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
AIM: Bernard-Soulier syndrome (BSS) is an inherited bleeding disorder characterized by macroplatelets and thrombocytopenia, prolonged bleeding time, and a prevalence of less than 1 in 1,000,000. In view of the recognition of the risk of bleeding and the management of daily surgical practice in these patients, adequate strategies are necessary to provide the safest care. This article aims to perform an integrative review of the literature on the management of invasive procedures in the oral cavity of individuals with BSS. METHOD: The PubMed/Medline and LILACS databases were searched using Boolean operators related to BSS, bleeding disorders, and oral care. RESULTS: As a result, only five articles with the main theme were included: one letter to the editor and four case reports, described chronologically as to date of publication, classification of the article, and medical/odontological measures taken. CONCLUSION: We conclude with this review the need for adequate knowledge of surgeons regarding coagulation disorders and the need to discuss and plan procedures with the hematology team, as well as the importance of the notion of management of possible complications resulting from invasive treatments in the oral cavity of patients with BSS.
Assuntos
Síndrome de Bernard-Soulier , Síndrome de Bernard-Soulier/complicações , Síndrome de Bernard-Soulier/terapia , Humanos , BocaRESUMO
BACKGROUND: Bernard-Soulier Syndrome is a rare congenital bleeding disorder, mainly inherited in an autosomal recessive pattern. It is characterized by a genetic defect on one of the four genes encoding the subunits of the transmembrane protein complex GPIb-V-IX, physiologically expressed only in platelets. The exact phenotype varies widely from individual to individual depending on the particular mutation presented. Currently, there is no consensus about ideal management of affected pregnant women, in face of the scarcity of cases. CASE PRESENTATION: We report on a 28-year-old Black Brazilian primigravida who was referred to our maternity hospital, a tertiary care center, for decision about the most adequate mode of delivery. She was admitted with a platelet count of 43.000 plt/µL, and hemoglobin of 13.6 g/dL. Platelet transfusion was regarded as a necessary prophylactic measure prior to delivery. Ten units of random donor platelets were administered on the course of three days, after which the patient was submitted to an elective cesarean section delivery under general anesthesia at 40 weeks of gestational age. A healthy male baby with a normal birthweight of 3.615 kg was delivered. After the delivery, the mother's state continued being assessed daily, with special attention taken to lochia and surgical wound healing. At one week postpartum, a complete blood count revealed a platelet count of 41.000 plt/µL, and hemoglobin of 13.3 g/dL. As there were no signs of neither evident nor occult hemorrhage, and surgical wound was healing accordingly, the patient was discharged, after being oriented about bleeding preventive measures. CONCLUSION: The peripartum period is regarded as the most crucial moment of pregnancy in women with Bernard-Soulier Syndrome, hence the importance of a judiciously planned mode of delivery, and of careful prophylaxis against bleeding beforehand. Furthermore, absence of complications during the peripartum period does not predict how the woman will do subsequently. Strict vigilance is warranted at least until six weeks postpartum, due to the virtual risk of secondary postpartum hemorrhage.
Assuntos
Síndrome de Bernard-Soulier/patologia , Adulto , Feminino , Humanos , GravidezRESUMO
La trombocitopenia es causa frecuente de consulta en hematología pediátrica. La mayoría de veces la baja de plaquetas es por desorden de destrucción autoinmune, raramente el padecimiento tiene un comportamiento familiar-hereditario. Se presenta el caso de una paciente de 11 años de edad, conocida desde los 3 años por trombocitopenia en el rango de 50,000/mm , fue evaluada por posibilidad de desórdenes autoinmunescon estudios inmunológicos básicos: complementos, ANA, Anti ADN, factor reumatoide y los resultados fueron normales. Tratada en varias ocasiones con prednisona oral, antiRh y con inmunoglobulina intravenosa (IGIV). Se le ha brindado seguimiento prolongado por trombocitopenia que resultó ser familiar; encontrando doce afectados, que incluyen abuela materna, madre, tíos, primos y hermana. Las características clínicas y la morfología plaquetaria fueron finalmente suficientes para conducir a diagnóstico inusual: el síndrome de Bernard-Soulier (SBS). El diagnóstico fue sugerido por el frotis de sangre periférica (FSP)...
