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1.
Bull Hosp Jt Dis (2013) ; 82(2): 124-133, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38739660

RESUMO

Postoperative venous thromboembolism (VTE) is a common and costly complication following total joint arthroplasty (TJA). Development of a refined thrombophilic screening panel will better equip clinicians to identify patients at high-est risk for developing VTEs. In this pilot study, 62 high-risk TJA recipients who had developed pulmonary emboli (PE) within 90-days of surgery were eligible to participate. Of these patients, 14 were enrolled and subsequently adminis-tered a pre-determined panel of 18 hematologic tests with the aim of identifying markers that are consistently elevated or deficient in patients developing PE. A separate cohort of seven high-risk TJA recipients who did not report a symp-tomatic VTE within 90-days of surgery were then enrolled and Factor VIII and lipoprotein(a) levels were assessed. The most common aberrance was noted in 10 patients (71.4%) who had elevated levels of Factor VIII followed by five patients (35.7%) who had elevated levels of lipoprotein(a). Factor VIII was significantly prevalent (p < 0.001) while lipoprotein(a) failed to achieve statistical significance (p = 0.0708). Of the patients who were within normal limits of Factor VIII, three-fourths were "high-normal" with Fac-tor VIII levels within 5% of the upper limit of normal. This study demonstrates the potential utility of this hematologic panel as part of a perioperative screening protocol aimed at identifying patients at risk for developing VTEs. However, future larger scale studies assessing the capabilities and limitations of our findings are warranted.


Assuntos
Embolia Pulmonar , Humanos , Projetos Piloto , Embolia Pulmonar/sangue , Embolia Pulmonar/etiologia , Embolia Pulmonar/diagnóstico , Feminino , Masculino , Pessoa de Meia-Idade , Idoso , Fatores de Risco , Medição de Risco/métodos , Valor Preditivo dos Testes , Complicações Pós-Operatórias/etiologia , Complicações Pós-Operatórias/diagnóstico , Complicações Pós-Operatórias/sangue , Fator VIII/análise , Biomarcadores/sangue , Lipoproteína(a)/sangue , Artroplastia de Substituição/efeitos adversos , Tromboembolia Venosa/etiologia , Tromboembolia Venosa/diagnóstico , Tromboembolia Venosa/sangue , Tromboembolia Venosa/epidemiologia
2.
Surg Infect (Larchmt) ; 25(4): 291-299, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38700750

RESUMO

Background: Packed red blood cell (PRBC) transfusion has been shown to increase nosocomial infection risk in the injured population; however, the post-traumatic infectious risk profiles of non-PRBC blood products are less clear. We hypothesized that plasma (fresh frozen plasma [FFP]), platelet (PLT), and cryoprecipitate administration would not be associated with increased rates of nosocomial infections. Patients and Methods: We performed a retrospective, matched, case-control study utilizing the American College of Surgeons National Trauma Data Bank data for 2019. We included all patients who received any volume of PRBC within four hours of presentation. Our outcome of interest was any infection. Controls were matched to cases using individual matching with a desired 1:3 case:control ratio. Bivariable analysis according to infection status, and multivariable logistic regression modeling the development of infection were then performed upon the matched data. Results: A total of 1,563 infectious cases were matched to 3,920 non-infectious controls. First four-hour transfusion volumes for FFP, PLT, and cryoprecipitate in the infection group exceeded those in the control group. The first four-hour FFP transfusion volume (per unit odds ratio [OR], 1.02; 95% confidence interval [CI], 0.99-1.04; p = 0.28) and cryoprecipitate transfusion volume (per unit OR, 1.01; 95% CI, 0.99-1.02; p = 0.43) were similar in cases and controls whereas PLT transfusion volume (per unit OR, 0.92; 95% CI, 0.86-0.98; p = 0.01) was lower in cases of infection than in controls. Conclusions: Fresh frozen plasma, PLT, and cryoprecipitate transfusion volumes were not independent risk factors for the development of nosocomial infection in a trauma population. PLT transfusion volume was associated with less infection.


