Effects of gemfibrozil and ciprofibrate on plasma levels of tissue-type plasminogen activator, plasminogen activator inhibitor-1 and fibrinogen in hyperlipidaemic patients. High plasminogen activator inhibitor and tissue plasminogen activator levels in plasma precede a first acute myocardial infarction in both men and women: evidence for the fibrinolytic system as an independent primary risk factor. A low-glycemic-index diet reduces plasma plasminogen activator inhibitor-1 activity, but not tissue inhibitor of proteinases-1 or plasminogen activator inhibitor-1 protein, in overweight women. Effect of simvastatin and fenofibrate on endothelium in Type 2 diabetes. Plasminogen activator inhibitor type 1 gene polymorphisms and haplotypes are associated with plasma plasminogen activator inhibitor type 1 levels but not with myocardial infarction or stroke. The effect of oral simvastatin on fibrinolytic activity after colorectal surgery-a pilot study. Fibrinolytic proteins and progression of coronary artery disease in relation to gemfibrozil therapy. Hyaluronan levels during laparoscopic versus open colonic resections Fibrin D-dimer, tissue plasminogen activator, plasminogen activator inhibitor, and the risk of major ischaemic heart disease in the Caerphilly Study. Interactions between fibrinolysis, lipoproteins and leptin related to a first myocardial infarction Supplementation with L-arginine favorably influences plasminogen activator inhibitor type 1 concentration in obese patients. A randomized, double blind trial Simvastatin inhibits tissue factor and plasminogen activator inhibitor-1 expression of glomerular mesangial cells in hypercholesterolemic rabbits. Systematic elucidation of effects of tranexamic acid on fibrinolysis and bleeding during and after cardiopulmonary bypass surgery. Effect of Atorvastatin on Haemostasis, Fibrinolysis and Inflammation in Normocholesterolaemic Patients with Coronary Artery Disease Randomized controlled trials of aprotinin in cardiac surgery: could clinical equipoise have stopped the bleeding? Comparative Effectiveness of Dipeptidylpeptidase-4 Inhibitors in Type 2 Diabetes: A Systematic Review and Mixed Treatment Comparison Effects of fluvastatin and bezafibrate combination on plasma fibrinogen, t-plasminogen activator inhibitor and C reactive protein levels in coronary artery disease patients with mixed hyperlipidaemia (FACT study). Fluvastatin Alone and in Combination Treatment. Oligofructose decreases serum lipopolysaccharide and plasminogen activator inhibitor-1 in adults with overweight/obesity. Intense nonpharmacological intervention in subjects with multiple cardiovascular risk factors: decreased fasting insulin levels but only a minor effect on plasma plasminogen activator inhibitor activity. Comparison of bezafibrate versus lovastatin for lowering plasma insulin, fibrinogen, and plasminogen activator inhibitor-1 concentrations in hyperlipemic heart transplant patients. Preeclampsia: haemostatic status and the short-term effects of methyldopa and isradipine therapy. Magnesium inhibits platelet activity--an infusion study in healthy volunteers. Insulin therapy in type 2 diabetic subjects suppresses plasminogen activator inhibitor (PAI-1) activity and proinsulin-like molecules independently of glycaemic control.
Evaluation of fibrate treatment in humans has focused primarily on its anti-lipidaemic effects . A potentially favourable haemostasis-modulating activity of fibrates has also been recognized but the data are not consistent . We sought to learn more about this variability by examining the effects of gemfibrozil and ciprofibrate on plasma levels of tissue-type plasminogen activator ( t-PA ) , plasminogen activator inhibitor-1 ( PAI-1 ) and fibrinogen in primary hyperlipidaemic patients after six and twelve weeks of treatment using different assay systems for PAI-1 and fibrinogen . Although both fibrates effectively lowered triglyceride and cholesterol levels , no effect on the elevated baseline antigen levels of t-PA and PAI-1 was observed after fibrate treatment . However , both fibrates influenced plasma fibrinogen levels , albeit in a different way . Fibrinogen antigen levels were elevated by 17.6 % ( p < 0.05 ) and 24.3 % ( p < 0.001 ) with gemfibrozil after six and twelve weeks , respectively , whereas with ciprofibrate there was no effect . Using a Clauss functional assay with either a mechanical end point or a turbidity-based end point , no significant change in fibrinogen levels was seen after six weeks of gemfibrozil treatment . However , after twelve weeks , gemfibrozil enhanced functional fibrinogen levels by 7.2 % ( p < 0.05 ) as assessed by the Clauss mechanical assay , but decreased functional fibrinogen levels by 12.5 % ( p < 0.0001 ) when a Clauss assay based on turbidity was used . After six or twelve weeks of ciprofibrate treatment , functional fibrinogen levels were decreased by 10.1 % ( p < 0.001 ) and 10.5 % ( p < 0.0001 ) , respectively on the basis of Clauss mechanical and by 14.2 % ( p < 0.001 ) and 28.2 % ( p < 0.0001 ) , respectively with the Clauss turbidimetric assay . A remarkable and consistent finding with both fibrates was the decrease in functionality of fibrinogen as assessed by the ratio of functional fibrinogen ( determined by either of the two Clauss assays ) to fibrinogen antigen . Taken together , our results indicate that at least part of the variability in the effects of fibrates on haemostatic parameters can be explained by intrinsic differences between various fibrates , by differences in treatment period and /or by the different outcomes of various assay systems . Interestingly , the two fibrates tested both