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1.
Journal of Experimental Hematology ; (6): 1791-1796, 2023.
Article in Chinese | WPRIM | ID: wpr-1010039

ABSTRACT

OBJECTIVE@#To analyze the results of activated partial thromboplastin time (APTT) mixing test in coagulation factor Ⅷ inhibitor-positive hemophilia patients, so as to increase the value of APTT mixing test in the screen of factor Ⅷ inhibitor.@*METHODS@#Eighty plasmas samples with different titers of coagulation factor Ⅷ inhibitors had been collected and diluted for routine immediate APTT mixing test and at 37 ℃ 2 hours incubation APTT mixing test. Fifteen samples were selected for immediate and normal temperature incubation for 15 min, 30min, 1 hour, 2 hours and 37 ℃ for 30 min, 1 hour, 2 hours APTT mixing test.@*RESULTS@#The results of APTT mixing test were significantly correlated with the titers of coagulation factor Ⅷ inhibitors. The ROC curve result showed that the best diagnostic cut-off value for 2 hours incubation APTT mixing test at 37 ℃ to determine the presence or absence of coagulation factor Ⅷ inhibitors was 43.8 s (sensitivity and specificity was 85.90% and 100%, respectively), while the best diagnostic cut-off value for distinguishing high-titer and low-titer Ⅷ inhibitors was 52.4 s (sensitivity and specificity was 98.18% and 95.65%, respectively). The critical coagulation factor Ⅷ inhibitor titer that could not be corrected by immediate APTT was 5.14 BU/ml, while that could not be corrected by 37 ℃ 2 hours incubation APTT was 1.31 BU/ml. Paired samples t -test was performed on the APTT mixing test results at different times and temperatures, and the differences were statistically significant (P < 0.05).@*CONCLUSIONS@#The APTT mixing test can be used as a screening index for coagulation factor Ⅷ inhibitors. APTT mixing test result shows a significant time-temperature dependence with lower titers of coagulation factor Ⅷ inhibitor. Patients with hemophilia who cannot be corrected by immediate APTT mixing test should be alert to the possibility of high titer of coagulation factor Ⅷ.


Subject(s)
Humans , Factor VIII , Hemophilia A/diagnosis , Blood Coagulation Tests/methods , Partial Thromboplastin Time , Blood Coagulation Factors
2.
Journal of Experimental Hematology ; (6): 1787-1790, 2023.
Article in Chinese | WPRIM | ID: wpr-1010038

ABSTRACT

OBJECTIVE@#To calculate the pharmacokinetic parameters of recombinant human coagulation factor Ⅷ using myPKFiT in patients with severe hemophilia A, and provide an individualized treatment plan for patients.@*METHODS@#A total of 42 patients with severe hemophilia A who were treated with recombinant human coagulation factor Ⅷ were included from January 2021 to December 2021. myPKFiT was used to calculate the pharmacokinetic parameters of FⅧ, and the individualized treatment plan for hemophilia A patients was formulated.@*RESULTS@#The median age of 42 patients with severe hemophilia A was 31(16-50) years old, the average weight was 54.0±9.9 kg, the half-life of FⅧ was 12.05±1.6 h, the time to more than 1% of the baseline was 62.3±15.3 h, and the 0 bleeding rate after the guidance of myPKFiT was significantly increased from 39% to 49%, the Annual bleeding rate was reduced from 3.6±2.5 to 2.1±2.0, and the Annual joint bleeding rate was reduced from 3.2±2.2 to 1.9±0.9, all of which were statistically different (P<0.05).@*CONCLUSION@#Individualized therapy in patients with severe hemophilia A who were guided by myPKFiT assay of pharmacokinetics parameters can significantly reduce the annual bleeding rate and annual joint bleeding rate of patients.


Subject(s)
Adult , Humans , Middle Aged , Adolescent , Young Adult , Blood Coagulation Factors , Factor VIII/pharmacokinetics , Hemophilia A , Hemorrhage , Recombinant Proteins/pharmacokinetics
3.
Chinese Journal of Hematology ; (12): 38-42, 2023.
Article in Chinese | WPRIM | ID: wpr-969705

ABSTRACT

Objective: To evaluate the clinical effects of low- and intermediate-dose factor Ⅷ (F Ⅷ) prophylaxis in Chinese adult patients with severe hemophilia A. Methods: Thirty adult patients with severe hemophilia A who received low- (n=20) /intermediate-dose (n=10) F Ⅷ prophylaxis at Nanjing Drum Tower Hospital affiliated with Nanjing University Medical College were included in the study. The annual bleeding rate (ABR), annual joint bleeding rate (AJBR), number of target joints, functional independence score of hemophilia (FISH), quality of life score, and health status score (SF-36) before and after preventive treatment were retrospectively analyzed and compared. Results: The median follow-up was 48 months. Compared with on-demand treatment, low- and intermediate-dose prophylaxis significantly reduced ABR, AJBR, and the number of target joints (P<0.05) ; the improvement in the intermediate-dose prophylaxis group was better than that in the low-dose prophylaxis group (P<0.05). Compared with on-demand treatment, the FISH score, quality of life score, and SF-36 score significantly improved in both groups (P<0.05), but there was no significant difference between the two groups (P>0.05) . Conclusion: In Chinese adults with severe hemophilia A, low- and intermediate-dose prophylaxis can significantly reduce bleeding frequency, delay the progression of joint lesions, and improve the quality of life of patients as compared with on-demand treatment. The improvement in clinical bleeding was better with intermediate-dose prophylaxis than low-dose prophylaxis.


