Evaluation of a novel kallikrein inhibitor on hemostatic activation in vitro.

Published

Journal Article

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 microg/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.

Full Text

Duke Authors

Cited Authors

  • Tanaka, KA; Szlam, F; Katori, N; Vega, JD; Levy, JH

Published Date

  • 2004

Published In

Volume / Issue

  • 113 / 5

Start / End Page

  • 333 - 339

PubMed ID

  • 15183046

Pubmed Central ID

  • 15183046

International Standard Serial Number (ISSN)

  • 0049-3848

Digital Object Identifier (DOI)

  • 10.1016/j.thromres.2004.03.022

Language

  • eng

Conference Location

  • United States