Assuntos
Plasma , Ferimentos e Lesões , Humanos , Estudos Retrospectivos , Masculino , Feminino , Adulto , Ferimentos e Lesões/complicações , Ferimentos e Lesões/terapia , Ferimentos e Lesões/epidemiologia , Pessoa de Meia-Idade , Estudos de Casos e Controles , Fibrinogênio/análise , Infecção Hospitalar/epidemiologia , Fator VIII , Transfusão de Componentes Sanguíneos/estatística & dados numéricos , Transfusão de Componentes Sanguíneos/efeitos adversos , Idoso , Bases de Dados Factuais , Adulto Jovem
4.
Expert Rev Hematol ; 17(6): 233-240, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38708599

RESUMO

INTRODUCTION: Acquired hemophilia A (AHA) is a rare hemorrhagic autoimmune disorder characterized by autoantibodies against coagulation factor VIII (FVIII). In approximately half of the cases AHA does not recognize any cause (idiopathic form), while in the other cases it may be triggered by autoimmune disorders, cancers, drugs, infections, or pregnancy. Besides treating the underlying disorder, specific AHA treatment includes management of bleeding, if necessary, and inhibitor eradication. AREAS COVERED: This narrative review summarizes the main epidemiological, clinical, laboratory, and therapeutic characteristics of AHA. In particular, it is focused on the current therapeutic options for the inhibitor eradication, also showing the latest findings on the innovative therapies. A literature search strategy was performed, without temporal limits, through Medline and PubMed electronic databases. EXPERT OPINION: Various first-line and second-line immunosuppressive agents are currently available for the management of AHA. Among the latter, the anti-CD20 monoclonal antibody rituximab has been the object of intense research during the last years from investigators as innovative promising eradicating therapy for AHA. Preliminary data from the studies support the use of this drug as a first-line option for newly diagnosed AHA cases.


Assuntos
Fator VIII , Hemofilia A , Imunossupressores , Humanos , Hemofilia A/tratamento farmacológico , Hemofilia A/terapia , Hemofilia A/imunologia , Fator VIII/uso terapêutico , Fator VIII/imunologia , Imunossupressores/uso terapêutico , Autoanticorpos/imunologia , Rituximab/uso terapêutico , Gerenciamento Clínico
5.
Adv Emerg Nurs J ; 46(2): 101-107, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38736094

RESUMO

Patients who develop an intracerebral hemorrhage (ICH) following thrombolysis in acute ischemic stroke (AIS) have a mortality rate as high as 50%. Treatment options include blood products, such as cryoprecipitate, or antifibrinolytics, such as tranexamic acid (TXA) or ε-aminocaproic acid (EACA). Current guidelines recommend cryoprecipitate first-line despite limited data to support one agent over another. In addition, compared to antifibrinolytics, cryoprecipitate is higher in cost and requires thawing before use. This case series seeks to characterize the management of thrombolytic reversal at a single institution as well as provide additional evidence for antifibrinolytics in this setting. Patients were included for a retrospective review if they met the following criteria: presented between January 2011-January 2017, were >18 years of age, were admitted for AIS, received a thrombolytic, and received TXA EACA, or cryoprecipitate. Twelve patients met the inclusion criteria. Ten (83.3%) developed an ICH, one (8.3%) experienced gastrointestinal bleeding, and one (8.3%) had bleeding at the site of knee arthroscopy. Eleven patients received cryoprecipitate (median dose: 10 units), three received TXA (median dose: 1,000 mg), and one patient received EACA (13 g). TXA was administered faster than the first blood product at a mean time of 19 min and 137 min, respectively. Hemorrhagic expansion (N = 8, 66.67%) and inhospital mortality (N = 7, 58.3%) were high. While limited by its small sample size, this case series demonstrates significant variability in reversal strategies for thrombolysis-associated bleeding. It also provides additional evidence for the role of antifibrinolytics in this setting.


Assuntos
Antifibrinolíticos , Fibrinogênio , AVC Isquêmico , Ácido Tranexâmico , Humanos , Antifibrinolíticos/uso terapêutico , Antifibrinolíticos/administração & dosagem , Estudos Retrospectivos , Masculino , Feminino , AVC Isquêmico/tratamento farmacológico , Fibrinogênio/uso terapêutico , Idoso , Ácido Tranexâmico/uso terapêutico , Ácido Tranexâmico/administração & dosagem , Terapia Trombolítica , Pessoa de Meia-Idade , Fator VIII/uso terapêutico , Ácido Aminocaproico/uso terapêutico , Idoso de 80 Anos ou mais , Hemorragia Cerebral/tratamento farmacológico
6.
Thromb Res ; 238: 185-196, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38729030

