The antithrombotic effect of aprotinin: actions mediated via the protease-activated receptor 1

Poullis, Michael; Manning, Richard A.; Laffan, Michael; Haskard, Dorian O.; Taylor, Kenneth M.; Landis, R. Clive

doi:10.1067/mtc.2000.108531

Cited by 109 publications

(66 citation statements)

References 32 publications

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“…Platelets were added to monocytes in a thrombin-activated form, reflecting the activated state we observed in our clinical studies and in keeping with techniques standard across the literature (34)(35)(36). In macrophages produced in vitro from platelet-matured monocytes, Mmp-1 is among the top five upregulated genes (24 There was a concurrent increase in the MMP-1 activating enzyme MMP-10, and upregulation was not associated with any concurrent increase in TIMP secretion.…”

Section: Discussionmentioning

confidence: 99%

Platelets Regulate Pulmonary Inflammation and Tissue Destruction in Tuberculosis

Fox

Kirwan

Whittington

et al. 2018

Am J Respir Crit Care Med

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Section: Discussionmentioning

confidence: 99%

Platelets Regulate Pulmonary Inflammation and Tissue Destruction in Tuberculosis

Fox

Kirwan

Whittington

et al. 2018

Am J Respir Crit Care Med

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“…30 Thrombin is a serine protease with an affinity for aprotinin that is much lower than that of plasmin. Another mechanism of anticoagulant activity by aprotinin was recently described by Poullis et al 31 These investigators studied the effect of aprotinin on the major thrombin receptor on platelets, protease-activated receptor 1. This receptor requires proteolytic cleavage to transmit platelet aggregation-activating signals.…”

Section: Discussionmentioning

confidence: 99%

Aprotinin in orthotopic liver transplantation: Evidence for a prohemostatic, but not a prothrombotic, effect

Molenaar

2001

Liver Transplantation

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Aprotinin reduces blood transfusion requirements in orthotopic liver transplantation (OLT). Concern has been voiced about the potential risk for thrombotic complications when aprotinin is used. The aim of this study is to evaluate the effects of aprotinin on the two components of the hemostatic system (coagulation and fibrinolysis) in patients undergoing OLT. As part of a larger, randomized, double-blind, placebo-controlled study, we compared coagulation ( H emostasis is the overall result of a balance between two proteolytic cascades: the coagulation and fibrinolytic systems. In end-stage liver disease, the delicate balance between coagulation and fibrinolysis is often disturbed. 1,2 One problem encountered in orthotopic liver transplantation (OLT) is the occurrence of hyperfibrinolysis, mainly caused by increased levels of tissue-type plasminogen activator (tPA). 3,4 Especially during the anhepatic and postreperfusion periods, tPA plasma levels are significantly increased, resulting in consumption of its naturally occurring inhibitor, plasminogen activator inhibitor (PAI-1). 5,6 High tPA activity during OLT stimulates the conversion of plasminogen into plasmin, which causes premature degradation of fibrin clots and subsequent increased blood loss and transfusion requirements. 6 Aprotinin is a serine protease inhibitor derived from bovine lung. 7 It has the ability to inhibit a wide range of proteases that have serine residues at their active site, such as plasmin, kallikrein, and trypsin, by forming reversible stoichiometric enzyme-inhibitor complexes. Inhibition of plasmin and kallikrein results in a strong reduction in fibrinolysis. Neuhaus et al 8 first reported on the blood-sparing effect of aprotinin in OLT. Recently, we completed the European Multicenter Study on the Use of Aprotinin in Liver Transplantation (EMSALT). Results of this randomized, double-blind, placebo-controlled study showed significant reductions in blood loss and transfusion requirements of 50% and 30%, respectively. 9 A potential adverse effect of a prohemostatic drug, such as aprotinin, could be an increased rate of thrombotic complications. Concern has been voiced about the potential risk for this type of complication when aprotinin is administered during OLT. 10 Although the antifibrinolytic activity of aprotinin in OLT has been studied before, data on the specific effects of aprotinin on coagulation and fibrinolysis separately, as well as their interaction in the same

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“…After 60 minutes, fluorescence intensity was measured. To assess the respective role of PAR 1 , PAR 2 , and PAR 4 in the influence of UC fecal supernatants on CPP: (i) P4-pal10 pepducin (final concentration 1 mol/L) (NeoMPS, Strasbourg, France), (ii) PAR 1 antagonist FLLRN (PheLeu-Leu-Arg-Asn, 10 mol/L, Peptides International, Louisville, KY), 13,14 (iii) PAR 2 antagonist FSLLRY (PheSer-Leu-Arg-Tyr, 10 mol/L, Bachem, Weil am Rhein, Germany), 15 or (iv) physiological saline, as a control, were added to the mucosal side of each chamber before administration at the mucosal side of either fecal supernatants or physiological saline. In another series of experiments, PAR 4 agonist peptide (Ala-Tyr-Pro-Gly-LysPhe-NH 2, 50 mol/L, Sigma) was added into the mucosal compartment, and CPP was measured after 1 hour.…”

Section: In Vitro Permeability Studiesmentioning

confidence: 99%

Luminal Cathepsin G and Protease-Activated Receptor 4

Dabek

Ferrier

Róka

et al. 2009

The American Journal of Pathology

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Impairment of the colonic epithelial barrier and neutrophil infiltration are common features of inflammatory bowel disease. Luminal proteases affect colonic permeability through protease-activated receptors (PARs). We evaluated: (i) whether fecal supernatants from patients with ulcerative colitis (UC) trigger alterations of colonic paracellular permeability and inflammation, and (ii) the roles of cathepsin G (Cat-G), a neutrophil serine protease, and its selective receptor, PAR 4 , in these processes. Expression levels of both PAR 4 and Cat-G were determined in colonic biopsies from UC and healthy subjects. The effects of UC fecal supernatants on colonic paracellular permeability were measured in murine colonic strips. Involvement of Cat-G and PAR 4 was evaluated using pepducin P4pal-10 and specific Cat-G inhibitor (SCGI), respectively. In addition, the effect of PAR 4 -activating peptide was assessed. UC fecal supernatants, either untreated or pretreated with SCGI, were infused into mice, and myeloperoxidase activity was determined. PAR 4 was found to be overexpressed in UC colonic biopsies. Increased colonic paracellular permeability that was triggered by UC fecal supernatants was blocked by both SCGI (77%) and P4pal-10 (85%). Intracolonic infusion of UC fecal supernatants into mice increased myeloperoxidase activity. This effect was abolished by SCGI. These observations support that both Cat-G and PAR 4 play key roles in generating and/or amplifying relapses in UC and provide a rationale for the development of new therapeutic agents in the treatment of this disease.

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The antithrombotic effect of aprotinin: actions mediated via the protease-activated receptor 1

Abstract: Aprotinin inhibits thrombin-induced platelet activation by preventing proteolysis of the PAR1 receptor. These findings argue against aprotinin being prothrombotic and suggest instead that aprotinin may have significant antithrombotic effects.

Cited by 109 publications

References 32 publications

Platelets Regulate Pulmonary Inflammation and Tissue Destruction in Tuberculosis

Platelets Regulate Pulmonary Inflammation and Tissue Destruction in Tuberculosis

Aprotinin in orthotopic liver transplantation: Evidence for a prohemostatic, but not a prothrombotic, effect

Luminal Cathepsin G and Protease-Activated Receptor 4

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