Insulin resistance is associated with increased circulating level of thrombin-activatable fibrinolysis inhibitor in type 2 diabetic patients

Hypofibrinolysis is a common finding in patients with diabetes mellitus (DM) and obesity and a risk factor for the development of cardiovascular disease. Recently, a new potent inhibitor of fibrinolysis, the thrombin-activatable fibrinolysis inhibitor (TAFI) has been isolated and characterized from human plasma. The present study was undertaken to assess the activity and circulating level of TAFI and its relation to fibrinolytic function and obesity in patients with type 2 DM. Fifty-seven patients with type 2 DM (38 men, 19 women) were enrolled in this study. DM patients were categorized in age-matched obese [body mass index (BMI) > or = 25] and nonobese (BMI < 25) groups. The plasma concentration and activity of TAFI were significantly (P < 0.05) higher in DM patients than in healthy controls. The plasma levels and activity of TAFI were significantly (P < 0.05) elevated in obese DM patients compared with nonobese DM and nonobese healthy subjects. RT-PCR demonstrated the expression of TAFI in human adipose tissue and in human endothelial cells. The plasma levels of TAFI were independently and significantly correlated with glucose intolerance (HbA(1c)), with obesity (BMI, visceral fat area), and with an indicator of insulin resistance (glucose infusion rate). This study showed that increased circulating level of TAFI may be an important causative factor of hypofibrinolysis in patients with type 2 diabetes, obesity and insulin resistance.     

凝血酶激活的纤溶抑制物与肺部疾病的关系

凝血酶激活的纤溶抑制物是近年发现的血浆羧肽酶原,在调节血浆凝块的纤溶过程中有着重要的作用,而最近研究发现,其生理功能并不限于控制纤溶系统,还有更广泛的抗炎作用.现就凝血酶激活的纤溶抑制物与肺血栓栓塞症、ALI、肺间质纤维化、支气管哮喘等肺部疾病的相关性作一综述.     

Increased plasma thrombin-activatable fibrinolysis inhibitor levels in normotensive type 2 diabetic patients with microalbuminuria

Hypofibrinolysis is a common finding in patients with diabetes mellitus and a risk factor for diabetic nephropathy. Recently, a new potent inhibitor of fibrinolysis, the thrombin-activatable fibrinolysis inhibitor (TAFI), has been isolated from human plasma. The possibility that TAFI also participates in the mechanism of hypofibrinolysis has not been appraised in diabetic patients with microalbuminuria. In the present study, we investigated the plasma levels of TAFI and its relation to urinary albumin excretion in normotensive diabetic patients with normo- and microalbuminuria. Thirty-nine normotensive nonobese type 2 diabetic patients (27 with normoalbuminuria, 12 with microalbuminuria) and 20 age-matched normal subjects were enrolled in this study. The plasma level of thrombin-antithrombin complex was significantly increased (22.1 +/- 2.6 vs. 8.3 +/- 1.0 nmol/liter; P < 0.05), whereas the D-dimer/thrombin-antithrombin complex ratio was significantly decreased (15.7 +/- 1.4 vs. 26.5 +/- 2.2; P < 0.05), showing the occurrence of hypercoagulability and hypofibrinolysis in diabetic patients. The plasma level of TAFI in diabetic patients was significantly elevated, compared with normal subjects (147.4 +/- 11.6 vs. 99.5 +/- 4.9%; P < 0.05). The plasma level of TAFI in diabetic patients with microalbuminuria was significantly higher than the level in diabetic patients with normoalbuminuria (194.1 +/- 24.5 vs. 128.8 +/- 12.3%; P < 0.02) or normal subjects (194.1 +/- 24.5 vs. 99.5 +/- 4.9%; P < 0.005). Univariate analysis showed that the plasma TAFI levels are significantly and proportionally correlated with urinary albumin excretion rate (r = 0.58; P < 0.005) and with plasma soluble thrombomodulin level, a marker of endothelial cell damage, in all diabetic patients (r = 0.42; P < 0.01). These data suggest that increased plasma level of TAFI may be involved in the mechanism of vascular endothelial damage in patients with type 2 diabetes mellitus.     