RESUMO

BACKGROUND: Plaque erosion, a type of coronary atherothrombosis, involves superficial injury to smooth muscle cell (SMC)-rich plaques. Elevated levels of coagulation factor VIII (FVIII) correlate with an increased ischemic heart disease risk. FVIII may contribute to thrombus formation on eroded plaques. AIMS: We aimed to elucidate the role of elevated FVIII in arterial thrombus formation within SMC-rich neointima in rabbits. METHODS AND RESULTS: We assessed the effect of recombinant human FVIII (rFVIII) on blood coagulation in vitro and platelet aggregation ex vivo. An SMC-rich neointima was induced through balloon injury to the unilateral femoral artery. Three weeks after the first balloon injury, superficial erosive injury and thrombus formation were initiated with a second balloon injury of the bilateral femoral arteries 45 min after the administration of rFVIII (100 IU/kg) or saline. The thrombus area and contents were histologically measured 15 min after the second balloon injury. rFVIII administration reduced the activated partial thromboplastin time and augmented botrocetin-induced, but not collagen- or adenosine 5'-diphosphate-induced, platelet aggregation. While rFVIII did not influence platelet-thrombus formation in normal intima, it increased thrombus formation on SMC-rich neointima post-superficial erosive injury. Enhanced immunopositivity for glycoprotein IIb/IIIa and fibrin was observed in rFVIII-administered SMC-rich neointima. Neutrophil count in the arterial thrombus on the SMC-rich neointima correlated positively with thrombus size in the control group, unlike the rFVIII group. CONCLUSIONS: Increased FVIII contributes to thrombus propagation within erosive SMC-rich neointima, highlighting FVIII's potential role in plaque erosion-related atherothrombosis.


Assuntos
Fator VIII , Miócitos de Músculo Liso , Neointima , Trombose , Coelhos , Animais , Neointima/patologia , Neointima/sangue , Trombose/sangue , Trombose/patologia , Masculino , Miócitos de Músculo Liso/patologia , Miócitos de Músculo Liso/efeitos dos fármacos , Túnica Íntima/patologia , Túnica Íntima/efeitos dos fármacos , Humanos , Agregação Plaquetária/efeitos dos fármacos , Artéria Femoral/patologia , Artéria Femoral/lesões
7.
Int J Mol Sci ; 25(7)2024 Mar 24.
Artigo em Inglês | MEDLINE | ID: mdl-38612447

RESUMO

Hemophilia A (HA) is a common X-linked recessive hereditary bleeding disorder. Coagulation factor VIII (FVIII) is insufficient in patients with HA due to the mutations in the F8 gene. The restoration of plasma levels of FVIII via both recombinant B-domain-deleted FVIII (BDD-FVIII) and B-domain-deleted F8 (BDDF8) transgenes was proven to be helpful. FVIII-Padua is a 23.4 kb tandem repeat mutation in the F8 associated with a high F8 gene expression and thrombogenesis. Here we screened a core enhancer element in FVIII-Padua for improving the F8 expression. In detail, we identified a 400 bp efficient enhancer element, C400, in FVIII-Padua for the first time. The core enhancer C400 extensively improved the transcription of BDDF8 driven by human elongation factor-1 alpha in HepG2, HeLa, HEK-293T and induced pluripotent stem cells (iPSCs) with different genetic backgrounds, as well as iPSCs-derived endothelial progenitor cells (iEPCs) and iPSCs-derived mesenchymal stem cells (iMSCs). The expression of FVIII protein was increased by C400, especially in iEPCs. Our research provides a novel molecular target to enhance expression of FVIII protein, which has scientific value and application prospects in both viral and nonviral HA gene therapy strategies.


Assuntos
Hemofilia A , Hemostáticos , Humanos , Fator VIII/genética , Hemofilia A/genética , Hemofilia A/terapia , Terapia Genética , Elementos Facilitadores Genéticos
8.
Thromb Res ; 237: 196-202, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38640641

