RESUMO
The von Willebrand factor (VWF) is analysed as a bleeding and thrombotic risk marker. When the VWF level is increased, it predicts a thrombotic phenotype and when VWF level is low in plasma, the phenotype varies to bleeding disorder. But it is quite challenging to define when the level is low, normal or high taking into account that these values are capricious and overlap. This matter should be solved by extensive epidemiologic studies. VWD is a hereditary disorder with several described mutations. VWF is a major acute-phase reactant, besides the physiological conditions such as blood group and pregnancy that affect plasmatic VWF levels. Subjects with O blood group have 25% less VWF than those of non O blood groups, and the latter show higher thrombus burden. VWF would be sensitive though not specific diagnostic marker of myocardial infarction. For the assessment of bleeding severity there are special surveys, scores and pictorial charts. The identification of VWF as a thrombotic risk marker has not been clearly established yet, but it has been involved in stroke and coronary disease. We only have the specific replacement therapy for the bleeding phenotype and we can speculate that enoxaparin and PEG-hirudin are able to blunt the VWF rise in patients with unstable angina pectoris and it is associated with a more favourable clinical outcome. Only two questions remain: does VWF as a bleeding risk marker have the same value as a thrombotic risk marker? Will successful treatments like those achieved for bleeding be also possible in the future for thrombosis?
Assuntos
Hemorragia/diagnóstico , Trombose/diagnóstico , Fator de von Willebrand , Hemorragia/etiologia , Humanos , Fatores de Risco , Trombose/etiologiaRESUMO
Most mutations identified in 2A VWD patients are localized in the A2 domain, although missense substitutions have also been recognized in the A1 domain. We describe a novel heterozygous missense mutation in the A1 domain of VWF gene responsible for type 2A phenotype. Analysis of the complete exon 28 was carried out in a patient and his mother with life-long histories of moderate to severe bleeding and laboratory data of type 2A VWD. The analysis of exon 28 of VWF gene showed a 3815 G â T transversion resulting in C1272F mutation. It is probably associated with a group I mechanism according to patients' clinical symptoms, and, in the case of the propositus, the lack of clinical response to treatment with desmopressin. The mutation was not found in 100 normal alleles. This substitution affected the normal S-S bound between C1272 and C1458, which is involved in A1 loop structure, altering the normal multimerization and function of VWF. The VWFpp/VWF:Ag ratio in the propositus and his mother was >3, suggesting a shortened survival of VWF. We believe it is important to report the complete clinical phenotype corresponding to the new mutation to increase the knowledge in the clinical field.
Assuntos
Mutação de Sentido Incorreto , Doença de von Willebrand Tipo 2/genética , Fator de von Willebrand/genética , Adolescente , Adulto , Desamino Arginina Vasopressina/uso terapêutico , Éxons/genética , Feminino , Hemostáticos/uso terapêutico , Humanos , Masculino , Fenótipo , Doença de von Willebrand Tipo 2/tratamento farmacológicoRESUMO
BACKGROUND AND OBJECTIVES: von Willebrand's disease (vWD) is a bleeding disorder with variable clinical expression. Our aim was to classify patients with vWD and to determine the phenotype in their relatives. DESIGN AND METHODS: The types and subtypes, blood group frequency and its relevance, bleeding sites, response to the desmopressin (DDAVP) test, transfusion requirements and clinical features in type 1 and 2A families were determined in 1,885 patients. RESULTS: Our findings were: type 1: 91%, type 2A: 3.1%, severe vWD: 1.3%; type 2N: 1.6%; type low intraplatelet: 2.7%; combined 1+ 2N: 0.3%. Blood group O prevalence was 70.5%. Bleeding and transfusion requirements were not correlated to blood groups. The most frequent symptoms were: ecchymoses-hematomas and epistaxis and, in females over 13 years, also menorrhagia. Normal levels of factor VIII:C were found in 38.4% of the patients. DDAVP was infused in 567 patients with a good response in 80.6%. About 9% of our patients needed transfusion therapy. The diagnosis of von Willebrand's disease is more likely in subjects belonging to families with type 2A disease than in members of families with type 1 vWD in spite of these being symptomatic. INTERPRETATION AND CONCLUSIONS: These observations provide a good strategy to identify, classify and treat vWD patients without performing molecular assays.
