RESUMO
Osteopenia and osteoporosis have increasingly become a recognized morbidity in those persons with hemophilia (PwH) receiving inadequate prophylactic clotting factor replacement. Animal models can control or eliminate genetic and environmental factors and allow for invasive testing not clinically permissible. Here, we describe the skeletal phenotype of juvenile and adult male mice with a genetically engineered deficiency in coagulation factor IX (FIX KO). Although the somatic growth of FIX KO mice matched that of their wild-type (WT) littermates at 10 and 20 weeks of age, the FIX KO mice displayed reduced bone mineral density (BMD), reduced cortical and cancellous bone mass, and diminished whole bone fracture resistance. These findings coupled with parallel observations in a murine model of hemophilia A (FVIII deficiency) point to an effector downstream of the coagulation cascade that is necessary for normal skeletal development. Further study of potential mechanisms underlying the bone disease observed in rare clotting factor deficiency syndromes may lead to new diagnostic and therapeutic insights for metabolic bone diseases in general.
Assuntos
Hemofilia A , Hemofilia B , Animais , Densidade Óssea , Modelos Animais de Doenças , Fator IX/genética , Hemofilia A/genética , Hemofilia B/genética , Masculino , CamundongosRESUMO
INTRODUCTION: Persons with haemophilia (PwH) have abnormally low bone density and increased risk of fractures. We previously demonstrated decreased skeletal health in factor VIII (FVIII)-deficient mice. Thus, we hypothesized factor deficiency is an independent risk factor for decreased skeletal health. AIM: We seek to identify differences in bone-related cytokine expression among PwH and healthy controls. METHODS: We evaluated plasma samples from 79 participants with severe FVIII deficiency and 51 age-matched healthy controls. Plasma samples were assessed for RANKL and OPG, cytokines that regulate bone metabolism, and CTX-1, a biomarker for bone resorption, as well as 10 bone-related cytokines. RESULTS: CTX-1 is higher among samples from FVIII-deficient participants compared to controls (P < .01) but not among participants with recent factor use (within 24 hours of sample collection) (P = .21). Among PwH greater than 16 years of age (PwH ≥ 16), OPG is increased with recent factor use (P < .01) but not without (P = .34). Lower levels of TNF-α (P < .01), interleukin (IL)-12 (P < .01) and IL-10 (P < .001) were found among samples from PwH. Controlling for subject age, IL-12 and IL-10 levels are lower in PwH ≥ 16 (P < .01, P < .001) but not PwH under 16 (PwH < 16) (P > .05). Levels of TNF-α were lower among PwH < 16 only (P < .05). These differences are not observed in participants with recent factor use. CONCLUSIONS: In PwH, markers of bone metabolism and circulating cytokine levels are abnormal. Recent factor use reverses many of these differences suggesting FVIII replacement ameliorates this pathology. This study suggests bone disease present in PwH is intrinsic to FVIII deficiency.
Assuntos
Doenças Ósseas , Hemofilia A , Adolescente , Biomarcadores , Osso e Ossos , Citocinas , Hemofilia A/complicações , HumanosAssuntos
Necessidades e Demandas de Serviços de Saúde/tendências , Mielofibrose Primária/epidemiologia , Pirazóis/uso terapêutico , Pirrolidinas/uso terapêutico , Sulfonamidas/uso terapêutico , Trombocitopenia/epidemiologia , Plaquetas/efeitos dos fármacos , Plaquetas/enzimologia , Plaquetas/patologia , Europa (Continente)/epidemiologia , Expressão Gênica , Humanos , Janus Quinase 2/antagonistas & inibidores , Janus Quinase 2/genética , Janus Quinase 2/metabolismo , Nitrilas , Médicos , Prevalência , Mielofibrose Primária/diagnóstico , Mielofibrose Primária/tratamento farmacológico , Mielofibrose Primária/patologia , Pirimidinas , Índice de Gravidade de Doença , Inquéritos e Questionários , Trombocitopenia/diagnóstico , Trombocitopenia/tratamento farmacológico , Trombocitopenia/patologia , Estados Unidos/epidemiologiaRESUMO
Introduction: Prophylaxis with factor replacement therapy is the gold standard for the treatment of hemophilia, but this often requires frequent infusions. A number of long-acting factor products have been developed to reduce the burden on patients. Areas covered: This is an overview of information presented at two symposia held at the World Federation of Hemophilia and International Society on Thrombosis and Haemostasis - Scientific and Standardization Committee annual meetings. The pharmacokinetic, safety and efficacy data for long-acting recombinant products are reviewed, with a focus on recombinant factor IX albumin fusion protein (rIX-FP) and rVIII-SingleChain. This overview also provides a guide for managing a patient's switch to long-acting products. Expert opinion: Long-acting products may allow patients to maintain or decrease bleeding rates whilst increasing their dosing interval, which may in turn reduce the burden on patients and caregivers. When switching patients to long-acting products health-care professionals should provide balanced and thorough education to the patient, whilst supporting their emotional well-being. Regimens should address patients' needs and goals but should also be guided by clinical phenotype and pharmacokinetic assessment. Follow-up should assess safety concerns, bleeding rates, joint health and the impact of the regimen on patients' lifestyle.
