Histidine-rich glycoprotein binds DNA and RNA and attenuates their capacity to activate the intrinsic coagulation pathway

Trang T. Vu; Beverly A. Leslie; Alan R. Stafford; Ji Zhou; James C. Fredenburgh; Jeffrey I. Weitz

doi:10.1160/TH15-04-0336

Thrombosis and Haemostasis, Table of Contents

Thromb Haemost 2016; 115(01): 89-98
DOI: 10.1160/TH15-04-0336

Coagulation and Fibrinolysis

Schattauer GmbH Schattauer

Histidine-rich glycoprotein binds DNA and RNA and attenuates their capacity to activate the intrinsic coagulation pathway

Trang T. Vu

¹Thrombosis and Atherosclerosis Research Institute, McMaster University, Hamilton, Ontario, Canada

²Department of Medical Sciences, McMaster University, Hamilton, Ontario, Canada

,

Beverly A. Leslie

¹Thrombosis and Atherosclerosis Research Institute, McMaster University, Hamilton, Ontario, Canada

³Department of Medicine, McMaster University, Hamilton, Ontario, Canada

,

Alan R. Stafford

¹Thrombosis and Atherosclerosis Research Institute, McMaster University, Hamilton, Ontario, Canada

³Department of Medicine, McMaster University, Hamilton, Ontario, Canada

,

Ji Zhou

¹Thrombosis and Atherosclerosis Research Institute, McMaster University, Hamilton, Ontario, Canada

³Department of Medicine, McMaster University, Hamilton, Ontario, Canada

,

James C. Fredenburgh

¹Thrombosis and Atherosclerosis Research Institute, McMaster University, Hamilton, Ontario, Canada

³Department of Medicine, McMaster University, Hamilton, Ontario, Canada

,

Jeffrey I. Weitz

¹Thrombosis and Atherosclerosis Research Institute, McMaster University, Hamilton, Ontario, Canada

²Department of Medical Sciences, McMaster University, Hamilton, Ontario, Canada

³Department of Medicine, McMaster University, Hamilton, Ontario, Canada

⁴Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, Ontario, Canada

› Author Affiliations

Abstract

Summary

When triggered by factor (F) XII and nucleic acids, we showed that thrombosis in HRG-deficient mice is accelerated compared with that in wild-type mice. In this study, we set out to identify the mechanisms by which nucleic acids promote contact activation, and to determine whether HRG attenuates their effects. DNA or RNA addition to human plasma enhances thrombin generation via the intrinsic pathway and shortens the clotting time. Their effect on the clotting time is seven- to 14-fold greater in HRG-deficient plasma than in control plasma. Investigations into the mechanisms of activation reveal that nucleic acids a) promote FXII activation in the presence of prekallikrein- and high molecular weight kininogen (HK), and b) enhance thrombin-mediated FXI activation by 10– to 12-fold. Surface plasmon resonance studies show that DNA and RNA bind FXII, FXIIa, HK, FXI, FXIa and thrombin with high affinity. HRG attenuates DNA- and RNA-mediated FXII activation, and FXI activation by FXIIa or by thrombin, suggesting that HRG down regulates the capacity of DNA and RNA to activate the intrinsic pathway. Therefore, HRG attenuates the procoagulant activity of nucleic acids at multiple levels.

Keywords

Coagulation - intrinsic pathway - histidine-rich glycoprotein - DNA - RNA

Full Text

References

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