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1.
Zhonghua Xue Ye Xue Za Zhi ; 41(1): 34-39, 2020 Jan 14.
Artigo em Chinês | MEDLINE | ID: mdl-32023752

RESUMO

Objective: To evaluate the effects of adeno-associated virus (AAV) carrying hFⅧ by serotype 8 (AAV8/hFⅧ) on hemophilia A (HA) mice by gene therapy strategy. Methods: pAAV-CB-EGFP, pH22 (serotype 2) and pfΔ6 (adenovirus helper) were used to package AAV into HEK-293 cells in different conditions (ratios of cells to plasmids). The efficiency of transfection and infection were evaluated using immunofluorescence microscope to seek an optimized package condition. pAAV-TTR-hFⅧ, pH 28 (serotype 8) and pfΔ6 were applied to package AAV8/hFⅧ in HEK-293 cells using the optimized package condition. The purified AAV8/hFⅧ were intravenously injected into HA mice and the effects of gene therapy were estimated. Results: The efficiency of package was evaluated according to the amount and intensity of enhanced green fluorescent protein (EGFP) under immunofluorescence microscope. Four package conditions including 10 cm-dish to transfect 10 µg plasmids, 20 cm-dish to 20 µg, 30 µg and 40 µg plasmids were employed, and the condition of 20 cm-dish to transfect 20 µg plasmids reached the highest transfection efficiency at 24 h, 48 h and 72 h after transfection. The small scale AAV-EGFP was packaged using the optimized condition and an AAV crude extract was harvested by a freeze-thaw method. HEK-293 and 16095 cells were infected by the AAV crude extract, and the preferential infection efficiency was recognized in 16095 cells under immunofluorescence microscope. Then, AAV8/hFⅧ was packaged and purified based on the optimized transfection condition, and the high purity of AAV8/hFⅧ was detected by Western blot. Fractions of AAV8/hFⅧ at the dose of 8×10(12) vg/kg were injected into HA mice through tail vein, an eye-bleeding was performed at every two weeks, and the activity of FⅧ was measured by aPTT assay. Results showed that the activity of FⅧ maintained at the therapeutic level and lasted up to 12 weeks after injection. Conclusion: The purified AAV8/hFⅧ based on the optimized package condition could play a role in HA mice gene therapy, and the long-term therapeutic effects of AAV8/hFⅧ were observed in vivo.


Assuntos
Dependovirus , Hemofilia A , Animais , Terapia Genética , Vetores Genéticos , Células HEK293 , Humanos , Camundongos
5.
Rev Med Suisse ; 16(676-7): 47-52, 2020 Jan 15.
Artigo em Francês | MEDLINE | ID: mdl-31961083

RESUMO

The current treatment of haemophilia relies on intravenous administration several times a week of clotting factors VIII (FVIII) or IX (FIX) concentrates, either derived from plasma or produced by biotechnology. This preventive treatment is burdensome, expensive and associated with the risk of developing neutralizing antibodies (inhibitors). Factor VIII and IX concentrates with a longer half-life, a bispecific monoclonal antibody mimicking the action of FVIII as well as various strategies modifying the physiological control of coagulation and administered subcutaneously represent new treatment options, validated or being evaluated. The first results of gene therapy studies also seem very promising. These developments offer hemophiliacs patients new perspectives of treatment if not cure that this article proposes to review.


Assuntos
Hemofilia A , Coagulação Sanguínea , Terapia Genética , Hemofilia A/terapia , Humanos
8.
N Engl J Med ; 382(1): 29-40, 2020 01 02.
Artigo em Inglês | MEDLINE | ID: mdl-31893514