reduced the functionality of fibrinogen BACKGROUND In patients with established ischemic heart disease , prospect i ve cohort studies have indicated that plasminogen activator inhibitor ( PAI-1 ) , the inhibitor of the fibrinolytic system , may predict cardiovascular events . So far , there have been no primary prospect i ve studies of PAI-1 . METHODS AND RESULTS The aim of the present study was to test whether plasma levels of PAI-1 , tissue-type plasminogen activator ( tPA ) , von Willebr and factor ( vWF ) , and thrombomodulin ( TM )  could predict the occurrence of a first acute myocardial infa rct ion ( AMI ) in a population with high prevalence of coronary heart disease by use of a prospect i ve nested case-control design . Mass concentrations of PAI-1 and tPA  were significantly higher for the 78 subjects who developed a first AMI compared with the 156 references matched for age , sex , and sampling time ; for tPA , this increase was independent of smoking habits , body mass index , hypertension , diabetes , cholesterol , and apolipoprotein A-I. The ratio of quartile 4 to 1 for tPA was 5.9 for a patient to develop a first AMI . The association between tPA and AMI was seen in both men and women .  Increased levels of vWF were associated with AMI in a univariate analysis . High levels of TM were associated with AMI in women but not in men . CONCLUSIONS The plasma levels of PAI-1 , tPA , and vWF are associated with subsequent development of a first AMI ; for PAI-1 and tPA , this relation was found in both men and women . For tPA but not for PAI-1 and vWF , this association is independent of established risk factors BACKGROUND The development of obesity has been suggested to involve plasminogen activator inhibitor-1 ( PAI-1 ) and tissue inhibitor of proteinases-1 ( TIMP-1 ) . Plasma PAI-1 is elevated in obesity . A low-glycemic-index ( LGI ) diet may have a beneficial effect on obesity through a decrease in plasma PAI-1 , but whether it affects plasma TIMP-1 in healthy humans has not been studied . OBJECTIVE We investigated whether a 10-wk intake of an LGI or a high-glycemic-index ( HGI ) , high-carbohydrate , low-fat , ad libitum diet is associated with decreases in plasma PAI-1 and TIMP-1 concentrations in overweight women . DESIGN Forty-four overweight women [ body mass index ( BMI ; in kg/m2 ) : 27.5+/-0.23 ] were r and omly assigned to consume an HGI or an LGI diet for 10 wk . A subgroup of 29 women was assigned to participate in an additional 4-h meal test on the last day of the 10-wk intervention . RESULTS PAI-1 activity decreased after 10 wk of the LGI diet and was significantly different between groups . Changes in PAI-1 antigen followed the same trend , but no significant difference was observed between groups . No difference in plasma TIMP-1 concentrations was observed between groups . PAI-1 and TIMP-1 concentrations after the 4-h meal test were not significantly different between groups . CONCLUSION An LGI diet reduces fasting plasma PAI-1 activity and therefore may be useful for diminishing the adverse cardiovascular effects of obesity . This trial was registered at clinical trials.gov as NCT00324090 Statins and fibrates influence endothelial activity and consequently atherogenesis but the mechanisms are not well understood . Twenty Type 2 diabetic patients with dyslipidemia were treated 3 months with simvastatin ( 20 mg daily ) and then 3 months with fenofibrate ( 200 mg daily ) with 2 months of wash-out between the two treatments . Laboratory parameters of oxidative stress , fibrinolysis and endothelial function were evaluated before and at the end of each treatment period . The significant decrease in serum total and LDL-cholesterol concentrations ( P<0.0001 ) caused by simvastatin was associated with an increase in serum N-acetyl-beta-glucosaminidase activity ( P<0.001 ) , ascorbic acid ( P<0.001 ) , plasminogen activator inhibitor ( PAI-1 ) ( P<0.01 ) , vonWillebr and factor ( P<0.05 ) , E-selectin ( P<0.01 ) and vascular endothelial growth factor ( P<0.05 ) concentrations and with a decrease in plasma glutathione ( P<0.01 ) levels . Fenofibrate caused a significant decrease in serum triglyceride concentration ( P<0.0001 ) associated with a decrease in plasma malondialdehyde ( P<0.001 ) and an increase in plasma PAI-1 ( P<0.05 ) and P-selectin ( P<0.05 ) concentrations . We conclude that simvastatin and fenofibrate interact , by different mechanisms , with oxidative stress , a key factor in the modification of fibrinolysis and endothelial function in Type 2 diabetes BACKGROUND The 4 G allele in the promoter region of the plasminogen activator inhibitor type 1 ( PAI-1 ) gene is associated with higher plasma PAI-1 levels and activity , but its association with cardiovascular diseases is unclear . We investigated the association of polymorphisms and common haplotypes of the PAI-1 gene with plasma PAI-1 levels , as well as the risk of myocardial infa rct ion and stroke . METHODS AND RESULTS This study is a prospect i ve analysis of 2995 community-based participants ( 41 % blacks and 51 % women ) aged 70 to 79 years old in the Health , Aging , and Body Composition Study . From 1997/1998 to 2001 , 177 myocardial infa rct ion events and 101 stroke events were identified . In addition to the 4G/5 G polymorphism , 2 potential functional variants and other 4 haplotype-tagging variants were genotyped . In general linear models , the 4 G allele was associated with higher PAI-1 levels after adjusting for age , sex , race , and site ( 26 , 29 , and 32 ng/mL for 5G/5 G , 4G/5 G , and 4G/4 G , respectively ; P for trend < .0001 ) , but none of the other 6 polymorphisms was associated with PAI-1 