Relationship between fibrinolytic and metabolic variables: a study in patients attending a lipid clinic

We investigated the relationship between plasma levels of metabolic and fibrinolytic variables in 163 fasted patients attending a lipid clinic. Of these patients, 118 had hypertriglyceridaemia (HTG) and 45 had normotriglyceridaemia (NTG). In HTG, basal fibrinolytic activity, ie tissue plasminogen activator (t-PA) activity, was impaired as a result of high plasminogen activator inhibitor type 1 (PAI-1) antigen and activity. Multiple stepwise regression analysis identified insulin and triglyceride levels as independent determinants of plasma PAI-1 levels (R2 = 0.18; P = 0.0001). When the patients were stratified into tertiles according to their levels of triglyceride and insulin, PAI-1 antigen levels were found to increase with rising levels of triglyceride in each insulin tertile. In contrast, the increase of PAI-1 with rising insulin levels was evident in the highest triglyceride tertile. In addition, subjects in the lowest tertile of both triglyceride and insulin had the lowest PAI-1 antigen levels, and subjects in the highest tertile of both triglyceride and insulin had the highest levels of PAI-1. Both basal and stimulated levels of t-PA antigen were significantly higher in HTG than in NTG. Multiple stepwise regression analysis identified triglyceride level as the sole major determinant of t-PA antigen levels (R2 = 0.13; P = 0.00003). The observation that both insulin and triglycerides correlate with PAI-1, whereas triglycerides were involved only in the increased secretion of t-PA, suggests that these two proteins are regulated by different mechanisms.

[1]  I. Juhan-vague,et al.  Regulation of Fibrinolysis in the Development of Atherothrombosis: Role of Adipose Tissue , 1999, Thrombosis and Haemostasis.

[2]  P. Halban,et al.  Storage of tissue-type plasminogen activator in Weibel-Palade bodies of human endothelial cells. , 1999, Arteriosclerosis, thrombosis, and vascular biology.

[3]  L. Weinehall,et al.  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. , 1998, Circulation.

[4]  P. McKeigue,et al.  Plasminogen activator inhibitor-1 activity is independently related to both insulin sensitivity and serum triglycerides in 70-year-old men. , 1998, Arteriosclerosis, thrombosis, and vascular biology.

[5]  J. Emeis,et al.  An Endothelial Storage Granule for Tissue-Type Plasminogen Activator , 1997, The Journal of cell biology.

[6]  W. Chandler,et al.  Clearance of tissue plasminogen activator (TPA) and TPA/plasminogen activator inhibitor type 1 (PAI-1) complex: relationship to elevated TPA antigen in patients with high PAI-1 activity levels. , 1997, Circulation.

[7]  R. Dechend,et al.  Update on the toxicology and pharmacology of rDSPA alpha 1 (Bat-PA) in animals and humans , 1997 .

[8]  P. Ridker.  Fibrinolytic and Inflammatory Markers for Arterial Occlusion: The Evolving Epidemiology of Thrombosis and Hemostasis , 1997, Thrombosis and Haemostasis.

[9]  M. Alessi,et al.  PAI-1, Obesity, Insulin Resistance and Risk of Cardiovascular Events , 1997, Thrombosis and Haemostasis.

[10]  E. Tremoli,et al.  Linoleic acid enhances the secretion of plasminogen activator inhibitor type 1 by HepG2 cells. , 1997, Journal of lipid research.

[11]  P. Ridker.  Endogenous fibrinolytic function and risks of future myocardial infarction and stroke: observations from the Physicians' Health Study , 1997 .

[12]  H. Ronday,et al.  Progress in clinical fibrinolysis , 1997 .

[13]  B. Sobel,et al.  Synergistic augmentation of expression of plasminogen activator inhibitor type‐1 induced by insulin, very‐low-density lipoproteins, and fatty acids , 1996, Coronary artery disease.

[14]  S. Thompson,et al.  Fibrinolytic factors and the risk of myocardial infarction or sudden death in patients with angina pectoris. ECAT Study Group. European Concerted Action on Thrombosis and Disabilities. , 1996, Circulation.

[15]  J. Yudkin,et al.  Diminished fibrinolysis in diabetes mellitus and its implication for diabetic vascular disease. , 1996, Coronary artery disease.

[16]  M. Alessi,et al.  Fibrinolysis and risk of coronary artery disease , 1996 .

[17]  B. Wiman.  Plasminogen Activator Inhibitor 1 (PAI-1) in Plasma: Its Role in Thrombotic Disease , 1995, Thrombosis and Haemostasis.

[18]  A. Hamsten,et al.  5 Fibrinolysis and atherosclerosis , 1995 .

[19]  S. Thompson,et al.  Hemostatic factors and the risk of myocardial infarction or sudden death in patients with angina pectoris. European Concerted Action on Thrombosis and Disabilities Angina Pectoris Study Group. , 1995, The New England journal of medicine.

[20]  J. Yudkin,et al.  Determinants of Plasminogen Activator Inhibitor-1 Activity in Survivors of Myocardial Infarction , 1995, Thrombosis and Haemostasis.

[21]  J. Yudkin,et al.  Determinants of Plasminogen Activator Inhibitor 1 Activity in Treated NIDDM and Its Relation to a Polymorphism in the Plasminogen Activator Inhibitor 1 Gene , 1995, Diabetes.

