Thrombin-activatable Fibrinolysis Inhibitor Levels Research Articles

High thrombin activatable fibrinolysis inhibitor levels are associated with an increased risk of premature peripheral arterial disease

BackgroundPrevious studies suggested that hypofibrinolysis is associated with increased risk of peripheral arterial disease. Thrombin activatable fibrinolysis inhibitor (TAFI) has been identified as an important inhibitor of fibrinolysis. The aim of our study was to assess the role of TAFI in young patients with peripheral arterial disease. MethodsIn a single-center case-control study we measured plasma TAFI antigen levels and functional TAFI in consecutive young patients (men 18-45years and women 18-55years) with a first manifestation of peripheral arterial disease and compared these with a population-based control group. ResultsA total of 47 peripheral arterial disease patients and 141 controls (mean age 43) were included. Intact TAFI antigen levels were significantly higher in patients with peripheral arterial disease (112.4±21.1%) than in controls (104.9±19.9%, p=0.03). The risk of peripheral arterial disease increased with 18% (OR 1.18; CI 1.01-1.34) per 10% increase of TAFI antigen. Functional TAFI levels were slightly higher in patients compared to controls, however this difference was not significant. For individuals with the highest functional TAFI levels, above the 90th percentile, the increased risk for peripheral arterial disease was most pronounced (OR 3.1; CI 1.02-9.41). ConclusionHigh TAFI levels are associated with increased risk of premature peripheral arterial disease.

Effect of Levothyroxine Suppression Therapy on Plasma Thrombin Activatable Fibrinolysis Inhibitor Antigen Levels in Benign Thyroid Nodules

Objective: The aim of this prospective study was to investigate the effect of LT4 suppression therapy on plasma thrombin activatable fibrinolysis inhibitor (TAFI) antigen and plasminogen activator inhibitor-1 (PAI-1) levels in benign thyroid nodules. We also compared hyperthyroid patients and healthy controls. Subjects and Methods: Twenty premenopausal women with benign thyroid nodules were given LT4 suppression therapy for 1 year. Plasma TAFI and PAI-1 antigen levels were measured at baseline and after LT4 suppression treatment. The endogenous hyperthyroid group was composed of 19 premenopausal females with newly diagnosed endogenous hyperthyroidism. Eighteen age-matched euthyroid healthy premenopausal women were enrolled as the control group. Results: TAFI antigen levels decreased after LT4 suppression treatment; however, the difference was not statistically significant (p = 0.057). LT4 treatment resulted in a nonsignificant increase in PAI-1 levels. Patients with endogenous hyperthyroidism had decreased levels of TAFI antigen and increased levels of PAI-1 antigen (p < 0.05). There was a negative correlation between the FT₄ and TAFI antigen levels. Serum TSH was positively correlated with the plasma levels of TAFI antigen. Conclusion: LT4 suppression therapy for benign thyroid nodules did not result in a significant decrease in TAFI antigen levels in premenopausal women, but endogenous hyperthyroidism was associated with significantly decreased levels of TAFI antigen.

The role of thrombin-activatable fibrinolysis inhibitor in diabetic wound healing

Introduction One of the major complications in patients with diabetes mellitus is impaired wound healing. The fibrinolytic system is involved in parts of the wound healing process and deficiency of thrombin-activatable fibrinolysis inhibitor (TAFI) results in delayed wound closure. Moreover, levels of TAFI are affected by diabetes mellitus. The aim of this study was to elucidate the effect of hyperglycaemia on TAFI and to determine the effect of deficiency of TAFI on wound healing under hyperglycaemic conditions. Materials and methods Hyperglycaemia was induced with streptozotocin (STZ) and used as a model for diabetes mellitus. TAFI plasma levels and TAFI gene expression in the liver were determined. Incisional and excisional wound healing were studied in non-treated and STZ-treated wild-type and TAFI-deficient mice. Wound closure was scored daily as open or closed. Results Mice treated with STZ showed hyperglycaemia, and TAFI plasma levels and TAFI gene expression were increased in diabetic mice. TAFI-deficient mice and diabetic wild-type and diabetic TAFI-deficient mice showed delayed wound healing of incisional wounds. No differences were observed between diabetic and non-diabetic TAFI-deficient mice and between diabetic wild-type and diabetic TAFI-deficient mice. Conclusions This study illustrated that TAFI was affected by hyperglycaemia and confirmed that TAFI is involved in wound healing. No additional effect was observed under hyperglycaemic conditions, indicating that deficiency of TAFI did not have an additive or synergistic effect in diabetic wound healing. Further research has to elucidate if TAFI and hyperglycemia affect wound healing via similar mechanisms.