levels . Haplotype analysis produced similar results . However , in Cox proportional hazard models , neither the polymorphisms nor the common haplotypes of the PAI-1 gene was associated with the risk of either myocardial infa rct ion or stroke . CONCLUSIONS The 4 G allele is associated with higher PAI-1 levels , but this study does not support an association of the PAI gene polymorphisms with the risk of either myocardial infa rct ion or stroke BACKGROUND Studies conducted in animal models have shown that statins ( 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors ) reduce adhesion formation by upregulating fibrinolysis . The aim of this study was to determine the effect of orally administered statins on the promoters and inhibitors of the fibrinolytic pathway . METHODS In a previously described double-blinded clinical trial , 144 patients undergoing elective colorectal resection , or reversal of Hartmann 's procedure were r and omized to receive 40 mg once daily oral simvastatin 3 - 7 d before surgery or placebo . For the purpose s of the present study , peritoneal drain fluid was collected postoperatively from patients to measure active tissue plasminogen activator ( tPA ) , tissue plasminogen activator total antigen , active plasminogen activator inhibitor-1 ( PAI-1 ) , plasminogen activator inhibitor total antigen ( PAI-1TA ) , plasminogen activator inhibitor-1 and tissue plasminogen activator complex ( PAI-1/tPA ) . These were analyzed using ELISA . The number of hospitalizations and complications related to small bowel obstruction ( SBO ) were recorded at 2 y after surgery . RESULTS A total of 95 patients ( 72 % ) had sufficient peritoneal drain fluid suitable for ELISA analysis . Of them , 46 patients ( 48 % ) were from the oral simvastatin group . Mean tPA and tPA total antigen concentrations in peritoneal fluid were similar between the two groups . Mean PAI-1 and PAI-1 TA concentrations in the statin and placebo group were also similar . Mean PAI-1/tPA complex concentration was similar between the two groups . The number of hospitalizations from SBOs were 5 and 4 in the statin and placebo groups respectively ( P = 0.46 ) . The overall mortality at 2-year post-surgery was similar between the two groups ( P = 0.59 ) . CONCLUSIONS In this pilot study involving humans , oral simvastatin had no measured effect on the peritoneal fibrinolytic pathway in the first 24 h after colorectal surgery . Analysis of clinical outcomes also showed that oral simvastatin did not reduce hospitalizations for SBO in the 2 y after surgery . Further studies may be useful to evaluate whether fibrinolytic pathways beyond 24 h are altered after systemic administration of statins and to evaluate the use of higher doses of statins , perhaps used intraperitoneally rather than systemically Impaired fibrinolytic function , mainly due to increased plasma plasminogen activator inhibitor-1 ( PAI-1 ) activity , is common in patients with manifest coronary artery disease ( CAD ) and a predictor of recurrent cardiovascular events . We investigated the relationships of plasma tissue-type plasminogen activator ( tPA ) and PAI-1 antigen levels , plasma PAI-1 activity and PAI 4/5-guanosine ( 4G/5 G ) genotype to CAD progression in 203 middle-aged men participating in the Lopid Coronary Angiography Trial ( LOCAT ) . A higher tPA antigen concentration , whether baseline or on-trial , was associated with a more severe global angiographic response ( p < 0.05 ) , an association mainly accounted for by progression of diffuse lesions in graft-affected segments ( change in per-patient means of average diameters of segments haemodynamically related to bypass grafts ) . Plasma PAI-1 activity and mass concentration and 4G/5 G PAI-1 genotype were unrelated to angiographic outcome measurements . tPA and PAI-1 antigen increased significantly in the gemfibrozil group ( + 11.3 % and + 16.4 % , respectively , p < 0.001 ) , whereas there was no treatment effect on PAI-1 activity ( median change 0.0 % ) . It is concluded that fibrinolytic function does not substantially influence progression of CAD as assessed by angiography in middle-aged men . Furthermore , pronounced long-term lowering of serum triglycerides by gemfibrozil treatment does not significantly affect the plasma PAI-1 activity level but increases the plasma tPA and PAI-1 antigen concentrations Background Plasma hyaluronan binds to fibrinogen , affecting intravascular fibrin polymerization and fibrin clot formation . It has been hypothesized that alterations in fibrin clot formation influence the risk of thromboembolism in those undergoing surgery . The aim of this study is to quantify the intravascular components , especially plasma hyaluronan levels , in laparoscopic and  conventional colorectal resections that contribute to thromboembolism formation . Methods Prospect i ve cohort analysis of consecutive patients which were participating in the prospect i ve r and omized multi-center trial Lapkon II comparing the long-term effects of laparoscopic and conventional resection for colon cancer . Plasma sample s were obtained from 15 patients at the beginning and the end of laparoscopic or conventional colorectal resections .  