Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:3.4.21.69 (APC)
 16,337 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The effects of physical conditioning on plasma fibrinolytic activity were studied in two groups of subjects. Volunteers not engaged in any sport were compared with individuals having been subjected to aerobic conditioning (middle-distance runners, defined as men running more than 80 km per week). Plasma concentrations of the different components of the fibrinolytic system were evaluated before and immediately after a maximal effort treadmill protocol. Comparison of the resting parameters revealed that under basal conditions for plasma concentrations of plasminogen, fibrinogen, alpha 2-antiplasmin, protein C and protein S there were no differences between the two groups. Concentrations of the fibrin degradation products (FbDP) and fibrinogen degradation products (FgDP) were significantly higher in the runners than in the control group, indicating an increased fibrinolytic potential that seemed to be a consequence of the reduced formation of tissue plasminogen activator-plasminogen activator inhibitor (t-PA-PAI) complexes. Acute maximal exercise resulted in pronounced fibrinolysis, evidenced by the elevation of FbDP and FgDP concentrations, in both groups of subjects. The acceleration of the fibrinolytic activity was larger in conditioned individuals, which could be accounted for by a higher t-PA release and reduced formation of t-PA-PAI complexes when compared to the untrained subjects.
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PMID:Changes in the fibrinolytic system associated with physical conditioning. 142 41

We studied the natural inhibitors (NI) of blood coagulation and fibrinolysis in 50 patients with lupus anticoagulant (LA), in order to identify possible alterations of these NI, that could favour thrombotic manifestations. We found no statistically significant difference in antithrombin III, protein C and alpha 2-antiplasmin between controls and patients with LA, irrespective of their clinical manifestations. We found an increase of plasminogen activator inhibitor (PAI, P < 0.001) and a decrease of free protein S (PSf, P < 0.001) and total protein S (PSt, 0.01 < P < 0.05) in the patients with LA when compared with the control group. We found no difference in the levels of NI between patients with thrombosis (n = 19) and without thrombosis (n = 31) nor between patients with (n = 25) or without thrombosis and/or foetal loss (n = 25). In contrast, we observed a decrease of PSf in women with foetal loss (n = 10) as compared with women without foetal loss (n = 22, 0.01 < P < 0.05) and a decrease of PSf when comparing 19 patients with systemic lupus erythematosus (SLE) with 31 patients without SLE (0.01 < P < 0.05). These findings show that the patients with LA had several abnormalities in the NI system, but there was no significant association between levels of PAI, PSf, PSt and a history of thrombosis.
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PMID:Natural inhibitors of blood coagulation and fibrinolysis in patients with lupus anticoagulant. 148 97

Six patients (three males and three females), mean age 35.2 years (range 31-43 years), with extensive venous thrombosis were studied. Initial laboratory data indicated that all patients had normal antithrombin III (ATIII), four patients had low protein C (PC), three patients had low protein S (PS) and two patients had low plasminogen. Four patients had high fibrinogen and all patients had reduced tissue-type plasminogen activator activity, elevated tissue plasminogen activator inhibitor and low fibrinolytic activity. All patients were treated with danazol, 5-7 mg/kg orally once daily. In all patients there was significant elevation of ATIII, PC, PS, and plasminogen, reduction in plasma fibrinogen and PAI and enhancement of fibrinolysis. During the 12-36 months period of follow-up, there were no symptoms or signs that suggested recurrence of thrombosis. Apart from weight gain of 5-10 kg and disturbed menstrual cycle in two women, no major side effects were seen. These data suggest that danazol is potentially useful therapy that may increase levels of natural anticoagulants in patients with thrombotic illnesses in which ATIII, PC and PS are low or normal. Further studies are needed to confirm these observations.
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PMID:Significant elevation of protein C and protein S levels in thrombotic disorders by low dose danazol. 183 83

Tissue plasminogen activator (t-PA) and its inhibitor (PAI) were assessed in venous blood drawn before and after venous occlusion (bvo, avo) for 33 patients with Raynaud's phenomenon (RP), 14 with primary RP (PRP), 9 with suspected secondary RP (SSRP), and 10 with definite collagen disease and secondary RP (SRP). There were significant differences in PAI values avo between PRP (and controls), SSRP, and SRP. PAI activity decreased significantly avo only in controls and in PRP, and there was significant t-PA antigen elevation avo in the same groups. In addition, since PAI is neutralized by activated protein C (PC), both PC antigen and PC activity were assessed avo and bvo. PC Ag remained unchanged in all groups, with PC activity significantly lower than controls in SRP and SSRP. Finally the authors looked for interference of anticardiolipin antibodies (ACA) and lupus-like anticoagulant (LAC) with the PC system in collagen disease-associated RP. Specific IgG ACA were found in only 1 patient with SRP. In conclusion, there is an endothelial derangement, involving t-PA release and PAI, in SSRP and SRP patients. The reduced PC activity in these latter groups appears to be due to increased PAI influence rather than to ACA/LAC.
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PMID:t-PA, PAI, and protein C before and after vascular occlusion of the upper limb in patients with Raynaud's phenomenon. 190 68