RESUMO

BACKGROUND: Adeno-associated virus (AAV)-mediated gene therapy is under investigation as a therapeutic option for persons with hemophilia A. Efficacy and safety data include 3 years of follow-up after a single administration of AAV5-hFVIII-SQ. METHODS: We report durable efficacy, long-term safety, and clinical and biologic results in 15 adults with severe hemophilia A (factor VIII level, ≤1 IU per deciliter) who had received a single infusion of AAV5-hFVIII-SQ at various dose levels. We evaluated the factor VIII level, annualized rate of bleeding events, use of factor VIII, safety, expression kinetics, and biologic markers of AAV transduction for up to 3 years. RESULTS: Three years after infusion, two participants (one who had received 6×1012 vector genomes [vg] per kilogram of body weight and one who had received 2×1013 vg per kilogram) had factor VIII expression of less than 1 IU per deciliter, as assessed on chromogenic assay. Seven participants (who had received 6×1013 vg per kilogram) had a median factor VIII expression of 20 IU per deciliter; the median number of annualized treated bleeding events was 0, and the median use of exogenous factor VIII was reduced from 138.5 infusions to 0 infusions per year. Bleeding in all target joints (major joints with ≥3 bleeding events within 6 months) in this cohort resolved (≤2 bleeding events within 12 months). Two years after infusion, six participants (who had received 4×1013 vg per kilogram) had a median factor VIII expression of 13 IU per deciliter; the median annualized rate of bleeding events was 0, and the median use of factor VIII was reduced from 155.5 infusions to 0.5 infusions per year. Bleeding in target joints resolved in five of six participants. The factor VIII pharmacodynamic profiles reflected cellular turnover in the blood and molecular events leading to episomal DNA stabilization for persistent expression, findings that are consistent with previous observations in two model systems. Transgene-derived human factor VIII (hFVIII) protein activity mirrored native hFVIII in hemostatic ability. No inhibitor development, thromboses, deaths, or persistent changes in liver-function tests were observed. CONCLUSIONS: Gene therapy with AAV5-hFVIII-SQ vector in participants with hemophilia A resulted in sustained, clinically relevant benefit, as measured by a substantial reduction in annualized rates of bleeding events and complete cessation of prophylactic factor VIII use in all participants who had received 4×1013 vg per kilogram or 6×1013 vg per kilogram of the gene therapy. (Funded by BioMarin Pharmaceutical; ClinicalTrials.gov number, NCT02576795; EudraCT number, 2014-003880-38.).


Assuntos
Dependovirus , Fator VIII/genética , Terapia Genética , Vetores Genéticos , Hemofilia A/terapia , Adulto , Biomarcadores , Coagulantes/uso terapêutico , Fator VIII/uso terapêutico , Seguimentos , Terapia Genética/efeitos adversos , Hemofilia A/complicações , Hemorragia/etiologia , Hemorragia/prevenção & controle , Humanos , Infusões Intravenosas , Masculino , Pessoa de Meia-Idade , Transgenes , Adulto Jovem
9.
World Neurosurg ; 133: 112-120, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31562972

RESUMO

BACKGROUND: Retroclival hematomas are a rare entity and may occur in 3 compartments, namely the epidural, subdural, and subarachnoid spaces. They are frequently secondary to trauma. Hemophilia is a clinical syndrome affecting usually men and characterized by the inherited tendency to bleed excessively after slight injury. Hemophilia is caused by a specific defect of coagulation factor VIII. The main concern associated with the disease is bleeding, especially after trauma and surgeries. The most serious site of bleeding is the central nervous system. CASE PRESENTATION: An 11-year-old boy diagnosed with hemophilia presented after sustaining a fall. On arrival to the emergency department, his vitals where within normal range and he was fully conscious. Neurologic examination was significant for bilateral abducens nerve palsy; the rest of the examination was unremarkable. Imaging studies with computed tomography (CT) scan and brain magnetic resonance imaging showed subacute retroclival subdural hemorrhage with left cerebellar and upper cervical spine extension. Follow-up imaging with CT scan showed progressive resolution of the hematoma, and the patient had a stable clinical course while receiving factor VII replacement. CONCLUSIONS: Retroclival subdural hematomas are rare and may present either spontaneously or after trauma. Conservative treatment is the usual course of treatment. Patients with hemophilia A are under a constant threat from bleeding, either spontaneous or after trivial injury. The most common cause of death in this patient population is intracranial hemorrhage. The most important aspect of intracranial hematoma management is the early replacement therapy of deficient coagulation factors in patients with hemophilia.


