Thrombin-activatable fibrinolysis inhibitor (TAFI) levels and its polymorphism rs3742264 are associated with dyslipidemia in a cohort of Brazilian subjects.

BACKGROUND: Dyslipidemia, a metabolic alteration that affects lipoprotein levels, is considered a major risk factor for atherosclerosis and its complications. Dyslipidemia also affects the hemostatic system, especially impairing fibrinolysis, and increased levels of thrombin-activatable fibrinolysis inhibitor (TAFI) have been associated with cardiovascular events. OBJECTIVES AND METHODS: This study evaluated the association of acquired risk factors (hypertension, body mass index - BMI, smoking, sedentary lifestyle, use or not of oral contraceptives and hormone replacement therapy, and post-menopause status), the polymorphisms Thr325Ile (rs1926447), Ala147Thr (rs3742264) and +1542C/G (rs940) in the TAFI gene, and TAFI plasma levels in 109 dyslipidemic and 105 normolipemic individuals. Biochemical analyses and TAFI levels were evaluated by colorimetric/turbidimetric assays and ELISA, respectively. Genotypic and allelic frequencies were determined by polymerase chain reaction (PCR). RESULTS: Hypertension, increased BMI, and menopause were more common in dyslipidemic individuals, who had higher TAFI levels. The alleles 325Ile, Ala147, and C showed association with lower TAFI levels. The rs3742264 polymorphism was associated with dyslipidemia in males. CONCLUSIONS: The results suggest that TAFI levels are independently associated to dyslipidemia and that the polymorphism rs3742264 may be related to cardiovascular risk in male subjects.

Association between genotype and plasma levels of thrombin-activated fibrinolysis inhibitor (TAFI) in the development of preeclampsia.

INTRODUCTION: The objective was to evaluate if thrombin-activated fibrinolysis inhibitor (TAFI) polymorphisms (G505A, C1040T, and G-438A), and TAFIa plasma levels are associated with preeclampsia. MATERIALS AND METHODS: In a case-control study design, we evaluated preeclampsia patients and women with uncomplicated pregnancies. The TAFI polymorphisms were determined by real-time PCR method, and TAFIa plasma levels were established with a chromogenic assay. RESULTS: We included 87 women in each group. The TAFIa levels in the preeclampsia group were 20.4 µg/mL (CI 95% 17.3-23.5), while in the control group, they were significantly lower: 13.3 µg/mL (12.0-14.5, p 0.003). There were no differences in the genotype distribution or allelic frequency of TAFI polymorphisms between the two groups. In preeclampsia patients and controls heterozygous for the G505A polymorphism, the TAFIa values were 22.8 (16.7-28.9 µg/mL) and 13.2 (11.3-15.0 µg/mL, p 0.019), respectively. In G505A homozygous polymorphism the TAFIa values were 25.7 (18.7-32.6 µg/mL) and 13.5 (1.6-21.9 µg/mL, p 0.041), respectively. In the C1040T and G-438A TAFI wild type polymorphisms, the TAFIa values were 18.3 (12.5-23.9 µg/mL) and 11.5 (9.9-35.0, p 0.033), and 19.4 (10.9-27.9 µg/mL) and 12.5 (10.8-14.2 µg/mL, p 0.006), respectively, without differences in other genotypes. CONCLUSIONS: Preeclampsia by itself may be responsible for the increase in TAFIa values rather than the presence of polymorphisms.

Influence of gestational age on fibrinolysis from birth to postnatal day 10.

OBJECTIVE: To compare components of the fibrinolytic cascade in newborns of gestational age ranging from extreme prematurity to full term, at birth and for the next 10 days, and in their mothers at delivery. STUDY DESIGN: We studied 10 extremely preterm neonates, 10 very preterm neonates, 10 moderately preterm neonates, 10 full-term neonates, and their mothers (n = 40). We measured the antigen levels of tissue-type plasminogen activator (t-PA), plasminogen activator inhibitors 1 (PAI-1) and 2 (PAI-2), and thrombin-activatable fibrinolysis inhibitor, as well as PAI-1 activity, in neonates at birth and on postnatal days 3 and 10 and in mothers at delivery. RESULTS: On day 10, both PAI-1 antigen and activity were higher in extremely preterm neonates than in full-term neonates (P = .004 and <.0006, respectively), and the t-PA/PAI-1 activity ratio was lower in the extremely preterm and very preterm neonates compared with the full-term neonates (P = .002 and .017, respectively). No significant differences in the fibrinolytic system components were seen among the 4 groups of mothers. CONCLUSIONS: The development of fibrinolysis suppression in extremely preterm infants within 10 days after birth may contribute to the increased risk of periventricular hemorrhagic infarction in these infants.

