title: Genome scan of clot lysis time and its association with thrombosis in a protein C-deficient kindred.
abstract: BACKGROUND
  Previously, we found increased clot-lysis time (CLT), as measured with a plasma-based assay, to increase the risk of venous thrombosis in two population-based case-control studies. The genes influencing CLT are as yet unknown.
  
  
  METHODS
  We tested CLT as risk factor for venous thrombosis in Kindred Vermont II (n = 346), a pedigree suffering from a high thrombosis risk, partially attributable to a type I protein C deficiency. Furthermore, we tested for quantitative trait loci (QTLs) for CLT, using variance component linkage analysis.
  
  
  RESULTS
  Protein C-deficient family members had shorter CLTs than non-deficient members (median CLT 67 min vs. 75 min). One standard deviation increase in CLT increased the risk of venous thrombosis 2.4-fold in non-deficient family members. Protein C deficiency without elevated CLT increased the risk 6.9-fold. Combining both risk factors yielded a 27.8-fold increased risk. The heritability of CLT was 42-52%. We found suggestive evidence of linkage on chromosome 11 (62 cM), partly explained by the prothrombin 20210A mutation, and on chromosome 13 (52 cM). Thrombin-activatable fibrinolysis inhibitor genotypes did not explain the variation in CLT.
  
  
  CONCLUSIONS
  Hypofibrinolysis appears to increase thrombosis risk in this family, especially in combination with protein C deficiency. Protein C deficiency is associated with short CLT. CLT is partly genetically regulated. Suggestive QTLs were found on chromosomes 11 and 13.
authors.affiliation: Department of Clinical Chemistry and Hematology, University Medical Center Utrecht, Utrecht, the Netherlands.
authors.forename: M E
authors.initials: ME
authors.lastname: Meltzer
authors.forename: S J
authors.initials: SJ
authors.lastname: Hasstedt
authors.forename: C Y
authors.initials: CY
authors.lastname: Vossen
authors.forename: P W
authors.initials: PW
authors.lastname: Callas
authors.forename: Ph G
authors.initials: PG
authors.lastname: DE Groot
authors.forename: F R
authors.initials: FR
authors.lastname: Rosendaal
authors.forename: T
authors.initials: T
authors.lastname: Lisman
authors.forename: E G
authors.initials: EG
authors.lastname: Bovill
mesh_terms: D001780:Blood Coagulation Tests; D025901:Carboxypeptidase B2 / Q000235:genetics; D002880:Chromosomes, Human, Pair 11; D002882:Chromosomes, Human, Pair 13; D005190:Family; D005342:Fibrinolysis / Q000235:genetics*; D008040:Genetic Linkage; D015894:Genome, Human / Q000502:physiology*; D006801:Humans; D009154:Mutation; D020151:Protein C Deficiency / Q000235:genetics / Q000503:physiopathology*; D011516:Prothrombin / Q000235:genetics; D040641:Quantitative Trait Loci; D013927:Thrombosis / Q000235:genetics*
chemical_list: D011516:Prothrombin; D025901:Carboxypeptidase B2