Assuntos
Doenças de von Willebrand/genética , Argentina/epidemiologia , Antígenos de Grupos Sanguíneos/análise , Estudos de Coortes , Saúde da Família , Feminino , Hemorragia/etiologia , Humanos , Masculino , Fenótipo , Prevalência , Doenças de von Willebrand/sangue , Doenças de von Willebrand/epidemiologiaRESUMO
We developed a new method for the detection of large von Willebrand factor (vWf) multimers binding to collagen and for the determination of vWf antigen (vWf:Ag) using flow cytometry. Collagen is coated on to polystyrene beads, allowing detection of found large vWf multimers. In addition, rabbit antibody against vWf is coated on to the beads allowing detection of all vWf:Ag. In plasma samples from healthy persons and patients (with type 1, 2A, 2N, or severe von Willebrand disease or hemophilia), 4 different assays were performed: vWf:Ag by immunoelectrophoresis; vWf ristocetin cofactor (vWf:RCof); CBA; and vWf:Ag based on an enzyme-linked immunosorbent assay using polystyrene beads. We assayed the flow cytometric method using 2 bead sizes. The optimal bead size was 3.136 microns. The results of CBA and vWf:Ag closely correlated with those of vWf:RCof and vWf:Ag (immunoelectrophoresis), respectively, and showed a low limit of detection. Interassay variance of cytometric methods was lower than interassay variance of traditional assays. In addition, we used the new assays to monitor desmopressin therapy.
Assuntos
Colágeno/metabolismo , Citometria de Fluxo/métodos , Fator de von Willebrand/metabolismo , Animais , Desamino Arginina Vasopressina/uso terapêutico , Ensaio de Imunoadsorção Enzimática , Hemofilia A/sangue , Hemofilia A/diagnóstico , Humanos , Imunoeletroforese , Microesferas , Peso Molecular , Poliestirenos , Ligação Proteica , Coelhos , Valores de Referência , Sensibilidade e Especificidade , Doenças de von Willebrand/sangue , Doenças de von Willebrand/diagnóstico , Doenças de von Willebrand/tratamento farmacológico , Fator de von Willebrand/análise , Fator de von Willebrand/imunologiaAssuntos
Plaquetas/fisiologia , Diabetes Mellitus Tipo 1/sangue , Diabetes Mellitus Tipo 2/sangue , Fibrinólise , Adulto , Idoso , Diabetes Mellitus Tipo 1/tratamento farmacológico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Feminino , Fibrinólise/efeitos dos fármacos , Humanos , Hipoglicemiantes/farmacologia , Hipoglicemiantes/uso terapêutico , Insulina/farmacologia , Insulina/uso terapêutico , Masculino , Pessoa de Meia-IdadeRESUMO
Intrinsic plasminogen activators (PA) were tested in euglobulins (eug) of platelet poor plasma (PPP) with and without washed platelets (WP), treated or not with urokinase (UK), streptokinase (SK), collagen (Col) and aspirin (ASA) using fibrin plates method. A significant decrease of the fibrinolytic activity related to the presence and number of platelets was observed. We confirm the presence of platelet anti-UK and anti-SK activities. The former appears to be higher than the other activity. Low and high concentrations of Col stimulated the release of plasminogen activator-inhibitors (PA-I) from platelets, and ASA could not modify this release. Besides ASA might inhibit some PA release. The high concentration of Col was capable to release anti-UK and anti-SK activities from platelets and perhaps other intrinsic PA-I. The low concentration of Col was only capable to release intrinsic PA-I, suggesting that anti-UK and anti-SK needed a stronger stimuli to be released than intrinsic PA-I. We must consider the possibility that the PA-I and/or activators could be released by different metabolic pathways other than cyclooxygenase pathway.