Subject(s)
Humans , Hemophilia A/drug therapy , Factor VIII/therapeutic use , Quality of Life , Retrospective Studies , Hemarthrosis/prevention & control , Hemorrhage/drug therapy
4.
Acta Academiae Medicinae Sinicae ; (6): 200-205, 2023.
Article in Chinese | WPRIM | ID: wpr-981253

ABSTRACT

Objective To evaluate the performance of myPKFiT,a tool guiding the dosing of antihemophilic factor (recombinant) plasma/albumin-free method (rAHF-PFM),in maintaining the coagulation factor Ⅷ (FⅧ) level above a target threshold at the steady state and estimating the pharmacokinetics (PK) parameters in hemophilia A patients in China. Methods The data of 9 patients with severe hemophilia A in a trial (CTR20140434) assessing the safety and efficacy of rAHF-PFM in the Chinese patients with hemophilia A were analyzed.The myPKFiT was used to predict the adequate dose to maintain a patient's FⅧ level above target threshold at the steady state.Furthermore,the performance of myPKFiT in estimating the pharmacokinetics parameters of individuals was evaluated. Results Twelve combinations of two dosing intervals and six sparse sampling schedules were investigated,and 57%-88% of the patients remained the FⅧ level above the target threshold of 1 U/dl (1%) for at least 80% of the dosing interval.The clearance and time to FⅧ level of 1% obtained from sparse sampling by myPKFiT were similar to those obtained from extensive sampling. Conclusions The myPKFiT can provide adequate dose estimates to maintain the FⅧ level above the target threshold at the steady state in Chinese patients with severe hemophilia A.Moreover,it demonstrates good performance for estimating key pharmacokinetics parameters,including clearance and time to FⅧ level of 1%.


Subject(s)
Humans , China , East Asian People , Factor VIII/pharmacokinetics , Hemophilia A/drug therapy
5.
Journal of Zhejiang University. Medical sciences ; (6): 473-484, 2023.
Article in English | WPRIM | ID: wpr-1009909

ABSTRACT

OBJECTIVES@#To investigate the role and mechanism of circRNA-SR-related CTD associated factor 8 (SCAF8) in regulating endothelial cell pyroptosis in high glucose environment.@*METHODS@#Human umbilical vein endothelial cells (HUVECs) were cultured and divided into six groups. The normal control group and high glucose control group were cultured in cell culture medium with 5 and 33 mmol/L glucose, respectively. The RNA control group, circRNA-SCAF8 inhibition group, miR-93-5p overexpression group and miR-93-5p inhibition group were added with non-functional siRNA, circRNA-SCAF8 inhibitor, miR-93-5p overexpression molecule and miR-93-5p inhibitor in high glucose environment, respectively. Cell viability and pyroptosis were detected by cell counting kit-8 (CCK-8) assay, flow cytometry and Hoechst 33342/propidium iodide fluorescence double staining. Western blotting and enzyme-linked immunosorbent assay were used to detect the expression of pyroptosis-related factors including apoptosis-associated speck-like protein containing a CARD (ASC), cysteine aspartic acid specific protease-1 (caspase-1) and Gasdermin D (GSDMD), NOD like receptor protein 3 (NLRP-3), thioredoxin interacting proteins (TXNIP), IL-18 and IL-1β. The expression of circRNA-SCAF8, miR-93-5p and TXNIP was detected by quantitative reverse transcription polymerase chain reaction (qRT-PCR). Fluorescence in situ hybridization (FISH) was used to locate circRNA-SCAF8 and miR-93-5p. Dual luciferase assay was used to verify the targeted regulatory relationship between miR-93-5p and upstream and downstream molecules.@*RESULTS@#Compared with the RNA control group, the cell survival rate of circRNA-SCAF8 inhibition group and miR-93-5p overexpression group increased (both P<0.01), the pyroptosis decreased (both P<0.01), and the expressions of pyroptosis-related factors such as TXNIP, NLRP-3, caspase-1, GSDMD, ASC, IL-18 and IL-1β were significantly decreased (all P<0.05). The expression of miR-93-5p was significantly increased after inhibition of circRNA-SCAF8 (P<0.01), and the expression of circRNA-SCAF8 tended to decrease after overexpression of miR-93-5p, but with no statistical significance (P>0.05). Dual luciferase assay showed that miR-93-5p downre-gulated circRNA-SCAF8 expression by binding to the 3 ´ UTR region of circRNA-SCAF8, and miR-93-5p downregulated TXNIP expression by binding to the 3 ´ UTR region of TXNIP. FISH showed that circRNA-SCAF8 and miR-93-5p were both located in the cytoplasm and were highly associated in the cells. qRT-PCR showed that the relative expression of TXNIP increased or decreased after overexpression or inhibition of miR-93-5p compared with the RNA control group, respectively (both P<0.05), suggesting that miR-93-5p could regulate TXNIP gene expression.@*CONCLUSIONS@#CircRNA-SCAF8/miR-93-5p/TXNIP axis is involved in the regulation of pyroptosis in HUVECs under high glucose.


Subject(s)
Humans , Factor VIII , RNA, Circular , Endothelial Cells , Interleukin-18 , Pyroptosis , In Situ Hybridization, Fluorescence , Caspase 1 , MicroRNAs/genetics , Carrier Proteins/genetics , RNA-Binding Proteins
6.
Journal of Central South University(Medical Sciences) ; (12): 789-794, 2023.
Article in English | WPRIM | ID: wpr-982349

ABSTRACT

Systemic lupus erythematosus (SLE) complicated with acquired hemophilia A (AHA) is a rare condition with frequently delayed diagnosis and a high mortality rate, so it is necessary to strengthen the understanding of this disease. In this study, the characteristics and treatment in 1 case of SLE complicated by AHA is reported and analyzed, and a literature review is conducted. The patient was a 29-year-old young female with a 10-year history of SLE, the main clinical manifestation was severe abdominal bleeding. Laboratory tests revealed that the activated partial thromboplastin time (APTT) was notably prolonged (118.20 s), and the coagulation factor VIII activity (FVIII꞉C) was extremely decreased (0.20%) with high-titer of factor VIII (FVIII) inhibitor (31.2 BU/mL). After treating with high-dose glucocorticoid, immunoglobulin, cyclophosphamide, rituximab, blood transfusion, and intravenous infusion of human coagulation FVIII, the coagulation function and coagulation FVIII꞉C were improved, and FVIII inhibitor was negative without serious adverse reactions. During the next 5-year follow-up, the patient's condition was stable and no bleeding occurred. In the case of coagulation dysfunction in SLE, especially with isolated APTT prolongation, AHA should be screened. When the therapeutic effects of glucocorticoid combined with immunosuppressants are not desirable, rituximab could be introduced.