Assuntos
Humanos , Feminino , Criança , Doenças Hematológicas , Síndrome de Bernard-Soulier/complicações , Trombocitopenia Neonatal Aloimune/diagnóstico , Homozigoto , Glicoproteínas da Membrana de PlaquetasRESUMO
The 22q11.2 deletion syndrome (22q11DS) is a common genetic disease characterized by broad phenotypic variability. Despite the small number of studies describing hematological alterations in individuals with 22q11DS, it appears that these abnormalities are more frequent than previously imagined. Thus, the objective of our study was to report on a patient with 22q11DS presenting thrombocytopenia and large platelets and to review the literature. The patient, a 13-year-old boy, was originally evaluated due to craniofacial dysmorphia and speech delay. He also had a history of behavioral changes, neuropsychomotor delay and recurrent otitis/sinusitis. The identification of a 22q11.2 microdeletion by fluorescent in situ hybridization diagnosed the syndrome. Despite his hematological alterations, he only had a history of epistaxis and bruising of the upper and lower limbs. Assessments of the prothrombin time, thrombin time, partial thromboplastin time, bleeding time, fibrinogen levels and platelet aggregation (including the ristocetin induced platelet aggregation test) were all normal. Hematological alterations observed in 22q11DS are directly related to the genetic disorder itself (especially in respect to deletion of the GPIb gene) and secondary to some clinical findings, such as immunodeficiency. Macrothrombocytopenia is increasingly being considered a feature of the broad spectrum of 22q11DS and may potentially be a clinical marker for the syndrome.
Assuntos
Humanos , Masculino , Adolescente , Síndrome de Bernard-Soulier , Plaquetas , Síndrome de DiGeorge , TrombocitopeniaRESUMO
Gals (galectins) are proteins with glycan affinity that are emerging as mediators of atherosclerosis. Despite the similarities in structure and sequence, different Gals exert distinct effects on their target cells. We have shown that Gal-1 triggers platelet activation, suggesting a role for Gals in thrombus formation. Since Gal-8 is expressed upon endothelial activation and also contributes to inflammation, to understand further the role of these lectins in haemostasis, we evaluated the effect of Gal-8 on human platelets. Gal-8 bound specific glycans in the platelet membrane and triggered spreading, calcium mobilization and fibrinogen binding. It also promoted aggregation, thromboxane generation, P-selectin expression and granule secretion. GP (glycoprotein) αIIb and Ib-V were identified as putative Gal-8 counter-receptors by MS. Studies performed using platelets from Glanzmann's thromboasthenia and Bernard-Soulier syndrome patients confirmed that GPIb is essential for transducing Gal-8 signalling. Accordingly, Src, PLC2γ (phospholipase C2γ), ERK (extracellular-signal-regulated kinase) and PI3K (phosphoinositide 3-kinase)/Akt downstream molecules were involved in the Gal-8 signalling pathway. Gal-8 fragments containing either the N- or C-terminal carbohydrate-recognition domains showed that activation is exerted through the N-terminus. Western blotting and cytometry showed that platelets not only contain Gal-8, but also expose Gal-8 after thrombin activation. These findings reveal Gal-8 as a potent platelet activator, supporting a role for this lectin in thrombosis and inflammation.
Assuntos
Plaquetas/fisiologia , Galectinas/fisiologia , Ativação Plaquetária/fisiologia , Animais , Síndrome de Bernard-Soulier/metabolismo , Plaquetas/efeitos dos fármacos , Plaquetas/metabolismo , Sinalização do Cálcio , Membrana Celular/metabolismo , Galectinas/química , Galectinas/genética , Humanos , Proteínas Imobilizadas/metabolismo , Integrina alfa2/metabolismo , Camundongos , Fragmentos de Peptídeos/metabolismo , Ativação Plaquetária/efeitos dos fármacos , Complexo Glicoproteico GPIb-IX de Plaquetas/metabolismo , Domínios e Motivos de Interação entre Proteínas , Isoformas de Proteínas/química , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , Transporte Proteico , Proteínas Recombinantes/química , Proteínas Recombinantes/metabolismo , Vesículas Secretórias/fisiologia , Solubilidade , Trombastenia/metabolismoRESUMO
Bernard-Soulier Syndrome (BSS) is an inherited recessive bleeding disorder. In some instances, diagnosis might be restricted to routine blood exams, including bleeding time, prothrombin time (PT), and partial thromboplastin time (APTT). Exams such as platelet aggregation, and testing for expression of ristocetin cofactor, or von Willebrand factor may not be commonly performed. This leads to misdiagnosis in a number of patients, which are subsequently treated erroneously. Flow cytometry has been used widely as a tool in the diagnosis of leukemias, lymphomas, and many other immuno-hematological diseases. The purpose of this study was to assess whether flow cytometry could be helpful in the diagnosis of Bernard-Soulier Syndrome in Brazilian patients. For this, we examined a selected group of 15 patients with suspected BSS based on classical diagnosis. We used a panel of antibodies to detect the expression of glycoproteins GPIbalpha, GPIIb, GPIIIa, GPIX, as well as CD9. Abnormalities of GPIb and GPIX were observed in nine of the 15 patients, which included severe reduction of both antigens, of one or the other, or normal levels but weak expression. Strikingly, this abnormality correlated with severely reduced expression of CD9 in all cases. We discuss the implications for flow cytometric diagnosis of BSS.
