Assuntos
Agregação Plaquetária/fisiologia , Testes de Função Plaquetária/métodos , Trombastenia/sangue , Autoanticorpos/sangue , Perda Sanguínea Cirúrgica/fisiopatologia , Plaquetas , Feminino , Hemorragia/diagnóstico , Hemorragia/etiologia , Humanos , Pessoa de Meia-Idade , Complexo Glicoproteico GPIIb-IIIa de Plaquetas/imunologia , Ristocetina/efeitos adversos , Trombastenia/metabolismo , Trombastenia/patologiaRESUMO
Von Willebrand disease (VWD)-type 2B originates from a gain-of-function mutation in von Willebrand factor (VWF), resulting in enhanced platelet binding. Clinical manifestations include increased bleeding tendency, loss of large multimers, thrombocytopenia, and circulating platelet aggregates. We developed a mouse model to study phenotypic consequences of VWD-type 2B mutations in murine VWF: mVWF/R1306Q and mVWF/V1316M. Both mutations allow normal multimerization but are associated with enhanced ristocetin-induced platelet aggregation, typical for VWD-type 2B. In vivo expression resulted in thrombocytopenia and circulating aggregates, both of which were more pronounced for mVWF/V1316M. Furthermore, both mutants did not support correction of bleeding time or arterial vessel occlusion in a thrombosis model. They further displayed a 2- to 3-fold reduced half-life and induced a 3- to 6-fold increase in number of giant platelets compared with wild-type VWF. Loss of large multimers was observed in 50% of the mice. The role of ADAMTS13 was investigated by expressing both mutants in VWF/ADAMTS13 double-deficient mice. ADAMTS13 deficiency resulted in more and larger circulating platelet aggregates for both mutants, whereas the full multimer range remained present in all mice. Thus, we established a mouse model for VWD-type 2B and found that phenotype depends on mutation and ADAMTS13.
Assuntos
Plaquetas/metabolismo , Metaloendopeptidases , Mutação de Sentido Incorreto , Multimerização Proteica , Doença de von Willebrand Tipo 2 , Fator de von Willebrand , Proteína ADAMTS13 , Substituição de Aminoácidos , Animais , Antibacterianos/efeitos adversos , Antibacterianos/farmacologia , Tempo de Sangramento , Modelos Animais de Doenças , Meia-Vida , Humanos , Metaloendopeptidases/genética , Metaloendopeptidases/metabolismo , Camundongos , Camundongos Mutantes , Agregação Plaquetária/efeitos dos fármacos , Agregação Plaquetária/genética , Ristocetina/efeitos adversos , Ristocetina/farmacologia , Índice de Gravidade de Doença , Trombocitopenia/genética , Trombocitopenia/metabolismo , Trombose/induzido quimicamente , Trombose/genética , Trombose/metabolismo , Doença de von Willebrand Tipo 2/genética , Doença de von Willebrand Tipo 2/metabolismo , Fator de von Willebrand/genética , Fator de von Willebrand/metabolismoRESUMO
OBJECTIVES: This study investigated the influence of the mechanical blood pump HeartMate II (HMII) (Thoratec Corporation, Pleasanton, California) on blood coagulation and platelet function. BACKGROUND: HMII is an implantable left ventricular assist device used for the treatment of heart failure. Patients treated with HMII have increased bleeding tendencies. METHODS: We measured agonist-induced platelet aggregation in 16 patients on HMII support. RESULTS: The von Willebrand factor (vWF)-dependent ristocetin-induced platelet aggregation was impaired in 11 of the 16 patients, of which 12 had experienced at least 1 minor or major bleeding episode. The impaired ristocetin-induced platelet aggregation was associated both with decreased specific activity of plasma vWF, presumably due to lack of high molecular weight vWF multimers, as well as with attenuated function of the platelets themselves. CONCLUSIONS: The results imply that HMII treatment is associated with impaired platelet aggregation, which may contribute to an increased tendency to bleed.
Assuntos
Plaquetas , Insuficiência Cardíaca/terapia , Coração Auxiliar/efeitos adversos , Agregação Plaquetária , Disfunção Ventricular Esquerda/terapia , Fator de von Willebrand/fisiologia , Adulto , Antibacterianos/efeitos adversos , Feminino , Hemorragia/etiologia , Hemorragia/fisiopatologia , Hemorragia/prevenção & controle , Humanos , Coeficiente Internacional Normatizado , Masculino , Pessoa de Meia-Idade , Inibidores da Agregação Plaquetária , Ristocetina/efeitos adversos , Volume Sistólico , Função Ventricular Esquerda , Adulto JovemRESUMO
Von Willebrand's disease is categorized into types and subtypes based on multimeric analysis of plasma von Willebrand's factor. Such categorization is of value because both the mode of inheritance and the choice of therapeutic material differ between subtypes. The Type IIB variant is characterized by hypersensitivity in vitro to ristocetin and thrombocytopenia after administration of desmopressin (DDAVP). Hypersensitivity to ristocetin has also been described in Type I variants but without thrombocytopenia after DDAVP. This report describes a new Type II variant characterized by the converse situation, absence of hypersensitivity to ristocetin in vitro but transient thrombocytopenia after intravenous administration of DDAVP.