Assuntos
Fator IX/uso terapêutico , Fator VIII/uso terapêutico , Hemofilia A/tratamento farmacológico , Hemofilia B/tratamento farmacológico , Gerenciamento Clínico , Fator IX/administração & dosagem , Fator IX/farmacocinética , Fator VIII/administração & dosagem , Fator VIII/farmacocinética , Hemorragia/prevenção & controle , Humanos , Proteínas Recombinantes/administração & dosagem , Proteínas Recombinantes/farmacocinética , Proteínas Recombinantes/uso terapêuticoAssuntos
Deficiência do Fator XI/cirurgia , Procedimentos Cirúrgicos Torácicos , Idoso , Idoso de 80 Anos ou mais , Valva Aórtica/cirurgia , Criança , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Período Perioperatório , Hemorragia Pós-Operatória/etiologia , Procedimentos Cirúrgicos Torácicos/efeitos adversosRESUMO
Thrombotic thrombocytopenia purpura (TTP) and the hemolytic uremic syndrome (HUS) are rare thrombotic microangiopathies that can be rapidly fatal. Although the acquired versions of TTP and HUS are generally highest on this broad differential, multiple rarer entities can produce a clinical picture similar to TTP/HUS, including microangiopathic hemolysis, renal failure, and neurologic compromise. More recent analysis has discovered a host of genetic factors that can produce microangiopathic hemolytic syndromes. This article discusses the current understanding of thrombotic microangiopathy and outlines the pathophysiology and causative agents associated with each distinct syndrome as well as the most accepted treatments.
Assuntos
Síndrome Hemolítico-Urêmica/fisiopatologia , Púrpura Trombocitopênica Trombótica/fisiopatologia , Microangiopatias Trombóticas/fisiopatologia , Proteína ADAMTS13/metabolismo , Adjuvantes Imunológicos/uso terapêutico , Anticorpos Monoclonais Humanizados/uso terapêutico , Síndrome Hemolítico-Urêmica/terapia , Humanos , Imunossupressores/uso terapêutico , Púrpura Trombocitopênica Trombótica/terapia , Microangiopatias Trombóticas/etiologia , Microangiopatias Trombóticas/genética , Microangiopatias Trombóticas/terapiaRESUMO
In this issue of Blood, Santagostino et al, in their phase 3 study, demonstrate efficacy and safety of recombinant fusion protein linking coagulation factor IX (FIX) with albumin (rIX-FP) which, along with the other 2 extended half-life FIX products, heralds a new era for the treatment of hemophilia B.
Assuntos
Albuminas/administração & dosagem , Albuminas/farmacocinética , Fator IX/administração & dosagem , Fator IX/farmacocinética , Hemofilia B/sangue , Hemofilia B/prevenção & controle , Humanos , MasculinoRESUMO
A major hurdle for hematopoietic stem cell (HSC) gene therapy for inherited bone marrow disorders, including Fanconi anemia (FA), is adequate engraftment of gene-modified cells. A phenotypic defect in DNA repair renders FA patients sensitive to alkylating agents such as cyclophosphamide (Cy); however, at lower doses, Cy is well tolerated in the FA transplant setting. We tested whether non-alkylating agents could replace Cy for pretransplant conditioning to enhance engraftment of FANCA gene-modified hematopoietic cells. We compared Cy preconditioning with fludarabine (Flu) or cytarabine (AraC) or no conditioning as a control in fanca ( -/- ) mutant mice receiving gene-modified bone marrow cells. Only mice conditioned with Cy exhibited appreciable engraftment of gene-modified cells by PCR and resistance to mitomycin C (MMC). Cy administration following transplantation increased gene marking levels in all animals treated, but highest gene marking and corresponding MMC resistance were observed in mice receiving Cy pre- and posttransplantation. Importantly, no cytogenetic abnormalities were observed in Cy-treated mice. We conclude that Cy is an effective and superior preparative regimen with respect to engraftment of lentivirus-transduced cells and functional correction in fanca ( -/- ) mice. Thus, appropriately dosed Cy may provide a suitable conditioning regimen for FA patients undergoing HSC gene therapy.
Assuntos
Ciclofosfamida/farmacologia , Anemia de Fanconi/genética , Condicionamento Pré-Transplante/métodos , Animais , Células da Medula Óssea , Citogenética , Modelos Animais de Doenças , Anemia de Fanconi/terapia , Citometria de Fluxo/métodos , Terapia Genética/métodos , Células HEK293 , Transplante de Células-Tronco Hematopoéticas/métodos , Humanos , Lentivirus/genética , Metilcelulose/química , Camundongos , Camundongos Transgênicos , Mitomicina/farmacologia , Agonistas Mieloablativos/farmacologia , Reação em Cadeia da Polimerase/métodosAssuntos
Modelos Animais de Doenças , Hemofilia A/patologia , Animais , Densidade Óssea , Humanos , Masculino , Camundongos , Camundongos KnockoutRESUMO
Gene therapy has the potential to control human immunodeficiency virus (HIV) in patients who do not respond to traditional antiviral therapy. In this study, we tested foamy virus (FV) vectors expressing three anti-HIV transgenes, both individually and in a combination vector. The transgenes tested in this study are RevM10, a dominant negative version of the viral rev protein, Sh1, a short hairpin RNA directed against a conserved overlapping sequence of tat and rev, and membrane-associated C46 (maC46), a membrane-attached peptide that blocks HIV cell entry. FV vectors efficiently transduce hematopoietic stem cells and, unlike lentivirus (LV) vectors, do not share viral proteins with HIV. The titers of the FV vectors described in this study were not affected by anti-HIV transgenes. On a direct comparison of FV vectors expressing the individual transgenes, entry inhibition using the maC46 transgene was found to be the most effective at blocking HIV replication. A clinically relevant FV vector expressing three anti-HIV transgenes effectively blocked HIV infection in primary macrophages derived from transduced, peripheral blood CD34-selected cells and in a cell line used for propagating HIV, CEMx174. These results suggest that there are potential benefits of using FV vectors in HIV gene therapy.