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Familial dysfibrinogenemia and thrombophilia. Structural defects and impaired fibrinolysis
ORAL COMMUNICATIONS H-4: Physiological and Population Studies: 2
53
FAMILIAL DYSFIBRINOGENEMIA AND THROMBOPHILIA. STRUCTURAL DEFECTS AND IMPAIRED FIBRINOLYSIS. ‘Haverkate F and ‘Samama MM ‘Gaubius Laboratory, TNO-PG, Leiden, The Netherlands, *Hotel Dieu, Paris, France.
and
Amongst 250 cases of dysfibrinogenemia reported, 26 are significantly associated with thrombophilia. To establish first a possible association between familial dystibrinogenemia and thrombophilia, we collected data of 187 relatives of 26 probands with thromhophilic dysfibrinogenemia. Kaplan-Meier analysis confirmed an association hetween defective structure and thrombophilia which was predominantly venous thrombosis at young age. To investigate an association between thrombophilia and structural defects and malfunction of the ahnormal fibrinogen, we (including J. Koopman and J. Grimbergen) determined by DNA sequencing the molecular defects in abnormal fibrinogen of, 11 Our unrelated patients with thromhophilic dysfibrinogenemia.
54
EPIDEYTOLOGY OF PLASMA D-DIMER,
tPA
A:JI) VON
WILLEBRAND FACTOR ANTIGENS: GLASGOW MONICA STIJDY. Lowe GDO, Rumley A, Lee AJ and Tunstall-Pedoe HD IJniversityDepartment of Medicine, Royal Infirmary, Glasgow and Cardiovascular Epidemiology JJnit , IJniversityof Dundee, 1J.Y. Recent studies suggest that plasma D-dimer, tPA and von Willebrand factor antigens are predictors of cardiovascular events: it is therefore important to define their relationships to biological, demographic and coronary risk factors in the general population. We studied this in a random sample of 603 men and women aged 25-64 years (Second Glasgow MONICA Survey), using ELISA assays (from AGEN, Biopool and DAY0 respectively). All variables increased significantly with age and the menopause; and decreased between 09.00 and 17.00 hours. D-dimer was higher in women, while tPA and VWF were higher in men. In men, all three variables were higher in smokers than non-smokers, and in those with prevalent coronary heart disease compared to those
55
FIBRINOLYTIC ACTIVITY IS NOT IMPAIRED IN REGULAR SMOKERS AND SNUFF DIPPERS - THE NORTHERN SWEDEN MONICA STUDY lEliasson M, 2 Asolund K, 3 Evrin P-E, 1Lundblad D Dept’s. of Internal Medicine. lLuleB Hosoital and *UmeB University Hospital and 3Clinical Chemistry, Central Hospital, Boden. Sweden Population studies of tobacco use with specific assays for fibrinolytic variables are lacking. Our aim was to study if regular smoking or snuff dipping was associated with changes in tissue plasminogen activator (tPA) activity or plasminogen activator inhibitor type 1 (PAI-1) activity in a randomly selected population sample. As a part of the WHO MONICA Project, 1 583 randomly selected men and women between 25 and 64 years were examined. 1 266 (80.0%) could be classified accordina to well defined tobacco habits. 581 were nontobacco isers, 238 ex-smokers, 356 current cigarette smokers and 90 snuff dippers. Tobacco use was not allowed during the hour preceding the examination. Self-reported tobacco use was validated by cotinine measurements.
