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Thromb Haemost 2001; 85(02): 274-279
DOI: 10.1055/s-0037-1615694
Review Article
Schattauer GmbH

Anticoagulant Dysfunction of Human Arg352Trp-Activated Protein C Caused by Defective Factor Va Inactivation

Claudia Rintelen   *
1   Departments of Molecular & Experimental Medicine and of Vascular Biology, The Scripps Research Institute, La Jolla, CA, USA
,
Subramanian Yegneswaran
1   Departments of Molecular & Experimental Medicine and of Vascular Biology, The Scripps Research Institute, La Jolla, CA, USA
,
John H. Griffin
1   Departments of Molecular & Experimental Medicine and of Vascular Biology, The Scripps Research Institute, La Jolla, CA, USA
› Author AffiliationsThis work was supported in part by an Alfred Schroedinger Fellowship (C.R.), an American Heart Association Fellowship (S.Y.) and National Institute of Health Grants HL52246, HL 21544, M01-RR00833.
Further Information

Publication History

Received 06 June 2000

Accepted after revision 13 September 2000

Publication Date:
08 December 2017 (online)

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Summary

The dysfunctional mutant R352W-protein C was found in two patients with venous thrombosis. The mutant R352A-protein C was constructed to define the contribution of charge/size of the residue at 352 on protein C (chymotrypsin numbering 187). Compared with wild type-protein C, R352W-protein C showed no difference in activation by thrombin·thrombomodulin or α-thrombin. However, R352W-activated protein C (APC) anticoagulant activity (aPTT assay) was reduced to ~65%. Although the catalytic efficiency of R352W-APC towards the oligopeptide substrate S-2366 was unperturbed, factor Va and R506Q-factor Va were not efficiently inactivated by R352W-APC compared with wild type-APC. R352A-APC showed reduced anticoagulant activity and reduced efficiency in factor Va inactivation and in factor VIIIa-inactivation in the presence of protein S. These observations suggest that the dysfunction of R352W-APC in factor Va inactivation may be one of the mechanisms leading to venous thrombosis in affected patients and that R352 plays an important role in the physiological functioning of APC.

Keywords

Venous thrombosis - protein C deficiency - point mutation - factor Va - dysfunction - anticoagulant

* Current address: Dr. Claudia Rintelen, Department of Hematology and Hemostaseology, University of Vienna, 1090 Vienna, Austria.


 

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