasminogen activator (t-PA) antigen in semen by a new immunoenzymatic method was done in 152 men without genito urinary pathology. The seminal value is one hundred higher than the blood value with a log normal distribution. These levels are not influenced by freezing temperature, by the sequences freezing-thawing, by centrifugation. From split ejaculates a correlation has been established between t-PA antigen and zinc and not with fructose. These results indicate the major prostatic origin of the t-PA antigen.

Haemostatic markers in patients with abdominal aortic aneurysm and the impact of aneurysm size

Introduction Abdominal aortic aneurysm is a common condition with high mortality when rupturing. However, the condition is also associated with nonaneurysmal cardiovascular mortality. A possible contributing mechanism for the thrombosis related cardiovascular mortality is an imbalance between the activation of the coagulation system and the fibrinolytic system. The aim of the present study was to investigate haemostatic markers in patients with nonruptured abdominal aortic aneurysm with special regard to the influence of aneurysm size and smoking habits. Methods Seventy-eight patients with infrarenal aortic aneurysm and forty-one controls without aneurysm matched by age, gender and smoking habits were studied. Thrombin-antithrombin (TAT), prothrombin fragment 1 + 2 (F 1 + 2) - markers of thrombin generation, and von Willebrand factor antigen (vWFag) - considered as a reliable marker of endothelial dysfunction - were measured. Plasma levels of tissue plasminogen activator antigen (tPAag), and plasminogen activator inhibitor type 1 (PAI-1) were measured as markers of fibrinolytic activity. D-dimer, a marker of fibrin turnover, was also measured. Results There were significantly higher levels of TAT and D-dimer in patients with abdominal aortic aneurysm. The highest level of TAT and D-dimer were detected in patients with large compared to small AAA. Conclusions The present data indicate a state of activated coagulation in patients with abdominal aortic aneurysm which is dependent by aneurysm size. The activated coagulation in AAA patients could contribute to an increased cardiovascular risk in patients also with small AAA. The possible impact of secondary prevention apart from smoking cessation has to be further evaluated and is maybe as important as finding patients at risk of rupture.

Adipokines, Inflammation, and Visceral Adiposity across the Menopausal Transition: A Prospective Study

Postmenopausal women have greater visceral adiposity compared with premenopausal women. Adipokines are associated with increased adiposity, insulin resistance, and atherosclerosis. The objective of the study was to assess changes in adipokines and inflammatory markers through the menopausal transition and correlate them with changes in visceral adiposity. This was a prospective cohort study of women through the menopausal transition conducted at the University of Washington. Sixty-nine healthy women were followed up longitudinally from premenopausal (aged 45-55 yr) to postmenopausal status (aged 49-60 yr). On premenopausal and postmenopausal visits, fasting blood was drawn for adiponectin, leptin, serum amyloid A (SAA), C-reactive protein (CRP), monocyte-chemotactic protein-1, tissue plasminogen activator antigen (tPA), IL-6, and TNF-alpha. Body composition measures were assessed by body mass index, whole-body dual x-ray absorptiometry scan, and computed tomography scan of the abdomen at the lumbar 4-5 level. Women had a statistically significant increase in SAA, tPA, monocyte-chemotactic protein-1, and adiponectin between the two measurement occasions (P = 0.04, P = 0.02, P = 0.001, and P < 0.001, respectively). The increase in intraabdominal fat was correlated positively with the change in SAA (r = 0.31, P = 0.02), CRP (r = 0.56, P < 0.001), tPA (r = 0.40, P = 0.002), and leptin (r = 0.41, P = 0.002) and negatively correlated with the change in adiponectin (r = -0.37, P = 0.005). After adjustment for change in sc abdominal fat, the correlation between change in CRP, tPA, leptin, and adiponectin remained significantly associated with change in intraabdominal fat. Women going through the menopausal transition have deleterious changes in inflammatory markers and adipokines that correlate with increased visceral adiposity.

Renal tubulointerstitial expansion is associated with endothelial dysfunction and inflammation in type 1 diabetes

