Effective lysis of model thrombi by a t-PA mutant (A473S) that is resistant to alpha2-antiplasmin

Robbie, Linda A.; Bennett, Bruce; Keyt, B. A.; Booth, Nuala A.

doi:10.1046/j.1365-2141.2000.02365.x

Cited by 10 publications

(12 citation statements)

References 44 publications

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“…Clot lysis experiments confirmed that the endogenous thrombolysis potential is significantly enhanced in α2-AP -/-mice, indicating a physiological role of α2-AP in fibrin surveillance [38]. We have previously reported that tPA increases the rate of clot lysis after endothelial injury [34] and other study showed the functional significance of α2-AP as a direct inhibitor of tPA, which explains the basis of the accepted role of α2-AP as a regulator of fibrin persistence and thrombus resistance to lysis [39].…”

Section: Pulmonary Embolismsupporting

confidence: 76%

Role of 2-Antiplasmin in Cardiovascular System

Shu¹,

Matsuno²,

Kitajima³

et al. 2005

LDDD

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Inhibition of the blood fibrinolytic system (plasminogen/plasmin) occurs either at the level of plasminogen activators, regulated by specific plasminogen activator inhibitors (PAIs) or at the level of plasmin, mainly regulated by α2-antiplasmin (α2-AP). In this contribution, we focused on the roles of α2-AP in acute myocardial infarction and vascular remodeling associated with cardiovascular diseases. Our findings have identified a new target for the development of new therapeutics for the clinical therapy of cardiovascular diseases.

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Section: Pulmonary Embolismsupporting

confidence: 76%

Role of 2-Antiplasmin in Cardiovascular System

Shu¹,

Matsuno²,

Kitajima³

et al. 2005

LDDD

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“…Model thrombi formed from whole blood lysed without the addition of proteases. This lysis occurred despite the high concentrations of inhibitors present in these thrombi (Robbie et al, 1997(Robbie et al, , 2000. After the initial observations in model thrombi prepared from whole blood, thrombi prepared from PRP and PMNs were used to allow the cellular contribution to lysis to be analysed more directly.…”

Section: Discussionmentioning

confidence: 99%

“…Thrombi formed in the Chandler loop system contain all these components and have structures similar to human in vivo thrombi (Robbie et al, 1997). The cellular elements are well placed to modify the lytic process, and platelets have already been identified as modifying lysis via their PAI-1 content (Robbie et al, 1993(Robbie et al, , 1997(Robbie et al, , 2000. This system is more appropriate to the study of thrombus lysis than homogeneous fibrin clots prepared from plasma in the absence of cells, which are often used.…”

Section: Discussionmentioning

confidence: 99%

“…Chandler model thrombi. Thrombi were formed in a Chandler system (Chandler, 1958) as described previously (Robbie et al, 1997(Robbie et al, , 2000. Citrated whole blood (0´9 ml) or PRP (0´9 ml) and leucocytes (generally 6 Â 10 6 ), along with FITC-labelled fibrinogen (75 mg/ml final concentration), were recalcified to a final concentration of 10 mmol/l CaCl 2 , all in a final volume of 1´15 ml, and placed in the tubing.…”

Section: Methodsmentioning

confidence: 99%

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Polymorphonuclear leucocytes mediate endogenous thrombus lysis via a u‐PA‐dependent mechanism

Moir

Booth

Bennett³

et al. 2001

Br J Haematol

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Summary. Many human thrombi lyse spontaneously without the administration of lytic drugs and cause no clinical symptoms. The mechanisms by which this occurs are incompletely understood. We found that model thrombi prepared from whole human blood in a Chandler loop also exhibited significant spontaneous lysis. Lysis was inhibited by chemical protease inhibitors, consistent with proteolysis resulting primarily from serine proteases, with a small contribution from matrix metalloproteinases. Whole blood was fractionated into platelet-rich plasma and cell populations. Significant spontaneous lysis was observed in plateletrich thrombi enriched with polymorphonuclear leucocytes (PMNs), whereas mononuclear cells (MCs) and erythrocytes did not contribute to lysis. Incorporation of antibodies to urokinase (u-PA) and its receptor u-PAR neutralized a large proportion of the activity. Incubation of plasma with PMNs generated free u-PA activity, which was also detectable in model thrombi and in vivo human thrombi. Purified neutrophils, free of eosinophils, generated activity identical to PMNs. Smaller contributions to lysis by tissue-type plasminogen activator (t-PA), elastase and cathepsin G were also identified. These findings suggest a major role for circulating PMNs in endogenous thrombus lysis.