Effects of Pegylated Interferon α on Fibrinolytic Parameters in Patients With Chronic Hepatitis C

Interferon (IFN) interacts with endothelial cells and modulates the functions of these cells. In our study, we aimed to determine the effects of treatment with pegylated IFN-α (peg-IFN-α) on fibrinolytic parameters in patients with chronic hepatitis C. Fifteen patients with chronic hepatitis C were treated with peg-IFN-α once per week plus daily oral ribavirin. Euglobulin lysis time (ELT), plasma levels of D-dimer, tissue-type plasminogen activator (t-PA), plasminogen activator inhibitor 1 (PAI-1), and thrombin activatable fibrinolysis inhibitor (TAFI) were determined before treatment, 2 weeks, 1 month, and 3 months after the initiation of the treatment. Plasma levels of t-PA increased significantly 1 month and 3 months after the treatment (P < .05). The PAI-1 and TAFI levels in 2 weeks, 1 month and 3 months after treatment were not statistically different as compared with pretreatment levels (P > .05) No significant difference in plasma D-dimer levels was observed during peg-IFN-α treatment (P > .05). There was a significant decrease in ELT 1 month and 3 months after the treatment (P < .05). Our results indicated that treatment with peg-IFN-α may be associated with enhanced fibrinolysis.

THROMBIN ACTIVATABLE FIBRINOLYSIS INHIBITOR (TAFI): Relationship to Hemostatic Alteration in Patients with β-Thalassemia

Profound hemostatic changes have been observed among thalassemic patients. Thrombin activatable fibrinolysis inhibitor (TAFI) is a newly discovered protein that potentially attenuates fibrinolysis. The authors aimed to investigate plasma level of TAFI in β-thalassemia patients in relation to clinical severity and hemostatic alteration. Fifty-one thalassemic patients (mean age 10.79 ± 5.59 years) (21 splenectomized thalassemia major patients, 18 nonsplenectomized thalassemia major patients, 12 nonsplenectomized thalassemia intermedia) were recruited from Pediatric Hematology Clinic, Ain Shams University; in addition, 32 healthy age- and sex-matched controls (10.31 ± 5.58 years) were also included. In addition to clinical assessment, laboratory investigations included complete blood count (CBC), hemoglobin electrophoresis, prothrombin time (PT), activated partial thromboplastin time (PTT), liver function tests, viral hepatitis markers, serum ferritin, and plasma TAFI levels. Nine out of 51 patients (17.5%) suffered from bleeding manifestations mainly in the form of epistaxis; none of the studied patients had thromboembolism. Significant reduction in TAFI levels was shown in thalassemic patients compared to controls (P < .0001), in splenectomized compared to nonsplenectomized thalassemia group (P < .0001), and in thalassemia major compared to thalassemia intermedia group (P < .0001). Negative correlation was present between TAFI levels and both liver enzymes and serum ferritin levels (P < .05). Thalassemic patients suffering from bleeding showed lower mean TAFI levels compared to those not suffering from bleeding (P < .001). Marked reduction in TAFI levels was observed in thalassemic patients with splenectomy, altered liver functions, and poor chelation who therefore might be at a higher risk for altered hemostasis.

Disseminated intravascular coagulation at an early phase of trauma is associated with consumption coagulopathy and excessive fibrinolysis both by plasmin and neutrophil elastase

