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Thromb Haemost 2012; 107(05): 854-863
DOI: 10.1160/TH11-10-0708
Blood Coagulation, Fibrinolysis and Cellular Haemostasis
Schattauer GmbH

Two missense mutations identified in venous thrombosis patients impair the inhibitory function of the protein Z dependent protease inhibitor

Laura K. Young
1   Department of Molecular Medicine and Pathology, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand
5   Department of Haematology, Auckland City Hospital, Auckland, New Zealand
,
Nigel P. Birch
2   School of Biological Sciences, University of Auckland, Auckland, New Zealand
,
Peter J. Browett
1   Department of Molecular Medicine and Pathology, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand
5   Department of Haematology, Auckland City Hospital, Auckland, New Zealand
,
Paul B. Coughlin
3   Australian Centre for Blood Diseases, Monash University, Melbourne, Australia
,
Anita J. Horvath
3   Australian Centre for Blood Diseases, Monash University, Melbourne, Australia
,
Neil S. Van de Water
4   Lab Plus, Auckland City Hospital, Auckland, New Zealand
,
Paul A. Ockelford
5   Department of Haematology, Auckland City Hospital, Auckland, New Zealand
,
Paul L. Harper
6   Department of Haematology, Palmerston North Hospital, Palmerston North, New Zealand
› Author Affiliations Financial support: This study was supported by a grant from the Auckland Medical Research Foundation.
Further Information

Publication History

Received: 13 October 2011

Accepted after major revision: 10 January 2012

Publication Date:
25 November 2017 (online)

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Summary

Protein Z-dependent protease inhibitor (ZPI) is a plasma inhibitor of factor (F)Xa and FXIa. In an earlier study, five mutations were identified within the ZPI gene of venous thrombosis patients and healthy controls. Two of these were nonsense mutations and three were missense mutations in important regions of the protein. Here we report that two of these latter three mutations, F145L and Q384R, impair the inhibitory function of ZPI in vitro. Recombinant wild-type and mutant proteins were prepared; stability in response to thermal challenge was similar. Inhibition of FXa in the presence of the cofactor protein Z was reduced 68-fold by the Q384R mutant; inhibition of FXIa by the F145L mutant was reduced two- to three-fold compared to the wild-type ZPI. An analysis of all five ZPI mutations was undertaken in a cohort of venous thrombosis patients (n=550) compared to healthy controls (n=600). Overall, there was a modest increase in incidence of these mutations in the thrombosis group (odds ratio 2.0, 1.05–3.7, p=0.044). However, in contrast to W324X (nonsense mutation), the Q384R missense mutation and R88X nonsense mutation were evenly distributed in patients and controls; F145L was rare. The final mutation (S143Y) was also rare and did not significantly alter ZPI function in laboratory studies. The F145L and particularly the Q384R mutation impaired the function of the coagulation inhibitor ZPI; however, there was no convincing association between these mutations and venous thrombosis risk. The functional role for ZPI in vivo has yet to be clarified.

Keywords

Coagulation factors - coagulation inhibitors - SERPINs - venous thrombosis
 

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