Hemophilia A(HA) is an X-linked recessive bleeding disorder caused by mutations in coagulation factor VIII. Nowadays, exogenous coagulation factor replacement therapy is the main treatment. With the continuous development of gene therapy, new research directions have been provided for the treatment of hemophilia A. CRISPR-Cas9 technology was applied to select suitable target sites, and mediate the targeted knock-in and efficient expression of exogenous B-domain-deleted FⅧ variant gene through corresponding vectors for the treatment of hemophilia A.CRISPR-Cas9 technology is an emerging gene editing tool with great efficiency, safety and effectiveness, and has been widely used in hemophilia gene therapy research. This paper reviews the vector selection, construction of therapeutic genes, gene editing technology and selection of expression target sites for hemophilia A gene therapy at this stage.
Humans ; Hemophilia A/therapy* ; CRISPR-Cas Systems ; Hemophilia B/therapy* ; Gene Editing ; Genetic Therapy ; Genetic Vectors

Factor IX/therapeutic use* ; Factor VIII ; Hemophilia A/drug therapy* ; Hemophilia B/drug therapy* ; Humans ; Recombinant Proteins/therapeutic use*

Asian Continental Ancestry Group ; Factor VIII ; Hemophilia A ; therapy ; Hemophilia B ; therapy ; Humans ; Practice Guidelines as Topic

OBJECTIVE: To investigate the joint health status of patients with hemophilia treated on-demand and to analyze the incidence trend of hemophilic arthritis, so as to probide the scientific clinical data for furture study. METHODS: The clinical data of patients with hemophilia admitlted in Tianjin municipal first central hospital form March 2016 to October 2017 were collected, the basic information of patients was recorded; the joint health status was evaluated by using the hemophillia Joint Health Score (HJHS) 2.1; the life guality of patients was analyzed by using the MOS item short form-36 health survey, SF-36; the correlation of joint function with life guatity was analyzed by pearson correlation test. RESULTS: 196 ont of 210 patients with hemophila were treated on demand. The average age of patients was 27.81(2-73) years old, Among 196 patients, 189 was hemophilia A (96.43%) and 9 was hemophilia B (3.57). The patients without joint involvement, patients with 1 joint and 32 jionts involvement accounted for 3.57%, 11.72% and 84.71% respectively. The incidonce of involvement in elbow, knae and ankle joints was 71.93%, 80.61% and 82.91% respectively. The joint invlvement rate in patients with mild, intermediate and severe hemphilia accounted for 61.66%, 72.40% and 80.73% respectively. The mean HJHS in intermediate and severe henophilia patients was 23.59±17.02 scores and 26.69±17.68 scores respectively, there was no statistical difference (P>0.05). The joint fanction in hemophilia patients negatively correlated with life gnality of patients (r = 0.076). CONCLUSION The incidence of arthritis in hemophilia patients is high, and at least 1 joint has been involved in patients aged over 10 years old, moreover the multiple joint involvement exrsts in most patients. The impairment of joint function affects the routine behavious and activities.
Adolescent ; Adult ; Aged ; Child ; Child, Preschool ; Health Status ; Hemophilia A ; Hemophilia B ; Humans ; Middle Aged ; Young Adult

Factor VIII ; Hemophilia A ; Hemophilia B ; Humans

BACKGROUND: Korean National Health Insurance reimburses factor VIII (FVIII) and factor IX (FIX) clotting factor concentrate (CFC) infusions to discrepant activity levels, allowing elevation of FVIII activity to 60 IU/dL and FIX to 40 IU/dL. We aimed to assess hemostatic response to these target levels using global hemostatic assays. METHODS: We enrolled 34 normal healthy men, 34 patients with hemophilia A, and 36 with hemophilia B, with residual factor activity of 3 IU/dL or less and without inhibitors. Patients with hemophilia A and B received injected CFCs according to reimbursement guidelines. Fifteen minutes after injection, we assessed hemostatic response with global hemostatic assays: thrombin generation assay (TGA), thromboelastography (TEG), and clot waveform analysis (CWA). RESULTS: Normal healthy men and patients with hemophilia A and B were 36.7, 37.2, and 35.1 years old, respectively. FVIII and recombinant FIX concentrate doses were 28.8 IU/kg and 43.6 IU/kg. Post-infusion FVIII activity rose from 0.5 IU/dL to 69.4 IU/dL, while FIX activity rose from 1.4 IU/dL to 46.8 IU/dL. Post-infusion peak thrombin concentrations in hemophilia A and B were 116.6 nM/L and 76.4 nM/L (P < 0.001). Post-infusion endogenous thrombin potential (ETP) in hemophilia A and B was 1349.8 nM/min and 915.6 nM (P < 0.001). TEG index of hemophilia A and B was 0.11 and −0.51 (P=0.006). CONCLUSION: Current reimbursed doses for FIX concentrates are insufficient to achieve hemostatic responses comparable to those after reimbursed doses for FVIII concentrates in terms of peak thrombin concentration, ETP, and TEG index.
Factor IX* ; Factor VIII* ; Hemophilia A ; Hemophilia B ; Humans ; Male ; National Health Programs ; Thrombelastography ; Thrombin

Central venous access devices (CVAD) provide hemophilic patients, particularly children, with prolonged reliable venous access to promote routine factor replacement therapy. However, one of the significant complications of CVAD use is infection. We report the case of a severe hemophilia B patient with an inhibitor who developed septic arthritis and infective endocarditis associated with methicillin-resistant Staphylococcus aureus infection originating from a CVAD. Our patient had an underlying condition of congenital heart disease, one of the risk factors for infective endocarditis. Unfortunately, the antibiotic therapy did not have a significant effect. An echocardiogram revealed vegetation on the right ventricular moderate band and surgery was determined to be the best course of action. Septic arthritis and endocarditis rarely occur in hemophilia patients, however, they must be taken into account in hemophiliacs with continuing bacteremia.
Adolescent* ; Arthritis, Infectious* ; Bacteremia ; Child ; Endocarditis* ; Heart Defects, Congenital ; Heart Septal Defects, Ventricular ; Hemophilia A* ; Hemophilia B* ; Humans ; Methicillin-Resistant Staphylococcus aureus ; Risk Factors