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“…Rates of clot lysis were determined in samples collected 2 h after electrolytic injury using the methods described by Robbie et al (2000). Plasma (100 l) was added to a 96-well plate, followed by the addition of various concentrations of human recombinant tPA and incubated at room temperature for 5 min.…”

Section: Downloaded Frommentioning

confidence: 99%

Evaluation of PAI-039 [{1-Benzyl-5-[4-(trifluoromethoxy)phenyl]-1H-indol-3-yl}(oxo)acetic Acid], a Novel Plasminogen Activator Inhibitor-1 Inhibitor, in a Canine Model of Coronary Artery Thrombosis

Hennan¹,

Elokdah²,

Leal³

et al. 2005

J Pharmacol Exp Ther

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We tested a novel, orally active inhibitor of plasminogen activator inhibitor-1 (PAI-1) in a canine model of electrolytic injury. Dogs received by oral gavage either vehicle (control) or the PAI-1 inhibitor PAI-039 [{1-benzyl-5-[4-(trifluoromethoxy)phenyl]-1H-indol-3-yl}(oxo)acetic acid] (1, 3, and 10 mg/kg) and were subjected to electrolytic injury of the coronary artery. PAI-039 caused prolongation in time to coronary occlusion (control, 31.7 Ϯ 6.3 min; 3 mg/kg PAI-039, 66.0 Ϯ 6.4 min; 10 mg/kg, 56.7 Ϯ 7.4 min; n ϭ 5-6; p Ͻ 0.05) and a reduced thrombus weight (control, 7.6 Ϯ 1.5 mg; 10 mg/kg PAI-039, 3.6 Ϯ 1.0 mg; p Ͻ 0.05). Although occlusive thrombosis was observed across all groups based upon the absence of measurable blood flow, a high incidence (Ͼ60%) of spontaneous reperfusion occurred only in those groups receiving PAI-039. Spontaneous reperfusion in the 10 mg/kg PAI-039 group accounted for total blood flow (area under the curve of coronary blood flow) of 99.6 Ϯ 11.7 ml after initial thrombotic occlusion (p Ͻ 0.05 compared with control). Plasma PAI-1 activity was reduced in all drug-treated groups (percentage of reduction in activity p Ͻ 0.05; 10 mg/kg PAI-039), whereas ADP-, 9,11-dideoxy-11␣,9␣-epoxymethanoprostaglandin F 2␣ (U46619)-, and collagen-induced platelet aggregation, as well as template bleeding and prothrombin time, remained unaffected by PAI-039. Ex vivo clot lysis analysis revealed normal clot formation but accelerated clot lysis in PAI-039-treated groups. The pharmacokinetic profile of PAI-039 indicated an oral bioavailability of 43 Ϯ 15.3% and a plasma half-life of 6.2 Ϯ 1.3 h. In conclusion, PAI-039 is an orally active prothrombolytic drug that inhibits PAI-1 and accelerates fibrinolysis while maintaining normal coagulation in a model of coronary occlusion.

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Effective lysis of model thrombi by a t-PA mutant (A473S) that is resistant to alpha2-antiplasmin

Cited by 10 publications

References 44 publications

Role of 2-Antiplasmin in Cardiovascular System

Role of 2-Antiplasmin in Cardiovascular System

Polymorphonuclear leucocytes mediate endogenous thrombus lysis via a u‐PA‐dependent mechanism

Evaluation of PAI-039 [{1-Benzyl-5-[4-(trifluoromethoxy)phenyl]-1H-indol-3-yl}(oxo)acetic Acid], a Novel Plasminogen Activator Inhibitor-1 Inhibitor, in a Canine Model of Coronary Artery Thrombosis

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