Plasma thrombin-activatable fibrinolysis inhibitor (TAFI) antigen levels in diabetic foot ulcers

Plasma TAFI may participate in arterial thrombosis in cardiovascular diseases (CVD) and may be involved in the mechanism of vascular endothelial damage in diabetic patients. The aim of this study was to investigate the association of plasma TAFI antigen level in the development of diabetic foot ulcer in Type 2 diabetes. The TAFI antigen levels were determined in 50 patients with diabetic foot ulcers and 34 patients without diabetic foot ulcers and 25 healthy individuals. We measured TAFIa/ai antigen in plasma samples with a commercially available ELISA Kit. Diabetic foot ulcer group and diabetic group were similar in terms of mean age and sex distribution. Diabetes duration, retinopathy, neuropathy, macrovascular disease and infection were related to diabetic foot ulcers. HbA1c, HDL-cholesterol and Folic Acid levels were decreased in the diabetic foot ulcer group. TAFI levels were 99.44?±?55.94% in control group, 135.21?±?61.05% in diabetic foot ulcer group, 136.75?±?59.38% in diabetic group and was statistically different (P??0.05). No significant difference in plasma TAFI levels were seen between diabetic foot ulcer stages. TAFI antigen levels are increased in Type 2 diabetic patients, but are not related to diabetic foot ulcer development.     

Increased thrombin-activatable fibrinolysis inhibitor and decreased tissue factor pathway inhibitor in patients with hypothyroidism

Various abnormalities of coagulation–fibrinolytic system have been reported in patients with thyroid dysfunction. Several studies indicate that coagulation and fibrinolytic system is disturbed in the patients with hypothyroidism. Also, the influence of hypothyroidism on hemostasis is controversial; both hypocoagulable and hypercoagulable states have been reported. The levels of plasma thrombin-activatable fibrinolysis inhibitor (TAFI) antigen and tissue factor pathway inhibitor (TFPI) have been investigated only once in patients with hypothyroidism. Therefore, the main purpose of this study was to evaluate the profile of coagulation and fibrinolytic parameters including TAFI and TFPI in patients with hypothyroidism. Fifteen patients with untreated hypothyroidism and 15 age-matched healthy controls were included in the study. Factors V(FV), VII (FVII), VIII (FVIII) activities, von Willebrand factor (vWF), protein C, protein S, thrombomodulin (TM), TFPI, and TAFI were measured. The relationships between serum thyroid hormones and these hemostatic parameters were examined. Compared with the control subjects, FVII activity, and TM Ag and TAFI Ag levels were significantly increased in patients with hypothyroidism, whereas FV, FVIII, vWF, protein C and protein S activities, and TFPI Ag levels were significantly decreased. We did not find any significant correlation between serum thyroid hormones and the hemostatic parameters that we measured. In conclusion, we found some important differences in the hemostatic parameters between the patients with hypothyroidism and healthy controls. Increased FVII, TM, and TAFI and decreased FV, FVIII, vWF, protein C, protein S, and TFPI in these patients represent a potential hypercoagulable and hypofibrinolytic state, possible endothelial dysfunction, which might augment the risk for atherosclerotic and atherothrombotic complications. Thus, disturbances of the hemostatic system may contribute to the excess mortality due to cardiovascular disease seen in patients with hypothyroidism.     

Deficiency of thrombin activatable fibrinolysis inhibitor in cirrhosis is associated with increased plasma fibrinolysis

Hyperfibrinolysis is thought to contribute to bleeding associated with advanced cirrhosis. Thrombin activatable fibrinolysis inhibitor (TAFI) is a plasma precursor of a carboxypeptidase (TAFIa) with antifibrinolytic activity and was recently shown to be reduced in cirrhosis. In this study, we evaluated the influence of TAFI deficiency on in vitro fibrinolysis in cirrhotic patients. Fifty-three patients with cirrhosis and 43 healthy controls were studied. TAFI antigen was measured by enzyme-linked immunosorbent assay and TAFI activity by chromogenic assay. Fibrinolysis was evaluated as tissue plasminogen activator-induced plasma clot lysis time in the absence and in the presence of a specific inhibitor of TAFIa. TAFI antigen and activity levels were markedly reduced in cirrhotic patients (P <.0001). In these patients, the lysis time of plasma clots was shorter than in controls (median, interquartile range: 25 minutes, 21-36 minutes vs. 48 minutes, 40-60 minutes, respectively; P <.0001) and was poorly influenced by the TAFIa inhibitor. Accordingly, TAFIa and thrombin activity, generated in cirrhotic samples during clot lysis, were significantly lower than in control samples. Addition of purified TAFI to cirrhotic plasma prolonged the lysis time and enhanced the response to TAFIa inhibitor in a dose-dependent manner. In conclusion, our results indicate that in vitro plasma hyperfibrinolysis in cirrhosis is largely due to a defective TAFIa generation resulting from low TAFI levels and probably from impaired thrombin generation. Impairment of the antifibrinolytic TAFI pathway might contribute to bleeding associated with this disease.     

