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Factor V and thrombotic disease: description of a janus-faced protein.

Nicolaes, Gerry A F and Dahlbäck, Björn LU (2002) In Arteriosclerosis, Thrombosis and Vascular Biology 22(4). p.530-538
Abstract
The generation of thrombin by the prothrombinase complex constitutes an essential step in hemostasis, with thrombin being crucial for the amplification of blood coagulation, fibrin formation, and platelet activation. In the prothrombinase complex, the activated form of coagulation factor V (FVa) is an essential cofactor to the enzyme-activated factor X (FXa), FXa being virtually ineffective in the absence of its cofactor. Besides its procoagulant potential, intact factor V (FV) has an anticoagulant cofactor capacity functioning in synergy with protein S and activated protein C (APC) in APC-catalyzed inactivation of the activated form of factor VIII. The expression of anticoagulant cofactor function of FV is dependent on APC-mediated... (More)
The generation of thrombin by the prothrombinase complex constitutes an essential step in hemostasis, with thrombin being crucial for the amplification of blood coagulation, fibrin formation, and platelet activation. In the prothrombinase complex, the activated form of coagulation factor V (FVa) is an essential cofactor to the enzyme-activated factor X (FXa), FXa being virtually ineffective in the absence of its cofactor. Besides its procoagulant potential, intact factor V (FV) has an anticoagulant cofactor capacity functioning in synergy with protein S and activated protein C (APC) in APC-catalyzed inactivation of the activated form of factor VIII. The expression of anticoagulant cofactor function of FV is dependent on APC-mediated proteolysis of intact FV. Thus, FV has the potential to function in procoagulant and anticoagulant pathways, with its functional properties being modulated by proteolysis exerted by procoagulant and anticoagulant enzymes. The procoagulant enzymes factor Xa and thrombin are both able to activate circulating FV to FVa. The activity of FVa is, in turn, regulated by APC together with its cofactor protein S. In fact, the regulation of thrombin formation proceeds primarily through the upregulation and downregulation of FVa cofactor activity, and failure to control FVa activity may result in either bleeding or thrombotic complications. A prime example is APC resistance, which is the most common genetic risk factor for thrombosis. It is caused by a single point mutation in the FV gene (factor V(Leiden)) that not only renders FVa less susceptible to the proteolytic inactivation by APC but also impairs the anticoagulant properties of FV. This review gives a description of the dualistic character of FV and describes the gene-gene and gene-environment interactions that are important for the involvement of FV in the etiology of venous thromboembolism. (Less)
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keywords
Venous Thrombosis : blood, Thrombin : metabolism, Protein S : physiology, Protein C : physiology, Protein C : genetics, Point Mutation, Phenotype, Activated Protein C Resistance : genetics, Blood Coagulation : physiology, Caucasoid Race, Factor V : biosynthesis, Factor V : genetics, Factor V : metabolism, Factor V : physiology, Factor VIII : genetics, Factor VIII : physiology, Factor Va : physiology, Factor Va : genetics, Factor Xa : metabolism, Factor Xa : physiology, Human, Venous Thrombosis : genetics
in
Arteriosclerosis, Thrombosis and Vascular Biology
volume
22
issue
4
pages
530 - 538
publisher
American Heart Association
external identifiers
  • pmid:11950687
  • wos:000175208700004
  • scopus:0036124011
ISSN
1524-4636
DOI
10.1161/01.ATV.0000012665.51263.B7
language
English
LU publication?
yes
id
57f7dc3b-a1e6-4a3c-abe1-e359e3e367c2 (old id 107635)
alternative location
http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11950687&dopt=Abstract
date added to LUP
2007-07-26 11:05:26
date last changed
2017-10-01 03:58:12
@article{57f7dc3b-a1e6-4a3c-abe1-e359e3e367c2,
  abstract     = {The generation of thrombin by the prothrombinase complex constitutes an essential step in hemostasis, with thrombin being crucial for the amplification of blood coagulation, fibrin formation, and platelet activation. In the prothrombinase complex, the activated form of coagulation factor V (FVa) is an essential cofactor to the enzyme-activated factor X (FXa), FXa being virtually ineffective in the absence of its cofactor. Besides its procoagulant potential, intact factor V (FV) has an anticoagulant cofactor capacity functioning in synergy with protein S and activated protein C (APC) in APC-catalyzed inactivation of the activated form of factor VIII. The expression of anticoagulant cofactor function of FV is dependent on APC-mediated proteolysis of intact FV. Thus, FV has the potential to function in procoagulant and anticoagulant pathways, with its functional properties being modulated by proteolysis exerted by procoagulant and anticoagulant enzymes. The procoagulant enzymes factor Xa and thrombin are both able to activate circulating FV to FVa. The activity of FVa is, in turn, regulated by APC together with its cofactor protein S. In fact, the regulation of thrombin formation proceeds primarily through the upregulation and downregulation of FVa cofactor activity, and failure to control FVa activity may result in either bleeding or thrombotic complications. A prime example is APC resistance, which is the most common genetic risk factor for thrombosis. It is caused by a single point mutation in the FV gene (factor V(Leiden)) that not only renders FVa less susceptible to the proteolytic inactivation by APC but also impairs the anticoagulant properties of FV. This review gives a description of the dualistic character of FV and describes the gene-gene and gene-environment interactions that are important for the involvement of FV in the etiology of venous thromboembolism.},
  author       = {Nicolaes, Gerry A F and Dahlbäck, Björn},
  issn         = {1524-4636},
  keyword      = {Venous Thrombosis : blood,Thrombin : metabolism,Protein S : physiology,Protein C : physiology,Protein C : genetics,Point Mutation,Phenotype,Activated Protein C Resistance : genetics,Blood Coagulation : physiology,Caucasoid Race,Factor V : biosynthesis,Factor V : genetics,Factor V : metabolism,Factor V : physiology,Factor VIII : genetics,Factor VIII : physiology,Factor Va : physiology,Factor Va : genetics,Factor Xa : metabolism,Factor Xa : physiology,Human,Venous Thrombosis : genetics},
  language     = {eng},
  number       = {4},
  pages        = {530--538},
  publisher    = {American Heart Association},
  series       = {Arteriosclerosis, Thrombosis and Vascular Biology},
  title        = {Factor V and thrombotic disease: description of a janus-faced protein.},
  url          = {http://dx.doi.org/10.1161/01.ATV.0000012665.51263.B7},
  volume       = {22},
  year         = {2002},
}