Increased thrombogenesis observed in systemic lupus erythematosus (SLE) is derived from multiple mechanisms, including: Enhanced coagulation factor VIII:VWf activity, lupus anticoagulants, anti-phospholipid antibodies, acquired deficiencies of natural anti-thrombotic mechanisms (protein C, protein S, anti-thrombin III), and impaired fibrinolytic mechanisms. We studied the fibrinolytic mechanisms of 18 patients with systemic lupus erythematosus, selected carefully to avoid other possible causes of abnormalities in the fibrinolytic activity. Despite the fact that the euglobulin lysis time in steady state was normal in all instances, disturbances in the tissue plasminogen activator/plasminogen activator inhibitor (TPA/PAI) system were found in all SLE patients: TPA activity was undetectable in all cases, whereas it was above 0.4 IU/ml in a control group. In 72 percent of patients, the undetectable TPA activity was correlated with abnormally high PAI activity; PAI levels were normal in all members of the control group, their mean value being 0.74 versus 8.63 IU/ml for SLE patients (P less than .01). Coagulation protein C deficiency was found in 3 patients (17%). Even though within normal range, fibrinogen levels were significantly higher in SLE than in normal controls (219 versus 192 mg/dl, P less than .01) and plasminogen levels were significantly higher in SLE than in controls (117 versus 78.2%, P less than .01). Cross-linked fibrin derivatives (D-D dimers) were negative in all patients with SLE. Sixty-eight percent of SLE patients had high levels of antiphospholipid antibodies, but no correlation with the disturbances of the TPA/PAI system was found. It is concluded that most patients with SLE display severe abnormalities in the TPA/PAI anti-thrombotic system and that these abnormalities may be related to the lupus thrombophilia, apparently multifactorial in its origin.
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PMID:Disturbances in the tissue plasminogen activator/plasminogen activator inhibitor (TPA/PAI) system in systemic lupus erythematosus. 190 23

Defibrotide, a deoxypolyribonuclide, has been found to modulate endothelial cell function causing increase in t-PA and decrease in PAI levels and also increase in PGI2 production. In addition, it increases platelet c-AMP levels and decreases MDA and TXB2 formation in human. Defibrotide inhibits platelet aggregate formation in vitro experiments as well as end-to-end anostomosis in rats. So, defibrotide inhibits the activation of platelets. Besides an increase of protein C and S levels a synergic action of heparin was observed in animal experiments. A strong antithrombotic effect has been observed in animal models. The drug has a beneficial effect in the cases of DVT, POVD, stroke and thromboembolism. Through its action we may say that the drug acts in a novel fashion in contrast to the other drugs used in this area. Defibrotide is a single-stranded polydeoxyribonucleotide obtained from deoxyribonucleic acid of mammalian lungs by controlled depolimerization. Since 1981 in our laboratory and in the clinical department we have been investigating a newly developed agent defibrotide in vitro experiments, animal experiments, and also its clinical pharmacology and clinical application. Some of our findings are already published and compared with literature (40, 43, 46). Because of the limited space we are not going to review the literature in detail but we are going to summarize our observations on this compound in the following order. I--in vitro experiments, II--Animal experiments, III--clinical pharmacology in human.
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PMID:The pharmacology and clinical pharmacology of defibrotide: a new profibrinolytic, antithrombotic and anti-platelet substance. 210 24

Because fibrinolysis is now recognized as an important factor in hypercoagulable states, we have developed and characterized an easily performed, rapid, and quantitative screening test that assesses a patient's fibrinolytic activity. This modification of the dilute whole blood clotting time (DWBCT) counts the number of intact erythrocytes released from the clot formed in samples obtained before and after the application of a venous occlusion cuff. Samples were corrected for the plasma volume changes that occurred during venous occlusion. This test was performed on nine healthy volunteers. Specimens were diluted 1:1 with PBS, rapidly clotted with thrombin and incubated at 37 C. Starting thirty minutes after the thrombin was added and then at twenty minute intervals until 110 minutes, the number of RBCs released from the clot were counted using a Coulter S Plus counter. There were consistently more RBCs released at each time period after venous occlusion (p less than 0.001). Aliquots were also obtained for measuring PAI activity and TPA levels. PAI activity was lower post-cuff at every point (p less than 0.001). TPA level was higher at every point (p less than 0.001) post-cuff. The addition of exogenous TPA, activated protein C, or anti-PAI antibodies increased the amount of clot lysis; while the addition of anti-TPA antibodies and EACA each prevented the post-cuff increase. Unlike the euglobulin lysis time (ELT) this modified DWBCT (mDWBCT) measures the patients intact fibrinolytic system, including PAI and erythrocytes, in a quantitative fashion. Unlike either the ELT or the DWBCT the mDWBCT can be performed within two hours, so results are rapidly available for clinical decisions. These studies have demonstrated an easily performed, inexpensive, quantitative screening test of a patient's overall fibrinolytic system that reacts appropriately to pharmacologic manipulations.
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PMID:A modified quantitative whole blood clot lysis method for general laboratory analysis of fibrinolysis. 211 74