Seminal thrombin-activatable fibrinolysis inhibitor: a regulator of liquefaction.

Several active components of the haemostatic system have been identified in human semen. Here we investigated the presence of thrombin-activatable fibrinolysis inhibitor (TAFI) in seminal plasma. Using an enzyme-linked immunosorbent assay, TAFI levels were measured in 36 semen specimens obtained from subfertile, normally fertile, fertile sperm donor and vasectomized individuals. TAFI was detectable in human semen. Its levels were highest in vasectomized individuals compared with the other groups, including a pooled normal semen parameter stratification group (by World Health Organization criteria). This elevation in the vasectomy group was found to be statistically significant in comparison with the normally fertile (P < 0.01) and the pooled normal semen parameter groups (P < 0.05). Seminal TAFI levels showed a significant positive correlation with total sperm count and sperm density. In contrast, a negative association was observed with semen volume, days of sexual abstinence and liquefaction time. The highly motile sperm group showed low TAFI levels. Our results establish the presence of TAFI in seminal plasma with a probable role in the protection of the seminal clot against lysis. It also suggests a downstream (post-testicular) source for its production. This reinforces the involvement of the conventional haemostatic system in the coagulation and liquefaction properties of human semen.     

t-PAA、PAIA活性测定在糖尿病肾病临床中的意义

目的：探讨糖尿病肾病（ＤＮ）临床中尿白蛋白排泄率（ＵＡＥＲ）与组织纤溶酶原激活物（ｔ－ＰＡＡ）、纤溶酶原激活物抑制物（ＰＡＩＡ）的相关性。地７１例糖尿病患者和３０例正常人的ＵＡＥＲ和ｔ－ＰＡＡ、ＰＡＩＡ进行测定,并对其相关性进行统计分析。结果：糖尿病组ｔ－ＰＡＡ随着ＵＡＥＲ的增高而降低,而ＰＡＩＡ则随着ＵＡＥＲ的增高而增高,糖尿病微量白蛋白尿组、临床蛋白尿组ｔ－ＰＡＡ与ＵＡＥＲ呈显著负相关（Ｐ〈０     

Increased circulating levels of thrombin-activatable fibrinolysis inhibitor in lung cancer patients

Impairment of fibrinolytic function plays an important role in the mechanism of thrombotic disorders in cancer patients. This study assessed the circulating level of thrombin-activatable fibrinolysis inhibitor in patients with lung cancer and its expression by several lung cancer cell lines. The plasma concentrations of thrombin-activatable fibrinolysis inhibitor were significantly increased in lung cancer patients compared to healthy subjects. The concentration of thrombin-activatable fibrinolysis inhibitor was particularly higher in patients with small cell carcinoma compared to those with adenocarcinoma or squamous cell carcinoma, and in cancer patients that responded to chemotherapy compared to non-responders. In vitro studies showed more expression of thrombin-activatable fibrinolysis inhibitor in small cell carcinoma than in adenocarcinoma cell lines and more expression in lung cancer cell lines sensitive to anti-cancer agents than in resistant cell lines. This study suggests that thrombin-activatable fibrinolysis inhibitor, in part secreted from lung cancer cells, may play a role in the pathogenesis of thrombotic disorders in lung cancer patients.     

Thrombin-activatable fibrinolysis inhibitor deficiency in cirrhosis is not associated with increased plasma fibrinolysis.

