Effects of aprotinin on coagulation and fibrinolysis enzymes

Christensen, Ulla; Schiødt, Jakob

doi:10.1016/s0268-9499(97)80052-5

Cited by 5 publications

(3 citation statements)

References 30 publications

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“…The inhibitory effect on the purified TF-VIIa complex is likely physiologically insignificant, as aprotinin did not inhibit TF-induced thrombin generation in plasma. Aprotinin increased thrombin generation via the extrinsic pathway in the presence of thrombomodulin, likely as a result of inhibition of activated protein C. 38,39 However, as aprotinin decreases thrombin generation in vivo, [5][6][7] it is unlikely this prohemostatic effect of aprotinin is clinically relevant. Collectively, our results suggest that plasmin and kallikrein are the only relevant hemostatic targets of aprotinin at clinically used concentrations in a plasma or whole blood environment.…”

Section: Discussionmentioning

confidence: 99%

Aprotinin Inhibits Thrombin Generation by Inhibition of the Intrinsic Pathway, but is not a Direct Thrombin Inhibitor

Lisman

Adelmeijer

Huskens

et al. 2021

TH Open

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Background Aprotinin is a broad-acting serine protease inhibitor that has been clinically used to prevent blood loss during major surgical procedures including cardiac surgery and liver transplantation. The prohemostatic properties of aprotinin likely are related to its antifibrinolytic effects, but other mechanisms including preservation of platelet function have been proposed. Aim Here we assessed effects of aprotinin on various hemostatic pathways in vitro, and compared effects to tranexamic acid(TXA), which is an antifibrinolytic but not a serine protease inhibitor. Methods We used plasma-based clot lysis assays, clotting assays in whole blood, plasma, and using purified proteins, and platelet activation assays to which aprotinin or TXA were added in pharmacological concentrations. Results Aprotinin and TXA dose-dependently inhibited fibrinolysis in plasma. Aprotinin inhibited clot formation and thrombin generation initiated via the intrinsic pathway, but had no effect on reactions initiated by tissue factor. However, in the presence of thrombomodulin, aprotinin enhanced thrombin generation in reactions started by tissue factor. TXA had no effect on coagulation. Aprotinin did not inhibit thrombin, only weakly inhibited the TF-VIIa complex and had no effect on platelet activation and aggregation by various agonists including thrombin. Aprotinin and TXA inhibited plasmin-induced platelet activation. Conclusion Pharmacologically relevant concentrations of aprotinin inhibit coagulation initiated via the intrinsic pathway. The antifibrinolytic activity of aprotinin likely explains the prohemostatic effects of aprotinin during surgical procedures. The anticoagulant properties may be beneficial during surgical procedures in which pathological activation of the intrinsic pathway, for example by extracorporeal circuits, occurs.

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Section: Discussionmentioning

confidence: 99%

Aprotinin Inhibits Thrombin Generation by Inhibition of the Intrinsic Pathway, but is not a Direct Thrombin Inhibitor

Lisman

Adelmeijer

Huskens

et al. 2021

TH Open

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“…Third is the disparity between the in vitro and in vivo (i.e., clinically effective concentration) K i values. This disparity is attributable to the inhibitory activity of aprotinin under such different conditions as in the presence or absence of endogenous serine protease inhibitors, fibrin, or unfractionated heparin (9)(10)(11). These observations suggest that the effective aprotinin concentration may change under different conditions of hemostatic activation and that calculation of the K i for a such given target protease as plasmin will require determination under conditions approximating the in vivo environment, such as during CPB (7).…”

Section: Aprotinin: Pharmacological Propertiesmentioning

confidence: 99%

“…In trying to discern the mechanism of action of aprotinin, it is important to distinguish between the biochemical efficacy and clinical efficacy of the drug. The biochemical efficacy will be influenced by the factors that affect the interaction of aprotinin with the target protease, such as pH, protein concentration, presence or absence of endogenous serine protease inhibitors, presence or absence of fibrin, and the type of anticoagulant (9)(10)(11). The clinical efficacy will be influenced by factors that influence the degree of blood activation during CPB, such as patient population, pre-operative medications, hemodilution, prime composition, use of ultrafiltration, temperature, the use of coronary suction, and the duration of CPB.…”

Section: Aprotinin: Pharmacological Propertiesmentioning

confidence: 99%

Biochemistry of Serine Protease Inhibitors and Their Mechanisms of Action: A Review

Wegner

2003

J Extra Corpor Technol

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Cardiopulmonary bypass (CPB) activates and disrupts the hemostatic and inflammatory systems, which, in turn, makes an impact on the clinical outcome of patients. Postoperative bleeding is one common complication of CPB. Many techniques have been used to reduce post-operative bleeding, and pharmacological agents have demonstrated the greatest efficacy. In particular, the serine protease inhibitor, aprotinin, consistently reduces post-operative bleeding. The hemostatic mechanism of action of aprotinin; however, remains to be elucidated fully. The purpose of this review is to discuss the probable mechanisms of aprotinin action from the perspective of its interactions within the hemostatic and inflammatory pathways.

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Effects of Agents, Used to Treat Bleeding Disorders, on Bleeding Time Prolonged by a Very High Dose of a Direct Thrombin Inhibitor in Anesthesized Rats and Rabbits

Elg

Carlsson

Gustafsson

2001

Thrombosis Research

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Effects of aprotinin on coagulation and fibrinolysis enzymes

Cited by 5 publications

References 30 publications

Aprotinin Inhibits Thrombin Generation by Inhibition of the Intrinsic Pathway, but is not a Direct Thrombin Inhibitor

Aprotinin Inhibits Thrombin Generation by Inhibition of the Intrinsic Pathway, but is not a Direct Thrombin Inhibitor

Biochemistry of Serine Protease Inhibitors and Their Mechanisms of Action: A Review

Effects of Agents, Used to Treat Bleeding Disorders, on Bleeding Time Prolonged by a Very High Dose of a Direct Thrombin Inhibitor in Anesthesized Rats and Rabbits

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