[22]  R. Bergman,et al.  Insulin sensitivity is not an independent determinant of plasma plasminogen activator inhibitor-1 activity. , 1994, Arteriosclerosis and thrombosis : a journal of vascular biology.

[23]  J. McGill,et al.  Factors Responsible for Impaired Fibrinolysis in Obese Subjects and NIDDM Patients , 1994, Diabetes.

[24]  I. Juhan-vague,et al.  Insulin resistance and alterations in the fibrinolytic system , 1993 .

[25]  J. Jansson,et al.  Predictive Value of Tissue Plasminogen Activator Mass Concentration on Long‐term Mortalit in Patients With Coronary Artery Disease A 7‐Year Follow‐up , 1993, Circulation.

[26]  M. Blankenstein,et al.  The cardiovascular risk factor plasminogen activator inhibitor type 1 is related to insulin resistance. , 1993, Metabolism: clinical and experimental.

[27]  P. Ridker,et al.  Endogenous tissue-type plasminogen activator and risk of myocardial infarction , 1993, The Lancet.

[28]  B. Sobel,et al.  Attenuated Fibrinolysis and Accelerated Atherogenesis in Type II Diabetic Patients , 1993, Diabetes.

[29]  B. Sobel,et al.  Stimulation by Proinsulin of Expression of Plasminogen Activator Inhibitor Type-I in Endothelial Cells , 1992, Diabetes.

[30]  B. Sobel,et al.  Augmentation of synthesis of plasminogen activator inhibitor type 1 by insulin and insulin-like growth factor type I: Implications for vascular disease in hyperinsulinemic states , 1991, Proceedings of the National Academy of Sciences of the United States of America.

[31]  J. Caro.  Clinical review 26: Insulin resistance in obese and nonobese man. , 1991, The Journal of clinical endocrinology and metabolism.

[32]  B. Sobel,et al.  Induction of Synthesis of Plasminogen Activator Inhibitor Type-1 byTissue-Type Plasminogen Activator in Human Hepatic and Endothelial Cells , 1990, Thrombosis and Haemostasis.

[33]  A. Hamsten,et al.  Secretion of plasminogen activator inhibitor-1 from cultured human umbilical vein endothelial cells is induced by very low density lipoprotein. , 1990, Arteriosclerosis.

[34]  W. Chandler,et al.  Effect of PAI-1 levels on the molar concentrations of active tissue plasminogen activator (t-PA) and t-PA/PAI-1 complex in plasma. , 1990, Blood.

[35]  P. Timmermans,et al.  Tissue plasminogen activator-induced secretion of type-1 plasminogen activator inhibitor in cultured human fibroblasts. , 1989, Thrombosis research.

[36]  T. Kooistra,et al.  Insulin Stimulates the Synthesis of Plasminogen Activator Inhibitor 1 by the Human Hepatocellular Cell Line Hep G2 , 1988, Thrombosis and Haemostasis.

[37]  W. A. Bradley,et al.  Normal but not hypertriglyceridemic very low-density lipoprotein induces rapid release of tissue plasminogen activator from cultured human umbilical vein endothelial cells. , 1988, Seminars in thrombosis and hemostasis.

[38]  M. Blombäck,et al.  PLASMINOGEN ACTIVATOR INHIBITOR IN PLASMA: RISK FACTOR FOR RECURRENT MYOCARDIAL INFARCTION , 1987, The Lancet.

[39]  M. Alessi,et al.  Correlation between blood fibrinolytic activity, plasminogen activator inhibitor level, plasma insulin level, and relative body weight in normal and obese subjects. , 1986, Metabolism: clinical and experimental.

[40]  J. Albers,et al.  Dextran sulfate-Mg2+ precipitation procedure for quantitation of high-density-lipoprotein cholesterol. , 1982, Clinical chemistry.

[41]  P. Tarbutton,et al.  Enzymatic Determination of Total Cholesterol in Serum , 1974 .

[42]  G Bucolo,et al.  Quantitative determination of serum triglycerides by the use of enzymes. , 1973, Clinical chemistry.

[43]  R. Levy,et al.  Estimation of the concentration of low-density lipoprotein cholesterol in plasma, without use of the preparative ultracentrifuge. , 1972, Clinical chemistry.

[44]  G R Cooper,et al.  Classification of Hyperlipidemias and Hyperlipoproteinemias , 1972, Arquivos brasileiros de cardiologia.

[45]  A. Clauss,et al.  Gerinnungsphysiologische Schnellmethode zur Bestimmung des Fibrinogens , 1957 .

[46]  D.,et al.  Basic and Clinical Aspects of Fibrinolysis and Thrombolysis , 2003 .

[47]  D. Baldassarre,et al.  Plasminogen activator inhibitor type-1 synthesis and mRNA expression in HepG2 cells are regulated by VLDL. , 1996, Arteriosclerosis, thrombosis, and vascular biology.

[48]  B. Sobel,et al.  Augmentation of the synthesis of plasminogen activator inhibitor type-1 by precursors of insulin. A potential risk factor for vascular disease. , 1994, Circulation.

[49]  T. Lüscher,et al.  Influence of lipoproteins on endothelial function. , 1994, Thrombosis research.

[50]  L. Mannucci,et al.  Hypertriglyceridemia and regulation of fibrinolytic activity. , 1992, Arteriosclerosis and thrombosis : a journal of vascular biology.

[51]  G R Cooper,et al.  Classification of hyperlipidaemias and hyperlipoproteinaemias. , 1970, Bulletin of the World Health Organization.