Subject(s)
Female , Humans , Adult , Hemophilia A/therapy , Rituximab , Glucocorticoids , Factor VIII , Lupus Erythematosus, Systemic/complications , Hemorrhage/complications
7.
Clin. biomed. res ; 43(1): 58-68, 2023.
Article in English | LILACS | ID: biblio-1435960

ABSTRACT

Hemophilia is an inherited X-linked coagulopathy defined by a deficiency or abnormality in the clotting function of factor VIII (Hemophilia A) or factor IX (Hemophilia B). Prophylaxis ­ the regular administration of therapeutic products to maintain hemostasis and prevent bleeding ­ is the mainstream of treatment. Addressing the development and scientific evidence for administrating prophylaxis is the goal of this review. Prophylaxis is the therapeutic modality of choice for people with severe hemophilia, being considered, in principle, a lifelong treatment. It should have an early onset, ideally as a primary, or at least secondary. Even lifelong tertiary prophylaxis seems to offer benefit, although further studies are still lacking. Individualized strategies should lead to an optimization of the dilemma between better joint outcomes versus involved costs.


Subject(s)
Humans , Male , Female , Factor VIII/therapeutic use , Hemophilia B/prevention & control , Hemophilia A/prevention & control
8.
Clin. biomed. res ; 43(1): 69-74, 2023.
Article in English | LILACS | ID: biblio-1435967

ABSTRACT

The history of hemophilia is ancient, with descriptions dated to the 2nd century AD. The first modern narratives appeared in 1800s, when total blood transfusion was the only available treatment and life expectancy was remarkably low. Advances occurred with the use of plasma and cryoprecipitate, but only the discovered of factor concentrates revolutionized the treatment. The implantation of prophylaxis allowed hemophilic patients to prevent bleeding and the development of chronic arthropathy, although with a significant burdensome with the regular infusions. In the past 20 years, this field has witnessed major improvements, including the development of gene therapy and other pharmacological approaches.


Subject(s)
Humans , History, 19th Century , History, 20th Century , History, 21st Century , Factor IX/history , Factor VIII/history , Hemophilia B/history , Hemophilia A/history , Hemophilia B/therapy , Hemophilia A/therapy
9.
Rev. med. Urug ; 38(4): e38402, dic. 2022.
Article in Spanish | LILACS, BNUY | ID: biblio-1424176

ABSTRACT

Introducción: la hemofilia A severa (HAS) es una enfermedad hemorrágica hereditaria causada por un déficit de factor VIII (FVIII) menor al 1%. Se presenta principalmente con sangrados articulares, los cuales provocan una artropatía hemofílica que afecta su independencia funcional. El uso de la profilaxis terciaria con FVIII ofrece beneficios en adultos disminuyendo la tasa anual de sangrado (TAS) y mejorando la independencia funcional. Objetivo: determinar el porcentaje de pacientes que logran mantener un nivel de FVIII mayor al 1%, conocer si existe una mejora en la independencia funcional, así como una disminución en la TAS con el régimen profiláctico empleado. Métodos: estudio observacional, analítico. Se incluyó a los pacientes con HAS que se controlaron en el Hospital de Clínicas "Dr. Manuel Quintela" durante 2020 en profilaxis con FVIII durante 12 meses. Se obtuvieron tres muestras separadas en el tiempo para dosificación de FVIII y se evaluó la TAS y la independencia funcional en cada paciente. Resultados: se analizaron ocho pacientes, todos presentaron valores de FVIII superiores al 1% a la hora y 24 horas posterior a la administración de FVIII. Los episodios de sangrado se redujeron 4,76 veces con el uso de la profilaxis (p = 0,019). La independencia funcional mostró que 5/8 pacientes mejoraron al menos 1 punto del score. Conclusiones: la profilaxis terciaria en estos pacientes fue beneficioso en reducir la TAS y mejorar su capacidad funcional.


Summary: Introduction: severe hemophilia A (SAH) is an hereditary hemorrhagic disease, caused by a factor VIII (FVIII) deficiency of less than 1%. It presents with joint bleeding mainly, which causes a hemophilic arthropathy, which affects its functional independence. The use of tertiary prophylaxis with FVIII offers benefits in adults by decreasing the annual bleeding rate (ABR) and improving functional independence. Objective: to determine the percentage of patients who manage to maintain an FVIII level greater than 1%, to know if there is an improvement in functional independence, as well as a decrease in the ABR with the prophylactic regimen used. Methods: observational, analytical study. Patients with SAH who were controlled at the Hospital de Clínicas "Dr. Manuel Quintela", during the year 2020, in prophylaxis with FVIII for 12 months were included. Three samples separated in time for FVIII dosing were obtained and the ABR and functional independence were evaluated in each patient. Results: 8 patients were analyzed, all presented FVIII higher than 1% at one hour and 24 hours after the administration of FVIII. The bleeding episodes were reduced 4.76 times with the use of Prophylaxis (p = 0.019). Functional independence showed that 5/8 patients improved at least 1 point in the Score. Conclusions: tertiary prophylaxis in these patients was beneficial in reducing SAD and improving their functional capacity.


Introdução: a hemofilia A grave (HAS) é uma doença hemorrágica hereditária, causada pela deficiência do fator VIII (FVIII) inferior a 1%. Apresenta-se principalmente com sangramento articular, que causa artropatia hemofílica, que afeta sua independência funcional. O uso de profilaxia terciária com FVIII oferece benefícios em adultos, reduzindo a taxa de sangramento anual (TAS) e melhorando a independência funcional. Objetivos: determinar a porcentagem de pacientes que conseguem manter um nível de FVIII maior que 1%, identificar uma possível melhora da independência funcional, bem como uma diminuição da TAS com o esquema profilático utilizado. Métodos: estudo observacional, analítico de pacientes com HAS controlados no Hospital das Clínicas "Dr. Manuel Quintela", durante o ano de 2020, em profilaxia com FVIII durante 12 meses. Foram obtidas três amostras separadas no tempo para dosagem de FVIII e avaliação da TAS e da independência funcional de cada paciente. Resultados: foram analisados 8 pacientes, todos apresentaram FVIII maior que 1% em uma hora e 24 horas após a administração do FVIII. Os episódios de sangramento foram reduzidos 4,76 vezes com o uso da profilaxia (p = 0,019). A independência funcional mostrou que 5/8 pacientes melhoraram pelo menos 1 ponto do escore FISH. Conclusões: a profilaxia terciária nesses pacientes foi benéfica na redução da TAS e na melhora da capacidade funcional.