BACKGROUND AND AIMS: The bleeding tendency of patients suffering from cirrhosis is in part ascribed to accelerated fibrinolysis. In this study, the role of the recently discovered inhibitor of fibrinolysis, thrombin-activatable fibrinolysis inhibitor (TAFI) in cirrhosis was examined. METHODS: In 64 patients with cirrhosis of varying severity, TAFI antigen levels were measured by enzyme-linked immunosorbent assay and compared with TAFI levels in control subjects. Furthermore, a plasma-based fibrinolysis assay was performed in the presence and absence of a specific inhibitor of activated TAFI. RESULTS: TAFI levels were decreased in cirrhosis. Mean TAFI levels were 66% in Child's A, 55% in Child's B, 47% in Child's C cirrhosis, and 26% in acute liver failure. Decreased TAFI antigen levels were highly correlated with antithrombin and alpha(2)-antiplasmin activity levels. Clot lysis times and clot lysis ratio (defined as ratio between clot lysis time in the absence and presence of a specific inhibitor of activated TAFI) of cirrhotics were not significantly different from healthy controls. CONCLUSIONS: Despite decreased levels of TAFI and other components of the fibrinolytic system, no evidence of increased plasma fibrinolytic potential in cirrhosis is observed using the plasma-based assay of this study. The reduction of antifibrinolytic factors in cirrhosis is compensated by the concomitant reduction in profibrinolytics.     

Different metabolic correlations of thrombin-activatable fibrinolysis inhibitor and plasminogen activator inhibitor-1 in non-obese type 2 diabetic patients

We investigated the plasma levels of thrombin-activatable fibrinolysis inhibitor (TAFI), plasminogen activator inhibitor-1 (PAI-1) and their relation with clinical and metabolic parameters in non-obese type 2 diabetic patients. The plasma levels of TAFI and PAI-1 were evaluated in 47 non-obese type 2 diabetic patients and 31 normal subjects. The intra-abdominal visceral and subcutaneous fat areas were measured by computed tomography (CT). The degree of insulin resistance was evaluated by the euglycemic-hyperinsulinemic clamp technique using artificial pancreas. The plasma levels of TAFI (169.0+/-108.8% versus 103.7+/-52.3%; p<0.001, mean+/-S.D.) and PAI-1 (82.7+/-54.5ng/ml versus 52.9+/-51.7ng/ml; p<0.05) were significantly higher in non-obese type 2 diabetic patients than in normal subjects. Univariate analysis showed that the plasma TAFI levels are significantly and inversely correlated with the glucose infusion rate (GIR) (r=-0.42, p<0.005) in all diabetic patients. Moreover, the plasma levels of TAFI were significantly correlated with fasting plasma glucose levels (r=0.47, p<0.001) and HbA(1c) (r=0.38, p<0.005) in all subjects. The plasma levels of PAI-1 were significantly and proportionally correlated with the visceral fat area (r=0.42, p<0.005) and body mass index (r=0.33, p<0.05). There was no significant correlation between plasma levels of TAFI and PAI-1 (r=0.04). These results show that the plasma levels of TAFI and PAI-1 differently correlate with insulin resistance and visceral fat accumulation, suggesting that different factors are implicated in the plasma elevation of TAFI and PAI-1 in non-obese type 2 diabetes mellitus.     

Plasma levels of thrombin-activatable fibrinolysis inhibitor in primary and secondary thrombocytosis.

An elevated platelet count is a common finding in both hospitalized and ambulatory patients. Thrombosis and bleeding complications are more frequently observed in patients with clonal thrombocytosis than secondary thrombocytosis. The aim of this study was to investigate the behaviors of thrombin-activatable fibrinolysis inhibitor (TAFI) activity, the inhibitor of fibrinolysis, and also prothrombin time (PT), active partial thromboplastin time, and D-dimer and fibrinogen levels in 21 patients affected with clonal thrombocytemia as compared with 21 patients with reactive thrombocytosis and 21 healthy controls. In the clonal thrombocytemia group, plasma levels of TAFI activity were significantly higher than in both the reactive thrombocytosis and the control group. Plasma levels of leukocyte and platelet counts were significantly higher in the clonal thrombocytemia group than in the other two groups and also higher in the reactive thrombocytosis group than in the control group, which was also significant. Fibrinogen and D-dimer levels were higher in patients than in the control group but showed no significant difference between the clonal and secondary thrombocytosis groups. Plasma levels of PT and aPTT were higher in secondary thrombocytosis group than the clonal thrombocytosis group. The results of this study showed for the first time that TAFI activity is increased in patients with clonal thrombocytosis. These increased levels in clonal thrombocytosis can be considered a factor to explain the thrombotic tendency in myeloproliferative disorders.     

