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D Collen

Publications and source records attributed to D Collen.

At least 415 records · Page 23Linked to original sources
PubMed1989

Binding properties of monoclonal antibodies against human fragment D-dimer of cross-linked fibrin to human plasma clots in an in vivo model in rabbits.

Two (MA-15C5 and MA-8D3) out of approximately 500 monoclonal antibodies, obtained by fusion of P3X63-Ag8-6.5.3 myeloma cells with spleen cells of mice immunized with purified fragment D-dimer from human fibrin, demonstrated a more than 1,000-fold higher affinity for fragment D-dimer than for native fibrinogen. MA-15C5 was directed against a neoantigenic determinant only expressed in fragment D-dimer. MA-8D3 reacted equally well with fragment D-dimer of crosslinked fibrin and with fragment D of non-crosslinked fibrin but not with fragment D of fibrinogen. Both monoclonal antibodies did not crossreact with rabbit fibrin and its degradation products. The binding of 125I-labeled Fab fragments to human plasma clots, introduced and aged for 1 hr in the jugular vein of heparinized rabbits was studied. Following injection of an equimolar mixture of Fab fragments derived from MA-15C5 and MA-8D3, the clot to blood ratios of radioactivity increased from 3.2 +/- 1.2 (mean +/- SD) at 4 hr to 7.2 +/- 1.4 at 17 hr. The binding of Fab fragments of MA-15C5 and MA-8D3 was independent of the age (1 to 72 hrs) of the clot and of heparin anticoagulation and was only slightly decreased (by 20%) in the presence of circulating human fibrinogen (90 mg/kg body weight) and of human cross-linked fibrin degradation products at a plasma concentration of 10 micrograms/ml. The binding of Fab fragments of MA-15C5 and MA-8D3 to occlusive human plasma clots in the femoral artery of rabbits was comparable to that of the non-occlusive human plasma clots in the jugular vein.(ABSTRACT TRUNCATED AT 250 WORDS)

Aging↗
PubMed1989

Absence of potentiation with murine antiplatelet GPIIb/IIIa antibody of thrombolysis with recombinant tissue-type plasminogen activator (rt-PA) in a canine venous thrombosis model.

F(ab')2 fragments of a murine monoclonal anti-platelet GPIIb/IIIa antibody (7E3) are a potent platelet aggregation inhibitor, which in a canine coronary artery thrombosis model accelerate lysis with recombinant tissue-type plasminogen activator (rt-PA) and prevent reocclusion (7). In the present study, we have investigated the potential value of platelet aggregation inhibition as adjunctive therapy to lysis of venous thrombi, by measuring the thrombolytic potency of 7E3-F(ab')2 and rt-PA used alone or in combination, in dogs with a 125I-fibrin labeled femoral vein thrombus. The dose-response of thrombolysis with rt-PA infused over 4 hours was linear: doses of 0.075 mg/kg, 0.15 mg/kg and 0.3 mg/kg produced 37 +/- 3, 57 +/- 11 and 83 +/- 4% lysis respectively, against a background value of 20 +/- 2%. With F(ab')2 fragments of 7E3 given as a bolus of 1.2 mg/kg, which saturated 70% of the platelet GPIIb/IIIa receptors and prolonged the bleeding to more than 30 min, lysis was not significantly increased over background. Combination of 0.3 or 0.6 mg/kg of 7E3-F(ab')2 with either 0.03 or 0.06 mg/kg of rt-PA did not produce more lysis than obtained with a comparable dose of rt-PA alone. No significant changes in plasma fibrinogen or alpha 2-antiplasmin were observed with either agent alone or with the combination. It is concluded that extensive inhibition of platelet aggregation does not potentiate the thrombolytic effect of rt-PA in this venous thrombosis model.

Animals↗
PubMed1989

Predictive value of increased plasma levels of fibronectin in gestational hypertension.

