Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P00750 (PLA)
 16,800 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The influence of a new hypolipidaemic agent, bezafibrate, on anticoagulant requirements and fibrinolysis was studied in 15 patients with hyperlipidaemia on long-term treatment with racemic phenprocoumon. Our results suggest a dose-dependent augmentation of the anticoagulant response to the coumarin drug. Treatment with bezafibrate at 450 and 600 mg daily required a reduction of the phenprocoumon dose by 18.5 and 33.5%, respectively. Correspondingly, the serum level of phenprocoumon decreased by 11.6 and 35.3%. No evidence for an altered drug elimination of racemic phenprocoumon could be found during treatment with bezafibrate. The results support the hypothesis that bezafibrate and analogous hypolipidaemic drugs enhance the response to oral anticoagulant drugs by increasing the affinity of the receptor site for coumarins or the rate of degradation of the vitamin-K-dependent clotting factors. The investigation of the fibrinolytic enzyme system demonstrated an increase of the fibrinolytic activity by enhancing the activity of the plasminogen activator. The lysis time for euglobulin clot was reduced significantly, plasma fibrinogen only moderately. The antiplasmin activity could not be altered substantially by a decrease of alpha1-antitrypsin and a slight increase of alpha2-macroglobulin. In contrast with the inhibition of platelet function the effect of bezafibrate on the fibrinolytic enzyme system showed no dose dependence.
Atherosclerosis 1978 Apr
PMID:The effect of bezafibrate on the fibrinolytic enzyme system and the drug interaction with racemic phenprocoumon. 66 91

The administration of ascorbic acid (1g/day) to healthy adults did not significantly influence the levels of serum cholesterol, plasminogen activator activity, plasminogen, fibrinogen, FR-antigen, partial thromboplastin time, platelet adhesiveness, a-1-antitrypsin or a-2-macroglobulin over the 3-month period of study.
Atherosclerosis
PMID:The effeCt of vitamin c supplements on serum cholesterol, coagulation, fibrinolysis and platelet adhesiveness. 80 25

Traditionally, plasmin generation has been conceptualized as a process oriented on the surface of a fibrin-containing thrombus. Recent work, however, indicated that plasminogen and its activators, tissue plasminogen activator (t-PA) and urokinase, can assemble on the surface of cultured human umbilical vein endothelial cells (HUVECs). On binding to HUVECs, plasminogen is activated by t-PA approximately 12-fold more efficiently than fluid-phase plasminogen, and is converted to a plasmin-modified form, possibly unique to cell surfaces. In addition, t-PA interacts with HUVECs at two sites. The major binding site preserves its activity and represents a true (relative molecular weight 40,000) membrane-associated exoreceptor. The low-density lipoprotein (LDL)-like lipoprotein, lipoprotein(a), is highly associated with atherosclerosis, bears striking sequence homology to plasminogen, and competes with plasminogen for cell surface binding. In summary, functional assembly of plasminogen and t-PA may represent an important thromboregulatory system.
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PMID:Assembly of plasmin-generating proteins on the surface of human endothelial cells. 134 92

Atherosclerosis is probably caused by multiple interacting factors such as disturbed lipid metabolism; endothelial cell damage, leading to platelet aggregation and monocyte invasion with the release of mitogenic factors; and disorders of fibrin balance, leading to persisting fibrin deposits. Deficient fibrinolysis may (1) predispose to fibrin deposition and contribute to the pathogenesis of atherosclerosis and (2) contribute to occlusive thrombus formation on fissured plaque, provoking atherothrombosis. Prospective epidemiologic studies have so far not provided definitive evidence that deficient fibrinolysis constitutes a significant risk factor for the development of atherosclerosis. Two recent findings, however, strongly suggest a contribution: (1) Increased lipoprotein(a) levels that reduce tissue-type plasminogen activator (t-PA)-mediated clot lysis are a clear risk factor for atherosclerosis; and (2) increased plasminogen activator inhibitor-1 (PAI-1) levels in patients with disturbed glucose tolerance predispose to an accelerated development of atherosclerotic disease. However, deficient fibrinolysis constitutes a risk factor for the development of thrombotic complications (acute myocardial infarction) in patients with coronary artery disease. The potential role of deficient fibrinolysis in the pathogenesis of atherosclerosis and of atherothrombosis suggests that drugs normalizing deficient endogenous fibrinolysis by either reducing PAI-1 synthesis or by stimulating endogenous t-PA synthesis may be of clinical value. Although regulation of the gene expression of PAI-1 and t-PA is presently under active investigation, no potent specific and safe agents to downregulate PAI-1 or to upregulate t-PA have as yet been identified. Retinoic acid appears to be a specific inducer of t-PA synthesis in human endothelial cells in culture and may constitute a model for the development of drugs that stimulate endogenous t-PA synthesis.
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PMID:On the role of coagulation and fibrinolysis in atherosclerosis. 134 93