Objective. Diabetic nephropathy has been considered to be primarily of glomerular origin, but there is now compelling evidence that disruption of the tubulointerstitial architecture determines the outcome of diabetic nephropathy in interplay with the glomerular damage. We investigated whether reactive oxidative species, pro‐inflammatory cytokines and endothelial dysfunction were implicated in the progression of tubulointerstitial damage in young subjects with type 1 diabetes. Material and methods. In a prospective study, we investigated 18 young subjects (mean age 21 years) with type 1 diabetes and microalbuminuria. Quantitative morphometry concerning glomerular and tubulointerstitial changes was performed at baseline (i.e. mean duration of diabetes 10 years) and 2.5 and 8 years later. Markers of endothelial activation and inflammation, intercellular adhesion molecule‐1, vascular cell adhesion molecule‐1, tumour necrosis factor‐α, interleukin‐6, interleukin‐8 and highly sensitive C‐reactive protein were measured at baseline and after 8 years. Tissue plasminogen activator antigen and plasminogen activator inhibitor (PAI‐1 activity) and asymmetric dimethylargine (ADMA) were measured at baseline and after 2.5 years. Results. PAI‐1 activity at baseline was a significant independent variable of the 8‐year increment in interstitial volume fraction (Vv(Int/cortex)). ADMA/L‐arginine ratio at baseline was associated with the increment in Vv(Int/cortex) during 2.5 years (p<0.01), still significant after adjustment for covariates (p = 0.02). No associations between Vv(Int/cortex) and glomerular parameters, HaemoglobinA1c and urinary albumin excretion were observed. Conclusions. Biomarkers involved in interstitial volume expansion seem to be different from those of mesangial expansion in early diabetic nephropathy. PAI‐1 activity may have a predictive role in the development of the tubulointerstitial expansion.

Coagulation and Fibrinolysis are in Balance After Moderate Exercise in Middle-aged Participants

Increased age is associated with a higher risk of thrombotic events. The aim of this study was to investigate the age-related changes in hemostasis before and after moderate exercise controlled by individual anaerobic threshold as recommended for rehabilitation training. In this study, 24 young (25 +/- 1 years) and 24 middle-aged healthy nonsmokers (48 +/- 1 years) underwent an individualized exercise test with 80% of individual anaerobic threshold (young individuals: 127 +/- 6 W; middle-aged individuals: 128 +/- 5 W; values are expressed as mean +/- standard error of mean) for 60 minutes. The blood samples were collected before and after the exercise. The age-related higher (P < or = .05) levels could be detected in factors II, VII, VIII, IX, XI, XII, prothrombin fragment 1+2, in tissue plasminogen activator antigen and activity, as well as in plasminogen. The relative exercise-induced increases in these parameters were similar in both groups, although beginning at a higher level for those in the middle-aged group.A statistically enhanced increase after exercise in the middle-aged group could be shown in prothrombin fragment 1+2 (young individuals: 98 +/- 6 to 102 +/- 6 pmol/L; middle-aged individuals: 138 +/- 7 to 156 +/- 8 pmol/L) and in thrombin-antithrombin complex (young individuals: 2.2 +/- 0.1 to 3.1 +/- 0.2 microg/L; middle-aged individuals: 2.4 +/- 0.3 to 3.9 +/- 0.6 microg/L); the latter only showing a tendency. The data show the age-related changes with a rise in blood coagulation and fibrinolysis in a healthy middle-aged group compared with younger participants. Moderate exercise leads to comparably relative increases in hemostatic parameters but starting at higher levels. However, the exercise-induced thrombin generation (prothrombin fragment 1+2) is enhanced in the middle-aged participants in comparison with younger participants, but may be compensated by a sufficient fibrinolysis, and therefore the hemostatic system remains in balance.

Peripartum Haemostatic Changes in Women in Labour

Abstract Introduction: Obstetric haemorrhage (OH) is a major cause of maternal mortality and morbidity worldwide. Appropriate management requires understanding of normal peripartum haemostatic changes during labour, and yet there are few studies. Aim: In this pilot study we aimed to evaluate peripartum haemostatic changes in healthy women. Methods: We collected blood samples from 20 women peripartum, into 0.102 M trisodium citrate tubes (ratio9:1) (Becton Dickinson) from the antecubital fossa using flawless venepuncture at the following time-points: antepartum; after delivery of the placenta; 24hrs post-partum and 48hrs post-partum. Plasma was aliquoted and stored in −70°C until the following ELIZA assays were performed: D-Dimer levels (Dade Behring, Sysmex UK), prothrombin fragments 1+ 2 (PF 1+2) (Dade Behring, Sysmex, UK) and tissue plasminogen activator antigen (t-PA:Ag) (Biopool, Trinity Biotech, UK). Prothrombin time (PT) (PT-Fib HS), activated partial thromboplastin time (APTT) (APTT micronized silica) and clauss fibrinogen (Fib-C), reagents were from Instrumentation Laboratories Ltd UK. Statistical analysis was performed using XLSTAT 2008. Results: The median (range) age was 28 (19–36) years and the body mass index (BMI) 28.9 (21.7– 35.3). Table 1: To show the median (range) for the haemostatic assays Assay (normal ranges) D-dimers (4–52ug/l) PF1+2 (0.2–1.2 pmol/l) t-PA:Ag: 3–11 ng/ml) PT (12–16s) APTT (26–38s) Fibrinogen (1.52–4.12 g/l) * p&amp;lt;0.05 using the Mann Whitney U test between the 1st and each of the other three samples Antepartum 231 (122–900) 570 (352–1533 12 (7.2–23) 12 (10–14) 31 (24–36) 5.2 (3.1–8.7) Post Labour 482 (117–1044) 968 (480–1858)* 18 (8.6–40.6)* 13 (10–15) 30 (24–36) 5.3 (2.2–9.8) 24h 309 (65–931) 568 (264–1080)* 7 (4–23)* 13 (10–16)* 33 (27–41)* 5.3 (4–11) 48hrs 235 (85–614) 648 (371–2287) 7 (3–18)* 12 (10–16) 31 (23–43) 5.7 (3.5–11) Conclusion: These findings demonstrate that peripartum haemostasis is prothrombotic with shortened PT, APTT and prolonged fibrinogen. There is increased thrombin generation and fibrinolytic activity. t-PA antigen is most notably elevated immediately post delivery.