RESUMO

INTRODUCTION: The most notable challenge facing hemophilia A treatment is the development of inhibitors against factor VIII, resulting in increased clinical and socioeconomic burdens due to the need for expensive bypassing agents (BPAs). Although immune tolerance induction (ITI) is currently the primary approach for inhibiting and reducing the inhibitors, the lengthy duration of ITI necessitates the continued use of BPA to manage bleeding episodes. In this study, we aimed to obtain real-world evidence on the clinical and economic aspects and associated burdens experienced by patients with hemophilia A with inhibitors undergoing ITI in Korea. METHODS: Claims data from January 1, 2007, to December 31, 2020, were used in this study. The study cohort comprised patients with hemophilia A undergoing ITI, who were categorized into three groups: successful, failed, or continuation of ITI. We evaluated clinical and economic burdens, including monthly healthcare visits, medication costs, and total medical expenses. RESULTS: The study involved 33 cases of ITI across 32 patients. Excluding seven continuation cases where success could not be determined at the observation point, the estimated success rate of ITI was 80.8 %. The median duration of ITI for all patients was 25.7 months. While no significant disparities were noted in the ITI duration between successful and unsuccessful cases (24.51 vs. 25.66 months), substantial discrepancies were observed in the duration of BPA usage (11.10 vs. 25.66 months) and the number of prescribed BPAs (1.79 vs. 2.97). CONCLUSION: Successful ITI reduced both clinical and economic burdens, resulting in decreased monthly medication expenses and overall medical costs.


Assuntos
Hemofilia A , Tolerância Imunológica , Humanos , Hemofilia A/economia , Hemofilia A/imunologia , Hemofilia A/tratamento farmacológico , República da Coreia , Masculino , Criança , Adulto , Adolescente , Pré-Escolar , Fator VIII/uso terapêutico , Fator VIII/imunologia , Fator VIII/economia , Efeitos Psicossociais da Doença , Adulto Jovem , Feminino , Lactente , Custos de Cuidados de Saúde
9.
Haemophilia ; 30 Suppl 3: 70-77, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38575518

RESUMO

Despite rapid technological advancement in factor and nonfactor products in the prevention and treatment of bleeding in haemophilia patients, it is imperative that we acknowledge gaps in our understanding of how hemostasis is achieved. The authors will briefly review three unresolved issues in persons with haemophilia (PwH) focusing on the forgotten function that red blood cells play in hemostasis, the critical role of extravascular (outside circulation) FIX in hemostasis in the context of unmodified and extended half-life FIX products and finally on the role that skeletal muscle myosin plays in prothrombinase assembly and subsequent thrombin generation that could mitigate breakthrough muscle hematomas.


Assuntos
Hemofilia A , Humanos , Hemofilia A/terapia , Hemostasia , Trombina , Hemorragia , Tromboplastina , Fator VIII
11.
Thromb Res ; 237: 184-195, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38631156

RESUMO

BACKGROUND AND AIMS: Blood disorders, such as sickle cell disease, and other clinical conditions are often accompanied by intravascular hemolytic events along with the development of severe coagulopathies. Hemolysis, in turn, leads to the accumulation of Fe(II/III)-protoporphyrin IX (heme) in the intravascular compartment, which can trigger a variety of proinflammatory and prothrombotic reactions. As such, heme binding to the blood coagulation proteins factor VIII (FVIII), fibrinogen, and activated protein C with functional consequences has been demonstrated earlier. METHODS: We herein present an in-depth characterization of the FVIII-heme interaction at the molecular level and its (patho-)physiological relevance through the application of biochemical, biophysical, structural biology, bioinformatic, and diagnostic tools. RESULTS: FVIII has a great heme-binding capacity with seven heme molecules associating with the protein. The respective binding sites were identified by investigating heme binding to FVIII-derived peptides in combination with molecular docking and dynamic simulation studies of the complex as well as cryo-electron microscopy, revealing three high-affinity and four moderate heme-binding motifs (HBMs). Furthermore, the relevance of the FVIII-heme complex formation was characterized in physiologically relevant assay systems, revealing a ~ 50 % inhibition of the FVIII cofactor activity even in the protein-rich environment of blood plasma. CONCLUSION: Our study provides not only novel molecular insights into the FVIII-heme interaction and its physiological relevance, but also strongly suggests the reduction of the intrinsic pathway and the accentuation of the final clotting step (by, for example, fibrinogen crosslinking) in hemolytic conditions as well as a future perspective in the context of FVIII substitution therapy of hemorrhagic events in hemophilia A patients.


