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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
1   Thrombosis and Atherosclerosis Research Institute, McMaster University, Hamilton, Ontario, Canada
2   Department of Medical Sciences, McMaster University, Hamilton, Ontario, Canada
,
Beverly A. Leslie
1   Thrombosis and Atherosclerosis Research Institute, McMaster University, Hamilton, Ontario, Canada
3   Department of Medicine, McMaster University, Hamilton, Ontario, Canada
,
Alan R. Stafford
1   Thrombosis and Atherosclerosis Research Institute, McMaster University, Hamilton, Ontario, Canada
3   Department of Medicine, McMaster University, Hamilton, Ontario, Canada
,
Ji Zhou
1   Thrombosis and Atherosclerosis Research Institute, McMaster University, Hamilton, Ontario, Canada
3   Department of Medicine, McMaster University, Hamilton, Ontario, Canada
,
James C. Fredenburgh
1   Thrombosis and Atherosclerosis Research Institute, McMaster University, Hamilton, Ontario, Canada
3   Department of Medicine, McMaster University, Hamilton, Ontario, Canada
,
Jeffrey I. Weitz
1   Thrombosis and Atherosclerosis Research Institute, McMaster University, Hamilton, Ontario, Canada
2   Department of Medical Sciences, McMaster University, Hamilton, Ontario, Canada
3   Department of Medicine, McMaster University, Hamilton, Ontario, Canada
4   Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, Ontario, Canada
› Author Affiliations Financial support:This work was supported in part by the Canadian Institutes of Health Research (FRN 3992, FRN 102735, and CTP 79846), the Heart and Stroke Foundation (T6357). T. T.V. was supported by a Natural Sciences and Engineering Research Council of Canada CGS D Award. J.I.W. holds the Heart and Stroke Foundation J. Fraser Mustard Endowed Chair in Cardiovascular Research and the Canada Research Chair (Tier 1) in Thrombosis.
Further Information

Publication History

Received: 23 April 2015

Accepted after major revision: 31 July 2015

Publication Date:
22 November 2017 (online)

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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
 

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