Relation of Cardiorespiratory Fitness to Inflammatory Markers, Fibrinolytic Factors, and Lipoprotein(a) in Patients With Type 2 Diabetes Mellitus

Increased inflammation, fibrinolytic factors, and lipoprotein(a) (LP[a]) were associated with increased cardiovascular events in patients with type 2 diabetes, whereas higher levels of cardiorespiratory fitness (CRF) were associated with a lower incidence of cardiovascular mortality. Whether CRF is associated with inflammatory markers, fibrinolytic factors, and LP(a) in patients with type 2 diabetes was investigated. A total of 425 men with type 2 diabetes (mean age 55 +/- 8 years) who participated in a medical screening program were studied. CRF was measured using peak oxygen uptake with expired gas analysis during a symptom-limited exercise test. CRF inversely correlated with C-reactive protein (CRP; r = -0.27, p <0.05), white blood cell count (r = -0.13, p <0.05), fibrinogen (r = -0.28, p <0.05), LP(a) (r = -0.53, p <0.05), tissue plasminogen activator (t-PA) antigen (r = -0.65, p <0.05), and plasminogen activator inhibitor-1 activity (r = -0.17, p <0.05). Men in the highest tertile of CRF had significantly lower CRP, white blood cell count, fibrinogen, LP(a), and t-PA than men in the lowest tertile of CRF (all p <0.05). In separate multivariable linear regression models that adjusted for age, body mass index, smoking, lipid profiles, glucose, and systolic blood pressure, CRP (beta = -0.23, p <0.05), white blood cell count (beta = -0.16, p <0.05), fibrinogen (beta = -0.24, p <0.05), LP(a) (beta = -0.28, p <0.05), and t-PA (beta = -0.69, p <0.05) were each inversely associated with CRF. Each MET increment higher peak oxygen uptake was associated with a lower odds ratio of having abnormal LP(a) (odds ratio 0.43, 95% confidence interval 0.20 to 0.91) in a multivariate logistic regression model. In conclusion, CRF was inversely associated with inflammatory markers, fibrinolytic factors, and LP(a) in men with type 2 diabetes.

Beneficial effects of dalteparin on haemostatic function and local tissue oxygenation in patients with diabetes, severe vascular disease, and foot ulcers

Conclusion: Local skin oxygenation, as measured by transcutaneous oxygen tension (TcPO2) and laser Doppler fluxmetry, is improved with dalteparin in patients with diabetes, peripheral arterial disease (PAD), and chronic foot ulcers. Summary: Patients with diabetes appear to have a state of fibrinolytic dysfunction and hypercoagulation that may contribute to disturbances in skin microcirculatory function with resulting impaired healing of foot ulcers. The authors have previously reported improved outcome of patients with chronic foot ulcers and diabetes who were treated with dalteparin (Diabetes Care 2003;26:2575-80). In this study, they sought to investigate the mechanisms of the effects of dalteparin on haemostatic function and skin microcirculation. This was a prospective, randomized, double-blind, placebo-controlled trial. The study randomized 87 patients with PAD, diabetes, and chronic foot ulcers to treatment with once daily subcutaneous injections of 5000 U of dalteparin (n = 44) or placebo (n = 43). Treatment continued until ulcer healing or for a maximum of 6 months. Plasma fibrinogen, fibrin gel structure (measured by permeability coefficient and fiber mass/length ratio), prothrombin fragment 1+2 antigen, plasminogen activator inhibitor-1 activity, and tissue plasminogen activator antigen were analyzed before randomization and at the end of treatment. Skin microcirculation was assessed with laser Doppler fluxmetry and TcPO2. Measurements of permeability coefficient, fiber mass/length ratio, tissue plasminogen activator, and TcPO2 were higher (P < .05) with treatment with dalteparin compared with placebo. Baseline plasma fibrinogen and the permeability coefficient significantly correlated with TcPO2. Comment: Patients with diabetes have impaired healing. Although much of this may be due to neuropathy, microcirculatory abnormalities have long been postulated as contributing to poor healing in patients with diabetes. Some of the microcirculatory abnormalities now appear responsive to dalteparin, and there is some suggestion these effects may have clinical relevance. Work in this area is still very preliminary, but it makes sense to target the microcirculation as a site for possible intervention in patients with diabetes and foot ulcers.

