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ABSTRACT: Reduced overall fibrinolytic capacity increases the risk of myocardial infarction (MI), as demonstrated in studies with predominantly male participants. We determined the influence of altered fibrinolysis on the risk of MI and ischaemic stroke (IS) in young women. The RATIO (Risk of Arterial Thrombosis In relation to Oral contraceptives) study is a population-based case-control study including young women with MI (n=203), IS (N=175) and 638 matched healthy controls. Fibrinolytic potential was determined with a tissue factor/tissue plasminogen activator induced clot-lysis assay. Odds ratios (OR) adjusted for cardiovascular risk factors were obtained with logistic regression. Clot-lysis time (CLT) was divided into tertiles based on the control group (T1-T3), with T2 as reference. Hypofibrinolysis (prolonged CLT) was associated with an increase in risk of MI (T3 vs. T2, OR 2·8; 95%confidence interval [CI] 1·7-4·7). Hyperfibrinolysis (decreased CLT) had no clear effect (T1 vs. T2, OR 1·6; 95% CI 0·9-2·9). Hypofibrinolysis did not affect the risk of IS (T3 vs. T2, OR 1·5; 95% CI 0·7-3·0), whereas hyperfibrinolysis increased this risk (T1 vs. T2, OR 4·1; 95% CI 2·1-8·0). Oral contraceptive use and smoking further increased these risks. Hypofibrinolysis increases the risk for MI in young women, a finding similar to previous studies. Counter-intuitively, hyperfibrinolysis increased the risk of IS four-fold, which suggests that MI and IS have different aetiologies.
British Journal of Haematology 11/2011; 156(2):252-8. · 4.94 Impact Factor
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ABSTRACT: Elevated plasma clot lysis time (CLT) increases risk of venous and arterial thrombosis. It is unclear which fibrinolytic factors contribute to thrombosis risk. In 743 healthy control subjects we investigated determinants of CLT. By comparison with 770 thrombosis patients, we assessed plasma levels of fibrinolytic proteins as risk factors for a first thrombosis. Plasminogen activator inhibitor-1 (PAI-1) levels were the main determinants of CLT, followed by plasminogen, thrombin-activatable fibrinolysis inhibitor (TAFI), prothrombin, and alpha2-antiplasmin. Fibrinogen, factor VII, X, and XI contributed minimally. These proteins explained 77% of variation in CLT. Levels of the fibrinolytic factors were associated with thrombosis risk (odds ratios, highest quartile vs lowest, adjusted for age, sex, and body mass index: 1.6 for plasminogen, 1.2 for alpha2-antiplasmin, 1.6 for TAFI, 1.6 for PAI-1, and 1.8 for tissue plasminogen activator [t-PA]). Adjusting for acute-phase proteins attenuated the risk associated with elevated plasminogen levels. The risk associated with increased t-PA nearly disappeared after adjusting for acute-phase proteins and endothelial activation. TAFI and PAI-1 remained associated with thrombosis after extensive adjustment. In conclusion, CLT reflects levels of all fibrinolytic factors except t-PA. Plasminogen, TAFI, PAI-1, and t-PA are associated with venous thrombosis. However, plasminogen and t-PA levels may reflect underlying risk factors.
Blood 04/2010; 116(1):113-21. · 9.90 Impact Factor
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ABSTRACT: Hypofibrinolysis as measured with overall clot lysis assays is associated with risk of arterial thrombosis. Individual components of the fibrinolytic system, however, have not been studied extensively in relation to arterial disease, or results of studies were inconsistent. The relation between plasminogen and alpha2-antiplasmin levels and cardiovascular risk factors and the association between plasminogen, alpha2-antiplasmin, tissue-plasminogen activator (t-PA), and plasminogen activator inhibitor-1 (PAI-1) and risk of myocardial infarction was investigated in the Study of Myocardial Infarctions Leiden (555 men with a first myocardial infarction and 635 controls). alpha2-antiplasmin was associated with age and lipid levels, whereas plasminogen correlated with lipids, C-reactive protein, and smoking. Increased levels of all fibrinolytic factors were associated with myocardial infarction. Age-adjusted odds ratios (ORs; 95% confidence interval) for quartile 4 compared with 1 were 1.7 (1.2-2.3) for plasminogen, 1.9 (1.3-2.6) for alpha2-antiplasmin, 1.7 (1.2-2.3) for t-PA, and 1.7 (1.2-2.4) for PAI-1. After adjusting for cardiovascular risk factors, only alpha2-antiplasmin levels remained associated with risk (OR, 1.4; [1.0-2.0]). t-PA and PAI-1 levels predominantly reflected lipid levels, whereas plasminogen reflected the inflammatory state. Concluding, elevated alpha2-antiplasmin levels are independently associated with risk of myocardial infarction. t-PA, PAI-1, and plasminogen levels appear to reflect other cardiovascular risk factors.