Blood pressure, proteinuria, and plasma fibronectin and plasminogen activator inhibitor-1 levels were measured in 120 apparently healthy normotensive primigravid women during the first, second, and third trimesters of pregnancy and 2 days post partum. Thirty-two women developed hypertension (diastolic blood pressure greater than or equal to 90 mm Hg) that in 17 women was associated with proteinuria (greater than 0.3 gm/day). Fibronectin levels were 83% +/- 22% of normal (mean +/- SD) during the first trimester and 75% +/- 20% at term in the healthy women but increased from 94% +/- 36% to 187% +/- 36% in the women who developed gestational hypertension (with or without proteinuria) (p less than 0.0001). Plasminogen activator inhibitor-1 levels increased from 26 +/- 19 ng/ml to 110 +/- 86 ng/ml in healthy women and from 32 +/- 35 ng/ml to 290 +/- 90 ng/ml in hypertensive women (p less than 0.001). Increased levels of fibronectin at 25 to 36 weeks of pregnancy (greater than or equal to mean + 2 SD of the healthy women, or greater than 140%) were found in 31 of the 32 women with gestational hypertension with or without proteinuria and in 5 of the 88 healthy women (sensitivity 96%, specificity 94%). Fibronectin levels increased 3.6 +/- 1.9 weeks earlier than the onset of hypertension and/or proteinuria. Increased levels of plasminogen activator inhibitor-1 at 25 to 32 weeks (greater than or equal to 280 ng/ml) were found in 16 of the 32 women who developed gestational hypertension with or without proteinuria and in 4 of the 88 healthy women (sensitivity 50%, specificity 95%). We conclude that increased fibronectin levels are the best predictor of gestational hypertension with or without proteinuria and that its level in plasma increases several weeks before the development of hypertension.

Female↗
PubMed1989

Increased serum levels of fibrinogen degradation products due to treatment with recombinant tissue-type plasminogen activator for acute myocardial infarction are related to bleeding complications, but not to coronary patency. European Co-operative Study Groups for rt-PA.

The association of increasing serum levels of fibrinogen degradation products after recombinant tissue-type plasminogen activator (rt-PA) therapy with bleeding and early coronary patency was assessed in 242 patients with acute myocardial infarction. After administration of 5,000 IU heparin, a median of 40 mg (range 35 to 60) of double chain rt-PA was given intravenously in 90 min. Bleeding occurred in 62 patients; in 73% of patients it was observed within the 1st 24 h and 84% of events consisted of hematoma or prolonged bleeding, or both, at puncture sites. Bleeding events occurred 2.12 times as often in patients with serum levels of fibrinogen degradation products greater than 85 mg/liter as in patients with serum levels less than 22 mg/liter (95% confidence interval 1.01 to 4.43). The infarct-related coronary vessel was patent in 65% of patients at 90 min after the start of rt-PA infusion. In patients with high serum levels of fibrin(ogen) degradation products, coronary patency at 90 min after the start of rt-PA infusion was not better (13% less, 95% confidence interval - 33%, 13%) than in patients with low serum levels. This uncoupling of thrombolytic effect in terms of coronary patency and systemic fibrinogenolysis confirms the experimentally demonstrated fibrin specificity of double chain rt-PA in human subjects. Because fibrin specificity of single chain rt-PA is at least similar to that of double chain rt-PA, the observations in this analysis most likely hold also for single chain rt-PA.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1989

A canine model of coronary artery thrombosis with superimposed high grade stenosis for the investigation of rethrombosis after thrombolysis.

A canine model was developed to investigate coronary artery thrombolysis and reocclusion in the setting of endothelial cell damage and fixed stenosis, which simulate anatomic features occurring in patients with acute myocardial infarction. In open chest dogs, endothelial cell damage was produced in the left anterior descending coronary artery by external compression with blunt forceps, greater than 90% stenosis was obtained by an external constrictor and thrombosis was induced by instillation of thrombin and fresh blood in an isolated arterial segment. In the absence of stenosis, intravenous infusion of 750,000 U of streptokinase over 1 h caused reperfusion in five of six dogs in 34 +/- 25 min (mean +/- SD). Urokinase, 600,000 U intravenously over 30 min followed by 600,000 U over 30 min by the intracoronary route, induced reperfusion in three of four dogs in 65 +/- 23 min. Recombinant two chain tissue-type plasminogen activator (rt-PA) (G11021), infused intravenously at a rate of 15 micrograms/kg per min for 30 min or until reflow, induced reperfusion in all 12 dogs in 28 +/- 13 min. In the absence of coronary artery stenosis, spontaneous reocclusion did not occur within 2 h after the end of the infusion. In the presence of the coronary artery constrictor, which reduced the blood flow to 40 +/- 10% of baseline, streptokinase, urokinase and rt-PA caused coronary thrombolysis to proceed at comparable or only slightly slower rates. Cyclical reocclusion during or after the end of infusion of these thrombolytic agents, caused by platelet-rich thrombus, was almost invariably observed, generally within 30 min after the onset of reperfusion.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1989

Thrombus imaging with an I-123-labeled F(ab')2 fragment of an anti-human fibrin monoclonal antibody in a rabbit model.