Subject(s)
Factor VIII , Hemophilia A , Functional Status
10.
Medwave ; 22(2): e002118, mar.2022. tab
Article in English, Spanish | LILACS | ID: biblio-1366391

ABSTRACT

Contexto La hemofilia es un trastorno hemorrágico de la coagulación que ocurre en uno de cada 5000 nacimientos masculinos. Los pacientes con hemofilia A grave no tratados tienen complicaciones hemorrágicas, incluyendo sangrados articulares y menor sobrevida. El emicizumab es un anticuerpo monoclonal aprobado por los Estados Unidos para la profilaxis rutinaria de pacientes pediátricos y adultos con hemofilia A grave con inhibidores del factor VIII de coagulación. Objetivos Realizar un estudio de costo-efectividad de la profilaxis con emicizumab para niños y adultos con hemofilia A grave, en comparación con el actual manejo de esos pacientes en el Ministerio de Salud y el Seguro Social de Salud de Perú. Metodología Se modeló la transición del paciente entre estados médicos con la metodología de Markov y se estimó a lo largo de su vida costos y efectos incrementales de emicizumab comparados con el actual manejo. Se estimó el impacto presupuestario de emicizumab proyectando costos netos anuales y su valor presente a cinco años. Resultados Emicizumab generaría ahorros en el Ministerio de Salud entre 14,6 y 16,0 por niño y 11,8 por adulto, en US$ millones actuales, y en el Seguro Social de Salud de 12,8 a 14,9 por niño y 40,1 por adulto. Además, se generan ganancias en efectividad, medidas en años de vida ajustados por calidad, de 0,36 por niño y 0,56 por adulto y de 0,25 por niño y 0,36 por adulto en esas respectivas instituciones. El impacto presupuestario sería un ahorro anual neto, en US$ millones, de 12,8 y 15,0 en esas entidades. Conclusión El actual manejo de la enfermedad es muy costoso y con resultados de salud inferiores a los posibles con emicizumab. Este fármaco produciría grandes ahorros y mejor salud. Ambas entidades debieran implementar protocolos para la profilaxis y tratamiento de la hemofilia y financiarla con presupuesto propio.


Settings Hemophilia is a coagulation disorder that occurs in one in 5000 male births. Patients with untreated severe hemophilia A have hemorrhagic complications, including joint bleeds and decreased survival. Emicizumab is a monoclonal antibody approved by the United States for routine prophylaxis of pediatric and adult patients with severe hemophilia A with factor VIII inhibitors. Objectives To perform a cost-effectiveness study of emicizumab prophylaxis for children and adults with severe hemophilia A compared with the current disease management in the Peruvian Ministry of Health and Social Security Health Insurance. Methods The patient transition between medical states was modeled with Markov methodology, and the lifetime costs and incremental effects of emicizumab compared to current management were estimated. The budgetary impact of emicizumab was estimated by projecting annual net costs and its five-year present value. Results In the Ministry of Health, emicizumab would generate savings between 14.6 and 16.0 per child and 11.8 per adult, in current US$ million. Social Security Health Insurance savings would be 12.8 to 14.9 per child and 40.1 per adult. In addition, this strategy would generate effectiveness gains, measured in quality-adjusted life-years, of 0.36 per child and 0.56 per adult and 0.25 per child, and 0.36 per adult in those respective institutions. The budgetary impact would be a net annual saving of 12.8 and 15.0 US$ million in those entities. Conclusions The current management of hemophilia A is very costly and has health outcomes inferior to those possible with emicizumab. This drug would produce significant savings and better patient health. The Ministry of Health and Social Health Insurance should implement hemophilia prophylaxis and treatment protocols and finance this drug.


Subject(s)
Humans , Male , Child , Adult , Hemophilia A/complications , Hemophilia A/drug therapy , Peru , Factor VIII/therapeutic use , Cost-Benefit Analysis , Antibodies, Bispecific , Antibodies, Monoclonal, Humanized , Hemorrhage/etiology
11.
Rev. Ciênc. Méd. Biol. (Impr.) ; 20(4): 568-574, fev 11, 2022. tab
Article in Portuguese | LILACS | ID: biblio-1359326

ABSTRACT

Introdução: o Brasil é o quarto país em casos de Hemofilia A. O tratamento é infundir o fator de coagulação ausente. Reações ao uso do fator podem incluir manifestações alérgicas, doenças virais transfusionais e aloanticorpos. Objetivo: analisar o perfil epidemiológico de pacientes com Hemofilia A, e as doenças associadas ao uso do fator VIII e fator VIII recombinante. Metodologia: estudo transversal descritivo e retrospectivo. A coleta de dados foi realizada nos prontuários de pacientes com diagnóstico de hemofilia A, preenchidos com mais de 70% das informações, na Fundação Hospitalar de Hematologia e Hemoterapia do Amazonas, Brasil. Resultados: o Ministério da Saúde identificou no Estado do Amazonas, o registro de 276 indivíduos com diagnóstico de Hemofilia A. Incluídos para análise neste estudo 164 prontuários. Características sociodemográficas: homens 99,4%, adolescentes (28%) e jovens (26,8%); de cor parda 67,1%, ensino fundamental incompleto 28,6% e, exercendo a ocupação de estudante 42,7%. Condição clínica: 36,6% classificados com hemofilia A grave. Todos os pacientes tiveram diagnóstico clínico e laboratorial. O parentesco mais comum é o de irmãos com 35,3%. Sintomas predominantes: hemartrose 45,4%; dor 31,9%; edema 24% e artropatia 8,5%. O fator VIII recombinante, administrado em 34,8% dos pacientes, enquanto o fator VIII plasmático em 28,0%. Administrados doses de 2000UI a 2999UI. As complicações: artralgia 77,4% e hemorragia 77,4%. Conclusão: cuidados qualificados dos profissionais de saúde auxiliam na prevenção de complicações sérias, resultando em qualidade de vida ao hemofílico.