Concentrations and activities of tissue plasminogen activator(t-PA ) , plasminogen activator inhibitor type 1(PAI-1 ) , t-PA/PAI complex , fibrinogen , d-dimers and hyaluronan were determined by using commercial enzyme-linked immunosorbent assay ( ELISA ) kits . Results No differences in age , sex and type of resection between the laparoscopic and conventional-surgery groups were observed . Laparoscopic procedures lasted longer ( p < 0.05 ) . Concentration and activities of t-PA , PAI-1 , t-PA/PAI complex , fibrinogen and d-dimers did not vary between the two groups . Plasma hyaluronan decreased from 28.6 to 17.9 IU/ml ( p < 0.05 ) during laparoscopic compared to conventional procedures . Plasma hyaluronan levels were significantly different at the end of operation between the two groups ( p < 0.05 ) . Conclusions Plasma hyaluronan levels were decreased in patients undergoing laparoscopic colorectal resections  , compared to those undergoing conventional procedures . Therefore , interactions between plasma hyaluronan and fibrinogen may be lower , with a sequential decrease in fibrin polymerization , and a possibly reduced risk of deep venous thrombosis Plasma levels of fibrin D-dimer , tissue plasminogen activator ( tPA ) and  plasminogen activator inhibitor ( PAI ) have been associated with ischaemic heart disease ( IHD ) . However their associations with incident IHD in sample s of the general population are not established .  D-dimer antigen , tPA antigen and PAI activity  were measured in stored , fasting plasma sample s from 1,998 men aged 45 - 65 examined between 1984 and 1988 , during the first re-examination of the Caerphilly Study cohort . These variables were related to major IHD events ( myocardial infa rct ion or IHD death ) which occurred in 129 men during a follow-up period which averaged 61 months . Mean fibrin D-dimer was higher in men who developed IHD events ( 90 vs. 71 ng/ml ; age-adjusted logarithmic mean difference 0.21 ; 95 % CI 0.11 , 0.30 ; p < 0.0001 ) . This association remained after adjusting for baseline IHD and for other risk factors including fibrinogen : the adjusted relative odds of IHD in the highest fifth of D-dimer were 3.5 ( 95 % CI 1.8 , 6.9 ; p = 0.0003 ) . Mean tPA antigen was also higher in men who developed IHD ( 12.6 vs. 11.6 ng/ml ; mean difference 0.9 ; 95 % CI 0.2 , 1.7 ; p = 0.02 ) ; however this difference largely disappeared after adjusting for other risk factors . PAI activity was not associated with risk of IHD Background The summarized importance of haemostatic and metabolic variables ( insulin , lipids including lipoprotein ( a ) [ Lp(a ) ] and leptin ) in predicting first  myocardial infa rct  ion , as well as possible interactions among these variables , have not been reported . Design A prospect i ve case-control study nested within the Northern Sweden Health and Disease Cohort . Methods Sixty-two men diagnosed with a first myocardial infa rct ion were sex- and age-matched with 124 controls .  Conditional logistic regression was conducted including established risk factors , plasma levels of  plasminogen activator inhibitor-1 ( PAI-1 ) , tissue plasminogen activator ( tPA ) mass concentration , von Willebr and factor , insulin , proinsulin , specific insulin , apolipoprotein A-I ( apo A-I ) , Lp(a ) , and leptin . Interaction analysis was also performed for tPA , apo A-I , Lp(a ) , leptin and proinsulin . Results Smoking , low plasma levels of apo A-I and high plasma levels of cholesterol , Lp(a ) , tPA , PAI-1 , proinsulin and leptin were associated with myocardial infa rct ion in univariate conditional logistic regression analysis . High tPA [ odds ratio ( OR ) , 21.3 ; 95 % confidence interval ( CI ) , 2.04 - 222 ] and Lp(a ) ( OR , 7.21 ; 95 % CI , 1.31 - 39.8 ) and low apo A-I ( OR , 0.15 ; 95 % CI , 0.02 - 0.93 ) remained significant risk determinants in multivariate analysis with smoking habits , body mass index , hypertension , cholesterol , and diabetes included as covariates . There were non-significant synergic interactions between high Lp(a ) and leptin and tPA , respectively , and between high Lp(a ) and low apo A-I. Conclusion Plasma levels of tPA , Lp(a ) , and apo A-I are independently associated with subsequent development of a first myocardial infa rct ion in men Background : Elevated plasminogen activator inhibitor type 1 ( PAI 1 ) plays an important role in the pathogenesis of excess blood coagulability in obese patients .  L-arginine supplementation has shown to be associated with enhanced cardiovascular and metabolic health . The aim of the study was to assess the effect of L-arginine supplementation on PAI 1 concentration and to evaluate the relation to changes in nitric oxide ( NO ) plasma level , insulin sensitivity ( M value ) , and total antioxidant status ( TAS ) in obese patients . Material /subjects and methods : A r and omized , double-blind , placebo-controlled study was conducted from March 2010 to June 2011 . Eighty-eight obese patients were r and omly assigned to receive either 9 g of L-arginine or placebo daily for 6 months . At baseline and after 6 months , selected anthropometrical measurements and blood biochemical analyses were performed , and PAI 1 , NO , TAS levels were assessed . Insulin sensitivity was evaluated using the hyperinsulinemic euglycemic clamp technique . Results : We found that 6-month L-arginine supplementation result ed in significant decrease of PAI 1 . Significant increase of NO , TAS , and insulin sensitivity level were noticed . In a group of patients treated with L-arginine , negative correlation between a change of insulin sensitivity value and a change of PAI 1 concentration was found . Conclusions : The present findings demonstrate favorable influence of L-arginine supplementation on PAI 1 concentration in obese patients . Beneficial influence is related to insulin sensitivity improvement . The potential therapeutic role of L-arginine administration in patients with obesity needs further investigation Tissue factor ( TF ) and plasminogen activator inhibitor-1 ( PAI-1 ) activity and /or expression are upregulated in hypercholesterolemia . Despite extensive research on anti-thrombotic effect of statins , little is known about their effects on TF and PAI-1 expression in glomerular mesangial cells under hypercholesterolemic condition . Male rabbits were fed on either normal or high-cholesterol diet for 8 weeks . Then cholesterol-fed rabbits were r and omly assigned to simvastatin or starch . At the end of 12 weeks , glomerular mesangial cells were collected . The concentrations of TF and PAI-1 mRNA were detected by RT-PCR . The plasma activities of TF and PAI-1 were determined with enzyme linked immunosorbent assay ( ELISA ) and chromogenic substrate method , respectively . The atherogenic diet caused a consistent increase in serum concentrations of total cholesterol ( TC ) and serum triglyceride ( TG ) ( p < 0.05 ) , increased TF and PAI-1 mRNA expression in glomerular mesangial cells and plasma activities as compared to the normal diet ( p < 0.01 ) . Four-week simvastatin treatment result ed in significant decrease of mesangial TF and PAI-1 mRNA ( p < 0.01 ) , and also of the plasma activities of TF ( p < 0.05 ) and PAI-1 ( p < 0.01 ) . These results suggest that simvastatin might protect kidney from the formation of microthrombus under hypercholesterolemic condition and might be a possible pathogenesis of obesity-related glomerulopathy The aim of this study was to systematic ally eluci date the effects of tranexamic acid on fibrinolysis and bleeding during and after  cardiopulmonary bypass ( CPB ) surgery . Twenty-two patients undergoing CPB surgery were r and omized to receive 100 mg/kg tranexamic acid or an equal volume of saline after anesthesia induction and prior to skin incision .  Plasma levels of tissue plasminogen activator ( t-PA ) antigen and activity , crosslinked fibrin degradation products ( D-dimer ) , alpha2-antiplasmin-plasmin complex , and plasminogen activator inhibitor-1 ( PAI-1 ) antigen were measured . Blood sample s were obtained after induction of anesthesia , before , during , and after CPB , at the end of surgery , and the next morning after surgery . Intraoperative and postoperative blood loss during 24 h after surgery was recorded . Patients ' demographics were similar between the two groups . No patients suffered from thrombotic complications after surgery . In the tranexamic acid group , fibrinolytic activity and secondary fibrinolysis as measured by t-PA activity and D-dimer were markedly suppressed during CPB surgery ( P=.042 and P=.015 , respectively ) . Decreased fibrinolytic activity and fibrinolysis were accompanied by reduction of perioperative bleeding in the tranexamic acid group . We could also find a good positive correlation between the peak levels of t-PA activity and D-dimer ( r(2)=.4203 , P=.0011 ) . No differences in the t-PA antigen , PAI-1 antigen release , and plasmin inhibition by alpha2-antiplasmin were apparent between the two groups . In a r and omized , prospect i ve trial of patients undergoing CPB surgery  , we demonstrated that the synthetic antifibrinolytic drug tranexamic acid effectively suppresses fibrinolysis by inhibiting t-PA and plasmin activity with clear reduction of perioperative blood loss . While tranexamic acid had no effects on the other important fibrinolytic inhibitors like PAI-1 and alpha2-antiplasmin Abstract Background : Treatment with HMG-CoA reductase inhibitors ( statins ) reduces the morbidity and mortality of coronary artery disease ( CAD ) . In addition to their lipid-lowering actions , pleiotropic effects of statins have been demonstrated . Objective : The aim of the present study was to assess if atorvastatin therapy has an impact on haemostasis , fibrinolysis and inflammation in normocholesterolaemic patients with CAD . Methods : Fifty-four patients with CAD who had received atorvastatin treatment for at least 8 weeks ( mean dosage 30 mg/day ) and 54 patients with CAD who had not received atorvastatin therapy were selected from a larger prospect i ve , r and omized , double-blind study for inclusion in this post hoc analysis . Patients were matched by their total cholesterol levels . All patients were normocholesterolaemic . Results : In the atorvastatin-treated patients significantly lower plasma levels of thrombin-antithrombin complexes ( p<0.05 ) , plasminogen activator inhibitor-1 activity ( PAI-1 ) [ p<0.05 ] , soluble vascular cell adhesion molecule-1 ( p<0.05 ) , soluble platelet selectin ( p < 0.05 ) and high-sensitivity C-reactive protein ( p < 0.05 ) were measured compared with patients not on atorvastatin therapy . Additionally , a strong trend towards lower soluble intercellular adhesion molecule-1 plasma levels was detected in patients treated with atorvastatin . No differences were found in tissue-type plasminogen activator antigen , plasmin-plasmin inhibitor complexes , fibrinogen , D-dimer and activated factor XII values . Conclusion : Atorvastatin appears to have an effect on coagulation activation , fibrinolysis and inflammation in patients with CAD . Reduction in PAI-1 and reduced thrombin formation may have an impact on cardiovascular morbidity and mortality in patients with CAD Background Aprotinin is a serine protease inhibitor used to limit perioperative bleeding and reduce the need for donated blood transfusions during cardiac surgery . R and omized controlled trials of aprotinin evaluating its effect on the outcome of perioperative transfusion have been published since 1987 , and systematic review s were conducted in 1992 and 1997 . Methods A systematic search was conducted for all RCTs of aprotinin  that used placebo controls or were open-label with no active control treatment . Data collected included the primary outcome , objective of each study , whether a systematic review was cited or conducted as part of the background and /or rationale for the study and the number of previously published RCTs cited . Cumulative meta-analyses were performed . Results Sixty-four r and omized , controlled trials of aprotinin were found , conducted between 1987 and 2002 , reporting an endpoint of perioperative transfusion .  