The aims of the present study were to confirm the consumption coagulopathy of disseminated intravascular coagulation with the fibrinolytic phenotype at an early phase of trauma and to test the hypothesis that thrombin-activatable fibrinolysis inhibitor, neutrophil elastase, and plasmin contribute to the increased fibrinolysis of this type of disseminated intravascular coagulation. Furthermore, we hypothesized that disseminated intravascular coagulation at an early phase of trauma progresses dependently to disseminated intravascular coagulation with a thorombotic phenotype from 3 to 5 days after injury. Fifty-seven trauma patients, including 30 patients with disseminated intravascular coagulation and 27 patients without disseminated intravascular coagulation, were studied prospectively. Levels of thrombin-activatable fibrinolysis inhibitor, tissue-type plasminogen activator plasminogen activator inhibitor-1 complex, plasmin alpha2 plasmin inhibitor complex, D-dimer, neutrophil elastase, and fibrin degradation product by neutrophil elastase were measured on days 1, 3, and 5 after trauma. The prothrombin time, fibrinogen, fibrin/fibrinogen degradation product, antithrombin, and lactate also were measured. Independent of the lactate levels, disseminated intravascular coagulation patients showed a prolonged prothrombin time, lesser fibrinogen and antithrombin levels, and increased levels of fibrin/fibrinogen degradation product on day 1. Disseminated intravascular coagulation diagnosed on day 1 continued to late-phase disseminated intravascular coagulation on days 3 and 5 after trauma. Increased levels of tissue-type plasminogen activator plasminogen activator inhibitor-1 complex, plasmin alpha2 plasmin inhibitor complex, D-dimer, neutrophil elastase, and fibrin degradation product by neutrophil elastase but not thrombin-activatable fibrinolysis inhibitor were observed in the disseminated intravascular coagulation patients. No correlation was observed between plasmin alpha2 plasmin inhibitor complex and fibrin degradation product by neutrophil elastase in disseminated intravascular coagulation patients. Multiple regression analysis showed the disseminated intravascular coagulation score and the tissue-type plasminogen activator plasminogen activator inhibitor-1 complex levels on day 1 to correlate with the total volume of transfused blood. Patient prognosis deteriorated in accordance with the increasing disseminated intravascular coagulation severity. Disseminated intravascular coagulation at an early phase of trauma is associated with consumption coagulopathy and excessive fibrinolysis both by plasmin and neutrophil elastase independent of hypoperfusion and continues to disseminated intravascular coagulation at a late phase of trauma. Increased fibrinolysis requires more blood transfusions, contributing to a poor patient outcome.

Thrombin-activatable fibrinolysis inhibitor (TAFI) deficient mice are susceptible to intracerebral thrombosis and ischemic stroke.

BackgroundThrombus formation is a key step in the pathophysiology of acute ischemic stroke and results from the activation of the coagulation cascade. Thrombin plays a central role in this coagulation system and contributes to thrombus stability via activation of thrombin-activatable fibrinolysis inhibitor (TAFIa). TAFIa counteracts endogenous fibrinolysis at different stages and elevated TAFI levels are a risk factor for thrombotic events including ischemic stroke. Although substantial in vitro data on the influence of TAFI on the coagulation-fibrinolysis-system exist, investigations on the consequences of TAFI inhibition in animal models of cerebral ischemia are still lacking. In the present study we analyzed stroke development and post stroke functional outcome in TAFI-/- mice.Methodology/Principal Findings TAFI-/- mice and wild-type controls were subjected to 60 min transient middle cerebral artery occlusion (tMCAO) using the intraluminal filament method. After 24 hours, functional outcome scores were assessed and infarct volumes were measured from 2,3,5-Triphenyltetrazoliumchloride (TTC)-stained brain slices. Hematoxylin and eosin (H&E) staining was used to estimate the extent of neuronal cell damage. Thrombus formation within the infarcted brain areas was analyzed by immunoblot. Infarct volumes and functional outcomes did not significantly differ between TAFI-/- mice and controls (p>0.05). Histology revealed extensive ischemic neuronal damage regularly including the cortex and the basal ganglia in both groups. TAFI deficiency also had no influence on intracerebral fibrin(ogen) formation after tMCAO.ConclusionOur study shows that TAFI does not play a major role for thrombus formation and neuronal degeneration after ischemic brain challenge.

Venous thrombosis risk associated with plasma hypofibrinolysis is explained by elevated plasma levels of TAFI and PAI-1

