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Salivary proteins of ticks can inhibit host hemostatic and inflammatory responses during the blood-sucking process of the parasites. A cDNA sequence, Hq021, was identified from a cDNA library of Haemaphysalis qinghaiensis. Hq021 encodes a mature protein containing 182 amino acids with a molecular mass of 20.5 kDa. The protein is rich in basic amino acids (lysine and arginine) at its C-terminus. Identification of no homologous proteins in databases suggested its novelty. A recombinant protein expressed with the cDNA in Escherichia coli could prolong the activated partial thromboplastin time (aPTT) of human plasma. We designated this basic tail-protein as Qinghaienin. Although Qinghaienin did not inhibit the amidolytic activities of some coagulation factors, it dose-dependently inhibited the generation of FXIIa, FXIa and kallikrein in plasma in the presence of silica-based aPTT reagent. By competing with FXII for the negatively-charged binding sites, Qinghaienin inhibited the activation of the zymogen and the coagulation processes. These findings suggest that Qinghaienin plays a critical role in both anticoagulation and anti-inflammatory processes during tick feeding and could serve as a potential candidate for the developing tick-derived anticoagulants., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Gao Jinliang reports financial support was provided by National Natural Science Foundation of China (Contract No. 81760375). Gao Jinliang reports financial support was provided by National Natural Science Foundation of China (Contract No. 82360406). Gao Jinliang reports financial support was provided by Natural Science Foundation of Inner Mongolia Autonomous Region of China (Contract No. 2021MS08063). Chen Kaiting reports financial support was provided by Natural Science Foundation of Inner Mongolia Autonomous Region of China (Contract No. 2023QN08005). Gao Jinliang reports financial support was provided by the Science and Technology Innovation Guiding Project of Inner Mongolia (2021). He Xiaofei reports financial support was provided by Education Department of Inner Mongolia Autonomous Region of China (Contract No. S20231198Z). Gao Jinliang, She Zhanfei, Gao Dongbing, Chen Kaiting, He Xiaofei, Guang Hui, Cao Meina, Zhao Wenbin, Bai Mengdie, Yang Yinran, Su Muya and Ma Linyuan has patent #A tick-derived anticoagulation protein Qinghaienin and its encoding gene as well as its application in anticoagulation,Patent No. ZL 202310665559.5 licensed to Gao Jinliang, She Zhanfei, Gao Dongbing, Chen Kaiting, He Xiaofei, Guang Hui, Cao Meina, Zhao Wenbin, Bai Mengdie, Yang Yinran, Su Muya and Ma Linyuan. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Lipopolysaccharide (LPS) is the primary pathogenic factor in Gram-negative sepsis. While the presence of LPS in the bloodstream during infection is associated with disseminated intravascular coagulation, the mechanistic link between LPS and blood coagulation activation remains ill-defined. The contact pathway of coagulation-a series of biochemical reactions that initiates blood clotting when plasma factors XII (FXII) and XI (FXI), prekallikrein (PK), and high molecular weight kininogen interact with anionic surfaces-has been shown to be activated in Gram-negative septic patients. In this study, using an in vivo baboon model of Gram-negative Escherichia coli sepsis, we observed activation of the contact pathway including FXII, FXI, and PK. We examined whether E.coli LPS molecules could bind and activate contact pathway members by quantifying the interaction and activation of either FXII, FXI, or PK with each of the three chemotypes of LPS: O111:B4, O26:B6, or Rd2. The LPS chemotypes exhibited distinct physicochemical properties as aggregates and formed complexes with FXII, FXI, and PK. The LPS chemotype O26:B6 uniquely promoted the autoactivation of FXII to FXIIa and, in complex with FXIIa, promoted the cleavage of FXI and PK to generate FXIa and plasma kallikrein, respectively. Furthermore, in complex with the active forms of FXI or PK, LPS chemotypes were able to regulate the catalytic activity of FXIa and plasma kallikrein, respectively, despite the inability to promote the autoactivation of either zymogen. These data suggest that the procoagulant phenotype of E.coli is influenced by bacterial strain and the physicochemical properties of the LPS chemotypes., Competing Interests: Conflicts of interest C. U. L. and E. I. T. are employees of Aronora, Inc, a company that may have a commercial interest in the results of this research. J. J. S. serves as a medical consultant for Aronora, Inc. This potential conflict of interest has been reviewed and managed by conflict of interest in research committee of the Oregon Health & Science University. The remaining authors declare that they have no conflicts of interest with the contents of this article., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Hereditary angioedema (HAE) is a rare genetic disorder characterized by local, self-limiting edema due to temporary increase in vascular permeability. HAE with normal C1 esterase inhibitor (C1INH) activity includes the form with mutations in the F12 gene encoding for coagulation factor XII (FXII-HAE) causing an overproduction of bradykinin (BK) leading to angioedema attack. BK binding to B2 receptors (BK2R) leads to an activation of phospholipase C (PLC) and subsequent generation of second messengers: diacylglycerols (DAGs) and possibly the endocannabinoids (eCBs), 2-arachidonoylglycerol (2-AG) and anandamide (AEA), and eCB-related N-acylethanolamines [palmitoylethanolamide (PEA) and oleoylethanolamide (OEA)]. To date, there are no data on the role of these lipid mediators in FXII-HAE., Methods: Here, we analyzed plasma levels of PLC, DAGs, and eCBs in 40 patients with FXII-HAE and 40 sex- and age-matched healthy individuals., Results: Plasma PLC activity was increased in FXII-HAE patients compared to controls. Concentrations of DAG 18:1-20:4, a lipid second messenger produced by PLC, were higher in FXII-HAE compared to controls, and positively correlated with PLC activity and cleaved high molecular kininogen (cHK). Also the concentrations of the DAG metabolite, 2-AG were altered in FXII-HAE. AEA and OEA were decreased in FXII-HAE patients compared to controls; by contrast, PEA, was increased. The levels of all tested mediators did not differ between symptomatic and asymptomatic patients. Moreover, C1INH-HAE patients had elevated plasma levels of PLC, which correlated with cHK, but the levels of DAGs and eCBs were the same as controls., Conclusions: BK overproduction and BKR2 activation are linked to alteration of PLCs and their metabolites in patients with FXII-HAE. Our results may pave way to investigations on the functions of these mediators in the pathophysiology of FXII-HAE, and provide new potential biomarkers and therapeutic targets., (© 2024 European Academy of Allergy and Clinical Immunology and John Wiley & Sons Ltd.)