Assuntos
Fossa Craniana Posterior/diagnóstico por imagem , Hematoma Subdural Intracraniano/complicações , Hemofilia A/complicações , Criança , Hematoma Subdural Intracraniano/diagnóstico por imagem , Hemofilia A/diagnóstico por imagem , Humanos , Masculino , Tomografia Computadorizada por Raios X
10.
J Assoc Physicians India ; 67(11): 52-55, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31793269

RESUMO

Aim: To assess effect of low dose prophylaxis in hemophilics in terms of bleeding, joint function, QoL and cost-effectiveness. Methods: Analytic study done during one year among 70 adult hemophilics. In observation period (12 weeks), on-demand factor and during prophylaxis (12 weeks), low dose factor was given (Factor VIII 10 IU/KgBW biweekly for haemophilia A and Factor IX 20 IU/KgBW weekly for haemophilia B). Clinical joint assessment was done by Gilbert score and improvement by WFH definitions. Results: Bleed reduced by 68.99% in moderate hemophilics (40 v/s 129) and 64.86% in severe hemophilics (26 v/s74) (p<0.05). During observation in moderate hemophilics, joint, soft tissue and mucosal bleeds occurred in frequency of 120, 1 and 8. This was reduced to 39 joint bleeds, 1 soft tissue bleed and no mucosal bleed during prophylaxis. In severe hemophilics, 70 joint, 2 soft tissue bleeds and 2 mucosal bleeds occurred during observation which reduced to 26 joint bleeds without soft tissue/mucosal bleed in prophylaxis. Bleeding episodes decreased by 65.79% in joints, 66.67% in soft tissues, 100% mucosal bleeds. After prophylaxis one joints (0.61 %) showed good improvement in joint function, thirty (18.18 %) joints showed moderate improvement and ninety two joints (55.76 %) showed mild improvement in joint function. Hospitalization reduced by 60.34% (163 v/s 411) and absenteeism by 53.73% (279 v/s 603). Factors consumption reduced by 12.33 % during prophylaxis period. Conclusion: The low dose prophylaxis strategy significantly decreased the subsequent episodes of total bleeds including joint bleeds and improved the joint function as well as quality of life.


Assuntos
Coagulantes , Hemartrose , Hemofilia A , Adulto , Coagulantes/economia , Coagulantes/uso terapêutico , Análise Custo-Benefício , Fator IX/economia , Fator IX/uso terapêutico , Fator VIII/economia , Fator VIII/uso terapêutico , Hemofilia A/tratamento farmacológico , Hemofilia A/etiologia , Hemofilia A/prevenção & controle , Humanos , Qualidade de Vida , Resultado do Tratamento
11.
Rinsho Ketsueki ; 60(11): 1567-1572, 2019.
Artigo em Japonês | MEDLINE | ID: mdl-31839636

RESUMO

A 72-year-old man was hospitalized because of thrombocytopenia (0.5×104/µl) and anemia. The bone marrow test result revealed excessive numbers of megakaryocytes and no platelet adhesion. Furthermore, platelet-associated immunoglobulin G levels were high, and he was tested positive for Helicobacter pylori antibody. On the basis of these findings, immune thrombocytopenia was diagnosed. The patient was initially treated with eradication therapy; prednisolone, 20 mg/day (0.5 mg/kg) and a thrombopoietin receptor agonist 12.5 mg/day. During the course of treatment, the anemia worsened. Detailed examination revealed marked prolongation of activated partial thromboplastin time and inhibition of factor VIII activity. Therefore, he was diagnosed with acquired hemophilia A. Although extensive muscle hemorrhage had occurred, hemostatic therapy comprising intensification of the immunosuppressive therapy and administration of recombinant activated factor VII resulted in successful hemostasis. As the treatment progressed, inhibition of factor VIII recurred temporarily; however, immunosuppressive therapy was continued. No recurrence was observed even after 1 year of the onset of both diseases.


Assuntos
Hemofilia A , Hemostáticos , Trombocitopenia , Idoso , Hemofilia A/complicações , Hemorragia , Humanos , Masculino , Trombocitopenia/complicações
12.
Rev Med Chil ; 147(5): 568-573, 2019 May.
Artigo em Espanhol | MEDLINE | ID: mdl-31859888

RESUMO

BACKGROUND: In patients with hemophilia, radionuclide synoviorthesis, or the intra-articular injection of a radionuclide to decrease the synovial hypertrophy tissue, aims to decrease or avoid hemarthrosis. AIM: To evaluate the effectiveness of radionuclide synoviorthesis in hemophilia. MATERIAL AND METHODS: Observational retrospective study of the evolution of 107 male patients aged 3 to 54 years who were subjected to radionuclide synoviorthesis between 2007 and 2015. RESULTS: Of 164 treated joints, in 65% treatment was successful, (defined as zero to two hemarthroses and absence of synovitis during the follow up period), in 17% it was partially successful (defined as two or less hemarthroses, but persistence of the synovitis) and failed in 18% of the procedures. No important complications were recorded. CONCLUSIONS: Radionuclide synoviorthesis has an overall 82% success rate, is minimally invasive, can be used at any age and is inexpensive We recommend its implementation in Chilean hemophilia treatment centers.


