RESUMO
Here we describe two new cases of complete deficiency of factor I (fI) in two sisters from a consanguineous Brazilian family. The eldest sibling (20-year-old) developed systemic lupus erythematosus (SLE) early during childhood while the youngest had been committed on several occasions owing to repeated infections although she was asymptomatic for auto-immune diseases. We also detected lower concentrations of C3 and factor B in both sisters. Biological functions dependent on complement activation such as the production of opsonins and killing of phagocytozed micro-organisms, chemotactic factors and haemolytic activity were all significantly reduced in both probands. Consistent with the absence of fI and low levels of fH, a deregulated production of C3b was observed by bidimensional electrophoresis in sera of both the probands.
Assuntos
Infecções Bacterianas/complicações , Transtornos de Proteínas de Coagulação/genética , Transtornos de Proteínas de Coagulação/imunologia , Fator H do Complemento/metabolismo , Fibrinogênio/genética , Lúpus Eritematoso Sistêmico/complicações , Adulto , Inibição de Migração Celular , Células Cultivadas , Pré-Escolar , Transtornos de Proteínas de Coagulação/complicações , Ativação do Complemento , Complemento C3/metabolismo , Complemento C3b/metabolismo , Saúde da Família , Feminino , Fibrinogênio/metabolismo , Predisposição Genética para Doença , Humanos , Imunoeletroforese Bidimensional , FagocitoseRESUMO
An 8-year-old son (L.A.S.) of consanguineous parents, presented recurrent bacterial infections, vasculitis and extremely low levels of serum C3 (0.15 microg/ml). The classical and alternative pathway haemolytic activities and the generation of opsonins and chemotactic factors derived from the activation of the complement system were markedly affected in the proband's serum. An in vitro addition of purified C3 restored the classical pathway-dependent haemolytic activity of his serum. Autoradiographs of the proband's lipopolysaccharide (LPS)-stimulated and 35S-labelled fibroblast supernatants after that the SDS-PAGE revealed no C3 alpha or beta chains. The amount of C3 mRNA synthesized by the proband's fibroblasts, as evaluated by reverse transcription-polymerase chain reaction (RT-PCR) assays, was greatly reduced.
Assuntos
Transtornos de Proteínas de Coagulação/genética , Complemento C3/deficiência , Complemento C3/genética , Inibição de Migração Celular , Células Cultivadas , Criança , Transtornos de Proteínas de Coagulação/imunologia , Complemento C3/biossíntese , Fibroblastos/metabolismo , Hemólise , Humanos , Masculino , Linhagem , Fagocitose , RNA Mensageiro/biossínteseRESUMO
Fibrinogen Caracas V is a thrombotic dysfibrinogenemia with an Aalpha 532 Ser-->Cys mutation characterized by a tight fibrin network formed of thin fibers responsible for a less porous clot than a normal one. In the present work, fibrinogen Caracas V is further characterized in order to understand the relationship between the structural defect and thrombophilia. This thrombotic disorder has been attributed to a tight fibrin network responsible for a decreased permeation of flow through the clot, leading to defective thrombus lysis due to a diminished availability of fibrinolytic enzymes to the inner fibrin surface. Correction of clot structure anomaly, by addition of dextran 40 to fibrinogen before clotting, induces an improvement in fibrin degradation that was attributed to an increase in porosity. The pulmonary embolism observed in this family has been related to an hyper rigidity of the clot, an anomaly that is also corrected by dextran. Furthermore, this abnormal fibrinogen binds more albumin than does normal fibrinogen, a phenomenon attributed to the mutation of serine in Aalpha-532 by cysteine. Therefore, this fibrinogen shows a striking similarity to the fibrinogen Dusart, allowing us to confirm that the alphaC-terminal part of fibrinogen plays an important role in fibrin structure, and to conclude that the anomaly of fibrin network observed in fibrinogen Caracas V is responsible for a deficient thrombus lysis.
Assuntos
Transtornos de Proteínas de Coagulação/fisiopatologia , Fibrinogênios Anormais/metabolismo , Albuminas/metabolismo , Substituição de Aminoácidos , Coagulação Sanguínea/efeitos dos fármacos , Coagulação Sanguínea/genética , Transtornos de Proteínas de Coagulação/sangue , Transtornos de Proteínas de Coagulação/genética , Dextranos/farmacologia , Fibrina/genética , Fibrina/metabolismo , Fibrina/ultraestrutura , Fibrinogênios Anormais/genética , Fibrinólise/efeitos dos fármacos , Fibrinólise/genética , Humanos , Microscopia Confocal , Mutação , Trombofilia/sangue , Trombofilia/genéticaRESUMO
Fibrinogen Caracas I is a dysfibrinogenemia with a mild bleeding diathesis and a defective wound healing. We have characterized this abnormal fibrinogen using transmission electron microscopy (TEM) in combination with turbidity and permeation studies. Turbidometric and permeability analysis showed that the abnormal fibrin had a significantly decreased mass:length ratio and fiber diameter. In addition, the permeability studies of plasma fibrin clots showed that the gel porosity of the abnormal fibrinogen was reduced. Images of the abnormal fibrin structure obtained using TEM showed that the fibers were thinner, much less branched and less ordered than normal fibers. Diminished fibrin fiber diameter and reduced fibrin gel porosity have been taken as hallmarks of thrombophilic dysfibrinogenemias. The results of the present study show that these features are not necessarily predictive of thrombophilia. Further studies performed on a larger number of dysfibrinogenemias need to be conducted in order to establish the implications of these parameters on the clinical outcome.