The murine monoclonal antibody MA-15C5 binds to cross-linked fibrin but not to fibrinogen. Fab or F(ab')2 fragments of MA-15C5, labeled with iodine-123, were injected intravenously into nine rabbits with a nonocclusive 0.2-mL human plasma clot in the jugular vein and into eight control rabbits. Scintigrams obtained at hourly intervals after injection of the F(ab')2 fragment revealed a significantly higher accumulation of tracer in the clot region than in the contralateral region. The relative excess of tracer in the jugular vein region was significantly greater in the study animals than in the control animals throughout the study period. Blind reading of serial scans revealed no visible tracer accumulation in seven of eight control rabbits, whereas the scans of seven of nine study rabbits showed clearly visible accumulation (sensitivity = 77%, specificity = 87%). The Fab fragment of MA-15C5 had a lower affinity and bound less avidly to the blood clot in vivo. These results suggest that the F(ab')2 fragment has better imaging properties than the Fab fragment and that it may be useful for imaging blood clots in man.

Animals↗
PubMed1989

Synergistic combinations of recombinant human tissue-type plasminogen activator and human single-chain urokinase-type plasminogen activator. Effect on thrombolysis and reocclusion in a canine coronary artery thrombosis model with high-grade stenosis.

The synergistic effects of recombinant human tissue-type plasminogen activator (rt-PA) and single-chain urokinase-type plasminogen activator (scu-PA) on coronary arterial thrombolysis were investigated in open-chest dogs with thrombosis of the left anterior descending coronary artery and a superimposed high-grade stenosis. A 90% stenosis was generated by external constriction, reducing blood flow to 40 +/- 10% of baseline. Localized thrombosis was produced by endothelial cell injury and instillation of thrombin and fresh blood. Intravenous infusion for 60 minutes of either 30 micrograms/kg/min rt-PA alone or 10 micrograms/kg/min scu-PA alone consistently produced coronary artery recanalization (six of eight dogs and five of five dogs, respectively) but was almost always associated with reocclusion during or shortly after the end of the infusion (four of six dogs and five of five dogs, respectively). Infusion of either 15 micrograms/kg/min rt-PA or 5 micrograms/kg/min scu-PA for 60 minutes did not cause coronary artery recanalization (none of four dogs in each group). Combined infusion of 7.5 micrograms/kg/min rt-PA and 2.5 micrograms/kg/min scu-PA for 60 minutes (one fourth of the minimum thrombolytic dose of each agent) induced coronary artery recanalization (six of six dogs) but was also associated with early reocclusion (six of six dogs). Combined infusion of 3.75 micrograms/kg/min rt-PA and 1.25 micrograms/kg/min scu-PA for 60 minutes did not consistently cause recanalization (one of four dogs). Combined infusion of 15 micrograms/kg/min rt-PA and 5 micrograms/kg/min scu-PA for 60 minutes caused recanalization in all of six dogs but was associated with reocclusion in all six.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1989

Differential sensitivity of erythrocyte-rich and platelet-rich arterial thrombi to lysis with recombinant tissue-type plasminogen activator. A possible explanation for resistance to coronary thrombolysis.

Acute myocardial infarction is triggered by coronary artery occlusion that may be recanalized by thrombolytic therapy with a success rate of up to 75% only. The resistance of coronary artery occlusion to thrombolysis may either be due to obstruction of the lumen by a nonthrombotic mechanism or by intrinsic resistance of thrombus to dissolution. Coronary arterial thrombi are composed of platelet-rich and erythrocyte-rich material in variable proportions. To evaluate the relative sensitivity of these thrombus components to thrombolysis, we have used two femoral arterial thrombosis models in the rabbit, consisting of erythrocyte-rich clot produced by injecting whole blood and thrombin in an isolated segment and of platelet-rich thrombus spontaneously formed on an everted (inside out) femoral arterial segment. Intravenous infusion of recombinant tissue-type plasminogen activator (rt-PA) at a rate of 30 micrograms/kg/min consistently reperfused arteries occluded with erythrocyte-rich clot (six of six animals compared with zero of six placebo-treated animals, p = 0.002), whereas infusion of 30 or 100 micrograms/kg/min was significantly less efficient for reperfusion of everted segments occluded with platelet-rich material (only four of 12 animals, p = 0.01). Intra-arterial infusion proximal to the occlusion, at a rate of 20 micrograms/kg/min reperfused six of seven rabbits with erythrocyte-rich clots but only one of seven rabbits with occluded everted segments (p = 0.03). A dose of 100 micrograms/kg/min was necessary to reperfuse platelet-rich occlusions in five of six rabbits.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1989

Correlation between template bleeding times and spontaneous bleeding during treatment of acute myocardial infarction with recombinant tissue-type plasminogen activator.