Introduction: Brazil is the fourth country in cases of Hemophilia A. The treatment is to infuse the missing clotting factor. Reactions to the use of the factor can include, allergic manifestations, transfusion viral diseases and alloantibodies. Objective: analyze the epidemiological profile of patients with Hemophilia A, and the diseases associated with the use of factor VIII and recombinant factor VIII. Methodology: descriptive and retrospective cross-sectional study. Data collection was carried out in the medical records of patients diagnosed with hemophilia A, filled with more than 70% of the information, at the Fundação Hospitalar de Hematologia e Hemoterapia do Amazonas, Brazil. Results: in the Ministry of Health of Brazil, it was identified, for the State from Amazonas, the registry of 276 individuals diagnosed with Hemophilia A. Included in the analysis for this study, 164 medical records. Sociodemographic characteristics: male, 99.4%, adolescents (28%) and young people (26.8%), brown skin color, 67.1%, incomplete elementary school, 28.6%, and working as a student, 42.7%. Clinical condition: 36.6% classified with severe hemophilia A. All patients had a clinical and laboratory diagnosis. The most common kinship is that of brothers, 35.3%. Predominant symptoms: hemarthrosis 45.4%, pain 31.9%, edema 24% and arthropathy 8.5%. Recombinant factor VIII, administered in 34.8% of patients, while plasma factor VIII in 28.0%. Doses of 2000 IU to 2999 IU were administered. Complications: arthralgia 77.4% and hemorrhage 77.4%. Conclusion: qualified care by health professionals helps to prevent serious complications, resulting in quality of life for the hemophiliac.


Subject(s)
Humans , Male , Female , Infant, Newborn , Infant , Child, Preschool , Child , Adolescent , Adult , Middle Aged , Health Profile , Factor VIII , Arthralgia , Edema , Hemarthrosis , Hemophilia A , Hemorrhage , Joint Diseases , Medical Records , Epidemiology, Descriptive , Cross-Sectional Studies , Retrospective Studies
12.
Chinese Journal of Medical Genetics ; (6): 72-75, 2022.
Article in Chinese | WPRIM | ID: wpr-928365

ABSTRACT

OBJECTIVE@#To report on a case with severe hemophilia A (HA) due to a large duplication of F8 gene.@*METHODS@#Inversion detection, Sanger sequencing, and multiplex ligation-dependent probe amplification (MLPA) were used to detect the mutation in the proband and his mother.@*RESULTS@#The patient, a 7-year-old boy, was diagnosed with severe HA at 8 months. No inhibitor was developed over 150 exposure days. Intronic inversion detection and Sanger sequencing have failed to identify pathogenic variants, while MLPA revealed a large duplication [Ex 1_22 dup (2 copies)] in the proband, for which his mother was a carrier [Ex 1_22 dup (3 copies)]. Large duplications of the F8 gene have so far been found in 24 HA patients, all of whom had a severe phenotype, only one had a history of inhibitors.@*CONCLUSION@#Large duplications of F8 gene are associated with severe HA. The diagnostic rate for HA may be increased by MLPA.


Subject(s)
Child , Humans , Male , Factor VIII/genetics , Gene Duplication , Hemophilia A/genetics , Introns , Mutation , Phenotype
13.
Arq. neuropsiquiatr ; 79(12): 1116-1122, Dec. 2021. tab, graf
Article in English | LILACS | ID: biblio-1355708

ABSTRACT

ABSTRACT Background: Bleeding in hemophiliacs can cause complications in the central and peripheral nervous system (CNS and PNS). The incidence of intracranial hemorrhage has reduced after the introduction of prophylactic treatment with factor VIII or IX, but the benefits of this therapy have not yet been evaluated on PNS complications. Objective: The aim of this study was to determine the prevalence of neurological complications in hemophiliacs and verify the effect of prophylactic therapy in these patients, including PNS disorders. Methods: We retrospectively evaluated the prevalence of CNS and PNS disorders caused by bleeding in hemophiliacs seen at the Hemocentro Regional Norte, Ceará, Brazil, from 1992 to 2018, and we compared the incidence in different periods (before and after the introduction of prophylactic treatment in 2011). Results: Of 75 hemophilia A patients evaluated (4.61/100.000 population), 13.3% (n=10) had either CNS (n=5) or PNS (n=5) disorders secondary to bleeding. Patients submitted to factor VIII replacement prophylactic therapy were less likely to have CNS events: from 1992 to 2011, 5 of 63 patients had CNS disease, while from 2011 to 2018, there were no new cases (p=0.0181). From 2011 to 2018, 5 PNS events occurred in patients without prophylactic therapy, whereas none occurred in those covered by prophylactic therapy (5/20 versus 0/29, p=0.0081). Conclusions: The prevalence of neurological complications in hemophiliacs in our cohort is similar to other studies. Similar to CNS, prophylactic therapy also reduces the risk of PNS complications. This is the first report in the literature showing this benefit.


RESUMO Antecedentes: O sangramento em hemofílicos causa complicações no sistema nervoso central e periférico (SNC e SNP). A incidência de hemorragia intracraniana diminuiu após a introdução da profilaxia com fator VIII ou IX, entretanto esse benefício ainda não foi avaliado no SNP. Objetivo: O objetivo deste estudo foi determinar a prevalência de complicações neurológicas em hemofílicos, verificando o efeito da terapia profilática também no SNP. Métodos: Avaliamos retrospectivamente a prevalência de complicações neurológicas causadas ​​por sangramentos em hemofílicos atendidos no Hemocentro Regional Norte, Ceará, Brasil, de 1992 a 2018, comparando a incidência em diferentes períodos (antes e depois da introdução do tratamento profilático em 2011). Resultados: Foram avaliados 75 pacientes com hemofilia A (4,61/100 mil habitantes). Deles, 13,3% (n=10) tinham distúrbios do SNC (n=5) ou do SNP (n=5) secundários a hemorragias. Os pacientes submetidos à terapia profilática com fator VIII apresentaram menor probabilidade de eventos do SNC: de 1992 a 2011, cinco de 63 pacientes apresentaram hemorragia no SNC, enquanto de 2011 a 2018 não ocorreram novos casos (p=0,0181). De 2011 a 2018, cinco eventos no SNP ocorreram entre pacientes sem terapia profilática, e nenhum ocorreu entre aqueles cobertos pela profilaxia (5/20 × 0/29, p=0,0081). Conclusões: A prevalência de complicações neurológicas em hemofílicos em nossa coorte é similar à de outros estudos. Assim como no SNC, a terapia profilática também reduz o risco de complicações no SNP. Este é o primeiro relato na literatura a mostrar esse benefício.