Relationship between maternal and cord blood hemostatic disturbances in preeclamptic pregnancies

Endothelial cell activation or damage is believed to play a key role in preeclampsia (PE) and may underlie the hemostatic changes observed in this syndrome. The aim of this study was to evaluate a relationship between maternal and cord blood hemostatic disturbances in preeclamptic pregnancies. We measured the plasma levels of tissue plasminogen activator (tPA) antigen and of plasminogen activator inhibitor type 1 (PAI-1) antigen, both markers of hemostatic and endothelial function, and fibrin fragment D-dimer. Maternal blood from uncomplicated ( n = 42) and PEc pregnancies ( n = 44) were collected before delivery, and umbilical cord blood (UCB) immediately after delivery. In preeclamptic cases, UCB presented significantly higher tPA values and significantly lower PAI-1/tPA ratio. Preeclamptic women also presented significantly higher tPA, as well as PAI-1 values, when compared with normal pregnant women; no significant difference was found for D-dimer. In preeclamptic women, proteinuria (a marker of PE severity) correlated positively and significantly with tPA and PAI-1 antigen levels. An inverse relationship between maternal tPA antigen levels and fetal birth weigh in PE was also observed. Our data show that the hemostatic maternal disturbances observed in preeclamptic women have similarities with the UCB circulation, and that endothelial dysfunction is the most plausible underlying cause. Moreover, maternal hemostatic disturbances seem to be associated with the severity of PE. Further studies are needed to strength the values of tPA and PAI-1 as markers of severity in PE.

Effects of Socioeconomic Position on Inflammatory and Hemostatic Markers: A Life-Course Analysis in the 1958 British Birth Cohort

The cumulative effects of socioeconomic position (SEP) on cardiovascular disease have been described, but the pathways are unclear. In this study, the authors examined the effects of life-course SEP on inflammatory and hemostatic markers: fibrinogen, C-reactive protein, von Willebrand factor antigen, and tissue plasminogen activator antigen. Data from the 1958 British birth cohort, including data on persons who underwent a biomedical follow-up in 2002-2004, were used. Social class was determined at three stages of respondents' lives: childhood (birth), early adulthood (age 23 years), and midlife (age 42 years). A cumulative indicator score of SEP was calculated that ranged from 0 (always in the highest social class) to 9 (always in the lowest social class). In men and women, associations were observed between cumulative indicator score and fibrinogen (p < 0.001), C-reactive protein (p < 0.001), von Willebrand factor antigen (p < or = 0.05), and tissue plasminogen activator antigen (p < 0.001 only in women). The trends in fibrinogen and C-reactive protein remained after adjustment for body mass index, smoking, and physical activity. However, the trends became nonsignificant for von Willebrand factor antigen and tissue plasminogen activator antigen in women. Risk exposure related to SEP accumulates across the life course and contributes to raised levels of fibrinogen and C-reactive protein, while childhood SEP influences hemostatic markers more than does adult SEP.

Development of Osteonecrosis Is Associated with Difference in Upregulation of Antithrombin, Protein C and Protein S after Four Weeks of Dexamethasone during Induction Treatment in Childhood Acute Lymphoblastic Leukemia.

Osteonecrosis (ON) is a serious complication of chemotherapy for pediatric acute lymphoblastic leukemia (ALL). Impairment of microcirculation seems to be involved in the pathogenesis of ON. We hypothesized that variation in hypercoagulability plays a role in the etiology of ON during treatment of ALL. Dexamethasone (dexa) and asparaginase (asp) are important drugs in the induction treatment of pediatric ALL that may influence the coagulation system. In the current study differences in coagulation parameters between pediatric ALL patients with and without ON were evaluated. Blood samples were taken at diagnosis and at several time-points during induction of the DCOG-ALL9 treatment schedule. Procoagulant factors (fibrinogen, factor II,V,VII,IX,X), anticoagulant factors (antithrombin (AT), protein C and protein S), parameters of thrombin generation (prothrombin fragment 1+2 (F1+2), thrombin antithrombin (TAT) complex) and of fibrinolysis (α2-antiplasmin (a2AP), plasminogen, plasmin-α2AP (PAP) complex, D-dimers) were determined. In total 137 patients without ON and 24 patients with ON were evaluated. In addition plasminogen activator inhibitor type 1 (PAI-1) activity and tissue plasminogen activator antigen (tPA-ag) concentration were studied in 25 patients, 15 without ON and 10 with ON. At diagnosis no significant differences in any of the coagulation parameters were found between patients with and without ON. After 4 weeks dexa treatment (day 29), AT, protein-C activity and protein-S total (anticoagulants) were significantly less upregulated in ON positive patients as compared to ON negative patients (respectively p=0.043, p=0.029, p=0.023). During tapering of dexa and administration of 4 doses asp at day 29, 33, 36 and 40 these parameters significantly decreased in both ON positive and negative patients. However, the nadir of these anticoagulant proteins reached lower levels in the ON positive patients as compared to ON negative patients and in ON positive patients levels even reached below lower limits of normal reference ranges. No other dexa or asp induced differences in any of the other coagulation parameters were found between ON negative and positive patients. These results indicate that development of ON in pediatric ALL patients seems to be associated with less upregulation of AT, protein C and protein S after 4 weeks treatment with dexa (day 29). ON positive patients subsequently declined below the lower limit of normal reference range during tapering of dexa and administration of asp in contrast to ON negative patients. This may suggest a therapy induced hypercoagulable state contributing to the development of ON.