Procarboxypeptidase U (TAFI) and the Thr325Ile proCPU polymorphism in patients with hereditary mucocutaneous hemorrhages.

BACKGROUND: Patients with hereditary mucocutaneous bleeding are difficult to diagnose and many of them fulfill the category of bleeders of unknown cause (BUC). The pathogenic role of hyperfibrinolysis has received little attention, despite the successful use of antifibrinolytic drugs in treating many of these patients. Theoretically, decreased plasma procarboxypeptidase U (proCPU) levels or lower carboxypeptidase U (CPU) stability would result in higher fibrinolytic activity and bleeding tendency. METHODS: We analyzed plasma proCPU and the distribution of the Thr325Ile proCPU polymorphism in 193 patients with mucocutaneous bleeding of whom 116 were bleeders of unknown cause (BUC), and in 143 healthy, age and sex-matched controls. RESULTS: ProCPU concentration was higher in women than in men, increased with age, and was significantly correlated with clot lysis time, platelet count, APTT, and PT. However, proCPU levels were unexpectedly higher in patients than in controls (968+/-134 vs. 923+/-147 U/L, p=0.004). The allele distribution of the Thr325Ile proCPU polymorphism was similar in both groups, with a low percentage of homozygous Ile/Ile. CONCLUSIONS: Our results indicate that the proCPU system is not of major importance in the bleeding pathogenesis of these patients. The higher proCPU levels in the patients may even modestly counteract the bleeding tendency.

Evaluación de inhibidores fisiológicos de la coagulación en pacientes diabéticos tipo 2 / Evaluation about coagulation physiological inhibitors in type 2 diabetic patients

La diabetes mellitus está asociada a disturbios en la hemostasis que pueden contribuir al desarrollo de enfermedad vascular diabética. El objetivo de este trabajo fue estudiar la coagulación en una población diabética de Uruguay y compararla con una población de referencia normal. Se trabajó con 100 pacientes diabéticos tipo 2, de ambos sexos (49 mujeres y 51 hombres), con edades comprendidas entre 42 y 79 años, y una población control representada por 130 individuos aparentemente sanos (73 mujeres y 57 hombres) cuyas edades oscilaron entre 37 y 78 años, los que fueron tomados como referencia. Se realizaron las determinaciones de tiempo de protrombina (TP), fibrinógeno (Fib), proteína C (PC), proteína S (PS), antitrombina III (ATIII) e inhibidor del activador de plasminógeno (PAI) en plasma citratado. El TP y el Fib se realizaron por nefelometría, la PC, ATIII y PAI se midieron cromogénicamente y la PS se determinó por coagulometría. Se encontró que los inhibidores fisiológicos de la coagulación PS y ATIII son significativamente menores en la población diabética, en tanto que los factores procoagulantes Fib y PAI son significativamente mayores, comparados con la población de referencia. De los hallazgos precedentes se confirma una tendencia a un disbalance hemostático que contribuiría al estado protrombótico que acompaña a un alto porcentaje de la población diabética.

Diabetes mellitus is associated with disturbances in hemostasis, which may contribute to the development of diabetic vascular disease. Coagulation tests were performed both in diabetic patients and healthy individuals in Uruguay. The results obtained were compared. Diabetic patients were 100, with ages between 42 and 79 years, 49 females and 51 males. Reference population were 130 healthy individuals between 37 and 78 years, 73 females and 57 males. Prothrombin time (PT), fibrinogen( Fib), protein C (PC), protein S (PS), antithrombin III (ATIII) and plasminogen activator inhibitor (PAI) were measured on citrated plasma. PT and Fib were determined nephelometrically, PC, ATIII y PAI were measured cromogenically and PS was determined by coagulometry. Coagulation physiological inhibitors outcomes such as PS and ATIII showed significantly lower levels in the diabetic patient than in the healthy person, and at the same time, Fib and PAI, which are procoagulant factors, have significantly higher concentrations in the diabetic patient than in the healthy person. These findings permit to assess that an impaired haemostatic balance is present in the diabetic population, which may contribute to the hypercoagulability that accompanies a high percentage of these patients.

