RESUMO
The utility of mouse models to dissect the molecular basis of hemostasis and thrombosis is now well established. The anucleate properties of circulating blood platelet and their specialized release from mature megakaryocytes makes the use of in vivo models all the more informative and powerful. Indeed, they are powerful but there do exist limitations. Here, we review the contributions of mouse models to the pathogenesis of the Bernard-Soulier syndrome, their use in platelet-specific gene expression, the recent development of mice expressing both human GPIb-IX and human von Willebrand factor (VWF), and finally the use of GPIb-IX mouse models to examine the impact of platelet biology beyond clotting. The humanization of the receptor and ligand axis is likely to be a major advancement in the characterization of therapeutics in the complex pathogenesis that drives thrombosis. When appropriate, we highlight some limitations of each mouse model, but this is not to minimize the contributions these models to the field. Rather, the limitations are meant to provide context for any direct application to the important mechanisms supporting human primary hemostasis and thrombosis.
Assuntos
Síndrome de Bernard-Soulier , Trombose , Animais , Síndrome de Bernard-Soulier/genética , Plaquetas/metabolismo , Modelos Animais de Doenças , Humanos , Camundongos , Complexo Glicoproteico GPIb-IX de Plaquetas/genética , Complexo Glicoproteico GPIb-IX de Plaquetas/metabolismo , Trombose/metabolismo , Fator de von Willebrand/genética , Fator de von Willebrand/metabolismoRESUMO
Shear-induced aggregation requires the platelet glycoprotein complexes (Gp), the von Willebrand factor (vWf) and ADP. The Bernard Soulier syndrome (BS) and the gray platelet syndrome (GPS) are platelet function defects characterized by absence of GP Ib/IX and alpha granules, respectively, with mucocutaneous hemorrhages, prolonged bleeding time (BT) and moderate thrombocytopenia in both syndromes. There are reports that desmopressin (DDAVP) shortens the BT in some patients with platelet dysfunction. The purpose of this study was to evaluate the response t(DDAVP) in four female patients (2 with GPS plus Marfan's disease and 2 BS). All had bleeding episodes, BTs > 10 minutes, platelet counts (PC) between 40-88 x 10(9)/L and defects in platelet aggregation. The DDAVP was administered at a dose of 0.3 microgram/kg in 15 to 30 mL of isotonic saline given by slow intravenous drip in 30 to 45 min. All patients were studied before and after DDAVP administration (BT, PC, platelet factor, mean platelet volume, factors F.VIII:C, FvW:Ag, FvW:RiC of, and platelet aggregation). After DDAVP infusion the patients had a BT < 6 min, and increased levels of F. VIII:C, FvW:Ag and FvW:RiC of (> 100 Ul/dL), and the bleeding disappeared. We conclude that there was a good response to DDAVP probably associated with improved platelet adhesion, and increases in the multimers of the von Willebrand factor.
Assuntos
Síndrome de Bernard-Soulier/tratamento farmacológico , Desamino Arginina Vasopressina/uso terapêutico , Adolescente , Adulto , Síndrome de Bernard-Soulier/sangue , Síndrome de Bernard-Soulier/complicações , Síndrome de Bernard-Soulier/genética , Biopolímeros , Tempo de Sangramento , Desamino Arginina Vasopressina/farmacologia , Avaliação de Medicamentos , Feminino , Humanos , Síndrome de Marfan/complicações , Pessoa de Meia-Idade , Adesividade Plaquetária/efeitos dos fármacos , Agregação Plaquetária/efeitos dos fármacos , Deficiência do Pool Plaquetário/sangue , Deficiência do Pool Plaquetário/complicações , Deficiência do Pool Plaquetário/genética , Estudos Prospectivos , Síndrome , Fator de von Willebrand/metabolismoRESUMO
Objetivo: Chamar a atençäo dos pediatras para uma causa rara de epistaxes severas de repetiçäo. Métodos: Os autoes descrevem um caso de criança com Síndrome de Bernard-Soulieur e fazem uma revisäo de relatos da Síndrome em língua inglesa existentes no MEDLINE desde 1970. Resultados: É descrito um menino de 3 anos e 3 meses, com quadro de epistaxes volumosas de repetiçäo, com importante repercussäo emodinâmica, no qual foram necessárias várias transfusöes de sangue e hemoderivados. Foram estabelecidas diversas suspeitas diagnósticas até que, pelo exame de sangue periférico, identificaram-se macroplaquetas. o diagnóstico final foi de Síndrome de Bernard-Soulieur, e procedeu-se à embolizaçäo da artéria maxilar para solucionar as epistaxes de repetiçä ...