Subject(s)
Humans , Hemophilia A/complications , Nervous System Diseases/prevention & control , Brazil , Factor VIII , Central Nervous System , Retrospective Studies , Peripheral Nervous System/physiopathology , Hemorrhage , Nervous System Diseases/etiology
14.
Medicina (B.Aires) ; 81(2): 286-288, June 2021. graf
Article in Spanish | LILACS | ID: biblio-1287282

ABSTRACT

Resumen Presentamos el caso de un varón de 86 años con un hematoma espontáneo en el músculo ilíaco izquierdo y diagnóstico previo de cáncer de colon en 1998 (estadio pT3N0M0), tratado quirúrgicamente mediante colectomía transversal, considerado en remisión completa. Tras realización de estudios complementarios se demostró la presencia de autoanticuerpos inhibidores del Factor VIII que confirmaron el diagnóstico de hemofilia adquirida. Durante el ingreso el paciente presentó un sangrado digestivo bajo que conllevó al descubrimiento de recidiva del adenocarcinoma colorrectal tratado previamente. Respondió de forma favorable a la terapia inicial con corticoides sistémicos y el complejo coagulante anti inhibidor que incluye el Factor VII activado [FEIBA].


Abstract We report the case of an 86-year-old man presenting with a spontaneous hematoma in the left iliac muscle and previous diagnosis of colon cancer in 1998 (stage pT3N0M0) treated with transverse colectomy and considered in complete remission. After a complete study, it was possible to identify the presence of Factor VIII inhibitors antibodies that confirmed the presence of acquired hemophilia. During hospitalization the patient presented a lower gastrointestinal bleeding leading to the diagnosis of recurrence of a previously treated colorectal adenocarcinoma. He responded to initial therapy with systemic corticoids and anti-inhibitory coagulant complex which includes activated VII Factor [FEIBA].


Subject(s)
Humans , Male , Aged, 80 and over , Colorectal Neoplasms/diagnosis , Hemophilia A/complications , Hemophilia A/diagnosis , Hemophilia A/drug therapy , Factor VIII , Neoplasm Recurrence, Local/diagnosis
15.
Int. j. morphol ; 39(2): 564-570, abr. 2021. ilus, tab, graf
Article in English | LILACS | ID: biblio-1385368

ABSTRACT

SUMMARY: Cancer known as a malignant tumor, is a class of diseases involving abnormal cell growth with the potential to invade or spread to other parts of the body. The Ehrlich tumor is a mammary adenocarcinoma of mice developed in solid and ascitic forms. This study was aimed to investigate the effects of paclitaxel on Netrin 1 and Factor 8 expression and also in tumor cell proliferation, apoptosis, angiogenesis, and development of tumor in Ehrlich solid tumors treated with paclitaxel. In this study, 26 adult Balb/C male mice were used. 6 of them were used as stock. Ehrlich ascites cells taken from animals in stock were injected subcutaneously from the neck area to all animals. The mice were randomly assigned to two groups of ten rats per group. Paclitaxel treatment group 10 mg/kg were administered to mice intraperitoneally (i.p.) 4,9, and 14th days. 15th day the animals were sacrificed and tumor tissues were taken. Paraffin-embedded solid tumor sections were stained Hematoxylin & Eosin, Masson's Trichrome. Also solid tumor sections were stained immunohistochemically with Netrin1 and Factor 8. Tunel method was applied to determine apoptosis. Paclitaxel applied as a therapeutic Ehrlich solid tumor reduced the volume of tumors in the treatment groups. At the end of the experiments, in the treatment groups' significantly reduced the Netrin 1 expression and microvessel density compared to the group control. Also paclitaxel in the treatment group increased the number of apoptotic cells. We suggest that decreasing the expression of Netrin 1 would be reduced vessel density and increased apoptosis.


RESUMEN: El cáncer, conocido como tumor maligno, es una clase de enfermedad que involucra un crecimiento celular anormal con potencial de invadir o diseminarse a otras partes del cuerpo. El tumor de Ehrlich es un adenocarcinoma mamario de ratones desarrollado en formas sólidas y ascíticas. Este estudio tuvo como objetivo investigar los efectos del paclitaxel en la expresión de Netrin 1 y Factor 8 y también en la proliferación de células tumorales, apoptosis, angiogénesis y desarrollo de tumores sólidos de Ehrlich tratados con paclitaxel. En esta investigación se utilizaron 26 ratones machos Balb / C adultos. Seis de ellos se utilizaron como stock. Se inyectaron por vía subcutánea células de ascitis de Ehrlich tomadas de animales en la zona del cuello. Los ratones se asignaron aleatoriamente a dos grupos de diez ratas por grupo. Se administraron 10 mg/kg del grupo de tratamiento con paclitaxel a ratones por vía intraperitoneal (i.p.) 4, 9 y 14 días. El día 15 se sacrificaron los animales y se extrajeron los tejidos tumorales. Las secciones de tumor sólido incluidas en parafina se tiñeron con hematoxilina y eosina y tricrómico de Masson. También se tiñeron inmunohisto-químicamente secciones de tumor sólido con Netrin1 y Factor 8. Se aplicó el método Tunel para determinar la apoptosis. El paclitaxel aplicado como tumor sólido terapéutico de Ehrlich redujo el volumen de tumores en los grupos de tratamiento. Al final de los experimentos, en los grupos de tratamiento se redujo significativamente la expresión de Netrin 1 y la densidad de microvasos en comparación con el grupo control. Además, el paclitaxel en el grupo tratamiento aumentó el número de células apoptóticas. Sugerimos que la disminución de la expresión de Netrin 1 reduciría la densidad de los vasos y aumentaría la apoptosis.


