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Familial thrombophilia : clinical and molecular analysis of Swedish families with inherited resistance to activated protein C or protein S deficiency

Zöller, Bengt LU (1996) In Scandinavian journal of clinical and laboratory investigation. Supplementum 56(226). p.19-46
Abstract

This report describes the characterization of Swedish families with inherited resistance to activated protein C (APC resistance) and/or protein S deficiency, two genetic disorders associated with functional impairment of the protein C anticoagulant pathway. The APC resistance phenotype was linked to the factor V gene locus in a kindred with independent inheritance of APC resistance and protein S deficiency. A point mutation changing Arg506 to a Gln (FV:Q506) in the factor V gene was the cause of APC resistance. In studies of 50 families with hereditary APC resistance, the FV:Q506 mutation was identified in 94% (47/50) of the families, and the thrombotic risk was found to be dependent on the factor V genotype. Moreover, 18 families with... (More)

This report describes the characterization of Swedish families with inherited resistance to activated protein C (APC resistance) and/or protein S deficiency, two genetic disorders associated with functional impairment of the protein C anticoagulant pathway. The APC resistance phenotype was linked to the factor V gene locus in a kindred with independent inheritance of APC resistance and protein S deficiency. A point mutation changing Arg506 to a Gln (FV:Q506) in the factor V gene was the cause of APC resistance. In studies of 50 families with hereditary APC resistance, the FV:Q506 mutation was identified in 94% (47/50) of the families, and the thrombotic risk was found to be dependent on the factor V genotype. Moreover, 18 families with hereditary deficiency of free protein S were investigated. Type I protein S deficiency (low free and total protein S) and type III deficiency (low free but normal total protein S) coexisted in 78% (14/18) of the families, suggesting the two types to be phenotypic variants of the same genetic disorder. Deficiency of free protein S was caused by equimolar relationship between protein S and beta-chain containing isoforms of C4BP. Though protein S deficiency was a strong risk factor for thrombosis, the FV:Q506 mutation was identified as an additional genetic risk factor in 39% of the families. Thus, familial thrombophilia is a multiple gene disorder. The thrombophilic tendency associated with APC resistance or protein S deficiency was related to increased levels of prothrombin fragment 1 + 2, reflecting increased activation of the common coagulation pathway.

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organization
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type
Contribution to journal
publication status
published
subject
keywords
activated protein C, blood clotting factor 5, familial disease, family, gene locus, heredity, human, phenotype, point mutation, priority journal, protein S deficiency, review, Sweden, thrombophilia
in
Scandinavian journal of clinical and laboratory investigation. Supplementum
volume
56
issue
226
pages
28 pages
external identifiers
  • scopus:0030478027
ISSN
0085-591X
language
English
LU publication?
yes
id
36dc4028-65e0-4e74-992f-4413dea994e8
date added to LUP
2017-10-19 15:24:20
date last changed
2017-11-07 09:15:33
@article{36dc4028-65e0-4e74-992f-4413dea994e8,
  abstract     = {<p>This report describes the characterization of Swedish families with inherited resistance to activated protein C (APC resistance) and/or protein S deficiency, two genetic disorders associated with functional impairment of the protein C anticoagulant pathway. The APC resistance phenotype was linked to the factor V gene locus in a kindred with independent inheritance of APC resistance and protein S deficiency. A point mutation changing Arg506 to a Gln (FV:Q506) in the factor V gene was the cause of APC resistance. In studies of 50 families with hereditary APC resistance, the FV:Q506 mutation was identified in 94% (47/50) of the families, and the thrombotic risk was found to be dependent on the factor V genotype. Moreover, 18 families with hereditary deficiency of free protein S were investigated. Type I protein S deficiency (low free and total protein S) and type III deficiency (low free but normal total protein S) coexisted in 78% (14/18) of the families, suggesting the two types to be phenotypic variants of the same genetic disorder. Deficiency of free protein S was caused by equimolar relationship between protein S and beta-chain containing isoforms of C4BP. Though protein S deficiency was a strong risk factor for thrombosis, the FV:Q506 mutation was identified as an additional genetic risk factor in 39% of the families. Thus, familial thrombophilia is a multiple gene disorder. The thrombophilic tendency associated with APC resistance or protein S deficiency was related to increased levels of prothrombin fragment 1 + 2, reflecting increased activation of the common coagulation pathway.</p>},
  author       = {Zöller, Bengt},
  issn         = {0085-591X},
  keyword      = {activated protein C,blood clotting factor 5,familial disease,family,gene locus,heredity,human,phenotype,point mutation,priority journal,protein S deficiency,review,Sweden,thrombophilia},
  language     = {eng},
  number       = {226},
  pages        = {19--46},
  series       = {Scandinavian journal of clinical and laboratory investigation. Supplementum},
  title        = {Familial thrombophilia : clinical and molecular analysis of Swedish families with inherited resistance to activated protein C or protein S deficiency},
  volume       = {56},
  year         = {1996},
}