The purpose of this study was to correlate bleeding complications during and after treatment with recombinant tissue-type plasminogen activator (rt-PA) with serial template bleeding time measurements, with ADP-induced platelet aggregation, with clinical characteristics, and with hemostatic parameters. Fifty-two of 55 consecutive patients with acute myocardial infarction and template bleeding times (Ivy method) of less than 9.5 minutes were treated with rt-PA in a total dose of 55-212 mg (mean, 109 mg) over 90 to 360 minutes (median, 240 minutes) combined with heparin. The mean bleeding time was significantly prolonged at 90 minutes (from 5.0 +/- 1.9 to 8.2 +/- 4.3 minutes, p less than 0.0001) but returned toward baseline after 4 hours (from a median of 8.0 to 7.0 minutes, p less than 0.05). Thirteen patients (25%) suffered relatively minor but spontaneous bleeding that did not correlate with age, hypertension, smoking, partial thromboplastin time, platelet count, ADP-induced platelet aggregation, steady-state rt-PA level, or extent of fibrinogen degradation. In multivariate analysis, only the 90-minute bleeding time correlated with spontaneous bleeding (p = 0.01). Prolongation of the 90-minute bleeding time to greater than or equal to 9 minutes, which occurred in 21 patients, correlated with spontaneous bleeding with a sensitivity of 69% (95% confidence interval, 39-90%) and a specificity of 69% (95% confidence interval, 52-83%). Retrospective analysis revealed that in 14 patients taking aspirin, the bleeding time at 90 minutes was significantly more prolonged (p less than 0.05) and spontaneous bleeding significantly more frequent (p less than 0.01) than in patients not taking aspirin.(ABSTRACT TRUNCATED AT 250 WORDS)

Adenosine Diphosphate↗
PubMed1989

Pharmacodynamics of thrombolysis with recombinant tissue-type plasminogen activator. Correlation with characteristics of and clinical outcomes in patients with acute myocardial infarction. The TAMI Study Group.

Coagulation analysis was performed on blood samples from 386 patients with acute myocardial infarction drawn before, during, and after a continuous intravenous infusion of 150 mg recombinant tissue-type plasminogen activator (rt-PA) (Activase). Plasma rt-PA rose to peak levels of 2.1 +/- 3.1 micrograms/ml (mean +/- SD). Fibrinogen levels measured by coagulation rate and by sulfite precipitation decreased from baseline levels of 3.0 +/- 0.9 and 3.2 +/- 1.0 g/l, respectively, to nadir levels of 1.4 +/- 0.75 and 1.8 +/- 0.92 g/l, respectively, and were associated with peak levels in serum of fibrinogen-degradation products (FDP) of 230 +/- 470 micrograms/ml. Forty percent of patients experienced a nadir functional-fibrinogen level of less than 1.0 g/l, whereas 20% fell below 0.5 g/l. Nadir fibrinogen levels did not correlate with patency of the infarct-related coronary artery at 90 minutes or with risk of coronary vessel reocclusion within 7-10 days. However, the risk of coronary artery reocclusion was inversely related to the baseline functional fibrinogen level (p = 0.0008), with the magnitude of its drop to nadir level (p = 0.0003) as well as to peak levels of FDP (p = 0.038). Quantitative blood loss correlated with all markers for systemic fibrinogenolysis including nadir fibrinogen level (r = -0.20, p = 0.0011), percent decrease of fibrinogen (r = 0.22, p = 0.001), and peak FDP levels (r = 0.14, p = 0.020). Both patients who experienced intracranial hemorrhage presented with high baseline fibrinogen levels and experienced extensive degradation of coagulable fibrinogen. Overall, patients at greatest risk of systemic fibrinogenolysis tended to be relatively older women with lower body weight.(ABSTRACT TRUNCATED AT 250 WORDS)

Blood Coagulation↗
PubMed1989

Recombinant plasminogen activator inhibitor-1 reverses the bleeding tendency associated with the combined administration of tissue-type plasminogen activator and aspirin in rabbits.

