- Email: [email protected]
Gene regulation of coagulation and fibrinolysis
PLENARY LECTURES
Wednesday June 27 1990
118 Plasminogen activator inhibitor 1 and its relation to thrombosis KRUIl-HOF EKO Hematology Division, Department of Medicine, CHW Lausanne, Switzerland Plasminogen activator inhibitor 1 (PA&l) is one of the primary inhibitors of the fibrinolytic system. A deficient fibrinolytic activity, often due to high levels of plasma PAI-1, is frequently found in patients with a history of venous thrombosis or with cardiovascular disease. The association of high PAI-1 levels and an increased risk of thrombotic complications has been established in a number of prospective studies. Thus: - in elective hip surgery, elevated preoperative levels of PAI- may constitute a risk factor for the development of postoperative deep vein thrombosis; - in young survivors of myocardial infarction high levels of PAL1 were associated with an increased risk of reinfarction.
119 Gene regulation of coagulation and fibrinolysis MEDCILFRL Hematology Divkion, UniversityMedical Center, CHW Lausanne, Switzerland In recent years, various molecular biological approaches have been employed to further our understanding of the regulation of biosynthesis of key components of the coagulation and fibrinolytic enzyme systems. The isolation of cDNA clones of tissue factor, and of urokinase- and tissuetype plasminogen activator, and plasminogen activator inhibitor (PAI)-l and PAI-2, has demonstrated that these proteins are regulated tissue- specifically, independently and coordinately by growth factors, cytokines and steroids at most levels of regulation, including gene transcription. For example, the inflammatory mediator, tumor necrosis factor suppresses fibrinolysis by inducing PAL1 and PAI-
Fibrinolysi~ (1990) 4. Supp. I, 48 0 I.onzg,m Group IJK Ltd 1990
Furthermore, in patients with septic shock extreme values of PAI- were associated with a high mortality. These results show that measurements of plasma PAL1 may be of value for diagnosing a prethrombotic state. Moreover, high plasma levels of PAI-1 have been observed in patients with obesity, hypertriglycerides and hyperinsulinemia, conditions which may contribute to the development of thromboembolic and/or atherosclerotic disease. Recent data seems to suggest the possibility to correct the abnormal PAI- levels by measures such as physical exercise and treatment with anabolic steroids or metformin, but the effect of such measures on the risk of thrombosis still needs to be established.
while simultaneously promoting clot formation by inducing tissue factor. Regulatory DNA elements which control transcriptional activity of most of these genes by acting as a binding site for specific nuclear proteins have been identified. Elucidation of the molecular processes controlling the interactions between these nuclear proteins with specific DNA elements may ultimately provide a means to selectively modulate gene expression of these proteins in-vivo.
Wednesday June 27 1990
118 Plasminogen activator inhibitor 1 and its relation to thrombosis KRUIl-HOF EKO Hematology Division, Department of Medicine, CHW Lausanne, Switzerland Plasminogen activator inhibitor 1 (PA&l) is one of the primary inhibitors of the fibrinolytic system. A deficient fibrinolytic activity, often due to high levels of plasma PAI-1, is frequently found in patients with a history of venous thrombosis or with cardiovascular disease. The association of high PAI-1 levels and an increased risk of thrombotic complications has been established in a number of prospective studies. Thus: - in elective hip surgery, elevated preoperative levels of PAI- may constitute a risk factor for the development of postoperative deep vein thrombosis; - in young survivors of myocardial infarction high levels of PAL1 were associated with an increased risk of reinfarction.
119 Gene regulation of coagulation and fibrinolysis MEDCILFRL Hematology Divkion, UniversityMedical Center, CHW Lausanne, Switzerland In recent years, various molecular biological approaches have been employed to further our understanding of the regulation of biosynthesis of key components of the coagulation and fibrinolytic enzyme systems. The isolation of cDNA clones of tissue factor, and of urokinase- and tissuetype plasminogen activator, and plasminogen activator inhibitor (PAI)-l and PAI-2, has demonstrated that these proteins are regulated tissue- specifically, independently and coordinately by growth factors, cytokines and steroids at most levels of regulation, including gene transcription. For example, the inflammatory mediator, tumor necrosis factor suppresses fibrinolysis by inducing PAL1 and PAI-
Fibrinolysi~ (1990) 4. Supp. I, 48 0 I.onzg,m Group IJK Ltd 1990
Furthermore, in patients with septic shock extreme values of PAI- were associated with a high mortality. These results show that measurements of plasma PAL1 may be of value for diagnosing a prethrombotic state. Moreover, high plasma levels of PAI-1 have been observed in patients with obesity, hypertriglycerides and hyperinsulinemia, conditions which may contribute to the development of thromboembolic and/or atherosclerotic disease. Recent data seems to suggest the possibility to correct the abnormal PAI- levels by measures such as physical exercise and treatment with anabolic steroids or metformin, but the effect of such measures on the risk of thrombosis still needs to be established.
while simultaneously promoting clot formation by inducing tissue factor. Regulatory DNA elements which control transcriptional activity of most of these genes by acting as a binding site for specific nuclear proteins have been identified. Elucidation of the molecular processes controlling the interactions between these nuclear proteins with specific DNA elements may ultimately provide a means to selectively modulate gene expression of these proteins in-vivo.