Kinetics of the activation of plasminogen by human tissue plasminogen activator. Role of fibrin.

Hoylaerts, Marc; Rijken, D.C.; Lijnen, H. Roger; Collen, D.

doi:10.1016/s0021-9258(19)81051-7

Cited by 1,188 publications

(132 citation statements)

References 20 publications

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“…In accordance with this, complexes between z2-antiplasmin and plasmin present in plasma were only of the Glu-type, as indicated by the absence of Lys-type heavy chains in reduced gels (results not shown). Moreover, the reaction rate between plasmin and a2-macroglobulin being considerably lower (K1 = 1.3 x 105+0.6 x 105m--s-1) [40] than that between plasmin and its primary inhibitor (K1=3.8x107+0.3x l0M-1s- 1) [31], the complexes were preferentially formed with the latter.…”

Section: Discussionmentioning

confidence: 99%

“…Activation of Glu-plasminogen by tissue-type plasminogen activator (t-PA; EC 3.4.21.-) in a homogeneous system such as plasma is kinetically ineffective because in the absence of fibrin the Km of Glu-plasminogen for t-PA is at least 30 times greater than the plasma plasminogen concentration (65/zM and 2,uM respectively [1]). In contrast, physiological fibrinolysis is a heterogeneous phase process localized at the plasma/fibrin interphase, where the kinetic parameters are efficiently improved and the specific interactions between the reactants t-PA, Gluplasminogen, a2-antiplasmin and fibrin lead to adsorption phenomena that limit the generation of plasmin (EC 3.4.21.7) at the fibrin surface.…”

Section: Introductionmentioning

confidence: 99%

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The mechanism of activation of plasminogen at the fibrin surface by tissue-type plasminogen activator in a plasma milieu in vitro. Role of α2-antiplasmin

Rouy

Anglès-Cano

1990

Biochemical Journal

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The mechanism of activation of human Glu-plasminogen by fibrin-bound tissue-type plasminogen activator (t-PA) in a plasma environment or in a reconstituted system was characterized. A heterogeneous system was used, allowing the setting of experimental conditions as close as possible to the physiological fibrin/plasma interphase, and permitting the separate analysis of the products present in each of the phases as a function of time. The generation of plasmin was monitored both by spectrophotometric analysis and by radioisotopic analysis with a plasmin-selective chromogenic substrate and radiolabelled Glu-plasminogen respectively. Plasmin(ogen)-derived products were identified by SDS/PAGE followed by autoradiography and/or immunoblotting. When the activation was performed in a plasma environment, the products identified on the fibrin surface were Glu-plasmin (90%) and Glu-plasminogen (10%), whereas in the soluble phase only complexes between Glu-plasmin and its fast-acting inhibitor were detected. Identical results were obtained with a reconstituted system comprising solid-phase fibrin, t-PA, Glu-plasminogen and and alpha 2-antiplasmin. In contrast, when alpha 2-antiplasmin was omitted from the solution, Lys-plasmin was progressively generated on to the fibrin surface (30%) and released to the soluble phase. In the presence of alpha 2-antiplasmin or in plasma, the amount of active plasmin generated on the fibrin surface was lower than in the absence of the inhibitor: in a representative experiment the initial velocity of plasmin generation was 2.8 x 10(-3), 2.0 x 10(-3) and 1.8 x 10(-3) (delta A405/min) for 200 nM-plasminogen, 200 nM-plasminogen plus 100 nM-alpha 2-antiplasmin and native plasma respectively. Our results indicate that in plasma or in a reconstituted purified system containing plasminogen and alpha 2-antiplasmin at a ratio similar to that found in plasma (1) the activation pathway of native Glu-plasminogen proceeds directly to the formation of Glu-plasmin, (2) Lys-plasminogen is not an intermediate of the reaction and therefore (3) Lys-plasmin is not the final active product. However, in the absence of the inhibitor, Lys-plasmin and probably Lys-plasminogen, which is more readily activated to plasmin than is Glu-plasminogen, are generated as well.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

