Activated Protein C Increases Fibrin Clot Lysis by Neutralization of Plasminogen Activator Inhibitor No Evidence for a Cofactor Role of Protein S

Fouw, N.J. de; Jong, Y.F. de; Haverkate, F.; Bertina, R. M.

doi:10.1055/s-0038-1647055

Cited by 67 publications

(28 citation statements)

References 18 publications

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“…This same value was obtained if PAI-1 inhibition of APC was monitored in the presence of 220 nM protein S and 0 -50 M PC/PS or PC/PS/PE vesicles (data not shown). These results are consistent with other data in the literature (8). Therefore, unlike the potent profibrinolytic effect observed for APC in vivo (4), in whole blood clot lysis assays (6), and in endothelial cell culture supernatants (5), kinetic data in the purified system suggest that human APC neutralization of PAI-1 by itself may not significantly contribute to up-regulation of the fibrinolytic cascade.…”

Section: Resultssupporting

confidence: 82%

“…This is probably due to the fact that prolonged incubation of human APC with high concentrations of PAI-1 results in a minimal decline in the activity of the proteinase. In support of this, results of an in vitro clot lysis assay using purified components of the APC anticoagulant pathway have disputed whether this mechanism can contribute to the profibrinolytic property of human APC in vivo (8). Such results have raised the possibility that other factor(s) in blood may be involved in APC up-regulation of the fibrinolytic cascade (8).…”

Section: Activated Protein C (Apc)mentioning

confidence: 92%

“…In support of this, results of an in vitro clot lysis assay using purified components of the APC anticoagulant pathway have disputed whether this mechanism can contribute to the profibrinolytic property of human APC in vivo (8). Such results have raised the possibility that other factor(s) in blood may be involved in APC up-regulation of the fibrinolytic cascade (8). In the current study, vitronectin, an abundant plasma and platelet glycoprotein (13)(14)(15), has been identified as the cofactor that dramatically improves the ability of APC to react with PAI-1.…”

Section: Activated Protein C (Apc)mentioning

confidence: 98%

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Vitronectin Functions as a Cofactor for Rapid Inhibition of Activated Protein C by Plasminogen Activator Inhibitor-1

Rezaie

2001

Journal of Biological Chemistry

123

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Activated protein C (APC) is a natural anticoagulant in plasma that down-regulates the coagulation cascade by degrading factors Va and VIIIa. In addition to its anticoagulant function, APC is also known to possess a profibrinolytic property. This property of APC has been attributed to its ability to neutralize PAI-1, thereby increasing the concentration of tissue plasminogen activator in plasma leading to up-regulation of the fibrinolytic cascade. This hypothesis, however, has not been well established, since the concentration of PAI-1 in plasma is low, and its reactivity with APC is very slow in a purified system. Here we demonstrate that vitronectin enhances the reactivity of PAI-1 with APC ϳ300-fold making PAI-1 the most efficient inhibitor of APC thus far reported (k 2 ‫؍‬ 1.8 ؋ 10 5 M ؊1 s ؊1 ). We further show that PAI-1 inhibition of the Glu 192 3 Gln mutant of APC is enhanced ϳ40-fold, independent of vitronectin, suggesting that vitronectin partially overcomes the inhibitory interaction of PAI-1 with Glu 192 . Additionally, we show that PAI-1 inhibition of the Lys 37 -Lys 38 -Lys 39 3 Pro-Gln-Glu mutant of APC is severely impaired, suggesting that, similar to tissue plasminogen activator, the basic 39-loop of APC plays a critical role in the reaction. Together, these results suggest that vitronectin functions as a cofactor to promote the profibrinolytic activity of APC.

