Thrombin-activatable fibrinolysis inhibitor in hypothyroidism and hyperthyroxinaemia.

Endocrine disorders affect both the coagulation and fibrinolytic systems, and have been associated with the development of cardiovascular diseases. Thrombin-activatable fibrinolysis inhibitor (TAFI) is a link between coagulation and the fibrinolytic system. The aim of this study was to determine the effect of thyroid hormone excess and deficiency on TAFI levels and function. The effect of hyperthyroxinemia on TAFI was studied in healthy volunteers who were randomised to receive levothyroxine or no medication for 14 days in a crossover design. The effect of hypothyroidism on TAFI was studied in a multicentre observational cohort study. Blood was drawn before treatment of patients with newly diagnosed hypothyroidism and when euthyroidism was achieved. Plasma clot-lysis times, activated TAFI (TAFIa)-dependent prolongation of clot-lysis and TAFI levels were measured. Thyroid hormone excess resulted in a hypofibrinolytic condition and in an enhanced TAFIa-dependent prolongation of clot lysis. A trend towards decreased plasma TAFI levels was observed in healthy volunteers who used levothyroxine. Hypothyroidism resulted in hyperfibrinolysis and a reduced TAFIa-dependent prolongation of clot lysis. In conclusion, alterations of TAFIa-dependent prolongation of clot lysis in patients with thyroid disorders may cause an impaired haemostatic balance. The disturbed haemostatic balance in patients with hyperthyroidism might make them prone to thrombosis, while the risk for bleeding may increase in patients with hypothyroidism.

The hemostatic system in patients with type 2 diabetes with and without cardiovascular disease.

The contribution of the hemostatic system in the development of cardiovascular disease (CVD) in patients with type 2 diabetes is not completely defined. The aim of this study was to elucidate associations of hemostatic factors with the development of CVD in patients with type 2 diabetes. Patients with type 2 diabetes without CVD (n = 113), with CVD (n = 94), and controls without CVD (n = 100) were enrolled in this study. Several hemostatic markers were measured. A disturbed hemostatic balance in patients with type 2 diabetes was observed as illustrated by hypofibrinolysis and increased levels of von Willebrand factor (vWF) and plasminogen-activator inhibitor 1 (PAI-1). Patients with type 2 diabetes with CVD have more thrombin generation compared to patients without CVD. This hemostatic imbalance might contribute to the development of CVD in patients with type 2 diabetes.

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.

The effects of hyperglycaemia on thrombin-activatable fibrinolysis inhibitor.

Epidemiological studies have shown a strong association between type 2 diabetes mellitus and cardiovascular diseases, and hypofibrinolysis may contribute to this phenomenon. The aim of this study was to determine the effect of hyperglycaemia on thrombin-activatable fibrinolysis inhibitor (TAFI). Hyperglycaemia was mimicked in vitro by incubation of TAFI with glyceraldehyde and in vivo by hyperglycaemic clamping of healthy volunteers. The effects of long-term hyperglycaemia in vivo on TAFI were investigated by comparing TAFI from poorly regulated and tightly regulated patients with type 2 diabetes. In vitro glycated TAFI showed an altered migration pattern on SDS-PAGE due to aggregation. Glycated TAFI showed decreased activity after activation by thrombin-thrombomodulin in a glyceraldehyde-dose-dependent manner and a reduced anti-fibrinolytic potential. In vivo, no differences in TAFI parameters were found after hyperglycaemic clamping of healthy volunteers and between tightly and poorly regulated patients with type 2 diabetes. Moreover, TAFI purified from poorly regulated and tightly regulated patients with type 2 diabetes migrated similarly on SDS-PAGE, indicating little or no glycation of the protein. Despite the deleterious effects of glycation of TAFI in vitro on its function, TAFI was neither affected by hyperglycaemic clamping, nor by long-term hyperglycaemia in patients with type 2 diabetes. This is in contrast to fibrinolytic factors as plasminogen-activator inhibitor I and tissue-type plasminogen activator, which are affected. We therefore hypothesise that a normally functioning TAFI under hyperglycaemic conditions may tip the haemostatic balance towards hypofibrinolysis, which may contribute to the development of cardiovascular diseases in type 2 diabetic patients.

Recent developments in thrombin-activatable fibrinolysis inhibitor research.

Thrombin-activatable fibrinolysis inhibitor (TAFI) provides an important molecular link between the coagulation and fibrinolytic systems. In this review, recent major advances in TAFI research, including the elucidation of crystal structures, the development of small inhibitors and the role of TAFI in systems other than hemostasis, are described and discussed.