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


CONCLUSIONS
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.
Tanaka
Kenichi A
KA
Division of Cardiothoracic Anesthesiology, Department of Anesthesiology, Emory University School of Medicine, Emory University Hospital, 1364 Clifton Road, NE, Atlanta, GA 30322, USA.
Szlam
Fania
F
Katori
Nobuyuki
N
Vega
J David
JD
Levy
Jerrold H
JH
D007611:Aprotinin / Q000494:pharmacology; D004353:Drug Evaluation, Preclinical; D006487:Hemostasis / Q000187:drug effects*; D006801:Humans; D066298:In Vitro Techniques; D007610:Kallikreins / Q000037:antagonists & inhibitors*; D009842:Oligopeptides / Q000494:pharmacology*; D010314:Partial Thromboplastin Time; D011517:Prothrombin Time; D011994:Recombinant Proteins / Q000494:pharmacology; D013916:Thrombelastography; D013917:Thrombin / Q000096:biosynthesis; D014914:Whole Blood Coagulation Time
D009842:Oligopeptides; D011994:Recombinant Proteins; D007611:Aprotinin; D007610:Kallikreins; D013917:Thrombin