Assuntos
Fator VIII , Heme , Humanos , Sítios de Ligação , Coagulação Sanguínea , Fator VIII/metabolismo , Fator VIII/química , Heme/metabolismo , Simulação de Acoplamento Molecular , Ligação Proteica , Relação Estrutura-Atividade
12.
Haemophilia ; 30(3): 638-647, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38578179

RESUMO

AIM: To characterise non-severe haemophilia A (HA) patients enrolled on the Australian Bleeding Disorders Registry (ABDR) treated through a state-wide Haemophilia Treatment Centre (HTC) with respect to their mutational profile, inhibitor risk and health-care burden. METHOD: We conducted a single-centre observational study of all non-severe HA patients treated at the Alfred Health HTC registered on the ABDR as of the 26th July 2023. Data were extracted from the ABDR and electronic medical record (EMR) regarding demographics, severity, genetic testing, treatment, inhibitors, bleeding events and procedures. Inhibitor risk was calculated as a function of exposure days (EDs) of FVIII replacement. RESULTS: There were 289 non-severe HA patients treated at the Alfred HTC registered on the ABDR as of July 2023, all of whom were adult patients aged > 18 years old. Genotyping had been performed in 228/289 (78.9%). Of the inhibitor analysis population, 14/193 (7.3%) had an inhibitor. The cumulative incidence of inhibitor development at 75 EDs was 31% (95% CI 13%-46%). The median cost of bypassing agents per inhibitor patient was $57,087.50/year. CONCLUSION: These results demonstrate a relatively high inhibitor prevalence and incidence risk in non-severe HA compared to previously published work, although this may partly reflect a smaller population size. High rates of genotyping have allowed representative mutational characterisation. The burden of care imposed by non-severe HA in terms of bleeding events, procedures and bypassing agent cost is larger than expected, particularly within the inhibitor population.


Assuntos
Hemofilia A , Mutação , Humanos , Hemofilia A/tratamento farmacológico , Hemofilia A/genética , Austrália , Adulto , Masculino , Pessoa de Meia-Idade , Fator VIII/uso terapêutico , Fator VIII/genética , Feminino , Adulto Jovem , Adolescente , Índice de Gravidade de Doença , Idoso , Custos de Cuidados de Saúde
13.
Haemophilia ; 30(3): 685-692, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38578720

RESUMO

INTRODUCTION: Despite the rapid uptake of emicizumab in the paediatric haemophilia A (HA) population, real-world data on the safety and efficacy is limited. AIM: To report on bleeding and safety in paediatric patients receiving emicizumab prophylaxis. METHODS: Data were extracted from the multicentre prospective observational PedNet Registry (NCT02979119). Children with haemophilia A, and ≥50 FVIII exposures or inhibitors present receiving emicizumab maintenance therapy were analysed. Data were summarized as medians with interquartile range (IQR, P25-P75). Mean (95% confidence interval (CI)), annualized (joint) bleeding rate (A(J)BR) during emicizumab and ≤2 years before emicizumab prophylaxis were modelled and compared using negative binomial regression. RESULTS: Total of 177 patients started emicizumab at median 8.6 years (IQR 4.8-13.1), most had no FVIII inhibitors (64%). Follow up before emicizumab was median: 1.68 years (IQR: 1.24-1.90) and during emicizumab: 1.32 years (IQR: .94-2.11). In patients without inhibitors, mean ABR reduced after starting emicizumab from 2.41 (CI 1.98-2.95) to 1.11 (CI .90-1.36, p < .001), while AJBR reduced from.74 (CI .56-.98) to.31 (CI .21-.46, p < .001). Concordantly, in patients with inhibitors, mean ABR reduced from 5.08 (CI 4.08-6.38) to .75 (CI .56-1.01, p < .001), while AJBR reduced from 1.90 (CI 1.42-2.58) to .34 (CI .21-.56, p < .001). Five emicizumab-related adverse events were reported (3% of the cohort), including one patient with antidrug antibodies. CONCLUSION: This study showed improved bleeding control compared to previous treatment and a favourable safety profile during emicizumab therapy in paediatric haemophilia A patients.