Hemophilia is an X-linked recessive disorder, which is classified into hemophilia A, defined by factor VIII deficiency and hemophilia B, defined by factor IX deficiency. The usual clinical presentation is spontaneous bleeding and prolonged activated partial thromboplastin time in a person without history of a coagulation disorder. The severity of hemophilia describes how serious a problem is and has been defined by a traditional classification into three forms: severe, moderate, mild. Hemophilia has never been reported after a rhinosinus surgery in otorhinolaryngology in Korea, but we encountered a 37-year-old man with hemophilia B who had undergone a rhinosinus surgery. He had no bleeding tendency in the past nor a family history for bleeding. But the patient presented with continuous nasal bleeding for a few days after surgery. We report this case of hemophilia B diagnosed after rhinosinus surgery that was cured with Factor IX replacement therapy with a review of the relevant literature.
Adult ; Classification ; Endoscopy ; Epistaxis ; Factor IX ; Hemophilia A* ; Hemophilia B* ; Hemorrhage ; Humans ; Korea ; Otolaryngology ; Partial Thromboplastin Time

Objective:b> To assess the feasibility of HEAD-US scale in the clinical application of hemophilic arthropathy (HA) and propose an optimized ultrasound scoring system. Methods:b> From July 2015 to August 2017, 1 035 joints ultrasonographic examinations were performed in 91 patients. Melchiorre, HEAD-US (Hemophilic Early Arthropathy Detection with UltraSound) and HEAD-US-C (HEAD-US in China) scale scores were used respectively to analyze the results. The correlations between three ultrasound scales and Hemophilia Joint Health Scores (HJHS) were evaluated. The sensitivity differences of the above Ultrasonic scoring systems in evaluation of HA were compared. Results:b> All the 91 patients were male, with median age of 16 (4-55) years old, including 86 cases of hemophilia A and 5 cases hemophilia B. The median (P₂₅, P₇₅) of Melchiorre, HEAD-US and HEAD-US-C scores of 1 035 joints were 2(0,6), 1(0,5) and 2(0,6), respectively, and the correlation coefficients compared with HJHS was 0.747, 0.762 and 0.765 respectively, with statistical significance (P<0.001). The positive rates of Melchiorre, HEAD-US-C and HEAD-US scale score were 63.0% (95%CI 59.7%-65.9%), 59.5% (95%CI 56.5%-62.4%) and 56.6% (95%CI 53.6%-59.6%) respectively, and the difference was statistically significant (P<0.001). Even for 336 cases of asymptomatic joints, the positive rates of Melchiorre, HEAD-US-C and HEAD-US scale score were 25.0% (95%CI 20.6%-29.6%), 17.0% (95%CI 12.6%-21.1%) and 11.9% (95%CI 8.4%-15.7%) respectively, and the difference was statistically significant (P<0.001). There were significant changes (P<0.05) in the ultrasonographic score of HA before and after onset of hemorrhage in 107 joints of 40 patients. The difference in variation amplitude of HEAD-US-C scores and HEAD-US scores before and after joint bleeding was statistically significant (P<0.001). Conclusion:b> Compared with Melchiorre, there were similar good correlations between HEAD-US, HEAD-US-C and HJHS. HEAD-US ultrasound scoring system is quick, convenient and simple to use. The optimized HEAD-US-C scale score is more sensitive than HEAD-US, especially for patients with HA who have subclinical state, which make up for insufficiency of sensitivity in HEAD-US scoring system.
Adolescent ; Adult ; Child ; Child, Preschool ; China ; Hemarthrosis ; Hemophilia A ; Hemophilia B ; Humans ; Male ; Middle Aged ; Ultrasonography ; Young Adult

Objective:b> To evaluate the efficacy and safety of a domestic human plasma derived coagulation Factor Ⅸ concentrate (pd-FⅨ) in patients with hemophilia B. Methods:b> The study was a multicenter, open-label and single-arm study. The efficacy of pd-F Ⅸ was evaluated by objective performance criteria. The doses of pd-FⅨ were calculated according to the bleeding symptom and disease severity. The infusion efficiency of pd-FⅨ and improvement of bleeding symptoms were measured at 30 minutes and (24±4) h after the first infusion, respectively. Adverse events were recorded. Viral infection and FⅨ inhibitor were detected 90 d after the first infusion. Results:b> All 36 subjects with hemophilia B were enrolled in the study. The median age of these patients was 31 years old and the median injection doses were 4 (1-17) times. The hemostatic effect of 27/36 (75.00%) and 9/36 (25.00%) acute bleeding events were rated as "excellent" and "better" , respectively. The recovery rate was 111.92% (65.55%-194.28%) at 30 minutes after infusion of FⅨ. There was no adverse event related to FⅨ. No reactivation of HBV, HCV or HIV and FⅨ inhibitor was detected at 90-104 d after the first FⅨ infusion. Conclusion:b> This domestically made human plasma derived FⅨ concentrate is safe and effective in the treatment of acute bleeding in patients with hemophilia B. Clinical trial registration:b> China food and Durg Administration, 2016L08027.
Adult ; China ; Factor IX ; Hemophilia A ; Hemophilia B/therapy* ; Hemorrhage ; Humans ; Plasma