AbstractElevated plasma clot lysis time (CLT) increases risk of venous and arterial thrombosis. It is unclear which fibrinolytic factors contribute to thrombosis risk. In 743 healthy control subjects we investigated determinants of CLT. By comparison with 770 thrombosis patients, we assessed plasma levels of fibrinolytic proteins as risk factors for a first thrombosis. Plasminogen activator inhibitor-1 (PAI-1) levels were the main determinants of CLT, followed by plasminogen, thrombin-activatable fibrinolysis inhibitor (TAFI), prothrombin, and α2-antiplasmin. Fibrinogen, factor VII, X, and XI contributed minimally. These proteins explained 77% of variation in CLT. Levels of the fibrinolytic factors were associated with thrombosis risk (odds ratios, highest quartile vs lowest, adjusted for age, sex, and body mass index: 1.6 for plasminogen, 1.2 for α2-antiplasmin, 1.6 for TAFI, 1.6 for PAI-1, and 1.8 for tissue plasminogen activator [t-PA]). Adjusting for acute-phase proteins attenuated the risk associated with elevated plasminogen levels. The risk associated with increased t-PA nearly disappeared after adjusting for acute-phase proteins and endothelial activation. TAFI and PAI-1 remained associated with thrombosis after extensive adjustment. In conclusion, CLT reflects levels of all fibrinolytic factors except t-PA. Plasminogen, TAFI, PAI-1, and t-PA are associated with venous thrombosis. However, plasminogen and t-PA levels may reflect underlying risk factors.

Effect of obesity on TAFI in postmenopausal period

The aim of the study was to evaluate how obesity effects the coagulation and fibrinolytic system in the postmenopausal period. Forty-eight obese (body mass index (BMI) ≥30 kg/m(2)) and 38 nonobese (BMI < 30 kg/m(2)) postmenopausal women were enrolled in the study. Fat mass and insulin resistance were calculated. Plasma levels of plasminogen activator inhibitor-1 (PAI-1), tissue plasminogen activator (tPA), d-dimer, thrombomodulin, and thrombin activatable fibrinolysis inhibitor (TAFI) antigen were determined by ELISA method. TAFI activity was measured using the chromogenic assay. Obese subjects had higher PAI-1 (73.5 ± 35.7 ng/mL vs. 57.1 ± 34.2 ng/mL, p < 0.05) levels but lower tPA/PAI-1 ratio (0.59 ± 0.50 vs. 38 ± 0.21, p < 0.05) than their nonobese counterparts. Obesity was not statistically significant for other haemostatic variables. BMI and fat mass were positively correlated with PAI-1 (r = 0.312, p = 0.003; r = 0.381, p = 0.005, respectively) and negatively correlated with tPA/PAI-1 ratio (r = -0.273, p = 0.01; r = -0.545, p = 0.01, respectively). HOMA scores were also positively correlated with PAI-1 levels (r = 0.236, p = 0.04). We found that tendency to hypercoagulability in the postmenopausal women was due to increased PAI-1 rather than TAFI levels, which may contribute to adverse cardiovascular outcomes in this cohort. Further studies should be undertaken to evaluate effects of weight loss on the coagulation and fibrinolytic system.

Valor pronóstico de la concentración del inhibidor de la fibrinolisis activable por trombina y del polimorfismo C1040T en el infarto agudo de miocardio tratado con fibrinolisis

To analyze the prognostic value of thrombin activatable fibrinolysis inhibitor (TAFI) and C1040T polymorphism in acute myocardial infarction treated with fibrinolysis. To analyze C1040T polymorphism influence on its plasma level. An observational, prospective study performed from November 2003 to November 2005 and with a 3 month follow-up. Intensive Medicine Service from a university-affiliated teaching hospital. A total of 53 patients with acute myocardial infarction with persistent ST segment elevation treated with the same fibrinolytic therapy. A control group of 53 biologically similar subjects was included. None. Baseline characteristics; frequency of wild-type genotype (Thr325Thr) and of those corresponding to the mutation (Thr325LLe and LLe325lle), TAFI levels at 6 h, 34 h and 3 months post-fibrinolysis; ejection fraction; Killip-Kimball; reperfusion; ischemic recurrence; death. No relationship was found between biological features and TAFI concentration. The latter was significantly higher in infarct patients (p<0.01) and in the mutation group (p<0.01). The homozygotic mutation (Ile325Ile) was significantly higher in infarct patients (p<0.01). Reperfusion was significantly associated with lower body mass index (p=0.02. OR 0.22. 95% CI), ejection fraction (p=0.004. OR 0.91. 95% CI), triglyceride level (p=0.01. OR 1.02. 95% CI) and cholesterol levels (p=0.001. OR=0.84. 95% CI). Mutation was associated to a significant fall in post-fibrinolysis concentration TAFI antigen and functional TAFI (p=0.01) and (p=0.02), and lower frequency of reperfusion. Reperfusion was associated with a significant post-fibrinolysis reduction in the level of TAFI antigen (p=0.02). Recurrence was associated to a significantly higher post-fibrinolysis level (p=0.05. OR=0.84. 95% CI). This was more frequent in mutation. Post-fibrinolysis TAFI antigen concentration was significantly lower in non-recurrence patients (p=0.028. OR=1.03. 95% CI). A higher concentration of TAFI is associated to a worse prognosis in reperfusion and recurrence in acute myocardial infarction treated with fibrinolysis. Homozygotic mutation was more frequent in myocardial infarction patients. Wild genotype is associated to a better prognosis. Mutation is associated to a higher expression of TAFI.

