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Effects of hemocoagulase agkistrodon on the coagulation factors and its procoagulant activities

Authors Li H, Huang Y, Wu X, Wu T, Cao Y, Wang Q, Qiu Y, Fu W, Zhang Q, Pang J

Received 7 December 2017

Accepted for publication 27 March 2018

Published 23 May 2018 Volume 2018:12 Pages 1385—1398

DOI https://doi.org/10.2147/DDDT.S159210

Checked for plagiarism Yes

Review by Single-blind

Peer reviewer comments 2

Editor who approved publication: Dr Qiongyu Guo


Haixin Li,1,* Ying Huang,2,* Xian Wu,3 Ting Wu,1 Ying Cao,1 Qimei Wang,1 Yuchang Qiu,1 Weiming Fu,1 Qun Zhang,4 Jianxin Pang1

1
Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, People’s Republic of China; 2Department of Pharmacy, Shenzhen Hospital, Southern Medical University, Shenzhen, People’s Republic of China; 3Department of Pharmacy, The Third Affiliated Hospital, Southern Medical University, Guangzhou, People’s Republic of China; 4Good Clinical Practice Development, The Third Affiliated Hospital, Southern Medical University, Guangzhou, People’s Republic of China

*These authors contributed equally to this work

Objective:
Hemocoagulase agkistrodon (HCA), a thrombin-like enzyme (TLE) from the venom of the Chinese moccasin snake (Deinagkistrodon acutus), has been used in clinical practice as a hemostatic compound. The aim of this study was to further investigate the pharmacological properties of HCA.
Materials and methods: Sodium dodecyl sulfate or native polyacrylamide gel electrophoresis (SDS- or N-PAGE) as well as enzyme linked immunosorbent assays (ELISAs) were conducted to study the effects of HCA on the human plasma fibrinogen and prothrombin levels, as well as its in vitro interactions with some coagulation factors. In addition, the bleeding time effects of HCA in the mouse tail-bleeding model as well as its effects on the fibrinogen levels in rabbits were determined in vivo.
Results: In vitro results revealed that HCA exerts its procoagulant activities by hydrolyzing fibrinogen into segments that are easier to be absorbed, reducing the risk of thrombus formation. Besides, HCA could significantly inhibit the activation of prothrombin at the concentration of 0.3 μM. Unexpectedly, we also found that HCA was able to strongly bind to factor X/Xa (in a ratio of 1:1) and thus inhibit the acceleration of active factor X to tissue plasminogen activator-catalyzed plasminogen activation, demonstrating that it could be less likely to lead to thrombus formation. Finally, in vivo results indicated that HCA could significantly shorten the bleeding time in the mouse tail-bleeding model and had no effect on the fibrinogen levels in rabbits.
Conclusion: In summary, HCA, a unique and new family member of TLEs, may become a new clinical drug for the prevention and treatment of hemorrhage due to its unique and complex interactions with the blood system. Clarification of these features will enable us to further understand the mechanism of action of HCA and then promote its further application in clinical practice as a therapeutic drug.

Keywords: thrombin-like enzymes, TLEs, coagulation factors, procoagulant activity, anticoagulant activity, FXa, t-PA

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