19
results, added to those of others demonstrate that thrombosis is predominantly associated with defects at the C-terminal end of the Aol-chain or y-chain, or at the N-terminal site of the BP-chain of fibrinogen. A mechanism to explain thrombophilia is a decreased lysis of abnormal fihrin as a consequence of defectivebinding to fibrin of fihrinolytic enzymes. A defective binding of t-PA was associated with defects at the N-terminal site of the BP-chain (2 cases), and a defective hinding of plasminogen to the C-terminal end of the Aor-chain (I case). Another mechanism to explain thrombosis is a defective binding of thromhin to abnormal fibrin assoc.iated with defects in the N-terminal site of the BP-chain (2 cases) of fibrinogen. Consequently, thrombosis is not associated with a defect in one particular region of the fibrinogen molecule. We conclude that an association between thrombosis and dysfihrinogenemia is plausible in some cases assuming a malfunction of fibrin in fibrinolysis or thromhin binding. Why a particular molecular defect leads to malfunction of fibrin is still
unclear.
without. All three variables correlated with cholesterol and triglyceride in women, as did tPA in men. tPA also correlated with body mass index, blood pressure and gamma glutamyl transpeptidase (the latter perhaps being a marker of liver metabolism/blood flow). Multivariate models for each variable are presented. We conclude that age, sex, time of day and coronary risk factors be considered when interpreting plasma leve.lsof D-dimer, tPA and VWF; and that risk factors may operate partly through endothelial disturbance and fibrin turnover. Prospective studies are in progress to further assess these variables in prediction of coronary risk. (Supported by a grant from the Scottish Office Home and Health Department).
Results. No significant differences in tPA activity was found between different groups of tobacco habits. Nor were there any significant univariate linear correlations between tPA activity and different measurements of tobacco exposure, except that tPA activity in men was .26 IUlml lower (95% Cl .07 to -.60. p=.O4) in the highest quintile of cigarettes consumption compared to the lowest quintile. In a multiple linear regression with age, anthropometric variables, blood pressure, serum lipids and insulin included, there was no influence of smoking or snuff use on tPA activity. PAI- activity did not differ between groups. No significant univariate or multivariate relations were found between tobacco exposure and PAI- activity. Still, male smokers in the highest quintile of cigarettes consumption had 5.7 U/ml higher PAI- activity (95% Cl 4.3 to 7.1, p=.OO6) than those in the lowest quintile. Conclusion. Regular cigarette smoking and snuff dipping are no major predictors of impaired fibrinolysis. A minor influence can not be excluded but may be restricted to men smoking a large numbers of cigarettes.
53
FAMILIAL DYSFIBRINOGENEMIA AND THROMBOPHILIA. STRUCTURAL DEFECTS AND IMPAIRED FIBRINOLYSIS. ‘Haverkate F and ‘Samama MM ‘Gaubius Laboratory, TNO-PG, Leiden, The Netherlands, *Hotel Dieu, Paris, France.
and
Amongst 250 cases of dysfibrinogenemia reported, 26 are significantly associated with thrombophilia. To establish first a possible association between familial dystibrinogenemia and thrombophilia, we collected data of 187 relatives of 26 probands with thromhophilic dysfibrinogenemia. Kaplan-Meier analysis confirmed an association hetween defective structure and thrombophilia which was predominantly venous thrombosis at young age. To investigate an association between thrombophilia and structural defects and malfunction of the ahnormal fibrinogen, we (including J. Koopman and J. Grimbergen) determined by DNA sequencing the molecular defects in abnormal fibrinogen of, 11 Our unrelated patients with thromhophilic dysfibrinogenemia.
