Differential Effects of c7E3 Fab on Thrombus Formation and rt-PA-Mediated Thrombolysis Under Flow Conditions

Huang, Trevor C.; Jordan, Robert E.; Hantgan, Roy R.; Alevriadou, B. Rita

doi:10.1016/s0049-3848(01)00260-2

Cited by 7 publications

(5 citation statements)

References 36 publications

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“…These data imply that platelets promote the resistance of clots to fibrinolysis. Recent in vitro findings by others revealed that an anti-GP IIb/IIIa MAb inhibits tissue factorinduced thrombin production, platelet factor-4 release, formation of procoagulant microparticles (42), and accelerates fibrinolysis (8,19). Taken together with these in vitro data, our results obtained in intact animals imply that it may be possible to accelerate pulmonary fibrinolysis or even lessen the propensity to form occlusive thrombi by impairing platelet function.…”

Section: Discussionsupporting

confidence: 79%

Platelets inhibit the lysis of pulmonary microemboli

Murciano

Harshaw

Neschis

et al. 2002

American Journal of Physiology-Lung Cellular and Molecular Phys

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Using tracings of 125 I-labeled fibrin(ogen) in rodents, we examined the hypothesis that platelets impede the lysis of pulmonary emboli.125 I-Microemboli (ME, 3-10 micron diameter) lodged homogeneously throughout the lungs after intravenous injection in both rats and mice (60% of injected dose), caused no lethality, and underwent spontaneous dissolution (50 and 100% within 1 and 5 h, respectively). Although lung homogenates displayed the most intense fibrinolytic activity of all the major organs, dissolution of ME was much slower in isolated perfused lungs (IPL) than was observed in vivo. Addition of rat plasma to the perfusate facilitated ME dissolution in IPL to a greater extent than did addition of tissue-type plasminogen activator alone, suggesting that permeation of the clot by plasminogen is the rate-limited step in lysis. Platelet-containing ME injected in rats lysed much more slowly than did ME formed from fibrin alone.125 I-Thrombi, formed in the pulmonary vasculature of mice in response to intravascular activation of platelets by injection of collagen and epinephrine, were essentially resistant to spontaneous dissolution. Moreover, injection of the antiplatelet glycoprotein IIb/IIIa antibody 7E3 F(abЈ) 2 facilitated spontaneous dissolution of pulmonary ME and augmented fibrinolysis by a marginally effective dose of Retavase (10 g/kg) in rats. These studies show that platelets suppress pulmonary fibrinolysis. The mechanism(s) by which platelets stabilize ME and utility of platelet inhibitors to facilitate their dissolution deserves further study. pulmonary embolism; plasminogen activators; platelets; fibrinolysis; animal model; glycoprotein IIb/IIIa THE LUNG SERVES as a natural filter for thromboemboli of diverse sizes (12). Thrombotic occlusion of the main or lobar pulmonary arteries by large clots (massive pulmonary embolism, PE) is a common cause of morbidity and mortality (15,20). In contrast, pulmonary deposition of microemboli (ME) often does not cause acute symptoms (silent ME). Nevertheless, pulmonary ME is a relatively common accompaniment to acute lung injury (adult respiratory distress syndrome), hyperoxia, bleomycin toxicity, sepsis, trauma, surgery on the lower extremities, and angioplasty (2,21,30,33,36,39,40,44,52,53). Microembolism may lead to inflammation and edema acutely and contribute to the development of pulmonary fibrosis and hypertension over time (4,9,22,27,31).The treatment of PE, as with other venous thromboembolic conditions, is typically restricted to agents such as heparin that retard fibrin clot formation, with a relatively limited use of agents that promote fibrinolysis. Despite the effectiveness of such therapy, PE remains a common cause of mortality and morbidity. Thus there is a continuing need for more effective means to prevent and treat both PE and ME, based on a more thorough understanding of the mechanisms that regulate clot dissolution in the lung.For example, the role of platelets in PE and ME has received relatively little study. Recently, it has been shown tha...