Assuntos
Síndrome de Bernard-Soulier/diagnóstico , Citometria de Fluxo/métodos , Adolescente , Adulto , Anticorpos Monoclonais , Antígenos CD/análise , Brasil , Criança , Pré-Escolar , Humanos , Glicoproteínas de Membrana/análise , Pessoa de Meia-Idade , Complexo Glicoproteico GPIb-IX de Plaquetas/análise , Glicoproteínas da Membrana de Plaquetas/análise , Tetraspanina 29 , Adulto JovemRESUMO
Las enfermedades genéticas plaquetarias son desórdenes heterogéneos, algunos de ellos muy raros, quese presentan en la medicina clínica, caracterizados por trobocitopenia, plaquetas grandes (macrotrombocitopenias)y signos variables de hemorragia, así como trombosis en otros casos. La patogénesis ypatofisiología es bastante desconocida y el propósito de este artículo es proveer una estructura lógicaque resuma el conocimiento actual.
Assuntos
Humanos , Doenças de von Willebrand , Síndrome de Bernard-Soulier , Transtornos da Coagulação Sanguínea , Transtornos Plaquetários , TrombasteniaRESUMO
A síndrome de Bernard-Soulier (SBS) trata-se de uma rara enfermidade que se caracteriza por tempo de sangramentoprolongado, presença de trombocitopenia e plaquetas gigantes. Clinicamente, os portadores sofrem de distúrbios hemorrágicos que vão de discretos a severos, como: epistaxes, menorragia, melena, sangramento gengival, entre outros. Trata-se de uma doença detransmissão hereditária autossômica recessiva, com maior prevalência em filhos de pais consangüíneos. A nível molecular, sua causa predominante deve-se a diversas mutações, como a deleção de dinucleotídeos, alterando a leitura estrutural da região que decodifica a glicoproteína (GP), produzindo, assim, proteínas alteradas que normalmente teriam um papel especial na conformação e estabilidade da expressão do complexo GP IbIX-V, que é responsável pela eficácia funcional das plaquetas. Esta revisão de literatura tem como objetivo mostrar a importância do conhecimento dessa alteração plaquetária, esclarecer dúvidas sobre a SBS e apontar que a presença de plaquetas bizarras no esfregaço sangüíneo é o mais importante indício desta síndrome, o que diferencia a SBS de outros distúrbios de hemostasia, como a Púrpura Trombocitopênica Imunológica e a Doença de Von Willebrand, na rotina laboratorial.
Assuntos
Humanos , Síndrome de Bernard-Soulier , Tempo de Sangramento , Coagulação Sanguínea , Transtornos Plaquetários , Plaquetas , Hemostasia , Contagem de Plaquetas , Complexo Glicoproteico GPIb-IX de PlaquetasRESUMO
En el presente estudio se comparó el desempeño de 56 novillas doble propósito que resultaron preñadas luego de la transferencia directa de embriones producidos in vitro cultivados en un medio suplementado con suero o en uno químicamente definido. No se observaron diferencias en las tasas de aborto (30,43% vs 24,24%), distocias (52,17% vs 51,52%) y parto normal (17,39% vs 24,24%) entre las novillas que recibieron embriones cultivados en el medio suplemento con suero y las que recibieron embriones cultivados en el medio químicamente definido. El sexo de la cría afectó significativamente el porcentaje de distocias, 83,33% para machos y 50% para hembras, (P<0,05). El peso al nacimiento de los becerros tampoco se vio afectado (p>0,05) por la suplementación sérica durante el cultivo (46,86 ± 2,04 kg, para los becerros derivados de los embriones cultivados en el medio suplementado con suero y 46,28 ± 1,42 kg, para los derivados de los embriones cultivados en el medio químicamente definido) ni por el sexo de la cría (machos 47,20 ± 1,50 kg y hembras, 45,45 ± 1,84 kg). El peso de los becerros que nacieron muertos o que murieron luego del nacimiento fue significativamente (P< 0,05) mayor (51,92 ± 1,76 kg) al de los becerros que sobrevivieron (43,88 ± 1,22 kg). La sobrevivencia perinatal no se vió afectada ni la suplementación sérica durante el cultivo embrionario, ni por el sexo de los becerros o el nacimiento de un parto distócico. En conclusión, la presencia de suero en el medio de cultivo no afectó el desempeño de las novillas doble propósito que resultaron preñadas luego de la transferencia de embriones producidos in vitro. En este estudio se observó la presencia de becerros con síndrome del recién nacido gigante evidenciado por un alto peso al nacimiento y una alta tasa de abortos y distocias.