Activation markers of coagulation and fibrinolysis in twins: heritability of the prethrombotic state.
BACKGROUND
Activation markers of coagulation and fibrinolysis are increased in individuals at risk of coronary-artery disease and other thrombotic disorders--a condition defined as the prethrombotic state. We aimed to find out the extent to which the prethrombotic state is determined by genetic factors.


METHODS
We analysed concentrations of prothrombin, prothrombin fragment 1+2, thrombin-antithrombin complex, crosslinked fibrin degradation product D-dimer, and thrombin-activatable fibrinolysis inhibitor by ELISA in 118 monozygotic and 112 dizygotic unselected female twins aged 21-73 years from the St Thomas' UK Adult Twin Registry. We used quantitative genetic-model fitting to estimate heritability.


RESULTS
We found significant heritabilities in concentrations of the activation markers in plasma. Genetic factors contributed 45, 40, and 65% of the variation in concentrations of fragment 1+2, thrombin-antithrombin complex, and D-dimer, respectively. Age was important only in fragment 1+2 concentrations, in which it accounted for 12% of the variation. The remaining variation could be attributed to unique environmental factors. Variation in concentrations of precursor prothrombin in plasma was determined by 57% heritability, and that of zymogen thrombin-activatable fibrinolysis inhibitor showed a very strong genetic component (82%).


CONCLUSIONS
The activation mechanisms of the coagulation and fibrinolytic systems, and therefore the prethrombotic state, are controlled to a substantial degree by genetic factors. Genes influencing activation of haemostasis are likely to be an important component of the overall thrombotic tendency in the general population.
Ariëns
Robert A S
RA
Academic Unit of Molecular Vascular Medicine, University of Leeds School of Medicine, Leeds, UK. r.a.s.ariens@leeds.ac.uk
de Lange
Marlies
M
Snieder
Harold
H
Boothby
May
M
Spector
Tim D
TD
Grant
Peter J
PJ
D000328:Adult; D000368:Aged; D000933:Antifibrinolytic Agents / Q000032:analysis; D000990:Antithrombin III; D001777:Blood Coagulation / Q000502:physiology*; D001779:Blood Coagulation Factors / Q000235:genetics*; D002352:Carrier Proteins / Q000097:blood; D003327:Coronary Disease / Q000235:genetics / Q000503:physiopathology*; D005260:Female; D005338:Fibrin Fibrinogen Degradation Products / Q000032:analysis; D005342:Fibrinolysis / Q000502:physiology*; D006801:Humans; D026901:Membrane Transport Proteins; D008875:Middle Aged; D010447:Peptide Hydrolases / Q000097:blood; D011516:Prothrombin / Q000032:analysis; D029701:Saccharomyces cerevisiae Proteins; D013927:Thrombosis / Q000235:genetics / Q000503:physiopathology*
C409889:ARN2 protein, S cerevisiae; D000933:Antifibrinolytic Agents; D001779:Blood Coagulation Factors; D002352:Carrier Proteins; D005338:Fibrin Fibrinogen Degradation Products; D026901:Membrane Transport Proteins; D029701:Saccharomyces cerevisiae Proteins; C046193:antithrombin III-protease complex; C036309:fibrin fragment D; D000990:Antithrombin III; D011516:Prothrombin; D010447:Peptide Hydrolases