Increase in plasma thrombin-activatable fibrinolysis inhibitor may not contribute to thrombotic tendency in antiphospholipid syndrome because of inhibitory potential of antiphospholipid antibodies toward TAFI activation

The causes of thrombosis in antiphospholipid syndrome (APS) remain unknown, though several hypotheses in regard to hypofibrinolysis have been proposed. To clarify the mechanism, we measured plasma levels of thrombin-activatable fibrinolysis inhibitor (TAFI) in APS patients. Both the TAFI antigen (TAFI:Ag) level measured with an ELISA, and thrombin-thrombomodulin-dependent TAFI activity (TAFI:Ac) were elevated in 68 APS patients as compared with those in 66 healthy controls, though they were lower than those in 46 patients with autoimmune diseases. As for the influence of antiphospholipid antibodies (aPL) on TAFI levels, the mean TAFI:Ac level in 39 SLE patients positive for APS was significantly lower than that in 27 SLE patients without APS, whereas there was no difference in TAFI:Ag between those groups. Furthermore, purified IgG from patients positive for aPL, and monoclonal aPL (EY2C9 and 23-1D) inhibited the activation of TAFI in a concentration dependent manner. These results suggest that aPL inhibits TAFI activation by affecting the function of thrombomodulin-thrombin complex through phospholipids. Although TAFI in plasma is elevated in autoimmune diseases including APS, we concluded that an elevated level is not likely a risk factor for thrombosis in APS patients, because of the inhibition of TAFI activation by aPL.

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). But no difference was seen in TAFI levels between the diabetic foot ulcer group and diabetic group (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.

Impaired fibrinolysis as a risk factor for Budd-Chiari syndrome

AbstractIn Budd-Chiari syndrome (BCS), thrombosis develops in the hepatic veins or inferior vena cava. To study the relationship between hypofibrinolysis and BCS, we measured plasma levels of fibrinolysis proteins in 101 BCS patients and 101 healthy controls and performed a plasma-based clot lysis assay. In BCS patients, plasminogen activator inhibitor 1 (PAI-1) levels were significantly higher than in controls (median, 6.3 vs 1.4 IU/mL, P < .001). Thrombin-activatable fibrinolysis inhibitor and plasmin inhibitor levels were lower than in controls (13.8 vs 16.9 μg/mL and 0.91 vs 1.02 U/L, both P < .001). Median plasma clot lysis time (CLT) was 73.9 minutes in cases and 73.0 minutes in controls (P = .329). A subgroup of cases displayed clearly elevated CLTs. A CLT above the 90th or 95th percentile of controls was associated with an increased risk of BCS, with odds ratios of 2.4 (95% confidence interval, 1.1-5.5) and 3.4 (95% confidence interval, 1.2-9.7), respectively. In controls, only PAI-1 activity was significantly associated with CLT. Analysis of single nucleotide polymorphisms of fibrinolysis proteins revealed no significant differences between cases and controls. This case-control study provides the first evidence that an impaired fibrinolytic potential, at least partially caused by elevated PAI-1 levels, is related to the presence of BCS.

Assessment of thrombin-activatable fibrinolysis inhibitor (TAFI) activation in acquired hemostatic dysfunction: a diagnostic challenge