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Section: Resultssupporting

confidence: 82%

Section: Activated Protein C (Apc)mentioning

confidence: 92%

Section: Activated Protein C (Apc)mentioning

confidence: 98%

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Vitronectin Functions as a Cofactor for Rapid Inhibition of Activated Protein C by Plasminogen Activator Inhibitor-1

Rezaie

2001

Journal of Biological Chemistry

123

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“…The relative amounts of plasminogen activators and APC at sites of hemostasis and thrombosis are not known and likely exhibit both spatial and temporal variability due to differing rates of synthesis, metabolism, and adsorption to surfaces. We found no accelerating effect on protein S, phospholipid, and CaClz on the inactivation of PA1 by APC in a purified, reconstituted system, results similar to those reported by de Fouw et al (1988). However, de Fouw et al (1986 have observed protein S to enhance the acceleration of whole human blood clot lysis by APC in vitro.…”

Section: Discussionsupporting

confidence: 91%

Platelet plasminogen activator inhibitor: purification and characterization of interaction with plasminogen activators and activated protein C

Fay

Owen²

1989

Biochemistry

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Plasminogen activator inhibitor (PAI) was purified in active form from porcine platelets under nondenaturing conditions. The purified inhibitor (Mr 47,000) reacts with tissue-type plasminogen activator (t-PA), urokinase (UK), and activated protein C (APC) to yield both SDS-stable complexes and a modified PAI of slightly reduced molecular weight. The second-order rate constants for the inhibition of t-PA and UK by PAI are 3.5 X 10(7) and 3.4 X 10(7) M-1 s-1, respectively. Activated protein C reacts with PAI with a second-order rate constant of 1.1 X 10(4) M-1 s-1. This rate is not accelerated by protein S, phospholipid, and calcium, or heparin. It is concluded that (1) PAI can function as both inhibitor and substrate of its target proteases, (2) if APC promotes fibrinolysis via inactivation of PAI, then APC must be present in concentrations several orders of magnitude greater than t-PA, or the interaction of APC and PAI must be accelerated by presently unknown mechanisms, and (3) in the absence of heparin, platelet PAI is the most rapid inhibitor of APC yet described.

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“…* rnent (UK). p < 0.05 vs. before urokinase treatpotentiating the activity of plasminogen acti vators [6,7], which is independent of protein S [10], Recent reports suggested the efficacy of protein C as an extrinsic antithrombotic agent [ l l-l 3] or as an agent to prevent reste nosis after percutaneous transluminal coro nary angioplasty [ 14],…”

Section: Discussionmentioning

confidence: 99%

Augmented Plasma Protein C Activity after Coronary Thrombolysis with Urokinase in Patients with Acute Myocardial Infarction

Goto

Handa²,

Kawai³

et al. 1992

Cardiology

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Coronary thrombolysis reduces morbidity and mortality in patients with acute myocardial infarction, however, the exact effects of thrombolytic agents on the status of intrinsic hemos-tases are not fully understood. In the present study, we examined serial changes in plasma thrombin and protein C activities of 6 patients with acute myocardial infarction treated with urokinase. Fibrinolysis occurred immediately after urokinase injection with an increase in the plasma thrombin-antithrom-bin III complex, suggesting a subsequent procoagulant state due to thrombin generation. Correspondent increases in plasma protein C activity were observed, however, protein S levels did not change at all. Our findings suggest that urokinase administration for coronary thrombolysis not only causes fibrinolysis, but also induces thrombin activity, which may be antagonized by augmented intrinsic protein C activity.

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Activated Protein C Increases Fibrin Clot Lysis by Neutralization of Plasminogen Activator Inhibitor No Evidence for a Cofactor Role of Protein S

Cited by 67 publications

References 18 publications

Vitronectin Functions as a Cofactor for Rapid Inhibition of Activated Protein C by Plasminogen Activator Inhibitor-1

Vitronectin Functions as a Cofactor for Rapid Inhibition of Activated Protein C by Plasminogen Activator Inhibitor-1

Platelet plasminogen activator inhibitor: purification and characterization of interaction with plasminogen activators and activated protein C

Augmented Plasma Protein C Activity after Coronary Thrombolysis with Urokinase in Patients with Acute Myocardial Infarction

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