1,721,021 research outputs found
Treatment of hemophilia in the near future
No full textAdvancements and debacles have characterized hemophilia treatment over the past 50 years. The 1970s saw the availability of plasma-derived concentrates making prophylaxis and home therapy possible. This optimistic perception changed extremely in the early 1980s, when most people with hemophilia were infected with HIV and hepatitis viruses. Then, also in the 1980s, the rapid progress in molecular biology led to the development of recombinant therapeutic products. This important advancement was a huge technological leap fresh off from the earlier 1980s disaster. Now in the 21st century, the newer bioengineering drugs open a new hopeful phase for the management of hemophilia. The current efforts are concentrated on producing novel coagulation factors with prolonged bioavailability, increased potency, and resistance to inactivation and potentially reduced immunogenicity; this phase of evolution is improving very quickly. 2014 is the year of marketing approval by the Food and Drug Administration of the first bioengineered FVIII and FIX long-acting drugs, using Fc-fusion strategy. This represents the first significant advance in the hemophilia therapy that dramatically transforms patient management by substantially reducing the frequency of injections, improving compliance, and simplifying prophylaxis and, in turn, refining the quality of life of hemophilia patients, offering them a nearly normal life expectancy, particularly to newborns with hemophilia B
The past and future of haemophilia : diagnosis, treatments, and its complications
No full textHaemophilia A and B are hereditary haemorrhagic disorders characterised by deficiency or dysfunction of coagulation protein factors VIII and IX, respectively. Recurrent joint and muscle bleeds lead to severe and progressive musculoskeletal damage. Existing treatment relies on replacement therapy with clotting factors, either at the time of bleeding (ie, on demand) or as part of a prophylactic schedule. The major complication of such therapy is the development of neutralising antibodies (ie, inhibitors), which is most frequent in haemophilia A. Treatment might improve considerably with the availability of new modified drugs, which might overcome existing prophylaxis limitations by reducing dosing frequency and thereby rendering therapy less distressing for the patient. Subcutaneous administration of some new therapies would also simplify prophylaxis in children with poor venous access. Gene therapy has the potential for a definitive cure, and important results have been obtained in haemophilia B. Despite improvements in haemophilia care, the availability of clotting factor concentrates for all affected individuals worldwide remains the biggest challenge
Future of coagulation factor replacement therapy
No full textOver a million patients worldwide currently suffer from hemophilia and other congenital clotting factor deficiencies. Patients affected with hemophilia A and B are treated by intravenous replacement therapy of factor VIII and factor IX, respectively. Current hemophilia treatments have favorably supported their efficacy, tolerability, and safety profiles. The onset of alloantibodies inactivating the infused coagulation factor is the main problem in hemophilia patients rendering replacement therapies ineffective; another disadvantage is the short half-life of the infused clotting factors with the need for multiple and frequent infusions to manage a bleeding episode. Now, the challenge in the management of hemophilia treatment is the prolongation of the half-life and reduction in the immunogenicity of recombinant clotting factors. The bioengineering strategies, previously applied successfully to other therapeutic proteins, encourage the current efforts to produce novel coagulation factors with more prolonged bioavailability, with increased potency and resistance to inactivation and potentially reduced immunogenicity
ADAMTS13 mutations and polymorphisms in congenital thrombotic thrombocytopenic purpura
No full textCongenital thrombotic thrombocytopenic purpura (TTP) (also known as Upshaw-Schulman syndrome, USS) is a rare, life-threatening disease characterized by thrombocytopenia and microangiopathic hemolytic anemia, associated with the deficiency of the von Willebrand factor-cleaving protease (ADAMTS13) due to mutations in the corresponding gene. The spectrum of clinical phenotype in congenital TTP is wide, encompassing neonatal-onset disease and adult-onset disease, forms with a single disease episode and chronic-relapsing forms. We review ADAMTS13 gene variants associated with inherited ADAMTS13 deficiency and congenital TTP. To date, 76 mutations of ADAMTS13 are reported in the literature. Missense mutations, which constitute nearly 60% of ADAMTS13 mutations, preferentially localize in the 5'-half of the gene encoding the N-terminal half of the protein, where the domains that are indispensable for ADAMTS13 catalytic function are situated. In vitro expression studies in cell cultures have shown that defects in protein secretion and catalytic activity are the main mechanisms responsible for the deficiency of ADAMTS13 in congenital TTP patients. Even if data from the literature suggest the existence of genotype-phenotype correlations, a clear relationship between the type and the effect of ADAMTS13 genetic defects with disease manifestations remains to be establishe
Role of the 2 adenine (g.11293_11294insAA) insertion polymorphism in the 3' untranslated region of the factor VII (FVII) gene : molecular characterization of a patient with severe FVII deficiency
No full textPolymorphic variants in the gene encoding factor VII (F7) affect the plasma levels of this coagulation protein and modify the clinical phenotype of FVII deficiency in some patients. In this study we report the in vitro functional analysis of a novel polymorphic variant located in the 3' untranslated region of F7: g.H293_11294insAA. To determine whether this variant regulates FVII expression, we initially compared an expression vector containing FVII cDNA with g.H293_11294insAA with the FVII wild-type (WT) construct. The kinetics of mRNA production showed that the insertion decreases the steady-state FVII mRNA levels. To assess whether the insertion influences the phenotype of FVII-deficient patients, we evaluated its effect on the expression of FVII in a patient with severe FVII deficiency (undetectable FVII activity and antigen) carrying two additional homozygous missense variations (p.Arg277Cys and p.Arg353Gln). The two substitutions alone reduced the expression of FVII activity and antigen in vitro, but with the insertion polymorphism in our expression vector the patient's phenotype of undetectable plasma FVII was recapitulated. The insertion polymorphism in the 3' untranslated region of F7 is another modifier of FVII expression that might explain the poor genotype-phenotype correlation in some FVII-deficient patient
Reproductive care in human immunodeficiency virus serodiscordant couples with haemophilia
No full textADAMTS-13 Binds Platelets in a Specific, Divalent Cation and Activation Dependent Manner
No full textPitfalls in molecular diagnosis in a family with severe factor VII (FVII) deficiency-misdiagnosis by direct sequence analysis using a PCR product
No full textMolecular diagnostic tests are becoming a routine analysis in many laboratories. These modern analyses are
widely used in clinical medicine, forensic, genetic and prenatal diagnosis and also in preimplantation genetic
diagnosis. The accuracy of analysis is highly dependent on the success achieved in minimising genotyping
errors. The pitfalls in molecular diagnostic tests can be due to a simple technique such as the polymerase chain
reaction (PCR) used universally. This technique is routinely used for its apparent accuracy, but it is also a
well-known source of errors. We report an error introduced during PCR reaction that leads to a wrong sequence
result and consequently to a ‘false’ molecular result in a next prenatal diagnosis in a family with severe factor
VII (FVII) deficiency. This error was verified using an unsuitable primer design in a rich repetitive sequence
of the FVII gene that leads to a false annealing and then to a wrong molecular diagnosis. It is essential to link
closely molecular data with clinical and phenotype analysis in order to avoid false-negative or false-positive
results, which is of great importance to diagnosis and molecular preventio
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