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Section: Discussionsupporting

confidence: 79%

Platelets inhibit the lysis of pulmonary microemboli

Murciano

Harshaw

Neschis

et al. 2002

American Journal of Physiology-Lung Cellular and Molecular Phys

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“…Blood perfusion studies have been used previously to illustrate the profibrinolytic effects of recombinant t‐PA and the antifibrinolytic effects of normal platelets on clot lysis induced by exogenous plasminogen activators [32]. Unlike this study, we observed that some fibrin degradation occurred with perfusion of normal blood samples, possibly because we followed clot lysis for a longer time and used citrate (not ACD) as the anticoagulant to maintain a more physiologic pH during the perfusion.…”

Section: Discussionmentioning

confidence: 81%

Insights into abnormal hemostasis in the Quebec platelet disorder from analyses of clot lysis

Diamandis

Adam

Kahr

et al. 2006

Journal of Thrombosis and Haemostasis

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Summary. Background: The Quebec platelet disorder (QPD) is inherited and characterized by delayed-onset bleeding following hemostatic challenge. Other characteristics include increased expression and storage of active urokinase-type plasminogen activator (u-PA) in platelets in the setting of normal to increased u-PA in plasma. There is also consumption of platelet plasminogen activator inhibitor-1 and increased generation of plasmin in platelets accompanied by proteolysis of stored a-granule proteins, including Factor V. Aims and Methods: Although fibrinolysis has been proposed to contribute to QPD bleeding, the effects of QPD blood and platelets on clot lysis have not been evaluated. We used thromboelastography Ò (TEG Ò ), biochemical evaluations of whole blood clot lysis, assessments of clot ultrastructure, and perfusion of blood over preformed fibrin to gain insights into the disturbed hemostasis in the QPD. Results: Thromboelastography was not sensitive to the increased u-PA in QPD blood. However, there was abnormal plasmin generation in QPD whole blood clots, generated at low shear, with biochemical evidence of increased fibrinolysis. The incorporation of QPD platelets into a forming clot led to progressive disruption of fibrin and platelet aggregates unless drugs were added to inhibit plasmin. In whole blood perfusion studies, QPD platelets showed normal adherence to fibrin, but their adhesion was followed by accelerated fibrinolysis. Conclusions: The QPD is associated with Ôgain-of-functionÕ abnormalities that increase the lysis of forming or preformed clots. These findings suggest accelerated fibrinolysis is an important contributor to QPD bleeding.

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“…In addition, it would be interesting to consider that the platelets themselves can suppress clot lysis by mechanical cross-linking, promotion of clot stability as well as release of fibrinolytic inhibitors [ 16 ]. Some recent in vivo studies [ 17 , 18 ] revealed that fibrinolysis can be accelerated by conjunctive use of anti-GP IIb/IIIa antibody. Hence, these findings imply that the RGD-SAK may accelerate lysis of platelet-rich clots via diverse mechanisms in vivo .…”

Section: Discussionmentioning

confidence: 99%

Characterization of a novel bifunctional mutant of staphylokinase with platelet-targeted thrombolysis and antiplatelet aggregation activities

Chen

et al. 2007

BMC Mol Biol

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Background: Although staphylokianse (SAK) is among the most promising blood dissolving agents, it is far from ideal. It is interesting to hypothesize that the clot lysis efficacy of SAK can be enhanced with direct active platelet binding ability, and at the same time the rethrombosis complication after successful recanalization can be minimized with an antiplatelet aggregation activity. The present study was performed to characterize the functional properties of RGD-SAK, a novel mutant of staphylokinase (SAK).

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Differential Effects of c7E3 Fab on Thrombus Formation and rt-PA-Mediated Thrombolysis Under Flow Conditions

Cited by 7 publications

References 36 publications

Platelets inhibit the lysis of pulmonary microemboli

Platelets inhibit the lysis of pulmonary microemboli

Insights into abnormal hemostasis in the Quebec platelet disorder from analyses of clot lysis

Characterization of a novel bifunctional mutant of staphylokinase with platelet-targeted thrombolysis and antiplatelet aggregation activities

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