Assuntos
Anticorpos Biespecíficos , Anticorpos Monoclonais Humanizados , Hemofilia A , Hemorragia , Sistema de Registros , Humanos , Criança , Anticorpos Monoclonais Humanizados/uso terapêutico , Anticorpos Biespecíficos/uso terapêutico , Anticorpos Biespecíficos/farmacologia , Hemofilia A/tratamento farmacológico , Masculino , Feminino , Adolescente , Pré-Escolar , Estudos Prospectivos , Fator VIII/uso terapêutico
15.
Haemophilia ; 30(3): 678-684, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38575526

RESUMO

INTRODUCTION: Tailored prophylaxis is the current treatment regimen for patients with severe haemophilia A. Recently, published guidelines describe two possible approaches, based on clinical characteristics or estimation of pharmacokinetic parameters. However, both have strengths and weaknesses, and their characteristics need to be integrated to optimize treatment appropriately. In this paper, we present a model that considers together the characteristics of prophylaxis and the relevance of each. METHODS: The age at initiation of prophylaxis, number of bleeding events, treatment regimen, therapeutic adherence, FVIII trough levels, and joint status were analyzed in 59 patients followed at La Paz University Hospital between January 2000 and December 2019. RESULTS: The mean duration of primary prophylaxis of 113.37 ± 57.79 months. Eighty-three percent (n = 49) had no joint status involvement at the end of follow-up (HJHS and HEAD-US = 0). The median ABR was 0.7 (IQR 0.2 -1.0) and 54.2% presented trough levels of FVIII during follow-up >1 IU/dL. 72,9% engaged in some type of physical activity and overall adherence was over 85% in all patients evaluated. The regression analysis performed, considering all these factors, showed that the initiation of prophylaxis before 21 months of age was the most relevant protective factor against the appearance of joint involvement (OR 88.33 p.031 CI 95% 1.49-5224.40) CONCLUSION: Early initiation of prophylaxis was the most relevant factor in the protection of joint status. More comprehensive analysis models adapted to the characteristics of each population, are needed to adequately individualize treatment.


Assuntos
Hemofilia A , Humanos , Hemofilia A/tratamento farmacológico , Masculino , Pré-Escolar , Criança , Lactente , Fator VIII/uso terapêutico , Hemartrose/prevenção & controle , Hemartrose/etiologia , Adolescente , Feminino , Adulto
16.
Haemophilia ; 30(3): 671-677, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38575549

RESUMO

INTRODUCTION: Primary prophylaxis is the gold standard in severe haemophilia A (SHA) but time to escalate the prophylaxis regimen varies. AIM: Assess prophylaxis implementation and long-term joint health outcomes in SHA with primary prophylaxis. METHODS: Adult male patients born after 1980, with SHA on primary prophylaxis, started before the age of 3 years and second joint bleed, and no history of FVIII inhibitors, were enrolled. Repeated joint-health examinations were performed with HJHS or HEAD-US; VERITAS-PRO assessed adherence. RESULTS: Thirty patients were enrolled with, at inclusion, median age 33.5 years, annualized bleed rate and joint bleed rate 0, and FVIII consumption 4232 IU/kg/year, respectively. The median age was 1.2 years, at prophylaxis start once weekly with a median FVIII dose of 47.7 IU/kg, and 1.7 years, by the time escalation to a final regimen had occurred, with a median infusion frequency of thrice weekly and FVIII dose 41.7 IU/kg, respectively. Older age correlated with later transition to escalated prophylaxis (p < .001). Longer time to escalated prophylaxis correlated to more bleeds (p < .001). Median HJHS increased slowly, reaching 4 at 35-40 years. HJHS at 15-20 years correlated with higher HJHS afterwards. Median total HEAD-US score was 1 and correlated with HJHS (p < .001). Median VERITAS-PRO score was 36, indicating good treatment adherence. CONCLUSION: Primary prophylaxis is effective but does not completely prevent the gradual development of arthropathy in SHA. Joint assessments with HJHS should start at an early age, as they correlate with arthropathy in later life. Prophylaxis escalation should proceed expeditiously to prevent bleeds.


Assuntos
Hemofilia A , Humanos , Hemofilia A/tratamento farmacológico , Hemofilia A/complicações , Masculino , Adulto , Suécia , Fator VIII/uso terapêutico , Fator VIII/administração & dosagem , Hemartrose/prevenção & controle , Hemartrose/etiologia , Resultado do Tratamento , Pré-Escolar , Adulto Jovem , Lactente , Pessoa de Meia-Idade , Hemorragia/prevenção & controle , Adolescente
18.
Front Immunol ; 15: 1341013, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38655263

