Aprotinin is a competitive inhibitor of the factor VIIa-tissue factor complex

Chabbat, J.; Porte, Patrick; Tellier, Marinka C.; Steinbuch, M

doi:10.1016/0049-3848(93)90095-6

Cited by 48 publications

(16 citation statements)

References 19 publications

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“…27 At greater concentrations, tissue factor-induced extrinsic coagulation also is inhibited by aprotinin in a competitive and dose-dependent manner. 28,29 In addition, aprotinin can directly inhibit thrombin. 30 Thrombin is a serine protease with an affinity for aprotinin that is much lower than that of plasmin.…”

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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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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“…Although aprotinin is characterized as a broad specificity inhibitor targeting proteases such as kallikrein, trypsin, chymotrypsin, thrombin and plasmin [17,18], it is usually perceived as an antifibrinolytic agent used for the reduction of blood loss during open-heart surgery and/or coronary artery bypass graft surgery with cardiopulmonary bypass [20][21][22]. Aprotinin, however, has been shown to bind, albeit with low affinity, to several procoagulant proteases, including thrombin [18,23], activated factor X [18,24] and the activated factor VII-tissue factor complex enzyme [25]. These observations suggest that aprotinin may act as an inhibitor of tissue factor-triggered thrombin generation either directly or by enhancing the inhibitory effect of other coagulation inhibitors.…”

Section: Introductionmentioning

confidence: 99%

Influence of bivalirudin on tissue factor-triggered coagulation

Butenas

Orfeo

Brummel‐Ziedins

et al. 2007

Blood Coagulation &Amp; Fibrinolysis

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Bivalirudin, a synthetic analog of the carboxy-terminus of hirudin, is a reversible thrombin inhibitor used during coronary balloon angioplasty. The objective of this study was to evaluate the influence of bivalirudin on thrombin generation. Three in-vitro models (numerical simulations, synthetic coagulation proteome and whole blood) of contact pathway-independent blood coagulation triggered with tissue factor were used in this study. Increasing concentrations of bivalirudin prolong the initiation phase of thrombin generation in a concentration-dependent manner. At subpharmacologic bivalirudin concentrations (0.5-2 micromol/l), total thrombin generation was significantly increased. At a pharmacologic concentration (5 micromol/l), bivalirudin suppressed thrombin generation in the synthetic coagulation proteome; in numerical simulations and contact pathway-inhibited whole blood, no thrombin generation was detected over 1200-2000 s and platelet activation was inhibited by 80%. The addition of a pharmacologic concentration (9 micromol/l) of a naturally occurring protease inhibitor aprotinin in the presence of at least 0.5 micromol/l bivalirudin provided limited enhancement of the bivalirudin inhibitory effect. In conclusion, bivalirudin at pharmacologic concentrations is an efficient inhibitor of thrombin generation, platelet activation and clot formation, which acts not as a modulator but as an 'on-off' switch of blood coagulation.

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“…Not all of the observed effects of aprotinin are caused directly by enzyme inhibition and effects on platelet function; some involve more complex interactions, which affect coagulation [18,19] and infl ammation [20] .…”

Section: Introductionmentioning

confidence: 99%

Comparison of Textilinin-1 with Aprotinin as Serine Protease Inhibitors and as Antifibrinolytic Agents

Flight

Johnson²,

Trabi³

et al. 2005

Pathophysiol Haemos Thromb

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Textilinin-1 (Q8008) was isolated from the venom of the Pseudonaja textilis and has a 47% sequence identity to the antihaemorrhagic therapeutic agent aprotinin. When equimolar concentrations of enzyme and aprotinin were pre-incubated, plasmin was inhibited 100%, plasma kallikrein 58%, and tissue kallikrein 99%. Under the same conditions, textilinin-1 inhibited plasmin 98%, plasma kallikrein 16% and tissue kallikrein 17%. Whole blood clot lysis was inhibited strongly by both aprotinin and textilinin-1, as shown by thrombelastography. At 2 µM inhibitor lysis initiated by t-PA was greater than 99% inhibited by aprotinin (LY60 = 0.4 ± 0.1) whereas textilinin-1, inhibited lysis by 91% (LY60 = 8.9 ± 0.7). The same trend was found with the lysis of euglobulin fractions. From these data textilinin-1 appears to be a more specific plasmin inhibitor than aprotinin but aprotinin inhibits clot lysis to a greater extent.

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Aprotinin is a competitive inhibitor of the factor VIIa-tissue factor complex

Cited by 48 publications

References 19 publications

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

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

Influence of bivalirudin on tissue factor-triggered coagulation

Comparison of Textilinin-1 with Aprotinin as Serine Protease Inhibitors and as Antifibrinolytic Agents

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