Fibrinolysis in patients with an abdominal aortic aneurysm with special emphasis on rupture and shock.

A ruptured abdominal aortic aneurysm (AAA) is associated with high mortality. Postoperative complications such as hemorrhage, multiple organ failure, myocardial infarction, and thromboembolism are common. An active and balanced hemostatic system is essential to avoid bleeding as well as thrombosis. When these activities are not properly regulated the patient is at risk of developing either excessive bleeding or thrombosis-related complications. Previous studies have shown a state of activated coagulation in patients with ruptured AAA. However, there are conflicting results regarding the fibrinolytic response. The aim of the present study was to investigate the fibrinolytic state pre-operatively in patients with ruptured and non-ruptured AAA in relation to the clinical outcome with special regard to the influence of shock. A prospective study was performed on 95 patients who underwent surgery for a ruptured AAA with shock (n = 43), a ruptured AAA without shock (n = 12), and a non-ruptured AAA (n = 40). Forty-one controls without an aneurysm were matched to the AAA patients according to age, gender and smoking habits. Plasma levels of tissue plasminogen activator antigen (tPAag), and plasminogen activator inhibitor type-1 (PAI-1) were measured as markers of fibrinolytic activity. D-dimer, a marker of fibrin turnover, was also measured. D-dimer was significantly higher in patients with a non-ruptured AAA compared with controls without AAA. There were significantly higher levels of D-dimer, tPAag, and PAI-1 in patients operated for ruptured compared with non-ruptured AAA. tPAag was also significantly higher in ruptured AAA patients with shock compared with without shock. No deaths occurred in patients operated on for a non-ruptured AAA or ruptured AAA without shock. There were 12 deaths after repair of a ruptured AAA with shock, of which two patients died from bleeding and the remaining 10 from multiple organ failure and cardiac failure. Our results indicate a state of activated coagulation in patients with a non-ruptured AAA, the state being intensified by rupture. The present data show normal fibrinolytic activities in patients with a non-ruptured AAA, but increased systemic fibrinolysis, as demonstrated by elevated tPAag level, in patients with a ruptured AAA. The elevated PAI-1 level indicates a simultaneous inhibition of the systemic fibrinolysis. Furthermore, the hyperfibrinolytic state was reinforced by shock in this study. However, the clinical outcome, with a relatively high incidence of thrombosis-related deaths, indicate a prothrombotic state instead of a hyperfibrinolytic state as a major point of attention in patients with shock as a result of a ruptured AAA.

Associations of von Willebrand factor, fibrin D-dimer and tissue plasminogen activator with incident coronary heart disease: British Women's Heart and Health cohort study

Associations of three markers of thrombotic tendency, von Willebrand factor, tissue plasminogen activator antigen and fibrin D-dimer, with coronary heart disease have been reported in meta-analyses. It is not known, however, whether findings are generalizable to older women. Prospective cohort of 3582 women aged 60-79 years randomly selected from 23 towns without evidence of cardiovascular disease at entry into the British Women's Heart and Health Study. Women were followed for 4.7 years for incident coronary heart disease. Cox proportional hazard models were used to compare the hazard ratio of coronary heart disease per doubling for each thrombotic factor. In models adjusting for age and town only there was no association between von Willebrand factor or D-dimer and incidence of coronary heart disease, but there was a positive association of tissue plasminogen activator: coronary heart disease hazard ratio per doubling was 1.37 (95% confidence interval: 1.08-1.75). Adjustment for potential confounders (socio-economic position, smoking, lung function, physical activity, alcohol consumption, body mass index, waist-to-hip ratio) attenuated association to 1.20 (0.92-1.58). Further adjustment for risk factors that may be part of the same pathophysiological process linking tissue plasminogen activator to coronary heart disease (high density lipoprotein cholesterol, triglycerides, blood pressure, fasting glucose, insulin, C-reactive protein, fibrinogen) attenuated the hazard ratio to 1.05 (0.79-1.40). In older women, tissue plasminogen activator was associated with incident coronary heart disease, but does not appear to be an independent risk factor for coronary heart disease as the association was attenuated by adjustment for confounding and other metabolic and vascular risk factors.