Blood 04/2010; 116(4):529-36. · 9.90 Impact Factor
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ABSTRACT: In this review we discuss the association of overall hypofibrinolysis and individual fibrinolytic protein levels with venous and arterial thrombosis. Decreased overall fibrinolytic potential and high plasma levels of thrombin-activatable fibrinolysis inhibitor have been consistently associated with risk of venous thrombosis, whereas little evidence exists for a role of plasminogen, alpha2-antiplasmin, tissue plasminogen activator, and plasminogen activator inhibitor 1. Overall fibrinolytic potential has been associated with arterial thrombosis in young individuals, but studies on the individual components gave conflicting results. These inconsistent results could be a consequence of nonfibrinolytic properties of fibrinolytic proteins, including roles in inflammation, vascular remodeling, atherosclerosis, and the metabolic syndrome. The nonfibrinolytic properties of these proteins may have opposing effects on development of arterial disease as compared with the lytic properties, which may explain opposite results in different studies with slightly different population characteristics. These properties may be more relevant in arterial than in venous thrombosis.
Seminars in Thrombosis and Hemostasis 08/2009; 35(5):468-77. · 4.52 Impact Factor
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ABSTRACT: Studies on the relation between thrombin activatable fibrinolysis inhibitor (TAFI) and arterial thrombosis have produced conflicting results. TAFI regulates fibrinolysis, but other roles of this inhibitor, including anti-inflammatory properties, have also been demonstrated.
We investigated the association between TAFI activity and the risk of myocardial infarction. Additionally, we studied the association of common single nucleotide polymorphisms in the TAFI gene with levels of the TAFI protein and risk of myocardial infarction.We included 554 men under 70 years old with a first myocardial infarction and 643 controls participating in the Study of Myocardial Infarctions Leiden (SMILE), a case-control study.
We found odds ratios (95% confidence intervals) of a first myocardial infarction of 2.4 (1.6-3.6), 3.2 (2.1-4.7) and 3.4 (2.3-5.1) for subjects whose TAFI levels were in the third, second and first quartiles (lowest TAFI levels), respectively, compared with the fourth quartile, after adjusting for arterial disease risk factors. The rare -438A and 1040T alleles were associated with lower, and the rare 505G allele with higher TAFI levels than the common alleles. Carriers of the -438A allele had an increased risk of myocardial infarction (odds ratio 1.6 (1.0-2.5) for AA; odds ratio 1.2 (0.9-1.5) for AG compared with GG). The other single nucleotide polymorphisms were not associated with myocardial infarction.
Low TAFI activity levels are associated with increased risk of a first myocardial infarction in men. The results on the association between TAFI single nucleotide polymorphisms and myocardial infarction were inconsistent.
Haematologica 05/2009; 94(6):811-8. · 6.42 Impact Factor
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ABSTRACT: Studies on the relationship between fibrinolysis and arterial thrombosis have been conflicting. Previously, we demonstrated that hypofibrinolysis, as measured by a plasma-based assay, increased the risk of venous thrombosis. The present study investigated increased clot lysis time (CLT) measured with the same assay as a risk factor for myocardial infarction in a case-control study including 421 men with a first myocardial infarction and 642 controls below 70 years. CLT was strongly associated with body-mass index, lipid levels, blood pressure and C-reactive protein. Overall, risk of myocardial infarction was 1.4-fold (95% confidence interval (CI) 1.0-1.9) increased for CLT in the fourth quartile (longest CLT) compared with the first quartile. After adjusting for cardiovascular risk factors this risk disappeared (OR 1.0, 95%CI 0.6-1.5). In men aged <50 years the association was pronounced (OR 3.2, 95%CI 1.5-6.7). After adjustment for cardiovascular risk factors the risk was nearly twofold increased (OR 1.8, 95%CI 0.7-4.8). In men aged > or = 50 years, no clear association between CLT and risk of myocardial infarction was found. Our study suggests that hypofibrinolysis increases the risk of a first myocardial infarction in young men, although the causality of this association remains to be determined.
