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Prohemostatic Activity of Factor X in Combination With Activated Factor VII in Dilutional Coagulopathy

Takeshita, Shusuke MD*; Ogawa, Satoru MD, PhD*; Nakayama, Yoshinobu MD, PhD*; Mukai, Nobuhiro MD, PhD*; Nakajima, Yasufumi MD, PhD; Mizobe, Toshiki MD, PhD*; Sawa, Teiji MD, PhD*; Tanaka, Kenichi A. MD, MSc

doi: 10.1213/ANE.0000000000003858
Hemostasis and Thrombosis: Original Laboratory Research Report

BACKGROUND: Recombinant activated factor VII (rFVIIa) concentrate reduces allogeneic blood transfusions, but it may increase thromboembolic complications in complex cardiac surgery. The mixture of activated factor VII (FVIIa) and factor X (FX) (FVIIa/FX) (FVIIa:FX = 1:10) is a novel bypassing agent for hemophilia patients. We hypothesized that the combination of FX and FVIIa could improve thrombin generation (TG) in acquired multifactorial coagulation defects such as seen in cardiac surgery and conducted in vitro evaluation of FVIIa/FX in parallel with other coagulation factor concentrates using in vitro and in vivo diluted plasma samples.

METHODS: Plasma samples were collected from 9 healthy volunteers and 12 cardiac surgical patients. We measured TG (Thrombinoscope) using in vitro 50% dilution plasma and in vivo dilution plasma after cardiopulmonary bypass, in parallel with thromboelastometry (ROTEM) and standard coagulation assays. In vitro additions of FVIIa/FX (0.35, 0.7, and 1.4 μg/mL, based on the FVIIa level), rFVIIa (1.4, 2.8, and 6.4 μg/mL), prothrombin complex concentrate (0.3 international unit), and 20% plasma replacement were evaluated.

RESULTS: In diluted plasma, the addition of either FVIIa/FX or rFVIIa shortened the lag time and increased the peak TG, but the effect in lag time of FVIIa/FX at 0.35 μg/mL was more extensive than rFVIIa at 6.4 μg/mL. Prothrombin complex concentrate increased peak TG by increasing the prothrombin level but failed to shorten the lag time. No improvement in any of the TG variables was observed after 20% volume replacement with plasma. The addition of factor concentrates normalized prothrombin time/international normalized ratio but not with plasma replacement. In cardiac patients, similar patterns were observed on TG in post–cardiopulmonary bypass samples. FVIIa/FX shortened clotting time (CT) in a concentration-dependent manner on CT on thromboelastometry. Plasma replacement did not improve CT, but a combination of plasma and FVIIa/FX (0.35 μg/mL) more effectively shortened CT than FVIIa/FX alone.

CONCLUSIONS: The combination of FVIIa and FX improved TG more efficiently than rFVIIa alone or plasma in dilutional coagulopathy models. The required FVIIa dose in FVIIa/FX was considerably lower than those reported during bypassing therapy in hemophilia patients (1.4–2.8 μg/mL). The combination of plasma could restore coagulation more efficiently compared to FVIIa/FX alone. Lesser FVIIa requirement to exert procoagulant activity may be favorable in terms of reducing systemic thromboembolic complications.

From the *Department of Anesthesiology, Kyoto Prefectural University of Medicine, Kyoto, Japan

Department of Anesthesiology, Kansai Medical University, Osaka, Japan

Department of Anesthesiology, University of Maryland School of Medicine, Baltimore, Maryland.

Published ahead of print 6 September 2018.

Accepted for publication September 6, 2018.

Funding: This work was supported by a grant-in-aid from the Japanese Society of Cardiothoracic Vascular Anesthesia.

The authors declare no conflicts of interest.

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Reprints will not be available from the authors.

Address correspondence to Satoru Ogawa, MD, PhD, Department of Anesthesiology, Kyoto Prefectural University of Medicine, Kawaramachi Hirokoji, Kamigyo-ku, Kyoto 8566, Japan. Address e-mail to

Copyright © 2018 International Anesthesia Research Society
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