Spousal Caregivers of Patients With Alzheimer's Disease Show Longitudinal Increases in Plasma Level of Tissue-Type Plasminogen Activator Antigen

To determine if caregivers of spouses with Alzheimer's disease demonstrate greater increase in tissue plasminogen activator (t-PA) antigen relative to noncaregiving controls. Caring for a spouse with Alzheimer's disease has been associated with increased mortality and reduced time to developing cardiovascular disease (CVD), possibly due to impaired fibrinolysis resulting from chronic stress. Annual in-home assessments of plasma t-PA antigen were collected from 165 participants (112 caregivers and 53 noncaregivers) enrolled in the University of California, San Diego Alzheimer caregiver study. Participants were married, living with their spouses, at least 55 years of age, and free of serious medical conditions (e.g., cancer). Caregivers provided in-home care for their spouse with Alzheimer's disease at the time of enrollment. Exclusion criteria included taking anticoagulant medication or evidenced severe hypertension (>200/120 mm Hg). Mixed (random effects) regression was used to assess slopes for t-PA antigen over the study period at the same time controlling for medical and demographic characteristics associated with t-PA antigen. Caregivers demonstrated significantly greater increases in t-PA antigen over the 5-year study period compared with noncaregiving controls (p = .02), even when controlling for body mass index, mean blood pressure, age, gender, and use of CVD medication. The accelerated rate of developing a prothrombotic environment including elevated t-PA antigen may provide one mechanism by which caregiving is associated with greater morbidity and mortality and the development of CVD.

A 24-week, multicenter, randomized, double-blind, placebo-controlled, parallel-group study of the efficacy and tolerability of combination therapy with rosiglitazone and sulfonylurea in african american and hispanic american patients with type 2 diabetes inadequately controlled with sulfonylurea monotherapy

Background: Type 2 diabetes mellitus is twice as prevalent in African Americans and Hispanic Americans as in non-Hispanic whites. However, the effectiveness and safety profile of rosiglitazone maleate used as combination therapy with sulfonylureas in the management of diabetes and its effect on cardiovascular disease (CVD) biomarkers/parameters have not been studied in these populations. Objective: The purpose of this study was to determine the efficacy and tolerability of the addition of rosiglitazone to a regimen of glyburide once daily in African American and Hispanic American patients with type 2 diabetes previously inadequately controlled with sulfonylurea monotherapy. Methods: This randomized, double-blind, placebo-controlled, parallel-group study was conducted at 38 centers in the United States. Eligible patients were aged ≤21 years, had type 2 diabetes, a fasting plasma glucose (FPG) level ≥140 mg/dL, and a glycosylated hemoglobin (HbA 1c) value ≥7.5%, and had been treated with sulfonylurea monotherapy for at least 2 months before screening. Patients were assigned to receive treatment with glyburide 10 or 20 mg/d plus rosiglitazone 8 mg (GLY+RSG) or placebo (GLY+PBO) PO (tablets) QD for 24 weeks. The primary efficacy end point was the change from baseline in HbA 1c after 24 weeks of treatment. Secondary end points included change in FPG; proportion of patients achieving HbA 1c targets (<7.0% and <6.5%); and changes in biomarkers for CVD risk, including C-reactive protein (CRP), plasminogen activator inhibitor (PAI)-I activity, fibrinogen, tissue plasminogen activator (tPA) antigen, von Willebrand factor (vWF), soluble vascular cell adhesion molecule (sVCAM), lipoprotein-associated phospholipase A 2 activity, and urinary albumin/creatinine ratio (UACR). Tolerability was assessed using physical examination, including vital-sign measurement, clinical laboratory tests, and adverse event (AE) reports collected at each study visit. Results: A total of 245 patients (101 African American and 144 Hispanic American) were enrolled. Demographic characteristics were comparable between the GLY+RSG and GLY+PBO groups: mean (SD) age (52 [11.9] vs 53 [10.4] years), HbA 1c (9.2% [1.3%] vs 9.4% [1.4%]), sex (men/women, 45.3%/54.7% vs 48.3%/51.7%), race (African American/Hispanic American, 43.6%/56.4% vs 37.9%/62.1%), and mean (SD) weight (86.3 [18.8] vs 88.3 [19.4] kg). In the overall study population, treatment with GLY+RSG was associated with a significantly greater mean (95% CI) reduction from baseline in HbA 1c compared with GLY+PBO (between-group Δ, −1.4% [−1.7% to −1.1%]; P < 0.001). When assessed by ethnicity, HbA 1c values were significantly reduced with GLY+RSG compared with GLY+PBO in African American patients (between-group Δ, -1.4%) and in Hispanic American patients (between-group Δ, −1.5%) (both, P < 0.001), as were FPG levels (between-group Δs, −3.1 mmol/L [57 mg/dL] and −3.8 mmol/L [−69 mg/dL], respectively; both, P < 0.001). With GLY+RSG, 9151 (17.6%) African American patients and 17/66 (25.8%) Hispanic American patients achieved HbA 1c <7%, compared with 2/44 (4.5%) and 1/72 (1.4%) patients, respectively, who achieved this goal with GLY+PBO. Homeostasis model assessment estimates of insulin sensitivity and β-cell function were significantly improved with GLY+RSG compared with GIX+PBO (between-group Δs, 29.3% and 78.4%, respectively; both, P < 0.001). With regard to CVD biomarkers, there were potentially deleterious changes compared with baseline in the GLY+PBO group for CRP (+29.4%; P = 0.042), PAI-1 activity (+27.0%; P = 0.006), fibrinogen (+15.7%; P = 0.007), and sVCAM (+7.0%; P = 0.035), whereas there were no significant increases in these factors in the GLY+RSG group. In the GLY+RSG group, there were significant improvements in tPA (−17.8%; P < 0.001), vWF (−11.3%; P = 0.019), and UACR (−17.2%; P = 0.028) over 24 weeks' treatment, whereas there were no significant changes in any of these factors in the GLY+PBO group. As a result, significant treatment effects were observed for CRP (−29.2%; P = 0.019), tPA (−18.4%; P < 0.001), vWF (−12.9%; P < 0.015), and UACR (−26.7%; P = 0.006) with GLY+RSG compared with GLY+PBO. The most frequently reported AEs with GLY+RSG were edema and weight increase (both 121121 [9.9%] patients) and with GLY+PBO were upper respiratory tract infection (18/124 [14.5%] patients). AEs were reported in 83/121 (68.6%) patients in the GLY+RSG group, of which 6/121 (5.0%) were assessed as severe, compared with 70/124 ( 56.5 % ) patients who received GLY+PBO, of which 31124 (2.4%) were assessed as severe. Conclusion: Add-on rosiglitazone administered for 24 weeks was effective and well tolerated in these African American and Hispanic American patients with type 2 diabetes previously inadequately controlled on sulfonylurea monotherapy.

