RESUMO
The reunification of Germany in 1990 brought with it major challenges in terms of unifying the care offered to haemophilia patients. At that time, most of the treatment centres belonged to the largest regional hospitals. The centre for paediatric haemophilia patients in Leipzig was at the University Hospital. In this centre, early prophylaxis was offered to all patients with severe haemophilia A or B. For over 20 years, the treatments of choice in the German Democratic Republic were cryoprecipitate for haemophilia A and prothrombin complex concentrate for haemophilia B. Cryoprecipitate was relatively effective during minor surgery, in cases of mild to moderate bleeding, and for prophylaxis; however, unpleasant, relevant side-effects and hepatitis virus transmission were frequently encountered in clinical practice. Reunification coincided with the availability of virus-safe, high-purity plasma-derived factor VIII concentrates (e.g. Beriate(®) P), which changed the outlook for patients in terms of convenience, tolerability, and virus safety; and these new products quickly became the treatments of choice for haemophilia A patients at the Leipzig Children's Hospital. Today, 20 years later, nearly all of the patients initiated on Beriate(®) P at the time of reunification continue with that treatment, and are still benefitting from its excellent efficacy, tolerability, and virus-safety profile.
Assuntos
Fator VIII/uso terapêutico , Fibrinogênio/uso terapêutico , Hemofilia A/terapia , Fator de von Willebrand/uso terapêutico , Combinação de Medicamentos , Fator VIII/história , Fibrinogênio/história , Alemanha Oriental/epidemiologia , Hemofilia A/epidemiologia , Hemofilia A/história , História do Século XX , História do Século XXI , Humanos , Proteínas Recombinantes/história , Proteínas Recombinantes/uso terapêutico , Fator de von Willebrand/históriaRESUMO
BACKGROUND: Severe hereditary coagulation factor XIII deficiency is a rare homozygous bleeding disorder affecting one person in every two million individuals. In contrast, heterozygous factor XIII deficiency is more common, but usually not associated with severe hemorrhage such as intracranial bleeding or hemarthrosis. In most cases, the disease is caused by F13A gene mutations. Causative mutations associated with the F13B gene are rarer. DESIGN AND METHODS: We analyzed ten index patients and three relatives for factor XIII activity using a photometric assay and sequenced their F13A and F13B genes. Additionally, structural analysis of the wild-type protein structure from a previously reported X-ray crystallographic model identified potential structural and functional effects of the missense mutations. RESULTS: All individuals except one were heterozygous for factor XIIIA mutations (average factor XIII activity 51%), while the remaining homozygous individual was found to have severe factor XIII deficiency (<5% of normal factor XIII activity). Eight of the 12 heterozygous patients exhibited a bleeding tendency upon provocation. CONCLUSIONS: The identified missense (Pro289Arg, Arg611His, Asp668Gly) and nonsense (Gly390X, Trp664X) mutations are causative for factor XIII deficiency. A Gly592Ser variant identified in three unrelated index patients, as well as in 200 healthy controls (minor allele frequency 0.005), and two further Tyr167Cys and Arg540Gln variants, represent possible candidates for rare F13A gene polymorphisms since they apparently do not have a significant influence on the structure of the factor XIIIA protein. Future in vitro expression studies of the factor XIII mutations are required to confirm their pathological mechanisms.
Assuntos
Códon sem Sentido , Deficiência do Fator XIII/genética , Fator XIIIa/química , Fator XIIIa/genética , Mutação de Sentido Incorreto , Mutação , Adulto , Idoso , Sequência de Aminoácidos , Criança , Pré-Escolar , Cristalografia por Raios X , Deficiência do Fator XIII/diagnóstico , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Dados de Sequência Molecular , Estrutura Terciária de Proteína/genética , Alinhamento de Sequência , Adulto JovemAssuntos
Extrofia Vesical/genética , Extrofia Vesical/patologia , Proteínas Motores Moleculares/genética , Cadeias Pesadas de Miosina/genética , Trombocitopenia/genética , Feminino , Haplótipos/genética , Humanos , Hibridização in Situ Fluorescente , Mutação de Sentido Incorreto/genética , Análise de Sequência de DNA , Trombocitopenia/congênitoRESUMO
Von Willebrand disease type Normandy (VWD 2N) is caused by mutations at the factor VIII (FVIII) binding site of VWF, located at the amino-terminus of mature VWF. It is inherited in a recessive fashion and both homozygous and compound heterozygous mutations have been identified. Homozygous mutations are correlated with a clinical phenotype indistinguishable from mild hemophilia A by conventional laboratory tests, whereas compound heterozygosity with a quantitative defect may appear as VWD type 1 (VWD1). We have now identified and expressed a novel heterozygous mutation (Y795C) which is responsible for both, a defective FVIII-binding and aberrant multimers in a female patient with mild FVIII deficiency. Additionally we expressed another mutation (E787K), previously identified by us in a male patient with a severe 'pseudohemophilic' phenotype. Analysis of the FVIII binding and the multimer structure of the respective recombinant VWF mutants reproduced the observed phenotype: the FVIII binding defect in addition to the aberrant multimer structure of the patient with Y795C and the FVIII binding defect only, in the patient with E787K. Our results demonstrate the causative nature of the two mutations and emphasize the impact of 'cysteine mutations' on the multimer structure of VWF.