Median trial size was 64 subjects , with a range of 20 to 1784 . A cumulative meta- analysis indicated that aprotinin greatly decreased the need for perioperative transfusion , stabilizing at an odds ratio of 0.25 ( p , 10 2 6 ) by the 12th study , published in June of 1992 . The upper limit of the confidence interval never exceeded 0.65 and results were similar in all subgroups . Citation of previous RCTs was extremely low , with a median of 20 % of prior trials cited . Only 7 of 44 ( 15 % ) of subsequent reports referenced the largest trial ( N 1/4 1784 ) , which was 28 times larger than the median trial size . Conclusions This study demonstrates that investigators evaluating aprotinin were not adequately citing previous research , result ing in a large number of RCTs being conducted to address efficacy questions that prior trials had already definitively answered . Institutional review boards and journals could reduce the number of redundant trials by requiring investigators to conduct adequate search es for prior evidence and conducting systematic review Objective To compare the safety and efficacy of the dipeptidylpeptidase-4 ( DPP-4 ) inhibitors in patients with type 2 diabetes and inadequate glycemic control . Design Systematic review of r and omized controlled trials ( RCTs ) , health economic evaluation studies , systematic review s , and meta-analyses , followed by primary Bayesian mixed treatment comparison meta-analyses ( MTCs ) , and secondary frequentist direct-comparison meta-analyses using a r and om-effects model . Outcomes were reported as weighted mean change from baseline , or odds ratio ( OR ) with 95 % credible interval . Data sources MEDLINE , MEDLINE In-Process , EMBASE , and BIOSIS via Dialog ProQuest ; Cochrane Central Register of Controlled Trials and Cochrane Data base of Systematic Review s via EBSCO ; four diabetes and two technical congress abstract s ; and health technology assessment organization websites . Eligibility criteria Patients with type 2 diabetes and inadequate glycemic control receiving any pharmacological anti-diabetic treatment . Data extraction and analysis Title/ abstract s were review ed for eligibility , followed by full-text review of publications remaining after first pass . A three-person team filtered articles and an independent review er checked a r and om selection ( 10 % ) of filtered articles . Data extraction and quality assessment of studies were also independently review ed . Five DPP-4 inhibitors ( alogliptin , linagliptin , saxagliptin , sitagliptin , and vildagliptin ) were compared via meta- analysis ( where data were available ) as monotherapy , dual therapy ( plus metformin , sulfonylurea , pioglitazone , or insulin ) , and triple therapy ( plus metformin/sulfonylurea ) . Results The review identified 6,601 articles ; 163 met inclusion criteria and 85 publications from 83 RCTs contained sufficient or appropriate data for analysis . MTCs demonstrated no differences between DPP-4 inhibitors in mean change from baseline in glycosylated hemoglobin ( HbA1c ) or body weight , or the proportions of patients achieving HbA1c < 7 % or experiencing a hypoglycemic event , apart from in patients on alogliptin plus metformin , who achieved HbA1c < 7 % more frequently than those treated with saxagliptin plus metformin [ OR 6.41 ( 95 % CI 3.15–11.98 ) versus 2.17 ( 95 % CI 1.56–2.95 ) ] . Conclusions This systematic review and MTC showed similar efficacy and safety for DPP-4 inhibitors as treatment for type 2 diabetes , either as monotherapy or combination therapy AIM OF THE STUDY We studied the effects of fluvastatin and bezafibrate in monotherapy and in combination on plasma fibrinogen , t-plasminogen activator inhibitor ( PAI-1 ) and C reactive protein ( CRP ) in patients with coronary artery disease ( CAD ) and mixed hyperlipidaemia . DESIGN In this r and omised , double blind , multicentre trial 333 patients with stable angina pectoris or previous myocardial infa rct ion or coronary revascularisation and mixed hyperlipidaemia ( LDL-cholesterol 135 - 250 mg/dl and triglycerides ( TG ) 180 - 400 mg/dl ) were r and omised to fluvastatin 40 mg , bezafibrate 400 mg , fluvastatin 20 mg + bezafibrate 400 mg or fluvastatin 40 mg + bezafibrate 400 mg treatments for 24 weeks . RESULTS Plasma fibrinogen significantly decreased after treatment with the combinations fluvastatin+bezafibrate ( -14 and -16 % ) and with bezafibrate monotherapy ( -9 % ) . No significant reduction was observed after fluvastatin monotherapy ( -4 % ) . No significant changes were observed in PAI-1 and CRP plasma levels . Combination therapy significantly decreased both LDL-C and TG , and significantly increased HDL-C. CONCLUSIONS The combined effects on fibrinogen and plasma lipids achieved by fluvastatin and bezafibrate combination treatment might be more useful than the simple reduction of cholesterol in preventing ischaemic cardiovascular disease OBJECTIVE To determine the effect of prebiotic supplementation on metabolic endotoxemia and systemic inflammation in adults with overweight and obesity . METHODS Sample s from a previously conducted r and omized , double-blind , placebo-controlled trial were used for analysis . Participants were r and omized to 21 g of oligofructose ( n = 20 ; BMI 30.4 kg/m2 ) or a maltodextrin placebo ( n = 17 ; BMI 29.5 kg/m2 ) for 12 weeks . A total of 37 participants had sample s available for the current analysis . Resistin , adiponectin , plasminogen activator inhibitor-1 ( PAI-1 ) , interleukin-6 ( IL-6 ) , tumor necrosis factor-α ( TNF-α ) , and macrophage chemoattractant protein-1 ( MCP-1 ) were quantified using MILLIPLEX ® assays . Lipopolysaccharide ( LPS ) was measured using PyroGene ™ Recombinant Factor C Assay . RESULTS Plasma LPS concentrations were reduced by 40 % in the oligofructose group over 12 weeks compared to a 48 % increase in the placebo group ( P = 0.04 ) . PAI-1 , a risk factor for thrombosis , was reduced to a greater extent in the oligofructose group ( -17.3 ± 2.6 ng/ml ) compared to the placebo group ( -9.7 ± 1.8 ng/ml ; P = 0.03 ) . Oligofructose did not affect IL-6 , TNF-α , MCP-1 , adiponectin , or resistin . CONCLUSIONS Oligofructose reduces metabolic endotoxemia and PAI-1 . Incorporating prebiotics into the diet through supplements or functional foods may help mitigate some markers of obesity-associated inflammation Increased plasma levels of insulin and the fibrinolytic inhibitor , plasminogen activator inhibitor type 1 ( PAI-1 ) , are two new cardiovascular risk factors . The extent to which these two risk factors can be affected by nonpharmacological intervention modalities has not been convincingly proven in subjects at high risk for cardiovascular disease . This study assesses the effects on fasting plasma insulin and plasma PAI-1 activity of an intervention program including a low-fat , high-fiber diet and regular daily physical exercise . The intervention was implemented by a 1-month learning and training session in a full-boarding wellness center and included a follow-up evaluation after 12 months . The study was conducted on 108 subjects ( 31 men and 77 women ) referred for multiple risk factor treatment . After 1 month of intense intervention , the physical condition improved significantly , and this effect was maintained during the year . The body mass index ( BMI ) , fasting plasma insulin , and plasma lipids were significantly decreased . In women , PAI-1 activity was significantly reduced . At follow-up study in both sexes , the BMI and fasting insulin were still significantly decreased . In women , PAI-1 activity reverted to the preintervention level . In subjects with multiple risk factors , ie , the insulin resistance syndrome , the plasma insulin level can be reduced by an intense nonpharmacological program . Also , at least in women , plasma PAI-1 activity can be modestly modified . However , the magnitude of the decrease in PAI-1 activity was probably too small to reverse the hypofibrinolytic state characteristic of these subjects Accelerated coronary artery disease is the most serious obstacle to long-term survival in heart transplant recipients . Hyperlipemia , hyperinsulinism , and changes in endothelial cell hemostatic function have been implicated in cardiac allograft vascular disease . Both lovastatin and bezafibrate are safe , effective , and well tolerated therapies for hyperlipidemia . Our study compares the effect of these lipid-lowering drugs in 21 patients with post-heart transplantation hyperlipidemia on different risk factors related to insulin resistance syndrome . Patients were given the same diet for 3 months , then r and omized to lovastatin or bezafibrate for a period of 8 weeks , and crossed over to an additional 8 weeks of either bezafibrate or lovastatin . Baseline parameters were also compared with those of a control group of healthy subjects and after both periods of pharmacologic treatment . Transplant patients had higher insulin ( 35 + /- 3 vs 24 + /- 3 microIU/L ) , fibrinogen ( 298 + /- 15 vs 261 + /- 14 mg/dl ) , and plasminogen activator inhibitor-1 ( PAI-1 ) ( 17 + /- 2 vs 11.7 + /- 2 arbitrary units/ml ) plasma levels than controls . Significant decreases in insulin ( -37 + /- 3 % ) , fibrinogen ( -12 + /- 4 % ) , and PAI-1 plasma levels ( -18 + /- 12 % ) were only observed after bezafibrate treatment . In conclusion , bezafibrate decreases plasma insulin , fibrinogen , and PAI-1 in hyperlipidemic heart transplant recipients OBJECTIVE To determine the haemostatic status in preeclampsia and to investigate the effects of short-term use of anti-hypertensive drugs , methyldopa and isradipine . METHODS Thirty preeclamptic ( PE ) women admitted to the hospital for observation and treatment were r and omized to receive either methyldopa or isradipine for 2 weeks . Their blood pressure were monitored for 24 h before treatment and again at 7 days and 14 days after treatment using the programmable automated ambulatory blood pressure ( ABP ) monitoring system . Blood sampling was performed before commencement of anti-hypertensive treatment , 7 days and 14 days after treatment and the haemostatic parameters studied was compared before treatment with normal pregnancy and the effect of anti-hypertensive treatment . Nineteen normal pregnant subjects with a total of 30 blood sampling at various gestation and good pregnancy outcome served as controls . The following haemostatic parameters were determined ; thrombelastography , fibrinogen , antithrombin III ( ATIII ) , thrombin-antithrombin (TAT)-complex , beta-thromboglobulin ( beta-TG ) , plasminogen activators ( t-PA , u-PA ) , plasminogen activator inhibitors ( PAI-1 , PAI-2 ) , and plasminogen . RESULTS Significant lowering of blood pressure was evident at Days 7 and 14 of therapy with either methyldopa or isradipine . Increased mean plasma fibrinogen and decreased ATIII levels were seen in preeclampsia together with decreased