Human thrombin activatable fibrinolysis inhibitor (TAFI) is a carboxypeptidase zymogen that was first described in 1995 [1]. It had been previously reported under different names such as carboxypeptidase basic (B), unstable (U), and arginine (R) [2]. The mature TAFI protein contains 401 amino acids, and after glycosylation, the molecular weight becomes 60 kDa. TAFI in its plasma zymogen form can be activated by thrombin, the thrombin-thrombomodulin complex, or plasmin. The activated TAFI (TAFIa) decays spontaneously into the inactive form of TAFI (TAFIai) through a temperature-dependent conformational change. TAFIa plays a role in the inhibition of fibrinolysis by cleaving the carboxyl-terminal lysine residues from partially degraded fibrin. In the coagulation cascade, the generated thrombin can activate TAFI, and the resulting TAFIa inhibits fibrinolysis, finally resulting in the formation of more stable clots [3]. Therefore, a deficiency of the coagulation factors might reduce the TAFIa levels via reduced thrombin generation, resulting in the formation of an unstable clot. In an animal study, TAFI was activated during a thrombotic event, and the inhibition of TAFIa activity enhanced the efficacy of thrombolytic therapy, thereby confirming its role as an inhibitor of fibrinolysis [4-6]. TAFIa also plays a role in the modulation of inflammation through down-regulation of pericellular plasminogen activation and inactivation of the inflammatory peptides bradykinin and anaphylatoxins C3a and C5a. In mice with Escherichia coli-induced sepsis, TAFI deficiency prevented liver damage via inactivation of C3a and C5a [7]. The plasma concentration of TAFI appears to be under the control of genetic factors and non-genetic factors such as sex hormones, cytokines, and lipids [2]. Several diseases, including diabetes, kidney transplantation, hypertension, nephritic syndrome, insulin resistance, obesity, and inflammatory bowel disease, have been shown to be positively associated with plasma TAFI levels [2]. Because TAFI is expressed in adipocytes, an increased TAFI level can be expected in metabolic disturbance. The TAFI levels were also elevated in thrombotic diseases. In keeping with the role of TAFI as an antifibrinolytic factor, high plasma level of TAFI is a risk factor for thrombotic diseases. Meanwhile, TAFI levels are reduced in acquired hemostatic dysfunctions, such as post-partum hemorrhage and sepsis accompanying disseminated intravascular coagulation [3], because the enhanced generation of thrombin or plasmin may result in enhanced TAFI activation and consequent consumption of the TAFI zymogen. Many different methods for measuring TAFI by using ELISA, enzymological methods, or functional methods have been described. All the methods have their inherent advantages and disadvantages, and to date, there is no reference standard for TAFI. Most studies have used the total antigen level of TAFI, but this has yielded ambiguous results, because of the existence of different isoforms and various degrees of activation. Ceres et al. [8] have reported the use of an ELISA that specifically detects TAFI activation. Since substantial TAFI activation occurs in acquired hemostatic dysfunction, ELISA that measures the extent of TAFI activation is potentially useful. In this issue of the Korean Journal of Hematology, Park et al. [9] reported high levels of TAFI activation in sepsis patients by measuring TAFIa/ai levels using an ELISA that they developed in-house. In the in-house ELISA, potato tuber carboxypeptidase inhibitor was used as a capture agent that specifically captured the activated and inactivated TAFI isoforms and did not capture the intact TAFI zymogen. Although only a few septic patients (n=25) were enrolled in the study, the activation status of TAFI could clearly differentiate septic patients from healthy controls. This result is in agreement with the results of a recent study [10] that reported a significant elevation of TAFI activation in meningococcal infection. Since decreases in total TAFI level are associated with increases of TAFI activation level, simultaneous determination of total TAFI and TAFI activation marker is required to interpret the role of TAFI in acquired hemostatic dysfunctions including sepsis. Although the principal physiologic role of TAFI is still a matter of debate, TAFI is reported to be an important protein in the fibrinolytic system. The advent of more accurate assays for measuring plasma TAFI levels may help validate the mechanism underlying TAFI activation in acquired hemostatic dysfunction. This information may help elucidate the contribution of the TAFI pathway to acquired hemostatic dysfunction and will form the basis of potential therapeutic strategies to manipulate the TAFI pathway for acquired hemostatic dysfunction.

