RESUMO
BACKGROUND: Cardiovascular disease (CVD) is characterized by slow progressive atherosclerosis and arterial thrombotic events, leading to occlusions. Whether either of these presentations is more likely in patients with a genetic predisposition for CVD is still unknown. We suggest that a genetic predisposition for CVD is related to recurrent events of the same nature. METHODS: We retrospectively investigated 275 patients with premature CVD and divided them in two groups according to their first event: an arterial thrombotic event or stable atherosclerosis. We used a Cox proportional-hazards model to estimate the effect of a positive family history for CVD on recurrent events of the same nature. This was tested in the entire cohort and in patients with coronary artery disease only. RESULTS: Patients with a first arterial thrombotic event and a positive family history had a threefold increased risk for a recurrent event of the same nature, compared to patients with a negative family history (hazard ratio 3.00, 95% confidence interval 1.32-6.81); p < 0.05). In contrast, a positive family history was not associated with an increased risk for a recurrent stable atherosclerosis (hazard ratio 0.98 (95% confidence interval 0.59-1.63). These findings were similar analysing the patients with coronary artery disease only. Additional adjustments for other risk factors did not change these associations. CONCLUSIONS: Patients with a first premature arterial thrombotic event and a positive family history for CVD have an increased risk for a second event of the same nature. This might be due to unknown hereditary mechanisms leading to recurrent acute events.
Assuntos
Arteriopatias Oclusivas/genética , Doenças Cardiovasculares/genética , Trombose/genética , Adulto , Idade de Início , Arteriopatias Oclusivas/diagnóstico , Arteriopatias Oclusivas/epidemiologia , Aterosclerose/epidemiologia , Aterosclerose/genética , Doenças Cardiovasculares/diagnóstico , Doenças Cardiovasculares/epidemiologia , Doença da Artéria Coronariana/epidemiologia , Doença da Artéria Coronariana/genética , Intervalo Livre de Doença , Feminino , Predisposição Genética para Doença , Hereditariedade , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Países Baixos/epidemiologia , Linhagem , Fenótipo , Modelos de Riscos Proporcionais , Recidiva , Estudos Retrospectivos , Medição de Risco , Fatores de Risco , Trombose/diagnóstico , Trombose/epidemiologiaRESUMO
BACKGROUND: Protein S, which circulates in plasma in a free and bound form, is an anticoagulant protein that stimulates both activated protein C (APC) and tissue factor pathway inhibitor (TFPI). Hereditary type I protein S deficiency (low total and low free protein S) is a well-established risk factor for venous thrombosis, whereas the thrombosis risk associated with type III deficiency (normal total and low free protein S) has been questioned. DESIGN AND METHODS: Kaplan-Meier analysis was performed on 242 individuals from 30 families with protein S deficiency. Subjects were classified as normal, type I deficient or type III deficient according to their total and free protein S levels. Genetic and functional studies were performed in 23 families (132 individuals). RESULTS: Thrombosis-free survival was not different between type I and type III protein S-deficient individuals. Type III deficient individuals were older and had higher protein S, TFPI and prothrombin levels than type I deficient individuals. Thrombin generation assays sensitive to the APC- and TFPI-cofactor activities of protein S revealed similar hypercoagulable states in type I and type III protein S-deficient plasma. Twelve PROS1 mutations and 2 large deletions were identified in the genetically characterized families. CONCLUSIONS: Not only type I, but also type III protein S deficiency is associated with a hypercoagulable state and increased thrombosis risk. However, these findings may be restricted to type III deficient individuals from families with mixed type I/III protein S deficiency, as these represented 80% of type III deficient individuals in our cohort.
Assuntos
Deficiência de Proteína S/genética , Proteína S/metabolismo , Trombofilia/sangue , Trombofilia/genética , Trombose Venosa/sangue , Trombose Venosa/genética , Adolescente , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Proteína S/classificação , Proteína S/genética , Deficiência de Proteína S/classificação , Deficiência de Proteína S/complicações , Fatores de Risco , Trombofilia/etiologia , Trombose Venosa/etiologia , Adulto JovemRESUMO
BACKGROUND: Protein S, which circulates in plasma in both free and bound forms, is an anticoagulant protein that stimulates activated protein C and tissue factor pathway inhibitor. Hereditary type I protein S deficiency (low total and low free protein S) is a well-established risk factor for venous thrombosis, whereas the thrombosis risk associated with type III deficiency (normal total and low free protein S) has been questioned. DESIGN AND METHODS: Kaplan-Meier analysis was performed on 242 individuals from 30 families with protein S deficiency. Subjects were classified as normal, or having type I or type III deficiency according to their total and free protein S levels. Genetic and functional studies were performed in 23 families (132 individuals). RESULTS: Thrombosis-free survival was not different between type I and type III protein S-deficient individuals. Type III deficient individuals were older and had higher protein S, tissue factor pathway inhibitor and prothrombin levels than type I deficient individuals. Thrombin generation assays sensitive to the activated protein C- and tissue factor pathway inhibitor-cofactor activities of protein S revealed similar hypercoagulable states in type I and type III protein S-deficient plasma. Twelve PROS1 mutations and two large deletions were identified in the genetically characterized families. CONCLUSIONS: Not only type I, but also type III protein S deficiency is associated with a hypercoagulable state and increased risk of thrombosis. These findings may, however, be restricted to type III deficient individuals from families with mixed type I/III protein S deficiency, as these represented 80% of type III deficient individuals in our cohort.
Assuntos
Deficiência de Proteína S/sangue , Trombofilia/etiologia , Trombose/etiologia , Adolescente , Adulto , Intervalo Livre de Doença , Família , Feminino , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Deficiência de Proteína S/classificação , Deficiência de Proteína S/genética , Adulto JovemRESUMO
Protein S expresses cofactor activity for activated protein C (APC) by enhancing the APC-catalyzed proteolysis at R(306) in factor Va. It is generally accepted that only free protein S is active and that complex formation with C4b-binding protein (C4BP) inhibits the APC-cofactor activity of protein S. However, the present study shows that protein S-C4BP expresses APC-cofactor activity and stimulates APC-catalyzed proteolysis at R(306) more than 10-fold, but instead inhibits proteolysis at R(506) by APC 3- to 4-fold. Free protein S stimulates APC-catalyzed cleavage at R(306) approximately 20-fold and has no effect on cleavage at R(506). The resulting net effect of protein S-C4BP complex formation on APC-catalyzed factor Va inactivation is a 6- to 8-fold reduction in factor Va inactivation when compared with free protein S, which is not explained by inhibition of APC-cofactor activity of protein S at R(306), but by generation of a specific inhibitor for APCcatalyzed proteolysis at R(506) of factor Va. These results are of interest for carriers of the factor V(Leiden) mutation (R(506)Q), as protein S-C4BP effectively enhances APC-catalyzed factor Va (R(306)) inactivation in plasma containing factor V(Leiden).