British Journal of Haematology 02/2009; 145(1):121-7. · 4.94 Impact Factor
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ABSTRACT: Previously, we demonstrated that hypofibrinolysis, a decreased capacity to dissolve a blood clot as measured with an overall clot lysis assay, increases the risk of venous thrombosis. Here, we investigated the combined effect of hypofibrinolysis with established risk factors associated with hypercoagulability.
Fibrinolytic potential was determined with a plasma-based clot lysis assay in 2,090 patients with venous thrombosis and 2,564 control participants between 18 and 70 y of age enrolled in the Multiple Environmental and Genetic Assessment (MEGA) of risk factors for venous thrombosis study, a population-based case-control study on venous thrombosis. Participants completed a standardized questionnaire on acquired risk factors. Hypofibrinolysis alone, i.e., clot lysis time (CLT) in the fourth quartile (longest CLT) (in absence of the other risk factor of interest) increased thrombosis risk about 2-fold relative to individuals with CLT in the first quartile (shortest CLT). Oral contraceptive use in women with CLT in the first quartile gave an odds ratio (OR) of 2.6 (95% confidence interval [CI] 1.6 to 4.0), while women with hypofibrinolysis who used oral contraceptives had an over 20-fold increased risk of venous thrombosis (OR 21.8, 95% CI 10.2 to 46.7). For immobilization alone the OR was 4.3 (95% CI 3.2 to 5.8) and immobilization with hypofibrinolysis increased the risk 10.3-fold (95% CI 7.7 to 13.8). Factor V Leiden alone increased the risk 3.5-fold (95% CI 2.3 to 5.5), and hypofibrinolysis in factor V Leiden carriers gave an OR of 8.1 (95% CI 5.3 to 12.3). The combination of hypofibrinolysis and the prothrombin 20210A mutation did not synergistically increase the risk. All ORs and 95% CIs presented are relative to individuals with CLT in the first quartile and without the other risk factor of interest.
The combination of hypofibrinolysis with oral contraceptive use, immobilization, or factor V Leiden results in a risk of venous thrombosis that exceeds the sum of the individual risks.
PLoS Medicine 06/2008; 5(5):e97. · 16.27 Impact Factor
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ABSTRACT: The fibrinolytic system is often regarded as just an innocent bystander in the pathogenesis of venous and arterial thrombosis, while (hyper)coagulation as a risk factor has been studied extensively. In this review, we evaluated studies that investigated the association between fibrinolysis and thrombosis.
There is some evidence for an association between impaired overall fibrinolytic activity and increased risk of venous or arterial thrombosis. Plasminogen levels were found not to be related to thrombosis. Plasma levels of tissue-type plasminogen activator were related to arterial thrombosis in a number of studies but not to venous thrombosis. Thrombin activatable fibrinolysis inhibitor levels appeared to be associated with venous thrombosis. Studies on the association between thrombin activatable fibrinolysis inhibitor or plasminogen activator inhibitor-1 and arterial thrombosis had conflicting results.
Current evidence on an association between fibrinolysis and thrombosis is inconclusive. Although overall assays point to an association, not all individual factors have an association with thrombosis. Most importantly, plasminogen deficiency is not related to thrombosis, which suggests that the fibrinolytic system as a whole is unimportant in the occurrence of thrombosis. Certain components of the fibrinolytic system, however, appear to be involved in processes unrelated to fibrin degradation but related to other processes important in the development of thrombosis.
Current Opinion in Hematology 06/2007; 14(3):242-8. · 4.52 Impact Factor