Discordant Hemodynamic and Fibrinolytic Adaptations Following a 6‐Week Cardiac Rehabilitation Program

The present study evaluated changes in hemodynamics and fibrinolysis during 6 weeks of participation in an exercise-based cardiac rehabilitation program. Fourteen patients trained for 3 days per week for 6 weeks using American College of Sports Medicine guidelines for intensity and duration. Blood samples were taken at baseline and after 3 and 6 weeks of participation and analyzed for tissue plasminogen activator (t-PA) activity and antigen, plasminogen activator inhibitor-1 (PAI-1) activity and antigen, and relative quantification of t-PA and PAI-1 RNA. Data were analyzed using repeated measures analysis of variance. Training elicited significant decreases in submaximal exercise heart rate and systolic blood pressure and resting systolic blood pressure (p<.05). There were no significant changes in plasma concentrations of t-PA or PAI-1, and no change was observed in t-PA or PAI-1 gene expression. The present findings suggest that favorable hemodynamic adaptations may occur after only 6 weeks of exercise-based cardiac rehabilitation, but longer training periods may be needed to elicit positive hemostatic adaptations.

Association between heart rate recovery after exercise testing and plasminogen activator inhibitor 1, tissue plasminogen activator, and fibrinogen in apparently healthy men

Objective Delayed heart rate recovery (HRR) following exercise testing, an indicator of decreased autonomic nervous system activity, is associated with an increased risk of cardiovascular events. Because autonomic nervous system function may be associated with fibrinolytic factors, we tested the hypothesis that delayed HRR is associated with elevated fibrinolytic factors. Methods In 547 (mean age 49.4 ± 6.9 years) healthy men who underwent exercise treadmill testing and fasting blood analysis for fibrinolytic factors, we calculated HRR as the difference between maximum heart rate during the test and heart rate 1 min after cessation of exercise. Results HRR was inversely correlated with plasminogen activator inhibitor 1 (PAI-1) activity ( r = −0.23, p < 0.001), tissue plasminogen activator (t-PA) antigen ( r = −0.19, p < 0.001), and fibrinogen ( r = −0.11, p < 0.05). Men in the lowest quartile of HRR had significantly higher PAI-1, t-PA, and fibrinogen than men in the highest quartile of HRR (all p trend <0.001). HRR was independently associated with PAI-1 ( β = −0.12, p < 0.01) and fibrinogen ( β = −0.09, p = 0.04) but not t-PA ( β = −0.06, p = 0.29) in a multiple regression analysis. Conclusions These results suggest that delayed HRR after exercise testing is associated with elevated fibrinolytic factors in cross-section. The presence of other CHD risk factors does not explain this association, but further research is needed to identify the direction of the association.

