Evaluation of a novel kallikrein inhibitor on hemostatic activation in vitro

Kenichi A. Tanaka, Fania Szlam, Nobuyuki Katori, J. David Vega, Jerrold H. Levy

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16 Citations (Scopus)

Abstract

Background: DX-88 is a potent kallikrein inhibitor that is being studied for the treatment of hereditary angioedema (HAE) and represents a potential alternative to aprotinin in cardiac surgical patients. The current study was designed to evaluate in vitro effects of DX-88 on coagulation in comparison with aprotinin. Methods: Blood samples were obtained from consented 12 healthy volunteers. DX-88 or aprotinin was added to blood at 200 and 800 kallikrein inhibitory units (KIU) per milliliter for aprotinin, and at 1.1, 2.2, or 8.8 μg/ml for DX-88. Thromboelastography (TEG®) was performed using celite, kaolin, or tissue factor (TF) activation. Kaolin-based activated clotting times (ACTs) were measured at different heparin levels. The whole blood prothrombin time (PT)/PTT values were also measured. The endogenous thrombin generation was assessed with a fluorogenic assay using platelet-poor plasma (PPP). Results: With celite and kaolin activation of TEG, the reaction time was prolonged with DX-88 and aprotinin. With tissue factor activation, TEG parameters were not affected. DX-88 caused dose-dependent kaolin-ACT prolongation that was augmented by increasing doses of heparin. DX-88 or aprotinin had no significant effects on the PT values, but PTT values were dose-dependently prolonged. Both agents delayed the onset of thrombin generation when PTT reagent was used as a trigger, whereas no change was observed when tissue factor was used. Conclusion; We found that DX-88 delayed contact activator induced coagulation without affecting tissue factor mediated coagulation. For evaluation of coagulation during DX-88 therapy, the use of PT or tissue factor-activated TEG may be preferable.

Original languageEnglish
Pages (from-to)333-339
Number of pages7
JournalThrombosis Research
Volume113
Issue number5
DOIs
Publication statusPublished - 2004 Jun 18

Keywords

  • Aprotinin
  • DX-88
  • Kallikrein inhibitor

ASJC Scopus subject areas

  • Hematology

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    Tanaka, K. A., Szlam, F., Katori, N., Vega, J. D., & Levy, J. H. (2004). Evaluation of a novel kallikrein inhibitor on hemostatic activation in vitro. Thrombosis Research, 113(5), 333-339. https://doi.org/10.1016/j.thromres.2004.03.022