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DOI	10.1073/pnas.2014810118
	Kallikrein directly interacts with and activates Factor IX, resulting in thrombin generation and fibrin formation independent of Factor XI
	Kearney K.J.; Butler J.; Posada O.M.; Wilson C.; Heal S.; Ali M.; Hardy L.; Ahnström J.; Gailani D.; Foster R.; Hethershaw E.; Longstaff C.; Philippou H.
发表日期	2021
ISSN	00278424
卷号	118 期号:3
英文摘要	Kallikrein (PKa), generated by activation of its precursor prekallikrein (PK), plays a role in the contact activation phase of coagulation and functions in the kallikrein-kinin system to generate bradykinin. The general dogma has been that the contribution of PKa to the coagulation cascade is dependent on its action on FXII. Recently this dogma has been challenged by studies in human plasma showing thrombin generation due to PKa activity on FIX and also by murine studies showing formation of FIXa-antithrombin complexes in FXI deficient mice. In this study, we demonstrate high-affinity binding interactions between PK(a) and FIX(a) using surface plasmon resonance and show that these interactions are likely to occur under physiological conditions. Furthermore, we directly demonstrate dose- and time-dependent cleavage of FIX by PKa in a purified system by sodium dodecyl sulfate-polyacrylamide gel electrophoresis analysis and chromogenic assays. By using normal pooled plasma and a range of coagulation factor-deficient plasmas, we show that this action of PKa on FIX not only results in thrombin generation, but also promotes fibrin formation in the absence of FXII or FXI. Comparison of the kinetics of either FXIa- or PKa-induced activation of FIX suggest that PKa could be a significant physiological activator of FIX. Our data indicate that the coagulation cascade needs to be redefined to indicate that PKa can directly activate FIX. The circumstances that drive PKa substrate specificity remain to be determined. © 2021 National Academy of Sciences. All rights reserved.
英文关键词	Plasma kallikrein \| prekallikrein \| Factor IX \| intrinsic pathway \| Factor XII
语种	英语
scopus关键词	blood clotting factor 12; blood clotting factor 9; dodecyl sulfate sodium; kallikrein; prekallikrein; Article; binding affinity; comparative study; enzyme activation; fibrin formation; human; mouse; nonhuman; polyacrylamide gel electrophoresis; priority journal; protein analysis; protein protein interaction; surface plasmon resonance; thrombin time
来源期刊	Proceedings of the National Academy of Sciences of the United States of America
文献类型	期刊论文
条目标识符	http://gcip.llas.ac.cn/handle/2XKMVOVA/180973
作者单位	Leeds Institute of Cardiovascular and Metabolic Medicine, University of Leeds, Leeds, LS2 9JT, United Kingdom; Faculty of Medicine, Department of Immunology and Inflammation, Imperial College London, Hammersmith Campus, London, W12 0NN, United Kingdom; Division of Hematology/Oncology, Vanderbilt Clinic, Vanderbilt University, Nashville, TN 37232, United States; School of Chemistry, University of Leeds, Leeds, LS2 9JT, United Kingdom; Division of Biotherapeutics, National Institute for Biological Standards and Control, Potters Bar,, Hertfordshire EN6 3QG, United Kingdom
推荐引用方式 GB/T 7714	Kearney K.J.,Butler J.,Posada O.M.,et al. Kallikrein directly interacts with and activates Factor IX, resulting in thrombin generation and fibrin formation independent of Factor XI[J],2021,118(3).
APA	Kearney K.J..,Butler J..,Posada O.M..,Wilson C..,Heal S..,...&Philippou H..(2021).Kallikrein directly interacts with and activates Factor IX, resulting in thrombin generation and fibrin formation independent of Factor XI.Proceedings of the National Academy of Sciences of the United States of America,118(3).
MLA	Kearney K.J.,et al."Kallikrein directly interacts with and activates Factor IX, resulting in thrombin generation and fibrin formation independent of Factor XI".Proceedings of the National Academy of Sciences of the United States of America 118.3(2021).