The mechanism of activation of plasminogen at the fibrin surface by tissue-type plasminogen activator in a plasma milieu in vitro. Role of α2-antiplasmin

Rouy

Anglès-Cano

1990

Biochemical Journal

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“…These interactions between the N-terminal domain and intramolecular residues are critical for maintaining plasminogen in a tight closed conformation. The proteolytic cleavage at Lys77 by plasmin results in the removal of the N-terminal region, which results in the formation of a truncated form of plasminogen called Lys-plasminogen [65][66][67]. This form of plasminogen is in a more open conformation.…”

Section: Structure and Function Of Plasminogen And Plasminmentioning

confidence: 99%

Plasmin and Plasminogen System in the Tumor Microenvironment: Implications for Cancer Diagnosis, Prognosis, and Therapy

Bharadwaj

Holloway

Miller

et al. 2021

Cancers

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The tumor microenvironment (TME) is now being widely accepted as the key contributor to a range of processes involved in cancer progression from tumor growth to metastasis and chemoresistance. The extracellular matrix (ECM) and the proteases that mediate the remodeling of the ECM form an integral part of the TME. Plasmin is a broad-spectrum, highly potent, serine protease whose activation from its precursor plasminogen is tightly regulated by the activators (uPA, uPAR, and tPA), the inhibitors (PAI-1, PAI-2), and plasminogen receptors. Collectively, this system is called the plasminogen activation system. The expression of the components of the plasminogen activation system by malignant cells and the surrounding stromal cells modulates the TME resulting in sustained cancer progression signals. In this review, we provide a detailed discussion of the roles of plasminogen activation system in tumor growth, invasion, metastasis, and chemoresistance with specific emphasis on their role in the TME. We particularly review the recent highlights of the plasminogen receptor S100A10 (p11), which is a pivotal component of the plasminogen activation system.

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“…Fibrinolysis occurs both on the thrombus and the surface of cells; however, the former process is more effective. The fibrin-bound tPa has significantly higher catalytic activity to activate plasminogen compared to the fluid phase [24]. In addition, the effect of A2AP is inactivated if the plasmin is bound to fibrin [25].…”

Section: Overview Of the Coagulation System And Fibrinolysis And The mentioning

confidence: 99%

Coagulation and Fibrinolysis in Obstructive Sleep Apnoea

Bikov

Mészáros

Schwarz

2021

IJMS

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Obstructive sleep apnoea (OSA) is a common disease which is characterised by repetitive collapse of the upper airways during sleep resulting in chronic intermittent hypoxaemia and frequent microarousals, consequently leading to sympathetic overflow, enhanced oxidative stress, systemic inflammation, and metabolic disturbances. OSA is associated with increased risk for cardiovascular morbidity and mortality, and accelerated coagulation, platelet activation, and impaired fibrinolysis serve the link between OSA and cardiovascular disease. In this article we briefly describe physiological coagulation and fibrinolysis focusing on processes which could be altered in OSA. Then, we discuss how OSA-associated disturbances, such as hypoxaemia, sympathetic system activation, and systemic inflammation, affect these processes. Finally, we critically review the literature on OSA-related changes in markers of coagulation and fibrinolysis, discuss potential reasons for discrepancies, and comment on the clinical implications and future research needs.

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Kinetics of the activation of plasminogen by human tissue plasminogen activator. Role of fibrin.

Cited by 1,188 publications

References 20 publications

The mechanism of activation of plasminogen at the fibrin surface by tissue-type plasminogen activator in a plasma milieu in vitro. Role of α2-antiplasmin

The mechanism of activation of plasminogen at the fibrin surface by tissue-type plasminogen activator in a plasma milieu in vitro. Role of α2-antiplasmin

Plasmin and Plasminogen System in the Tumor Microenvironment: Implications for Cancer Diagnosis, Prognosis, and Therapy

Coagulation and Fibrinolysis in Obstructive Sleep Apnoea

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