Hemostatic and thrombotic markers in patients with hemoglobin E/β‐thalassemia disease

Increased frequency of thrombosis has been observed in patients with hemoglobin E/beta-thalassemia (Hb E/beta-thal) disease, particularly those who have previously been splenectomized. We compared various hemostatic and thrombotic markers in blood from 15 Hb E/beta-thal patients who were not splenectomized (NS), 15 who had been splenectomized (S), and 15 normal controls (NC). Levels of plasma thrombin-antithrombin, beta2 thromboglobulin, C-reactive protein, tissue plasminogen activator antigen were significantly higher in the S group than in either the NS or the NC groups, and levels of prothrombin fragment 1.2 were significantly higher in the S than in the NC group. Levels of plasminogen activator inhibitor-1 antigen were significantly higher in the S than in the NS group. Levels of protein C, protein S, antithrombin, and fibrinogen were significantly lower in the S and NS groups than in the NC group. Plasma lipoprotein(a) levels in the S and NS groups were not statistically different from NC. Our findings indicated that there is evidence of chronic low-grade coagulation and platelet activation, chronic low-grade inflammation, endothelial cell injury, impaired fibrinolysis, and decreased naturally occurring anticoagulants in splenectomized Hb E/beta-thal patients. These changes may account for the increased risk of thrombosis in these patients.

Dynamic changes and significance of antithrombin and fibrinolytic function in advanced lung cancer patients during chemotherapy

The prethrombotic state can be observed in advanced lung cancer patients. The aim of this study is to determine the dynamic changes and significance of antithrombin and fibrinolytic function in advanced lung cancer patients during chemotherapy. Antithrombin activity (AT:A), fibrinogen (FIB), D-dimer (D-D), plasminogen activity (PLG), tissue plasminogen activator antigen (t-PA:Ag) and plasminogen activator inhibitor-1 antigen (PAI-1:Ag) were measured in 33 advanced lung can-cer patients before and after chemotherapy, and 30 healthy people as controls. Before chemotherapy, lung cancer patients had significantly lower AT:A (P < 0.01) and higher D-D, PLG:A, PAI-1:Ag and FIB (P < 0.01) than those of controls. There was no significant difference in t-PA:Ag between lung cancer patients and controls (P > 0.05). During the chemotherapy, AT:A, D-D and t-PA:Ag of lung can-cer patients remarkably decreased (P < 0.01), and PLG:A, PAI-1:Ag and FIB remarkably increased (P < 0.01) compared to those before chemotherapy. Chemotherapy may enhance the prethrombotic state in advanced lung cancer patients. Dynamic observation of antithrombin and fibrinolytic function during chemotherapy might be useful for preventing pulmonary hemorrhage and pulmonary infarct and estimating prognosis of those patients.

The effects of nebivolol on fibrinolytic parameters in mild and moderate hypertensive patients

The aim of the present study was to investigate the effects of nebivolol (5 mg daily) on plasma levels of hemostatic and fibrinolytic endothelial function markers in mild or moderate hypertensive patients. Thirty-five (22 female, 13 male; mean +/- SD 54.7 +/- 11.3 years of age) mild and moderate hypertensive patients were included the study. The mean systolic blood pressure [BP] was 160 mmHg (range 150 mmHg to 165 mmHg) and the mean diastolic BP was 100 mmHg (range 90 mmHg to 100 mmHg). Plasma tissue plasminogen activator antigen (tPA-Ag), plasminogen activator inhibitor type 1 antigen (PAI-1-Ag), PAI-1 activity, tPA-Ag/PAI-1-Ag index, fibrinogen and euglobulin lysis time were determined before and after two months of therapy. tPA-Ag and PAI-Ag levels were measured by ELISA. After this period, treatment with nebivolol (5 mg/day) in all patients was associated with a significant decrease in systolic BP and diastolic BP (P<0.001 for each), heart rate (P<0.01), fibrinogen (P<0.005) and euglobulin lysis time (P<0.01). The tPA-Ag and tPA-Ag/PAI-1-Ag index levels were increased significantly (P<0.001 for each) in all patients, but the PAI-1-Ag (P>0.05) and PAI-1 activity (P>0.05) did not show significant change. In the present study, there was no correlation between decreases in arterial BP and decreases in fibrinolytic parameters (P>0.05), but there was a positive, statistically significant correlation between fibrinogen and body mass index (P<0.001). The results indicated that, compared with no treatment, a two-month treatment trial with nebivolol was associated with a more favourable modification of hemostatic and fibrinolytic status in addition to antihypertensive effects.