Assuntos
Hemartrose/terapia , Hemofilia A/terapia , Radioisótopos/administração & dosagem , Rênio/uso terapêutico , Sinovite/terapia , Radioisótopos de Ítrio/uso terapêutico , Adolescente , Adulto , Criança , Pré-Escolar , Hemartrose/diagnóstico por imagem , Hemartrose/fisiopatologia , Hemofilia A/fisiopatologia , Humanos , Injeções Intra-Articulares , Masculino , Pessoa de Meia-Idade , Reprodutibilidade dos Testes , Estudos Retrospectivos , Sinovite/diagnóstico por imagem , Sinovite/fisiopatologia , Fatores de Tempo , Resultado do Tratamento , Adulto Jovem
15.
Medicine (Baltimore) ; 98(46): e17998, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31725667

RESUMO

Giant abdominal hemophilic pseudotumor is exceedingly rare, thus may bring great challenges to the timely and proper diagnosis and treatment of clinicians. The only definitive management is complete removal of the abdominal hemophilic pseudotumor. The objective of this article is to report surgical treatment and follow-up outcomes of three unusual cases with giant abdominal hemophilic pseudotumor.We describe 3 patients with giant hemophilic pseudotumor involving the abdomen who were successfully treated with tumor resection. On presentation to our institution, the patients all had signs of giant cystic lesions in abdomen, and the patients' most outstanding complaints were aggravated abdominal pain. All of three patients underwent complete excision of abdominal hemophilic pseudotumor. The patients showed adequate pain relief compared with the previous status.Surgical resection is the most effective treatment option for patients with giant abdominal hemophilic pseudotumor who can undergo appropriate surgical treatment. This represents a safe and reasonable approach to sustainably relieve pain and other symptoms with giant hemophilic pseudotumor in the abdomen. Perioperative coagulation factor replacement therapy is also of great significance in reducing the risks and complications.


Assuntos
Hematoma/complicações , Hematoma/cirurgia , Hemofilia A/complicações , Adulto , Humanos , Masculino , Pessoa de Meia-Idade
17.
Rinsho Ketsueki ; 60(9): 1275-1282, 2019.
Artigo em Japonês | MEDLINE | ID: mdl-31597853

RESUMO

Hemophilia is a congenital bleeding disorder that occurs due to quantitative and functional abnormalities of FVIII or FIX. It has a long history, dating as far back as the Babylonian era, with many high profile reports, including the British royal family and the last prince of the Romanov dynasty. The treatment used to be blood transfusion, consisting of plasma derived products from the 1970s onwards and recombinant products introduced later in the 1990s. In the 2000s, due to various modifications of factor protein, extended half-life (EHL) products have appeared and replaced conventional products. In EHL research, new products are also being developed that further the extension of the half-life and are more convenient. In 2018, an antibody-based medicine arrived, exhibiting a mechanism different from factor replacement therapy. Some other therapeutic agents used to suppress bleeding, called nonfactor agents, are currently under development. Recently, gene therapy has finally come into the clinical trial space in Japan and can be expected to be a treatment which aims at "cure," as it can be used with no exposure to bleedings for several years with one injection. This article outlines the future of hemophilia treatment.