Plasmin inhibition by alpha 2-antiplasmin (alpha 2AP) is regulated by the vascular components fibrin(ogen) fragments, plasminogen and lipoprotein (a). Kinetic analysis demonstrates that CNBr-derived fibrinogen fragments completely protect plasmin from alpha 2AP. Plasminogen and 6-aminohexanoic acid decrease the rate of inhibition by 5- and 10-fold respectively. These studies show that CNBr-derived fibrinogen fragments and 6-aminohexanoic acid bind plasmin kringle(s) with binding constants of 2 micrograms/ml and 120 microM respectively, and that plasminogen binds to alpha 2AP with an affinity of 0.5 nM. The unmodulated inhibition is not effected by the presence of lipoprotein (a), but in the presence of protective CNBr-derived fibrinogen fragments the rate of inhibition is increased by the presence of the lipoprotein. The kinetics demonstrate that lipoprotein (a) binds to CNBr-derived fibrinogen fragments with an affinity of 4 nM, displacing plasmin from the protective surface. In addition, tissue-type plasminogen activator and trypsin inhibition by alpha 2AP is not slowed by the presence of CNBr-derived fibrinogen fragments or plasminogen (Pg), respectively. These kinetics suggest that the initial reversible interaction between plasmin and alpha 2AP is mediated by binding of the inhibitor to the kringle 1 domain of plasmin, with a reversible inhibition constant (Ki) of 5.0 x 10(-10) M. Under conditions where this kringle-inhibitor interaction is blocked, the reversible inhibition still occurs between the plasmin and alpha 2AP, but the initial Ki is increased to 5.0 x 10(-9) M. These data suggest that, in the circulation, plasmin inhibition by alpha 2AP may be down-regulated by fibrin, fibrin(ogen) fragments and Pg, but up-regulated by lipoprotein (a) in the presence of fibrin or fibrin(ogen) fragments. The lipoprotein (a)-mediated promotion of plasmin inhibition may provide an additional mechanism by which the lipoprotein impairs fibrinolysis and promotes atherosclerosis.
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PMID:Lipoprotein (a) promotes plasmin inhibition by alpha 2-antiplasmin. 138 85

The increased risk of thromboembolism in people with diabetes mellitus is in part due to changes in the hemostatic mechanism including abnormal platelet function leading to platelet activation, increase in several coagulation factors, decrease in natural anticoagulants, and impaired fibrinolytic activity. Both microangiopathy and atherosclerosis in people with diabetes will enhance the thrombotic potential of these abnormal hemostatic changes. The recent recognition of a role of the components of the plasminogen-plasmin system in many biologic functions at the cellular level has led to studies showing that the angiopathic complications of diabetes may also be caused by impaired plasminogen activator function.
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PMID:Changes in blood coagulation, platelet function, and plasminogen-plasmin system in diabetes. 138 26

A 29-year-old man with congenital protein C deficiency and acute myocardial infarction is reported. Four hours after the onset of chest pain, he was treated intravenously with tissue-type plasminogen activator. Subsequent coronary angiography revealed only slight stenosis of the left anterior descending coronary artery without any atherosclerosis. The propositus, his brother, and his mother, showed low levels of both protein C activity and antigen, while plasma thrombomodulin levels were normal. His grandfather had died from acute myocardial infarction at 38 years of age. We investigated several other risk factors for arterial thrombosis, including factor VII, fibrinogen, heparin cofactor II, lipoprotein (a), and anticardiolipin antibodies. No other haemostatic abnormalities apart from factor VII hyperactivity were detected in this family. To study the effects of protein C and factor VII on procoagulant activity, prothrombin time was measured after the addition of activated protein C and factor VII to protein C-deficient plasma. The prothrombin time ratio decreased along with an increase in the factor VII level. It also decreased with a decrease in the activated protein C level. These findings indicated that the procoagulant activity of factor VII was enhanced by low protein C levels, suggesting that concomitant factor VII hyperactivity may cause acute myocardial infarction in patients with protein C deficiency.
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PMID:Congenital protein C deficiency and myocardial infarction:concomitant factor VII hyperactivity may play a role in the onset of arterial thrombosis. 144 May 17