The major side effect of thrombolytic therapy is bleeding; however, the pathogenesis of this potential complication is not well understood. Accordingly, we examined the effects of aspirin and recombinant human tissue-type plasminogen activator (rt-PA) on serial template bleeding times and on hemostasis parameters in rabbits. The administration of intravenous aspirin (15 mg/kg) produced a slight prolongation in bleeding times, from 2.1 +/- 0.5 to 2.6 +/- 0.5 min (mean +/- SD, n = 26, P less than 0.01), whereas rt-PA (1 mg/kg per h for 2 h) lengthened the bleeding time from 2.4 +/- 0.3 to 3.2 +/- 0.6 min (n = 5, P = NS). Combination of aspirin with 0.5 mg/kg per h of rt-PA for 2 h prolonged the bleeding time from 2.5 +/- 0.4 to 6.2 +/- 0.9 min (n = 10, P less than 0.01), with an associated fibrinogen decrease of approximately 15%. The combination of aspirin with 1 mg/kg per h of rt-PA for 2 h prolonged the bleeding time from 3.0 +/- 0.3 to 8.3 +/- 1.4 min (n = 8, P less than 0.01) and simultaneously induced a decrease of plasma fibrinogen by approximately 40%. Virtually all animals treated with rt-PA and aspirin manifested a bleeding tendency, as evidenced by spontaneous rebleeding at sites of previously performed template bleeding times or oozing at the femoral venous catheterization site. Intravenous bolus injection of 1 mg/kg of guanidine hydrochloride-reactivated recombinant human plasminogen activator inhibitor-1 (rPAI-1) at the end of the rt-PA infusion resulted in complete reversal, within 5 min, of the prolongation of the bleeding time, and in a disappearance of the bleeding tendency. Nonreactivated rPAI-1 and tranexamic acid were significantly less potent in reversing the bleeding time prolongation. These findings indicate that aspirin and rt-PA given separately do not markedly affect the template bleeding time, but in combination induce a marked prolongation associated with a significant bleeding tendency. This bleeding time prolongation can be rapidly normalized by the administration of reactivated rPAI-1.

Animals↗
PubMed1989

Tissue-type plasminogen activator. A review of its pharmacology and therapeutic use as a thrombolytic agent.

Coronary arterial thrombolysis is becoming an established treatment of acute myocardial infarction. If given early enough, it recanalises occluded coronary arteries, salvages myocardial function and reduces mortality. A reduction of mortality in patients with acute myocardial infarction has now been demonstrated for streptokinase, anisoylated plasminogen streptokinase activator complex (APSAC; anistreplase) and recombinant tissue-type plasminogen activator (rt-PA). From the biochemical point of view, rt-PA has several attractive properties. It is similar to or identical with the physiological plasminogen activator in blood, it does not induce an antibody response, and it is more fibrin-specific than most or all other currently known thrombolytic agents. The rate of recanalisation of occluded coronary arteries with rt-PA is about 60 to 80% in non-comparative and placebo-controlled trials. rt-PA was similar in efficacy to urokinase in the only trial to compare the 2 agents. In 2 comparative trials evaluated by meta-analysis, rt-PA appeared more effective than streptokinase for the early recanalisation of occluded arteries. Both agents were comparable in their effects on left ventricular function in 2 comparative trials, but further study is needed to conclusively evaluate this parameter. Moreover, both agents reduce inhospital mortality, but much larger direct comparative trials are required before scientifically valid statements can be made on the relative clinical efficacy of available thrombolytic agents in terms of their effects on both morbidity and mortality. Thus, rt-PA constitutes a notable contribution of recombinant DNA technology to the treatment of thromboembolic disease, the main cause of death and disability in Western societies.

Animals↗
PubMed1989

Thrombolytic properties of human tissue-type plasminogen activator, single-chain urokinase-type plasminogen activator, and synergistic combinations in venous thrombosis models in dogs and rabbits.