Assuntos
Hemofilia A/terapia , Hemofilia B/terapia , Fator IX , Fator VIII , Terapia Genética/tendências , Hemostáticos/uso terapêutico , Humanos , Japão
18.
Hematology ; 24(1): 631-636, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31514689

RESUMO

Objectives: Acquired hemophilia A (AHA) is a rare disease resulting from autoantibodies against coagulation factor VIII that leads to spontaneous bleeding. This study reports the clinical characteristics and treatment outcomes of a relatively sizable cohort of patients with AHA. Methods: We retrospectively analyzed the characteristics and outcomes of 42 patients with AHA diagnosed in our center from January 2014 through December 2018. Results: The FVIII activity (FVIII: C) was significantly suppressed (median 1.5%; interquartile range [IQR]: 0.9-3.5) by FVIII inhibitor (median 8 BU/mL; IQR: 4.0-16.0). Bypassing agents, PCC or FVIIa, were used in 14 patients for bleeding control without any adverse reaction; and most patients (90.5%, 38/42) were placed on immunosuppressive regimen, corticosteroid alone or in combination with cyclophosphamide. Patients treated with corticosteroids alone had a lower median inhibitor titer (8 BU/mL) than those treated with combination corticosteroids of cyclophosphamide (16 BU/mL) (p < 0.001). 97.4% (37/38) patients achieved complete remission (CR) after immunosuppression therapy, and the median time to CR in patients treated with corticosteroids alone was shorter than those with combination corticosteroids of cyclophosphamide (median 40 days; IQR: 31-65 vs. 51 days; IQR: 38-83, p = 0.301). 10 (26.3%) patients relapsed thereafter and were placed on combined corticosteroid and cyclophosphamide treatment, which yielded second remission in 8 patients (80%). Two patients died, one from uncontrolled post-surgical retroperitoneal hemorrhage and one from sepsis complicating corticosteroid therapy. Conclusion: The corticosteroid achieves a satisfactory outcome, particularly with low inhibitors titers; and combination of cyclophosphamide will facilitate remission in sever patients with high titers of inhibitors.


Assuntos
Testes de Coagulação Sanguínea/métodos , Hemofilia A/terapia , Hemorragia/tratamento farmacológico , Adolescente , Adulto , Idoso , Criança , China , Feminino , Hemofilia A/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Adulto Jovem
19.
Blood Coagul Fibrinolysis ; 30(1S Suppl 1): S1-S3, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31517707

RESUMO

: Prophylaxis entails long-term continuous intravenous administration of concentrates of the deficient factor with a view to preventing spontaneous bleeds and the development of hemophilic arthropathy. Initiation of prophylaxis at an early age and continuous uninterrupted factor administration in patients with hemophilia have been hailed as essential by such organizations.The most widely used prophylaxis regimens include the Swedish (Malmö), the Dutch and the Canadian protocols. Different international groups have hailed prophylaxis as the most effective treatment in patients with hemophilia.Prophylaxis is effectiveness in preventing bleeding and arthropathy in children with (particularly early-onset) hemophilia. Although some retrospective trials confirm the benefits of prophylaxis, others point to a lack of conclusive data to support switching adult patients with established hemophilic arthropathy who always received on-demand treatment to prophylactic treatment.The potential effects of prophylaxis on the patients' sex lives, renal status, prostate involvement and cataract must be analyzed before indicating prophylactic treatment in elderly patients.The high efficacy of prophylactic treatment in patients with hemophilia and inhibitors has been widely reported in the literature.


Assuntos
Hemofilia A/prevenção & controle , Administração Intravenosa , Adulto , Idoso , Criança , Fator VIII/administração & dosagem , Fator VIII/uso terapêutico , Hemartrose/prevenção & controle , Hemorragia/prevenção & controle , Humanos , Artropatias/prevenção & controle
20.
Blood Coagul Fibrinolysis ; 30(1S Suppl 1): S4-S6, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31517708

RESUMO

: In persons with hemophilia, the severity and spontaneity of bleeding episodes depends on the degree of factor deficiency present in the patients. Severe hemophilia is classically characterized by a factor VIII (FVIII) or factor IX (FIX) coagulant activity below 1% of normal (spontaneous and severe bleeds). Moderate hemophilia is associated with factor activity between 1 and 5% of normal (milder spontaneous and traumatic bleeds). Finally, mild hemophilia has factor activity in excess of 5% of normal (traumatic bleeds in general). Nonetheless, this classification is rather simplistic. It is a known fact that there are subjects with identical clotting factor levels who have different bleeding phenotypes. We will analyze different factors to justify this.


Assuntos
Fator IX/análise , Fator VIII/análise , Hemofilia A/sangue , Coagulação Sanguínea , Fator IX/metabolismo , Fator VIII/metabolismo , Hemofilia A/metabolismo , Hemorragia/sangue , Hemorragia/metabolismo , Humanos
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