The association of TAFI (Thrombin-activatable fibrinolysis inhibitor) with insulin resistance and components of metabolic syndrome in patients with metabolic syndrome

To investigate the association of TAFI with components of metabolic syndrome and insulin resistance in patients with metabolic syndrome. Materials and methods: Patients between 20 and 70 years of age, who met at least 3 of the metabolic syndrome criteria, and had no known coronary artery disease were included in the study. The control group consisted of 20 healthy subjects with demographic characteristics similar to the patients. Fasting blood glucose, HbA1c, lipid profile, insulin, microalbumin, and TAFI Ag levels were investigated in the patients and controls. Insulin resistance was calculated according to the HOMA-IR [(fasting plasma insulin (\muIU/ml) x fasting plasma glucose (mmol/L))/22.5] formula. Results: There was a significant difference (P < 0.01) between patients with metabolic syndrome (MS) and healthy individuals with respect to TAFI Ag levels. However, when patients with MS were divided into 2 groups according to HOMA-IR values, an indicator of insulin resistance, no association was detected between the levels of HOMA-IR and TAFI Ag. In metabolic syndrome group, there was a positive correlation only between the triglyceride and plasma TAFI Ag levels (P < 0.05). Conclusion: These findings suggest that increased TAFI levels in metabolic syndrome may contribute to prothrombotic state and impaired fibrinolysis, and that hypertriglyceridemia may play part in this process.

Blood coagulation, fibrinolysis and lipid profile in patients with prolactinoma

Although the strong association between hyperprolactinaemia and platelet aggregation is well recognized, there are no studies on changes in coagulation and fibrinolytic status in patients with prolactinoma. To our knowledge, tissue plasminogen activator inhibitor-1 (PAI-1), plasma tissue factor pathway inhibitor (TFPI) and thrombin-activatable fibrinolysis inhibitor (TAFI) levels in these patients have not been investigated. Therefore, the main purpose of this study was to evaluate the markers of endogenous coagulation/fibrinolysis, including TFPI and TAFI, and to investigate the relationships between prolactin (PRL) and these haemostatic parameters and serum lipid profile in patients with prolactinoma. Twenty-two patients with untreated, newly diagnosed prolactinoma and 20 age-matched healthy controls were included in the study. Platelet count, mean platelet volume, prothrombin time, activated partial thromboplastin time, fibrinogen, factors V, VII, VIII, IX and X activities, von Willebrand factor, antithrombin III (AT-III), protein C, protein S, tissue plasminogen activator (t-PA), PAI-1, TFPI and TAFI, as well as common lipid variables, were measured. The relationships between serum PRL and these haemostatic parameters were evaluated. Compared with the control subjects, total cholesterol, low density lipoprotein cholesterol, apolipoprotein B, platelet count, fibrinogen, AT-III, PAI-1 and PAI-1/t-PA ratio were significantly increased in patients with prolactinoma (P < 0.0001, P < 0.001, P < 0.05, P < 0.05, P < 0.0001, P < 0.05, P < 0.0001 and P < 0.0001, respectively), whereas TFPI levels were significantly decreased (P < 0.01). Plasma TAFI Ag levels were not significantly different in patients with prolactinoma compared with the controls. In patients with prolactinoma, serum PRL was positively correlated with plasma FVII levels and apo B (r: 0.679, P < 0.05; r: 0.548, P < 0.05, respectively). We found some important differences in the haemostatic parameters between the patients with prolactinoma and healthy controls. Increased platelet count, fibrinogen, PAI-1 and decreased TFPI in patients with prolactinoma may represent a potential hypercoagulable and hypofibrinolytic state, which might augment the risk for atherosclerotic and atherothrombotic complications. Thus, disturbances of the haemostatic system and dyslipidaemia may lead to the excess mortality in patients with prolactinoma.

The Role of Fibrinolytic and Antifibrinolytic Activities in the Pathophysiology of HELLP Syndrome

Objective. To determine the role of the fibrinolytic and antifibrinolytic systems in HELLP syndrome. Methods. This study consisted of patients with HELLP Syndrome (study group, n = 17), women who were admitted for routine prenatal care (pregnant control group, n = 21) and those presenting for routine gynecologic examination (non-pregnant control group, n = 21). Plasma tissue-type plasminogen activator (tPA), thrombin-activatable fibrinolysis inhibitor (TAFI), plasminogen activator inhibitor-1 (PAI-1), thrombin-antithrombin complex (TAT) and thrombomodulin (TM) were measured at admission for all groups. They were again measured after 7 days of biochemical improvement in HELLP Syndrome group. Results. The mean ages of women in the study, pregnant, and non-pregnant control groups were 29.82 ± 4.98, 29.71 ± 5.64, and 27.60 ± 4.21, respectively. Demographically, the patients in all three groups were similar with regard to maternal age, race, and body mass index. Compared to the control groups, the mean tPA, PAI-1, TAFI, TAT, and TM levels were significantly increased in HELLP Syndrome. The mean plasma TAFI antigen concentration 7 days after delivery was significantly lower compared to the baseline (5.84 ± 7.14 % change, p < 0.01). Significant decreases in the mean plasma concentrations were also found in tPA (21.78 ± 20.93 ng/mL mean difference, p < 0.01), PAI-1 (14.22 ± 10.38 ng/mL mean difference, p < 0.001), TAT (0.93 ± 1.19 ng/mL mean difference, p < 0.01), and TM (0.54 ± 0.94 ng/mL mean difference, p < 0.05). Conclusion. It is likely that the impaired fibrinolytic and antifibrinolytic systems, in response to thrombus formation, affect the pathophysiology of HELLP syndrome.