A locus on chromosome 13 influences levels of TAFI antigen in healthy Mexican Americans.

When activated, thrombin activatable fibrinolysis inhibitor (TAFI) inhibits fibrinolysis by modifying fibrin, depressing its plasminogen binding potential. Polymorphisms in the TAFI structural gene (CPB2) have been associated with variation in TAFI levels, but the potential occurrence of influential quantitative trait loci (QTLs) located elsewhere in the genome has been explored only in families ascertained in part through probands affected by thrombosis. We report the results of the first genome-wide linkage screen for QTLs that influence TAFI phenotypes. Data are from 635 subjects from 21 randomly ascertained Mexican American families participating in the San Antonio Family Heart Study. Potential QTLs were localized through a genome-wide multipoint linkage scan using 417 highly informative autosomal short tandem repeat markers spaced at approximately 10-cM intervals. We observed a maximum multipoint LOD score of 3.09 on chromosome 13q, the region of the TAFI structural gene. A suggestive linkage signal (LOD = 2.04) also was observed in this region, but may be an artifact. In addition, weak evidence for linkage occurred on chromosomes 17p and 9q. Our results suggest that polymorphisms in the TAFI structural gene or its nearby regulatory elements may contribute strongly to TAFI level variation in the general population, although several genes in other regions of the genome may also influence variation in this phenotype. Our findings support those of the Genetic Analysis of Idiopathic Thrombophilia (GAIT) project, which identified a potential TAFI QTL on chromosome 13q in a genome-wide linkage scan in Spanish thrombophilia families.

Identification of polymorphisms in the 5'-untranslated region of the TAFI gene: relationship with plasma TAFI levels and risk of venous thrombosis.

BACKGROUND AND OBJECTIVES: Thrombin activatable fibrinolysis inhibitor (TAFI) plays an important role in hemostasis, functioning as a potent fibrinolysis inhibitor. TAFI gene variations may contribute to plasma TAFI levels and thrombotic risk. DESIGN AND METHODS: We sequenced a 2083-bp region of the 5'-regulatory region of the TAFI gene in 127 healthy subjects searching for variations, and correlated identified polymorphisms with plasma TAFI levels. TAFI polymorphisms were examined as risk factors for venous thrombosis by determining their prevalence in 388 patients with deep venous thrombosis (DVT) and in 388 controls. RESULTS: Seven novel polymorphisms were identified: -152 A/G, -438 A/G, -530 C/T, -1053 T/C, -1102 T/G, -1690 G/A, and -1925 T/C. -152 A/G, -530 C/T and -1925 T/C were found to be in strong linkage disequilibrium, as were the -438 A/G, -1053 T/C, -1102 T/G and -1690 G/A. Plasma TAFI levels were higher in -438GG/-1053CC/-1102GG/-1690AA homozygotes than in -438AG/-1053TC/-1102TG/-1690GA heterozygotes, and -438AA/-1053TT/-1102TT/-1690GG homozygotes had the lowest TAFI levels (p=0.0003). TAFI concentrations in -152AA/-530CC/-1925TT homozygotes were somewhat higher but not significantly different from levels observed for -152AG/-530CT/-1925TC heterozygotes. Taken in combination, -438AG/-1053TC/-1102TG/-1690GA and -438AA/-1053TT/-1102TT/-1690GG yielded an OR for DVT of 0.8 (95%CI: 0.6-1). In subjects aged <35 years the OR was 0.7 (95%CI: 0.5-1.1). The OR for -152AG/-530CT/-1925TC was 1 (95%CI: 0.5-2.2) in the whole group of patients and controls, whereas in subjects aged <35 years the OR was 0.1 (95%CI: 0.02-0.9). INTERPRETATION AND CONCLUSIONS: Polymorphisms in the TAFI promoter determine plasma antigen levels and may influence the risk of venous thrombophilia.