RESUMO

Recombinant Factor VIII-Fc fusion protein (rFVIIIFc) is an enhanced half-life therapeutic protein product used for the management of hemophilia A. Recent studies have demonstrated that rFVIIIFc interacts with Fc gamma receptors (FcγR) resulting in the activation or inhibition of various FcγR-expressing immune cells. We previously demonstrated that rFVIIIFc, unlike recombinant Factor IX-Fc (rFIXFc), activates natural killer (NK) cells via Fc-mediated interactions with FcγRIIIA (CD16). Additionally, we showed that rFVIIIFc activated CD16+ NK cells to lyse a FVIII-specific B cell clone. Here, we used human NK cell lines and primary NK cells enriched from peripheral blood leukocytes to study the role of the FVIII moiety in rFVIIIFc-mediated NK cell activation. Following overnight incubation of NK cells with rFVIIIFc, cellular activation was assessed by measuring secretion of the inflammatory cytokine IFNγ by ELISA or by cellular degranulation. We show that anti-FVIII, anti-Fc, and anti-CD16 all inhibited indicating that these molecules were involved in rFVIIIFc-mediated NK cell activation. To define which domains of FVIII were involved, we used antibodies that are FVIII domain-specific and demonstrated that blocking FVIII C1 or C2 domain-mediated membrane binding potently inhibited rFVIIIFc-mediated CD16+ NK cell activation, while targeting the FVIII heavy chain domains did not. We also show that rFVIIIFc binds CD16 with about five-fold higher affinity than rFIXFc. Based on our results we propose that FVIII light chain-mediated membrane binding results in tethering of the fusion protein to the cell surface, and this, together with increased binding affinity for CD16, allows for Fc-CD16 interactions to proceed, resulting in NK cellular activation. Our working model may explain our previous results where we observed that rFVIIIFc activated NK cells via CD16, whereas rFIXFc did not despite having identical IgG1 Fc domains.


Assuntos
Fator VIII , Proteínas Ligadas por GPI , Fragmentos Fc das Imunoglobulinas , Células Matadoras Naturais , Ativação Linfocitária , Receptores de IgG , Proteínas Recombinantes de Fusão , Humanos , Degranulação Celular/imunologia , Fator VIII/química , Fator VIII/imunologia , Proteínas Ligadas por GPI/imunologia , Proteínas Ligadas por GPI/metabolismo , Hemofilia A/imunologia , Hemofilia A/tratamento farmacológico , Fragmentos Fc das Imunoglobulinas/imunologia , Interferon gama/metabolismo , Células Matadoras Naturais/imunologia , Células Matadoras Naturais/metabolismo , Ativação Linfocitária/imunologia , Ativação Linfocitária/efeitos dos fármacos , Ligação Proteica , Receptores de IgG/metabolismo , Receptores de IgG/imunologia
19.
Blood Adv ; 8(11): 2726-2739, 2024 Jun 11.
Artigo em Inglês | MEDLINE | ID: mdl-38564770

RESUMO

ABSTRACT: Rurioctocog alfa pegol is an extended-half-life full-length recombinant factor VIII (FVIII) bound to 20-kDa polyethylene glycol (PEG) that has been shown to be well tolerated and efficacious in the treatment and prevention of bleeding events in previously treated patients with severe hemophilia A. Here, we present a comprehensive analysis of immunogenicity data collected during 6 clinical studies of rurioctocog alfa pegol, including a total of 360 unique previously treated patients with severe hemophilia A. The analysis included treatment-emerging FVIII-neutralizing antibodies (FVIII inhibitors); preexisting and treatment-emerging antibodies binding to FVIII, PEG-FVIII, or PEG; and treatment-emerging antibodies binding to Chinese hamster ovary host cell proteins. Moreover, the potential association between the presence of these binding antibodies and adverse events (AEs) observed in patients was investigated, and the potential impact of these antibodies on the incremental recovery of rurioctocog alfa pegol in patients was analyzed. Overall, the data indicate that rurioctocog alfa pegol is not associated with any unexpected immunogenicity characteristics. Of 360 patients, 1 patient developed a transient FVIII inhibitor with a titer of 0.6 Bethesda units per mL, which was not associated with any serious AEs. Antibodies binding to FVIII, PEG-FVIII, or PEG were not detected at the time when the inhibitor was present. Moreover, 54 of 360 patients either entered the clinical studies with preexisting binding antibodies or developed these antibodies after exposure to rurioctocog alfa pegol. These antibodies were transient in most patients and did not show any causal relationship to either AEs or spontaneous bleeding episodes.


