Recent investigations suggest that microthrombi formation in bowel capillaries could be a determinant factor in inflammatory bowel disease (IBD) pathogenesis. To evaluate the implication of the hemostatic system during these thrombotic events, we analyzed plasmatic values of prothrombotic state markers, physiologic inhibitors of coagulation, and endothelial lesion markers in 112 IBD patients. We found an increase in thrombin-antithrombin complexes and a decrease in antithrombin III, probably due to consumption, demonstrating an increase in thrombin generation. High levels of D-dimer reflect increased fibrin formation, but there is no correlation between thrombin generation markers and D-dimer, possibly suggesting the presence of inadequate fibrinolysis. Levels of tissue factor pathway inhibitor were higher in patients than in controls. Nine patients with Crohn's disease (35% of our sample) had levels of this marker under 70% (range 37-69%). Von Willebrand factor values were increased and those of thrombomodulin only in active patients. Most of the changes were detected in patients with inflammatory activity, and there were no differences between ulcerative colitis and Crohn's disease. In conclusion, these results support the hypothesis that there is an endothelial lesion with sustained coagulation activation in IBD patients.

Background and Purpose-Recently, a novel procarboxypeptidase B-like proenzyme, called thrombin-activatable fibrinolysis inhibitor (TAFI), has been described. It plays an important role in the delicate balance between coagulation and fibrinolysis. TAFI leads to potent inhibition of tissue plasminogen activator-induced fibrinolysis. The relevance of TAFI in thromboembolic disease is unclear. We have investigated the risk of ischemic stroke (IS) in relation to plasma levels of functional TAFI. Methods-In a case-control study, we enrolled 264 individuals; 114 had IS, and 150 were recruited as controls who were age and sex matched and had no history of arterial disease. The individuals supplied information on their personal and family histories of cardiovascular diseases and conventional cardiovascular risk factors. Functional TAFI assays were performed by use of a method based on the activation of TAFI with thrombin-thrombomodulin and the measure of the TAFI activity generated. Other hemostatic parameters assayed were factor VIIIc, anti-phospholipid antibodies, fibrinogen, factor V Leiden, and the prothrombin gene G20210A mutations (PT20210A). Results-Functional TAFI levels were significantly higher in patients with IS (113.7Ϯ25%; range, 57% to 209%) than in controls (102.6Ϯ19%). The odds ratio for IS in patients with functional TAFI levels Ͼ120% was 5.7 (95% confidence interval, 2.3 to 14.1). Conclusions-We found that functional TAFI levels in plasma (Ͼ120%) increased the risk of IS Ϸ6-fold. Further studies should elucidate the physiological role of TAFI in arterial disease and possibly provide clues to therapeutic approaches.

Activated protein C resistance (APCR) is the most prevalent risk factor for thrombosis, accounting for 20% to 60% of familial thrombophilia. A mutation in the F5 gene, factor V Leiden (FVL), is a major determinant of pathological APCR in some populations. However, APCR predicts risk for thrombosis independently of FVL. This suggests that other genetic factors may influence risk of thrombosis through quantitative variation in APCR. To search for these unknown loci, we conducted a genome-wide linkage screen for genes affecting normal variation in APCR in the 21 Spanish families from the Genetic Analysis of Idiopathic Thrombophilia (GAIT) project. Conditional on FVL, the strongest linkage signal for APCR was found on chromosome 18 near D18S53. Bivariate linkage analyses with a genetically correlated trait, levels of clotting factor VIII, strengthened evidence for the chromosome 18 quantitative trait locus (QTL; logarithm of the odds [LOD], 4.5; P ‫؍‬ 3.08 ؋ 10 ؊5 ). However, the region on chromosome 1 that contains the F5 structural gene showed little evidence of linkage to APCR (LOD, < 1). This indicates that apart from the FVL, the F5 locus itself plays a relatively minor role in normal variation in APCR, including the HR2 IntroductionVenous and arterial thrombosis may be life-threatening events and are of great importance in public health. Very little is known about the relative importance of genetic factors in thrombosis risk in the general population. 1 Recently, as part of the GAIT (Genetic Analysis of Idiopathic Thrombophila) project, we have quantified the genetic contribution to susceptibility to thrombosis and related phenotypes in the Spanish population. 2,3 Of the quantitative risk factors studied, activated protein C resistance (APCR) had the highest heritability (0.71), and it was genetically correlated with thrombosis ( g ϭ Ϫ 0.65; P ϭ 1 ϫ 10 Ϫ6 ), 2,3 indicating that some of the genes that influence quantitative variation in this phenotype also influence susceptibility to thrombosis.APCR is the most prevalent risk factor for thrombosis, 4 accounting for 20% to 60% of familial thrombophilia. 5 A mutation in the F5 gene (factor V Leiden [FVL]) produces a coding change from Arg506 to Gln at the first cleavage site, where APC acts to inactivate FV. As a consequence, this mutation produces a protein that is intrinsically resistant to APC, causing the APCR pathological phenotype. 6 Prevalence of FVL in different European countries ranges between 2% and 6%. 7 Moreover, APCR is a genetic risk factor for thrombosis independent of FVL. 8,9 Therefore, because of its implication in thrombotic disease, there has been a growing interest in studying other genetic factors that are likely to affect thrombosis risk through quantitative variation in this important intermediate phenotype. The APCR phenotype could theoretically result from a variety of other mutations of critical sites in the F5 or F8 genes. However, no mutations of F8 have yet been identified in patients with the APCR phenotype, 10,11 whereas 2 point ...