黄芩苷对动脉粥样硬化大鼠凝血酶激活纤溶抑制物水平及血脂、凝血纤溶指标的影响

目的 观察黄芩苷对动脉粥样硬化(AS)模型大鼠的凝血酶激活纤溶抑制物(TAFI)水平及血脂、凝血纤溶指标的影响,探讨黄芩苷在干预AS进程中的机制.方法 40只健康雄性Wistar大鼠随机分为正常对照组、模型组、黄芩苷治疗组、辛伐他汀组,每组10只.正常对照组给予普通饲料喂养,其余3组在给予高脂饲料喂养的基础上行主动脉球囊损伤术,喂养4个月,以复制大鼠AS模型.用全自动生化仪测定血浆总胆固醇(TC)、三酰甘油(TG)、高密度脂蛋白胆固醇(HDL-C)、低密度脂蛋白胆固醇(LDL-C),用全自动血凝仪测定凝血酶原时间(PT)、活化部分凝血活酶时间(APTT)、纤维蛋白原(Fib),发色底物法测定血浆TAFI的活性.结果 与正常对照组相比,其余各组大鼠的TC、TG、LDL-C、Fib和TAFI活性均明显升高 (P<0.01或P<0.05),PT、APTT明显缩短(P<0.01或P<0.05);实验结束时,与模型组相比,黄芩苷治疗组与辛伐他汀组的TC、TG、LDL-C、Fib和TAFI活性明显低于模型组(P<0.01或P<0.05),PT、APTT明显延长(P<0.01或P<0.05);与辛伐他汀组比较,黄芩苷治疗组TC、TG、LDL-C、Fib、PT、APTT改善程度稍低(P<0.05),而TAFI活性则无明显统计学差异(P>0.05).结论 黄芩苷可能通过降血脂、改善凝血纤溶系统平衡、下调TAFI水平等途径干预了AS的形成.     

Reduced activity of TAFI (thrombin-activatable fibrinolysis inhibitor) in acute promyelocytic leukaemia

Acute promyelocytic leukaemia (APL) is a disease that is distinguished from other leukaemias by the high potential for early haemorrhagic death. Several processes are involved, such as disseminated intravascular coagulation and hyperfibrinolysis. Recently, TAFI (thrombin-activatable fibrinolysis inhibitor) was identified as a link between coagulation and fibrinolysis. TAFI can be activated by thrombin, and in its activated form potently attenuates fibrinolysis by removing C-terminal lysine and arginine residues that are important for the binding and activation of plasminogen. Activation of TAFI by the coagulation system results in a down-regulation of fibrinolytic activity and, thereby, prevents a rapid dissolution of the fibrin clot. To establish whether TAFI was involved in the severity of the bleeding complications in APL, the TAFI antigen and activity levels were determined in a group of 15 patients. The TAFI antigen concentration was normal, but the activity of TAFI was severely reduced in APL by approximately 60%. The reduction of TAFI activity was most probably caused by the action of plasmin on TAFI because in vitro experiments revealed that plasmin slightly reduced antigen levels but severely reduced TAFI activity. The acquired functional TAFI deficiency in APL may contribute to the severity of the haemorrhagic diathesis because of the impaired capacity of the coagulation system to protect the fibrin clot from fibrinolysis.     

Total thrombin-activatable fibrinolysis inhibitor (TAFI) antigen and pro-TAFI in patients with haemophilia A