Assuntos
Fator VIII , Hemofilia A , Polietilenoglicóis , Humanos , Fator VIII/imunologia , Fator VIII/uso terapêutico , Fator VIII/efeitos adversos , Hemofilia A/tratamento farmacológico , Hemofilia A/imunologia , Hemofilia A/sangue , Polietilenoglicóis/uso terapêutico , Masculino , Anticorpos Neutralizantes/imunologia , Adulto , Adolescente , Animais , Proteínas Recombinantes/uso terapêutico , Proteínas Recombinantes/imunologia , Criança , Adulto Jovem
20.
Adv Ther ; 41(6): 2267-2281, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38616241

RESUMO

INTRODUCTION: A prospective, non-interventional study (270-902) followed 294 adults with severe hemophilia A (SHA) receiving prophylactic factor VIII (FVIII). From these participants, 112 rolled over into a single-arm, multicenter, phase 3 trial (GENEr8-1; NCT03370913) that evaluated efficacy and safety of valoctocogene roxaparvovec, a gene therapy that provides endogenous FVIII in individuals with SHA. Participants from 270-902 who did not roll over provide an opportunity for a contemporaneous external control. Therefore, the comparative effectiveness of valoctocogene roxaparvovec vs FVIII prophylaxis was evaluated using propensity scoring (PS). METHODS: This post hoc analysis compared 112 participants from GENEr8-1 (treated cohort) to 73 participants in 270-902 who did not enroll in GENEr8-1 (control cohort). The primary analysis used standardized mortality ratio weighting to re-weight baseline characteristics of the control cohort to better match the treated cohort. Mean annualized bleeding rates (ABR) for treated and all bleeds were compared between cohorts along with the proportion of participants with zero bleeds (treated and all bleeds). Sensitivity and scenario analyses were also conducted. RESULTS: PS adjustments reduced differences in baseline characteristics between cohorts. Mean treated (4.40 vs 0.85; P < 0.001) and all (5.01 vs 1.54; P < 0.001) ABR were significantly lower, and the proportions of participants with zero treated bleeds (82.1% vs 32.9%; P < 0.001) and all bleeds (58.0% vs 28.5%; P < 0.001) were significantly higher in GENEr8-1. CONCLUSIONS: PS-adjusted analyses were consistent with prior intra-individual comparisons. Compared with participants receiving prophylactic FVIII, the participants receiving valoctocogene roxaparvovec experienced lower ABR, and a higher proportion had zero bleeds. TRAIL REGISTRATION: ClinicalTrials.gov identifier, NCT03370913.


Hemophilia A is a bleeding disorder where blood is unable to clot properly because of a missing protein called factor VIII (FVIII). Individuals with hemophilia A have an increased risk of prolonged bleeding episodes that can be deadly. To prevent bleeding, people with severe hemophilia A need to routinely inject treatment into the skin or vein (prophylaxis). While effective, some people find the time and effort needed to maintain frequent injections difficult, since some forms of the prophylaxis must be administered in a hospital setting. Valoctocogene roxaparvovec is a gene therapy where a single injection provides instructions to the liver of individuals with hemophilia A to make the missing protein (FVIII). Then, their own liver cells can produce FVIII protein and prevent bleeding episodes. The valoctocogene roxaparvovec clinical trial compared the number of treated bleeding episodes participants had prior to gene therapy, while using prophylaxis, with the number of treated bleeding episodes after gene therapy. On average, after gene therapy, participants had 4.1 fewer treated bleeding episodes per year. In this study, mathematical models were used to explore how differences in participant's physical characteristics, such as body weight or medical history, might influence the effectiveness of gene therapy. Even when considering differences in the participants' physical characteristics, the gene therapy reduced treated bleeding episodes by 3.6 events per year. This study confirms results originally presented from the valoctocogene roxaparvovec clinical trial and reinforces confidence in the ability of valoctocogene roxaparvovec to reduce bleeding outcomes for participants with hemophilia A.


Assuntos
Fator VIII , Hemofilia A , Humanos , Hemofilia A/tratamento farmacológico , Hemofilia A/complicações , Fator VIII/uso terapêutico , Masculino , Adulto , Estudos Prospectivos , Feminino , Pessoa de Meia-Idade , Hemorragia/prevenção & controle , Terapia Genética/métodos , Resultado do Tratamento , Adulto Jovem
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