Hemostatic variables are increasingly recognized as atherothrombotic risk markers and their susceptibility to lifestyle changes has therefore considerable interest. To study this subject knowledge of the spontaneous variability of measures of coagulation and fibrinolysis is required. We monitored 17 young male adults with constant lifestyles for a year and here present characteristics of the observed variability of factor VII coagulant activity (F VIIc), fibrinogen, fibrinolytic variables and blood lipids. The variables differed considerably with regard to total variability (range of CV (%): 13-54) and with respect to relative size of the inter- and intrapersonal components of variation. None of the variables showed seasonal changes of biological significance. Descriptive statistics of the same variables measured in 74 young healthy adults (19 women, 55 men) are also reported. These values may be used as a reference for comparable groups of individuals. Serum triglycerides were significantly associated with F VIIc (Spearman's Rs = 0.24, P < 0.05) and plasma concentrations fo the plasminogen activator inhibitor type I (Spearman's RS = 0.23, P = 0.05). An increased thrombotic tendency with elevated triglyceride levels was thus indicated. Serum cholesterol was not associated with hemostatic variables, except for plasminogen activator activity (Spearman's Rs = 0.31, P < 0.05).
Atherosclerosis 1992 Oct
PMID:The variability of and associations between measures of blood coagulation, fibrinolysis and blood lipids. 146 54

To assess the relationship between the fibrinolytic system and coronary risk factors, several fibrinolytic parameters were measured in 72 male survivors of myocardial infarction and in 53 age-matched healthy controls. The coronary patients had significantly higher plasminogen activator inhibitor (PAI) activity than the control subjects, while t-PA antigen did not differ between the groups. After stratifying the coronary patients in 14 diabetic and 58 nondiabetic patients, the elevated PAI activity remained limited to the diabetic group. PAI activity correlated significantly with systolic blood pressure, blood glucose, body mass index and LDL cholesterol. In multivariate regression analysis, significant associations persisted between PAI and diabetes, body mass index and LDL cholesterol. Coronary disease had no impact on the regression model. Our results suggest that the increased PAI-1 in selected groups of coronary patients is not a consequence of coronary disease itself, but is rather related to the metabolic risk factors of atherosclerosis, especially diabetes.
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PMID:Increased plasminogen activator inhibitor activity in survivors of myocardial infarction is associated with metabolic risk factors of atherosclerosis. 146 21

Decreased fibrinolytic capacity has been suggested to accelerate the process of arterial atherogenesis by facilitating thrombosis and fibrin deposition within developing atherosclerotic lesions. Type 1 plasminogen activator inhibitor (PAI-1) is the primary inhibitor of tissue-type plasminogen activator and has been found to be increased in a number of clinical conditions generally defined as prothrombotic. To investigate the potential role of this inhibitor in atherosclerosis, we examined the expression of PAI-1 mRNA in segments of 11 severely diseased and 5 relatively normal human arteries obtained from 16 different patients undergoing reconstructive surgery for aortic occlusive or aneurysmal disease. Densitometric scanning of RNA (Northern) blot autoradiograms revealed significantly increased levels of PAI-1 mRNA in severely atherosclerotic vessels (mean densitometric value, 1.7 +/- 0.28 SEM) compared with normal or mildly affected arteries (mean densitometric value, 0.63 +/- 0.09 SEM; P less than 0.05). In most instances, the level of PAI-1 mRNA was correlated with the degree of atherosclerosis. Analysis of adjacent tissue sections from the same patients by in situ hybridization demonstrated an abundance of PAI-1 mRNA-positive cells within the thickened intima of atherosclerotic arteries, mainly around the base of the plaque. PAI-1 mRNA could also be detected in cells scattered within the necrotic material and in endothelial cells of adventitial vessels. In contrast to these results, PAI-1 mRNA was visualized primarily within luminal endothelial cells of normal-appearing aortic tissue. Our data provide initial evidence for the increased expression of PAI-1 mRNA in severely atherosclerotic human arteries and suggest a role for PAI-1 in the progression of human atherosclerotic disease.
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PMID:Increased type 1 plasminogen activator inhibitor gene expression in atherosclerotic human arteries. 149 92


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