Subject(s)
Animals , Male , Mice , Carcinoma, Ehrlich Tumor/drug therapy , Paclitaxel/administration & dosage , Netrin-1/antagonists & inhibitors , Antineoplastic Agents, Phytogenic/administration & dosage , Factor VIII , Immunohistochemistry , Paclitaxel/pharmacology , Apoptosis , Cell Proliferation/drug effects , Microvascular Density/drug effects , Mice, Inbred BALB C , Neovascularization, Pathologic , Antineoplastic Agents, Phytogenic/pharmacology
16.
Frontiers of Medicine ; (4): 302-312, 2021.
Article in English | WPRIM | ID: wpr-880973

ABSTRACT

Cullin-RING E3 ubiquitin ligase (CRL)-4 is a member of the large CRL family in eukaryotes. It plays important roles in a wide range of cellular processes, organismal development, and physiological and pathological conditions. DDB1- and CUL4-associated factor 8 (DCAF8) is a WD40 repeat-containing protein, which serves as a substrate receptor for CRL4. The physiological role of DCAF8 is unknown. In this study, we constructed Dcaf8 knockout mice. Homozygous mice were viable with no noticeable abnormalities. However, the fertility of Dcaf8-deficient male mice was markedly impaired, consistent with the high expression of DCAF8 in adult mouse testis. Sperm movement characteristics, including progressive motility, path velocity, progressive velocity, and track speed, were significantly lower in Dcaf8 knockout mice than in wild-type (WT) mice. However, the total motility was similar between WT and Dcaf8 knockout sperm. More than 40% of spermatids in Dcaf8 knockout mice showed pronounced morphological abnormalities with typical bent head malformation. The acrosome and nucleus of Dcaf8 knockout sperm looked similar to those of WT sperm. In vitro tests showed that the fertilization rate of Dcaf8 knockout mice was significantly reduced. The results demonstrated that DCAF8 plays a critical role in spermatogenesis, and DCAF8 is a key component of CRL4 function in the reproductive system.


Subject(s)
Animals , Male , Mice , Cullin Proteins/genetics , DNA-Binding Proteins/genetics , Factor VIII , Mice, Knockout , Spermatogenesis/genetics , Ubiquitin-Protein Ligases
17.
Article in Spanish | LILACS, UY-BNMED, BNUY | ID: biblio-1142109

ABSTRACT

La hemofilia A es una coagulopatía congénita causada por la deficiencia o el mal funcionamiento del factor VIII de la coagulación. Una de las complicaciones más graves del tratamiento de la hemofilia A es el desarrollo de inhibidores que hacen que la terapia de reemplazo con FVIII sea ineficaz, dificultando la prevención y el control de los sangrados. El emicizumab es un anticuerpo monoclonal humanizado biespecífico dirigido contra los factores FIXa y FX, que imita la función de cofactor del FVIII. El tratamiento profiláctico con emicizumab es seguro y eficaz para prevenir hemorragias en los pacientes con hemofilia A con y sin inhibidores. Se presenta el caso del primer paciente tratado con emicizumab en Uruguay.


Haemophilia A is a congenital coagulopathy caused by a deficiency or malfunction of coagulation factor VIII. One of the most serious complications of haemophilia A treatment is the development of inhibitors that render FVIII replacement therapy ineffective, making it difficult to prevent and control bleeding. Emicizumab is a humanized bispecific monoclonal antibody directed against factors FIXa and FX, which mimics the cofactor function of FVIII. Emicizumab has been shown to be safe and effective as prophylaxis to prevent bleeding in haemophilia A patients with or without inhibitors to FVIII. We report the first patient treated with emicizumab in Uruguay.


A hemofilia A é uma coagulopatia congênita que se caracteriza pela ausência ou mau funcionamento do factor VIII da coagulação. Uma das complicações mais sérias do tratamento da hemofilia A é o desenvolvimento de inibidores que tornam a terapia de reposição do FVIII ineficaz, dificultando a prevenção e o controle do sangramento. O emicizumab é um anticorpo monoclonal biespecífico humanizado dirigido contra os fatores FIXa e FX, que imita a função de cofator do FVIII. O tratamento profilático com emicizumab é seguro e eficaz na prevenção de sangramento em pacientes com hemofilia A com e sem inibidores. É apresentado o caso do primeiro paciente tratado com emicizumabe no Uruguai.


Subject(s)
Humans , Male , Adult , Factor VIII/antagonists & inhibitors , Antibodies, Bispecific/therapeutic use , Antibodies, Monoclonal, Humanized/therapeutic use , Hemophilia A/prevention & control , Hemorrhage/prevention & control , Acute Disease , Chronic Disease , Treatment Outcome
18.
Rev. chil. pediatr ; 91(2): 232-238, abr. 2020. tab
Article in Spanish | LILACS | ID: biblio-1098896

ABSTRACT

Resumen: Introducción: El desarrollo de aloanticuerpos neutralizantes anti-factor VIII en hemofilia A es la complicación más seria relacionada al tratamiento. La inducción de tolerancia inmune (ITI) o inmunotolerancia es el único tratamiento que erradica inhibidores, permitiendo utilizar nuevamente factor VIII para el tratamiento o profilaxis de eventos hemorrágicos. Objetivo: reportar la experiencia en niños sometidos a inmunotolerancia en la red pública del país. Pacientes y Método: Análisis retrospectivo y descriptivo de 13 niños con Hemofilia A severa e inhibidores persistentes de alto título, que recibieron ITI y seguimiento completo. Se utilizó concentrado de FVIII plasmático en dosis de 70-180 UI/Kg/diarias, definiendo éxito como la negativización del inhibidor y recu peración de la vida media del FVIII. Resultados expresados en media (rango). Resultados: En 13 pacientes se identificó el inhibidor, a una edad de 17,6 meses (2-48), tras 35,2 días (9-112) de exposición a FVIII. Once pacientes (84,6%) recuperaron la vida media del FVIII, tras 49,6 meses (26-70) de tratamiento. En los pacientes que respondieron, el título del inhibidor se negativizó en 7,3 meses (1-20). Conclusiones: En niños con hemofilia A e inhibidores persistentes de alto título, la ITI tiene un elevado éxito. Dado que el tiempo de respuesta es variable, la inmunotolerancia debe ser personalizada.


Abstract: Introduction: The development of anti-factor VIII neutralizing antibodies in hemophilia A is the most severe com plication related to treatment. Immune tolerance induction (ITI) is the only known treatment for eradicating inhibitors. A successful ITI allows using factor VIII (FVIII) again for the treatment or prophylaxis of hemorrhagic events. Objective: To report the experience of pediatric patients who underwent ITI in the country's public health care network. Patients and Method: Retrospective and descriptive analysis of 13 pediatric patients with severe Hemophilia A and high-titer inhibitors persis tence who underwent ITI and complete follow-up. Plasma-derived FVIII concentrate was used at 70 180 IU/kg/day doses. The success of the treatment is defined by achieving a negative titer and a half life recovery of the FVIII. The results were expressed in median (range). Results: In 13 patients, the inhibitor was identified at an average age of 17.6 months, after 35.2 days of exposure to the FVIII. 11 patients (84.6%) recovered the half-life of FVIII after 49.6 months of treatment. In the patients who responded to treatment, the inhibitor titer was negative at 6 months on average. Conclusions: ITI is the treatment of choice for patients with hemophilia A and inhibitors persistence. ITI must be perso nalized since the time response is variable in each patient.


