In plasma, the zymogens factor XII (FXII) and prekallikrein reciprocally convert each other to the proteases FXIIa and plasma kallikrein (PKa). PKa cleaves high-molecular-weight kininogen (HK) to release bradykinin, which contributes to regulation of blood vessel tone and permeability. Plasma FXII is normally in a "closed" conformation that limits activation by PKa. When FXII binds to a surface during contact activation it assumes an "open" conformation that increases the rate of activation by PKa. Mutations in FXII that disrupt the closed conformation have been identified in patients with conditions associated with excessive bradykinin formation. Using FXII structures predicted by AlphaFold, we generated models for the closed form of human FXII that we tested with site-directed mutagenesis. The best model predicts multiple interactions between the fibronectin type 2, kringle and catalytic domains involving highly conserved amino acids that restrict access to the FXII activation cleavage sites. Based on the model, we expressed FXII with single amino acid substitutions and studied their effects on FXII activation by PKa. Replacements for Arg36 in the fibronectin type 2 domain; Glu225, Asp253 or Trp268 in the kringle domain, or Lys346 near the activation cleavage site were activated >10-fold faster by PKa than wild type FXII. Adding these proteins to plasma resulted in rapid HK cleavage due to markedly enhanced reciprocal activation with PK. The results support a model that explains the behavior of FXII in solution. Conformational changes involving the identified amino acids likely occur when FXII binds to a surface to facilitate activation.
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http://dx.doi.org/10.1182/bloodadvances.2025015842 | DOI Listing |
Blood Adv
January 2025
Vanderbilt University Medical Center, Nashville, Tennessee, United States.
In plasma, the zymogens factor XII (FXII) and prekallikrein reciprocally convert each other to the proteases FXIIa and plasma kallikrein (PKa). PKa cleaves high-molecular-weight kininogen (HK) to release bradykinin, which contributes to regulation of blood vessel tone and permeability. Plasma FXII is normally in a "closed" conformation that limits activation by PKa.
View Article and Find Full Text PDFAnn Hematol
January 2025
Department of Clinical Laboratory, Key Laboratory of Clinical Laboratory Diagnosis and Translational Research of Zhejiang Province, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China.
Analyze the clinical phenotype and gene mutations of a family with hereditary FXII deficiency, and preliminarily explore its phenotypic manifestations. The routine coagulation indicators and related coagulation factors were measured.Thromboelastography and thrombin generation tests simulated coagulation and anticoagulation states in vitro and in vivo.
View Article and Find Full Text PDFBMC Cardiovasc Disord
January 2025
Department of Laboratory Medicine, Zhujiang Hospital, Southern Medical University, 253 Industrial Avenue Central, Guangzhou, 510280, P. R. China.
Objective: To establish the reference intervals of plasma Plasminogen, Factor XII activity, and Factor XIII Antigen in healthy adults in Guangzhou.
Methods: A total of 168 young people (75 males and 93 females, aged 18-65 years) who underwent physical examination in Zhujiang Hospital of Southern Medical University from 2020 to 2022 were recruited. Sysmex CS5100 automatic coagulation analyzer and matching reagents were used to detect Plasminogen.
Toxins (Basel)
December 2024
Adaptive Biotoxicology Lab, School of the Environment, University of Queensland, St Lucia, QLD 4072, Australia.
This study examined the pathophysiological effects of venoms from neonate and adult specimens of the viperid snake , focusing on their ability to activate various blood clotting factors in human plasma. All venoms exhibited strong procoagulant properties. In concentration-response tests, the clotting potency of the neonate venoms fell within the range of their parents' maximum clotting velocities and areas under the curve.
View Article and Find Full Text PDFInt J Biol Macromol
December 2024
Laboratory of Molecular Medicine, Ordos Central Hospital, Inner Mongolia Autonomous Region, Ordos 017000, China; Ordos Clinical Medical College, Inner Mongolia Medical University, Ordos 017000, China; Baotou Medical College, Inner Mongolia University of Science and Technology, Baotou 014000, China. Electronic address:
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.
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