Kallikrein augments the anticoagulant function of the protein C system in thrombin generation

J. Wan, N. Vadaq, J. Konings, M. Jaeger, V. Kumar, B. de Laat, L. Joosten, M.G. Netea, A.J. van der Ven, P.G. de Groot, Q. de Mast, M. Roest*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

Background Genetics play a significant role in coagulation phenotype and venous thromboembolism risk. Resistance to the anticoagulant activated protein C (APC) is an established risk for thrombosis. Herein, we explored the genetic determinants of thrombin generation (TG) and thrombomodulin (TM)-modulated TG using plasma from the Human Functional Genomics Project. Methods Calibrated TG was measured both in absence and presence of TM using tissue factor as trigger. Genetic determinants of TG parameters and protein C pathway function were assessed using genome-wide single-nucleotide polymorphism (SNP) genotyping. Plasma samples were supplemented with purified apolipoprotein A-IV, prekallikrein, or kallikrein to test their influence on the anticoagulant function of TM and APC in TG. Results Thrombin generation data from 392 individuals were analyzed. Genotyping showed that the KLKB1 gene (top SNP: rs4241819) on chromosome 4 was associated with the normalized sensitivity ratio of endogenous thrombin potential to TM at genome-wide level (nETP-TMsr, P = 4.27 x 10(-8)). In vitro supplementation of kallikrein, but not prekallikrein or apolipoprotein A-IV, into plasma dose-dependently augmented the anticoagulant effect of TM and APC in TG. Variations of rs4241819 was not associated with the plasma concentration of prekallikrein. Association between rs4241819 and nETP-TMsr was absent when TG was measured in presence of a contact pathway inhibitor corn trypsin inhibitor. Conclusions Our results suggest that kallikrein plays a role in the regulation of the anticoagulant protein C pathway in TG, which may provide a novel mechanism for the previously observed association between the KLKB1 gene and venous thrombosis.
Original languageEnglish
Pages (from-to)48-57
Number of pages10
JournalJournal of Thrombosis and Haemostasis
Volume20
Issue number1
Early online date28 Sep 2021
DOIs
Publication statusPublished - Jan 2022

Keywords

  • genetic association
  • kallikrein
  • protein C
  • thrombin
  • thrombosis
  • GENOME-WIDE ASSOCIATION
  • APOLIPOPROTEIN-A-IV
  • HUMAN FACTOR-VIII
  • VENOUS THROMBOSIS
  • FACTOR-V
  • PLASMA KALLIKREIN
  • FACTOR-XIA
  • RISK
  • IDENTIFICATION
  • INACTIVATION

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