To assess the role of the fibrinolytic system in the pathogenesis of restenosis after percutaneous transluminal coronary angioplasty (PTCA), we determined the components of this system in a retrospective study, including 16 patients with restenosis (gr. A) and 19 patients with long-term success (gr. B). In both groups at baseline fibrinolytic activity (FA) is unchanged, whereas tissue plasminogen activator antigen (tPA-Ag) is significantly increased (gr. A: 147.0%; gr. B: 139.8%; p less than 0.01). Fibrinolytic capacity (FC) and tPA-Ag release are significantly reduced in the restenosis group (FC: 46.5%, p less than 0.05; tPA-Ag release: 48.3%, p less than 0.01) compared to normal controls as well as to gr. B (FC: 84.3%, p less than 0.05; tPA-Ag release: 79.0%, p less than 0.05). Relating to the contact activation system, F XII (79.5%, p less than 0.05) is significantly, and F XI (82.3%) is clearly reduced in gr. A. Protein C (PC) is significantly elevated in gr. B (117.5%, p less than 0.05). There is a negative correlation between plasminogen activator inhibitor (PAI 1) and HDL-cholesterol (r = 0.37, p less than 0.05). It appears, that there is a typical pattern of defective fibrinolysis in patients with restenosis after PTCA and that this might be a pathogenetic factor in the development of restenosis.
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PMID:Impaired fibrinolytic capacity and tissue plasminogen activator release in patients with restenosis after percutaneous transluminal coronary angioplasty (PTCA). 251 Mar 51

In the past few years there has been increasing interest in the role of the vascular endothelium as an active modulator of biological responses. Endothelial cells exert antithrombotic activity by the release of prostacyclin [23] and adenine nucleotides [16], the availability on the cell surface of heparin-like substances [3], and thrombomodulin-mediated activation of protein C [8]. In addition, endothelium is involved in the regulation of fibrinolysis by releasing soluble factors, such as tissue plasminogen activator (tPA; [10]) and plasminogen activator inhibitor (PAI; [22, 11]), as well as in the control of vascular responsiveness by the production of smooth muscle relaxing and contracting factors. Endothelial cells have also been shown to synthesize and to express procoagulant activities [18]. Many data on endothelial cell functions has been obtained from two experimental models, namely endothelial cell cultures and perfused segments of animal and human vessels. Both are subject to methodological criticism since they only represent in part in vivo conditions, and the necessary experimental manipulations and laboratory procedures greatly modify the naturally occurring cellular functions. In order to overcome such difficulties as far as possible, a new in vivo model has been employed to provide easily assessable and reliable data on the properties of endothelial cells in man. A venous segment was isolated functionally by cannulating a dorsal vein in the hand and a cubital vein in the same arm. Changes observed ex vivo in blood from the cubital vein following infusion into the hand vein of an active drug, can mainly be attributed to its local effect on the venous wall. At the same time, a cubital vein in the other arm was cannulated in order to provide information to distinguish systemic from regional effects.
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PMID:New in vivo model to assess venous endothelial cell functions. Effect of defibrotide. 255 18

We have investigated the effect of purified immunoglobulin G (IgG) on endothelial cell functions in 16 patients with lupus anticoagulant, 9 of whom had systemic lupus erythematosus (SLE). Spontaneous or thrombin-stimulated secretion of prostacyclin (PGI2) by cultured human endothelial cells from umbilical cord vein (HUVEC) was not inhibited by the patient's IgG. Nor was spontaneous release of tissue plasminogen activator (t-PA) or of its inhibitor (PAI) modified in the presence of patient's IgG. The rate of activation of purified protein C (PC) by HUVEC in the presence of thrombin was significantly lowered by patient's IgG or Fab' fragment (inhibition of 43%). Neutralization of this effect was obtained by incubation of a greater quantity of phospholipids (phosphatidylcholine, phosphatidylserine) with the patient's IgG. Activation of PC was also performed using purified rabbit thrombomodulin (TM) and a similar inhibition of the patient IgG was observed (inhibition of 48%) but the activation of Gla-domainless PC was not modified.
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PMID:Effect of lupus anticoagulant on antithrombogenic properties of endothelial cells--inhibition of thrombomodulin-dependent protein C activation. 284 52


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