Pro-thrombin-activatable fibrinolysis inhibitor (pro-TAFI), also known as TAFI, procarboxypeptidase U, or procarboxypeptidase B, is a relatively recently described plasma glycoprotein synthesized in the liver. It can be catalysed into its active form, TAFI (TAFIa, carboxypeptidase U or B) by a complex of thrombin/thrombomodulin. TAFI can potentially inhibit fibrinolysis by removing carboxyterminal lysine residues from partially degraded fibrin, decreasing plasminogen binding on the surface of fibrin, which thereby results in a decrease of the fibrinolytic activity. As TAFI represents a connection between coagulation and fibrinolysis, it can be expected that TAFI levels are altered in different thrombotic and haemorrhagic diseases, such as haemophilia A. Total TAFI antigen (including pro-TAFI, TAFI and the inactive form of TAFI [TAFIi]) and pro-TAFI were determined in 17 patients with haemophilia A. Thirteen healthy age-matched volunteers served as controls. No significant difference in levels of total TAFI antigen was observed between controls and patients with haemophilia, although it was slightly decreased in patients with haemophilia. Pro-TAFI was significantly reduced in haemophilia patients compared to controls (P=0.0113). TAFI antigen levels similar to controls have already been described in different clinical conditions, including haemophilia A. Decrease of pro-TAFI in haemophilia A can be an additional factor, together with decrease in thrombin generation, which induces impaired activation of pro-TAFI to TAFI, and could cause accelerated fibrinolysis. This supports the validity of usage of antifibrinolytics in the treatment of haemophilia A. In this paper we use new nomenclature for TAFI, and we believe that this recommended terminology for different forms of TAFI can simplify further standardization in TAFI investigation.     

Genetic variation in the neuropeptide y gene promoter is associated with increased risk of tobacco smoking

Background: Neuropeptide Y (NPY) is a strong candidate gene regarding the pathophysiology of tobacco dependence. It has been associated with various addictive and psychiatric disorders, and closely interacts with the brain reward system. The aim of the present study was to test for association between a functional genetic variant in the NP-Y promoter gene (SNP rs16147) and tobacco smoking. Methods: In a population-based case-control multicenter study designed for tobacco addiction research, a total of 550 Caucasian current smokers, and 544 never-smokers were genotyped for SNP rs16147 and behaviorally characterized with the State-Trait Anxiety Inventory (STAI). Results: Subjects with TT genotype of the SNP rs16147 were significantly more frequently smokers than never-smokers (p = 0.046). In addition, TT genotype exhibited increased state anxiety scores compared to carriers of the C allele (p = 0.037). Conclusions: Our results provide evidence for an involvement of the functionally relevant SNP rs16147 in the pathophysiology of tobacco dependence. Further studies are needed to confirm our findings.     

Genetic variation in the promoter of DNMT3B is associated with the risk of colorectal cancer

Purpose  

DNA methyltransferase-3B (DNMT3B) plays an important role in the generation of aberrant methylation in carcinogenesis. Polymorphisms of the DNMT3B gene may influence DNMT3B enzyme activity on DNA methylation, thereby modulating the susceptibility to colorectal cancer (CRC).     

Fenofibrate improves endothelial function and decreases thrombin-activatable fibrinolysis inhibitor concentration in metabolic syndrome

Procoagulant state, inflammation, and endothelial dysfunction have been documented in metabolic syndrome. Endothelial dysfunction is a strong predictor of cardiovascular events. Studies on the association of thrombin-activatable fibrinolysis inhibitor and thrombosis are still controversial, but substantial evidence suggests that increased thrombin-activatable fibrinolysis inhibitor or thrombin-activatable fibrinolysis inhibits or protects against arterial thrombosis. This study aimed to assess concomitantly the effects of fenofibrate therapy on thrombin-activatable fibrinolysis inhibitor concentrations and endothelial functions in patients with metabolic syndrome. Twenty-five patients (16 women; mean age 50.4 +/- 7.0) were enrolled in the study. Plasma thrombin-activatable fibrinolysis inhibitor, C-reactive protein, and fibrinogen levels were measured before fenofibrate administration and after 8 weeks of fenofibrate treatment. Endothelial function was assessed by endothelial-dependent flow-mediated dilatation from brachial artery. Pretreatment (baseline) thrombin-activatable fibrinolysis inhibitor level was 52.3 (1.2-119.7) decreasing to 7.7 (0.9-51.2; P < 0.001) after 8 weeks of fibrate treatment. Endothelial functions, which were measured with flow-mediated dilatation, were significantly improved after treatment (mean flow-mediated dilatation was 6.76 +/- 2.21 at baseline and 10.66 +/- 1.17% after 8 week of fenofibrate treatment, P < 0.001). Fenofibrate decreases thrombin-activatable fibrinolysis inhibitor levels and improves endothelial function in metabolic syndrome and, thus, suggests a potential for protection against cardiovascular effects. Further studies are warranted to confirm the effects of fibrates on thrombin-activatable fibrinolysis inhibitor and for conclusive evidence on the association between thrombin-activatable fibrinolysis inhibitor and thrombosis.