Subject(s)
Humans , Male , Female , Infant , Child, Preschool , Child , Factor VIII/therapeutic use , Hemophilia A/therapy , Immune Tolerance/immunology , Immunotherapy/methods , Isoantibodies/immunology , Factor VIII/immunology , Retrospective Studies , Follow-Up Studies , Treatment Outcome , Hemophilia A/immunology
19.
Gac. méd. Méx ; 156(1): 67-77, ene.-feb. 2020. tab, graf
Article in English, Spanish | LILACS | ID: biblio-1249872

ABSTRACT

Resumen La hemofilia adquirida (HA) es un trastorno hemostático autoinmune ocasionado por autoanticuerpos dirigidos contra el factor VIII: C. En 52 % de los casos, la causa se desconoce o no se asocia con otra entidad patológica; en el resto, existen factores concomitantes: lupus, artritis reumatoide, cáncer, embarazo y medicamentos. En México no existe registro ni conciencia de la enfermedad entre el personal de salud. Los grupos de mayor incidencia son las mujeres en edad reproductiva y los individuos mayores de 70 años. Se caracteriza por hemorragia grave, sobre todo posterior a traumatismos y parto o cesárea, y equimosis grandes en tronco y extremidades. La sospecha es simple, basta que concurran hemorragia súbita, grave y un TTPa prolongado que no se corrige con plasma. El tratamiento consiste en lograr la hemostasia y erradicar el anticuerpo; lo primero se logra con el factor VII activado recombinante o concentrado del complejo de protrombínico activado. La ciclofosfamida, prednisona o rituximab sirven para erradicar el anticuerpo. La mayoría de los casos no son diagnosticados y la mortalidad es alta. Ya que los médicos desconocen el problema, no se sospecha, no se diagnostica y no se trata. Este documento revisa los datos más recientes de la HA y abunda en el diagnóstico y tratamiento.


Abstract Acquired hemophilia (AH) is an autoimmune hemostatic disorder mediated by autoantibodies directed against factor VIII: C. In 52% of cases, the cause is unknown or is not associated with other pathological entities; in the rest, there are concomitant factors: lupus, rheumatoid arthritis, cancer, pregnancy, and medications. In Mexico, there is not a registry of AH, and awareness of the disease among health personnel is low. The groups with the highest incidence are women of childbearing age and individuals older than 70 years. It is characterized by severe bleeding, especially after trauma and normal childbirth or cesarean delivery, and large ecchymoses in the trunk and extremities. The suspicion is simple, it just takes for sudden, severe hemorrhage and a prolonged activated partial thromboplastin time that is not corrected with plasma to concur in an individual. Treatment involves achieving hemostasis and eradicating the antibody. The former is achieved with recombinant activated factor VII or activated prothrombin complex concentrate. Cyclophosphamide, prednisone or rituximab are used to eradicate the antibody. Most cases of AH are not diagnosed, which translates into a high mortality rate. Given that awareness about the disease among physicians is low, it is not suspected, neither diagnosed, and nor is it treated. This document reviews the most recent data on AH and expands on its diagnosis and treatment.


Subject(s)
Humans , Male , Female , Pregnancy , Adult , Middle Aged , Aged , Young Adult , Autoantibodies/immunology , Factor VIII/immunology , Hemophilia A/immunology , Pregnancy Complications, Hematologic/etiology , Prognosis , Ecchymosis/etiology , Hemophilia A/complications , Hemophilia A/therapy , Hemophilia A/epidemiology , Hemorrhage/etiology , Immunosuppressive Agents/therapeutic use
20.
Journal of Experimental Hematology ; (6): 948-955, 2020.
Article in Chinese | WPRIM | ID: wpr-827180

ABSTRACT

OBJECTIVE@#To transinfect SD adipose tissue-derived stem cell (ADSC) in vitro with a recombinant adenoviral vector containing human B-domain-deleted FVIII (BDDhFⅧ), so as to lay the foundation for the treatment of hemophilia A by using ADSC combined with BDDhFⅧ gene.@*METHODS@#ADSCs were isolated from the inguinal adipose tissue of SD rats and passed to third passage for identification. Third passage ADSCs were transfected in vitro with recombinant adenovirus vector Ad-BDDhFⅧ-GFP. The experiments were divided into Ad-BDDhFⅧ-GFP-transfected ADSCs group (A), Ad-GFP-transfected ADSC group (B), and untransfected ADSC group (C). CCK-8 method was used to detect the proliferation of transfected cells in three groups, and the expression level of hFⅧ antigen in cell supernatant was detected by ELISA. RT-PCR and Western blot respectively were used to detect the mRNA and protein expression of BDDhFⅧ in the three groups after transfection.@*RESULTS@#The growth curve of third passage cells isolated and cultured showed an inverted "S" shap; the flow cytometry detection showed the positive expression of CD29, CD90, CD44, and the negative expression of CD45 in third passage cells. After the adipogenic and osteogenic induction, the cells could transformed to adipogenic and osteogenic directions. CCK-8 detection showed that the proliferation of cells in 3 groups not was influenced. ELISA showed that the expression of hFⅧAg in group A was significantly higher than that in group B and C (P<0.05). RT-PCR showed that compared with group A, there was no target band in B and C groups, and BDDhFⅧ gene was not expressed. The results in group A were consistent with the length of amplified fragments, and BDDhFⅧ target gene was expressed. Western blot analysis showed that the expression of hFⅧ protein in group A was significantly higher than that in group B and C. (P<0.05).@*CONCLUSION@#Recombinant adenovirus Ad-BDDhFⅧ-GFP can effectively transfect rat ADSC in vitro, which lays an experimental foundation for gene therapy of hemophilia A.


Subject(s)
Animals , Humans , Rats , Adenoviridae , Adipose Tissue , Cell Differentiation , Cells, Cultured , Factor VIII , Rats, Sprague-Dawley , Stem Cells , Transfection
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