54
EPIDEYTOLOGY OF PLASMA D-DIMER,
tPA
A:JI) VON
WILLEBRAND FACTOR ANTIGENS: GLASGOW MONICA STIJDY. Lowe GDO, Rumley A, Lee AJ and Tunstall-Pedoe HD IJniversityDepartment of Medicine, Royal Infirmary, Glasgow and Cardiovascular Epidemiology JJnit , IJniversityof Dundee, 1J.Y. Recent studies suggest that plasma D-dimer, tPA and von Willebrand factor antigens are predictors of cardiovascular events: it is therefore important to define their relationships to biological, demographic and coronary risk factors in the general population. We studied this in a random sample of 603 men and women aged 25-64 years (Second Glasgow MONICA Survey), using ELISA assays (from AGEN, Biopool and DAY0 respectively). All variables increased significantly with age and the menopause; and decreased between 09.00 and 17.00 hours. D-dimer was higher in women, while tPA and VWF were higher in men. In men, all three variables were higher in smokers than non-smokers, and in those with prevalent coronary heart disease compared to those
55
FIBRINOLYTIC ACTIVITY IS NOT IMPAIRED IN REGULAR SMOKERS AND SNUFF DIPPERS - THE NORTHERN SWEDEN MONICA STUDY lEliasson M, 2 Asolund K, 3 Evrin P-E, 1Lundblad D Dept’s. of Internal Medicine. lLuleB Hosoital and *UmeB University Hospital and 3Clinical Chemistry, Central Hospital, Boden. Sweden Population studies of tobacco use with specific assays for fibrinolytic variables are lacking. Our aim was to study if regular smoking or snuff dipping was associated with changes in tissue plasminogen activator (tPA) activity or plasminogen activator inhibitor type 1 (PAI-1) activity in a randomly selected population sample. As a part of the WHO MONICA Project, 1 583 randomly selected men and women between 25 and 64 years were examined. 1 266 (80.0%) could be classified accordina to well defined tobacco habits. 581 were nontobacco isers, 238 ex-smokers, 356 current cigarette smokers and 90 snuff dippers. Tobacco use was not allowed during the hour preceding the examination. Self-reported tobacco use was validated by cotinine measurements.
19
results, added to those of others demonstrate that thrombosis is predominantly associated with defects at the C-terminal end of the Aol-chain or y-chain, or at the N-terminal site of the BP-chain of fibrinogen. A mechanism to explain thrombophilia is a decreased lysis of abnormal fihrin as a consequence of defectivebinding to fibrin of fihrinolytic enzymes. A defective binding of t-PA was associated with defects at the N-terminal site of the BP-chain (2 cases), and a defective hinding of plasminogen to the C-terminal end of the Aor-chain (I case). Another mechanism to explain thrombosis is a defective binding of thromhin to abnormal fibrin assoc.iated with defects in the N-terminal site of the BP-chain (2 cases) of fibrinogen. Consequently, thrombosis is not associated with a defect in one particular region of the fibrinogen molecule. We conclude that an association between thrombosis and dysfihrinogenemia is plausible in some cases assuming a malfunction of fibrin in fibrinolysis or thromhin binding. Why a particular molecular defect leads to malfunction of fibrin is still
unclear.
without. All three variables correlated with cholesterol and triglyceride in women, as did tPA in men. tPA also correlated with body mass index, blood pressure and gamma glutamyl transpeptidase (the latter perhaps being a marker of liver metabolism/blood flow). Multivariate models for each variable are presented. We conclude that age, sex, time of day and coronary risk factors be considered when interpreting plasma leve.lsof D-dimer, tPA and VWF; and that risk factors may operate partly through endothelial disturbance and fibrin turnover. Prospective studies are in progress to further assess these variables in prediction of coronary risk. (Supported by a grant from the Scottish Office Home and Health Department).
Results. No significant differences in tPA activity was found between different groups of tobacco habits. Nor were there any significant univariate linear correlations between tPA activity and different measurements of tobacco exposure, except that tPA activity in men was .26 IUlml lower (95% Cl .07 to -.60. p=.O4) in the highest quintile of cigarettes consumption compared to the lowest quintile. In a multiple linear regression with age, anthropometric variables, blood pressure, serum lipids and insulin included, there was no influence of smoking or snuff use on tPA activity. PAI- activity did not differ between groups. No significant univariate or multivariate relations were found between tobacco exposure and PAI- activity. Still, male smokers in the highest quintile of cigarettes consumption had 5.7 U/ml higher PAI- activity (95% Cl 4.3 to 7.1, p=.OO6) than those in the lowest quintile. Conclusion. Regular cigarette smoking and snuff dipping are no major predictors of impaired fibrinolysis. A minor influence can not be excluded but may be restricted to men smoking a large numbers of cigarettes.