ORIGINAL ARTICLE: Thrombin Activatable Fibrinolysis Inhibitor and Clot Lysis Time in Pregnant Patients with Antiphospholipid Syndrome: Relationship with Pregnancy Outcome and Thrombosis

Antiphospholipid syndrome (APS) pregnancies are associated with thrombotic obstetric complications, despite treatment. This study evaluated Thrombin Activatable Fibrinolysis Inhibitor (TAFI) levels, TAFI gene polymorphisms and Clot Lysis Time (CLT) in pregnant patients with APS in relation to pregnancy outcome and thrombosis. Group 1 consisted of 67 pregnant patients with APS. Group 2 included 66 pregnant patients with uneventful term pregnancies and delivery. Patients were sampled during each trimester and at baseline. TAFI antigen and CLT and two polymorphisms of the TAFI gene, Ala147Thr and +1542C/G, were determined. Significantly prolonged CLT was found at baseline in Group 1. Allele distribution of the TAFI gene polymorphisms was similar in both groups. Basal TAFI and CLT in patients with APS having an adverse or a good obstetrical outcome were similar. Comparison of TAFI and CLT baseline levels in patients with APS with or without previous thrombosis showed no statistical differences. Patients with APS have impairment in fibrinolysis evidenced by prolonged CLT at baseline. TAFI and CLT do not seem to be useful as markers of obstetric outcome or risk of thrombosis in patients with APS.

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

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 hyperthyroidism. The levels of plasma thrombin-activatable fibrinolysis inhibitor (TAFI) antigen and tissue factor pathway inhibitor (TFPI) have been very rarely investigated in patients with hyperthyroidism. Therefore, the main purpose of this study was to evaluate the profile of coagulation and fibrinolytic parameters including TAFI and TFPI in patients with hyperthyroidism. We also investigated the relationships between serum thyroid hormones and hemostatic parameters in these patients. Thirty patients with untreated hyperthyroidism and 25 age- and sex-matched healthy controls were included in the study. Factor V (FV), protein C, protein S, TFPI, and TAFI were measured. The relationships between serum thyroid hormones and these hemostatic parameters were examined. Compared with the control subjects, TAFI Ag levels were increased significantly in patients with hyperthyroidism [mean ± SD (ranges)] [177.03 ± 20.37 (131-206%) versus 145.9 ± 23.0 (89-169%)] (P < 0.001), whereas FV [89.8 ± 21.02 (49-124%) versus 116.1 ± 31.4 (56.4-200%)], protein C [72.8 ± 46.22 (2-149%) versus 144.0 ± 26.3 (74-158%)] and protein S [60.06 ± 42.82 (9-156%) versus 151 ± 33 (76-231%)] activities and TFPI Ag levels [69.56 ± 17.63 (39-140 ng/ml) versus 87.5 ± 15.9 (64-121 ng/ml)] were decreased significantly (P < 0.001 for all of them). We did not find a significant difference between Graves' disease and toxic nodular goiter for hemostatic parameters. In patients with Graves' disease, serum-free T₃ levels were inversely correlated with TFPI Ag levels (r: -0.57, P < 0.05). In conclusion, we found some important differences in the hemostatic parameters between the patients with hyperthyroidism and healthy controls. Increased TAFI and decreased FV, protein C, protein S, and TFPI in these patients represent a potential hypercoagulable and hypofibrinolytic state, 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 hyperthyroidism.

Inflammation and thrombin generation cause increased thrombin activatable fibrinolysis inhibitor levels in experimental human endotoxemia

Inflammation and thrombin generation cause increased thrombin activatable fibrinolysis inhibitor levels in experimental human endotoxemia