u-PA and t-PA activity levels in contrast to increased t-PA antigen and beta-TG . No significant differences were seen for TAT-complex , PAI-1 , plasminogen and D-dimer levels although their mean levels were higher than observed in non-pregnant subject except for PAI-2 , the level was significantly reduced when compared with normal pregnancy . Two-way analysis of variance showed no significant alteration on all haemostatic parameters studied in preeclamptic women receiving either methyldopa or isradipine after 7 and 14 days of therapy . CONCLUSION Enhance activation of coagulation was observed together with raised fibrinolysis in normal pregnancy and PE . However , in PE a further reduction in ATIII , u-PA and PAI-2 with increased fibrinogen and platelet activation could lead to an imbalance in the coagulation/fibrinolysis equilibrium which favours fibrin deposition . All these changes seen in PE including the coagulation kinetics were not altered by the short term effects of methyldopa and isradipine even though significantly lowered blood pressure were observed during therapy Magnesium ( Mg ) has shown the ability to inhibit arterial thrombus formation in some experimental animal studies . This effect may be due to an inhibition of platelet reactivity as in vitro studies have demonstrated that Mg inhibits platelet aggregation . In order to evaluate the in vivo effect of Mg in humans measurements of platelet activity , fibrinolytic activity , as well as measurements of prostacyclin ( PGI2 ) , and nitric oxide ( NO ) release were performed after infusion of magnesium sulphate ( MgSO4 ) in healthy volunteers . In a placebo controlled , cross-over study in 14 healthy male subjects , 8 mmol MgSO4 was given as an intravenous bolus over 15 min followed by 3 mmol MgSO4/h . The mean S-Mg concentration increased from 0.85 to 1.50 mM during the Mg infusion period . A transient decrease in blood pressure was observed during the initial bolus infusion of Mg .  Haemodynamic parameters were otherwise unstable . The bleeding time increased by 48 % during the Mg infusion ( p < 0.005 ) , and in accordance with this , ex vivo platelet aggregation in platelet rich plasma was significantly inhibited , both following collagen ( p = 0.02 ) and ADP ( p = 0.04 ) stimulation . There were no significant changes in plasma beta-thromboglobulin concentration or the excretion of 2,3-dinor-thromboxane B2 in the urine . Neither tissue plasminogen activator (t-PA)activity , tissue plasminogen activator (t-PA)antigen nor plasminogen activator inhibitor (PAI)antigen changed during the Mg infusion period . There was no sign of increased release of PGI2 from the vessel wall as judged by urinary concentration of 2,3-dinor-6-keto-prostagl and in F1 alpha . Nor was there any sustained increase in the release of NO , measured as nitrate concentration in urine . However , a transient increase in NO release was observed during one sample period . In conclusion a reduced platelet activity and increased bleeding time , was found during  Mg infusion in healthy volunteers .  Fibrinolytic activity showed no changes . An anti-platelet effect may in part be responsible for the beneficial effect of Mg , described in patients with acute myocardial infa rct ion ( MI ) and preeclampsia Eleven Type 2 diabetic subjects ( 10 male 1 female : age 56.2 + /- 9.7 ( SD ) yr ) were treated in r and om order either with insulin or with sulphonylureas for 8 weeks each , without attempting to alter glycaemic control between the two treatment periods . Insulin treatment was associated with suppression of endogenous insulin secretion ( fasting C-peptide levels -35.0 + /- 24.2 % ; p = 0.006 ) , and of intact proinsulin ( -43.1 + /- 36.8 % ; p = 0.03 ) and 32,33 split proinsulin -20.1 + /- 27.0 % ; p = 0.03 ) . Activity of plasminogen activator inhibitor ( PAI-1 ) , a fast acting inhibitor of fibrinolysis , decreased significantly ( -14.3 % + /- 27.5 % ; p = 0.02 ) but no changes occurred in concentration of lipoproteins or apoproteins between therapies . Changes in concentrations of 32,33 split and intact proinsulin were closely and significantly related ( rs = 0.83 ; p < 0.001 ) to each other but not with changes in concentrations of C-peptide ( intact proinsulin rs = -0.41 ; p = 0.11 ) and 32,33 split proinsulin rs = -0.27 ; ( p = 0.21 ) . Percentage changes in intact proinsulin concentrations were positively correlated with those in PAI-1 ( rs = 0.51 ; p = 0.05 ) . There was , however a paradoxical negative relationship between changes in C-peptide concentrations and those of PAI-1 ( rs = -0.73 ; p = 0.006 ) . These preliminary observations suggest that insulin treatment in Type 2 diabetic subjects without any changes in glycaemic control is associated with a reduced activity of PAI-1 , but is without effect on any other cardiovascular risk factors . Concentrations of insulin precursor molecules may play a role in determining fibrinolytic activity
The estimated effects of fibrate therapy on plasma concentration and activity of PAI-1 were independent of treatment duration and changes in plasma triglyceride levels in the meta-regression analysis .
This meta- analysis of RCTs suggested that fibrate therapy does not reduce plasma concentration or activity of PAI-I. The putative benefits of fibrate therapy in patients with cardiovascular disease appear to be exerted via mechanisms independent of effects on PAI-1
OBJECTIVE The aim of this systematic review was to perform a meta- analysis of r and omized controlled trials ( RCTs ) examining the efficacy of fibrate therapy in reducing plasma concentration or activity of plasminogen activator inhibitor 1 ( PAI-1 ) .