Thrombolysis with single and combined four-hour intravenous (IV) infusions of recombinant tissue-type plasminogen activator (rt-PA), recombinant single-chain urokinase-type plasminogen activator of 54,000 molecular weight (mol wt) (rscu-PA), and rscu-PA-32 kD, an rscu-PA derivative of 32,000 mol wt was studied in a femoral vein thrombosis model in the dog and in a jugular vein thrombosis model in the rabbit. In both species, the dose-response curves were linear, and no systemic activation of the fibrinolytic system or fibrinogen breakdown was observed. The steady-state levels of rt-PA-, rscu-PA-, and rscu-PA-32 kD-related antigens in plasma were proportional to the infusion rates. In the dog model, 25% lysis was obtained with 0.11 mg/kg rt-PA, 0.8 mg/kg rscu-PA, and 0.37 mg/kg rscu-PA-32 kD. Combinations of rt-PA and rscu-PA were 2.6 times more active (P less than .005) than anticipated on the basis of their pharmacologic additive effects, whereas combinations of rt-PA and rscu-PA-32 kD were 2.7 times more active (P less than .05). In the rabbit model, 25% lysis was obtained with 0.24 mg/kg rt-PA, 0.75 mg/kg rscu-PA, and 1.25 mg/kg rscu-PA-32 kD. Combinations of rt-PA and rscu-PA have a fivefold synergistic interaction, but surprisingly no synergism was observed between rt-PA and rscu-PA-32 kD. This study shows that synergism between rt-PA and rscu-PA occurs both in rabbits and dogs in a relatively narrow concentration range that allows a fractional reduction of the total equipotent dose by a factor of 2.5-fold to fivefold. Combination therapy is not associated with systemic fibrinolytic activation. This range of synergistic interaction, although limited, may be useful in devising the best thrombolytic therapy for patients with thromboembolic disease.

Animals↗
PubMed1989

New developments in thrombolytic therapy.

Thrombotic complications of cardiovascular disease are a main cause of death and disability and, consequently, thrombolytic therapy with plasminogen activators could favorably influence the outcome of such life-threatening diseases as acute myocardial infarction (AMI). Five thrombolytic agents are either available or under clinical investigation: streptokinase (SK), urokinase (UK), recombinant tissue-type plasminogen activator (rt-PA), anisoylated plasminogen streptokinase activator complex (APSAC) and single chain urokinase-type plasminogen activator (scu-PA, pro-urokinase). The first generation thrombolytic agents, SK (and probably also UK), are only moderately efficacious; rt-PA is a more effective and fibrin-specific thrombolytic than SK; APSAC has a thrombolytic efficacy and fibrin-specificity that is probably similar or somewhat superior to that of SK and can be administered by bolus injection; scu-PA is more fibrin-specific than UK but it is only in the early stage of clinical investigation. Reduction of infarct size, preservation of ventricular function and/or reduction in mortality has been observed with SK, rt-PA and APSAC, but comparative trials with mortality endpoints are not yet available. Intravenous SK recanalizes 40-45 percent of occluded coronary arteries in patients with AMI and reduces mortality by 25 percent. rt-PA produces both more rapid and more frequent (65-70 percent) reperfusion. The choice of agent for the treatment of AMI at present must be based on considerations of lower cost of streptokinase versus higher efficacy for coronary recanalization of rt-PA. All available thrombolytic agents suffer shortcomings, including submaximal efficacy, limited fibrin-specificity and bleeding side effects. New developments towards improved efficacy and fibrin-specificity include combinations of synergistic thrombolytic agents, mutants of t-PA or scu-PA, chimeric t-PA/scu-PA molecules, antibody-targeted thrombolytic agents, and/or combinations of fibrin-dissolving agents with anti-platelet strategies.

Clinical Trials as Topic↗
PubMed1988

Insulin stimulates the synthesis of plasminogen activator inhibitor 1 by the human hepatocellular cell line Hep G2.

Secretion of plasminogen activator inhibitor 1 (PAI-1) by cultures of human umbilical vein endothelial cells and human hepatocellular cell line Hep G2 was evaluated after insulin stimulation. The secretion of PAI-1 antigen and activity was measured in the conditioned medium and the cellular extracts after incubation of confluent cultures with 1% serum medium for 24 hours. Insulin induced a dose dependent increase of the PAI-1 secretion by Hep G2 cell line. At 10(-8) M a two fold increase of PAI-1 antigen and activity were observed whereas alpha 2 antiplasmin and fibrinogen were not significantly modified. No effect of insulin was observed on PAI-1 antigen and PAI activity production by human endothelial cells whereas endotoxin resulted in a two fold increase in PAI-1 secretion. In recent clinical studies we have demonstrated that the level of plasma insulin correlated with that of PAI-1. Thus we hypothesize that hepatocytes represent a physiological source of plasma PAI-1 which is modulated by plasma insulin level.

Animals↗