Patients' and parents' satisfaction with, and preference for, haemophilia A treatments: a cross-sectional, multicentre, observational study.

INTRODUCTION: Reports on patients' satisfaction and preferred characteristics for treatments would be worthwhile when choosing an optimal treatment reflecting patients' perspectives. AIM: To identify the characteristics and treatment patterns of patients with haemophilia A, or their caregivers, in Korea and explore patient preferences and satisfaction with their treatment. METHODS: This cross-sectional, multicentre, observational study was conducted from April 2018 to September 2019 at six nationwide hospitals and three Korea Hemophilia Foundation clinics. Patients aged ≥16 years, or legal caregivers of paediatric patients, who had used factor VIII (FVIII) concentrates for ≥1 month were enrolled. Satisfaction with treatment was measured using the Treatment Satisfaction Questionnaire for Medication (TSQM); preference was evaluated using discrete choice experiment (DCE), with 10 series of two hypothetical treatment options created from D-efficient block design, which varied across five attributes. RESULTS: Overall, 505 patients (mean age 31 years) were enrolled in the study. Patients had received FVIII concentrate for an average of 102.9 months (prophylaxis: 53.5%; on-demand: 22.2%). Mean TSQM scores were 64.6 (effectiveness domain), 97.9 (side effects), 57.1 (convenience) and 66.8 (global satisfaction). The number of vials per injection, and the frequency of drug administration, was significantly associated with treatment satisfaction. According to DCE, simpler treatment options were preferred by patients/caregivers. CONCLUSION: The lowest satisfaction levels were shown in the treatment convenience domain. Patients/parents preferred simpler and easier treatment characteristics. In an attempt to enhance the overall satisfaction of patients and caregivers with treatment, consideration of more convenient characteristics is required in future decisions regarding treatment selection.

Long-term safety and efficacy results from the phase 3b, open-label, multicentre Continuation study of rurioctocog alfa pegol for prophylaxis in previously treated patients with severe haemophilia A.

INTRODUCTION: Previous studies reported the efficacy and safety profile of extended half-life PEGylated recombinant factor VIII (FVIII) rurioctocog alfa pegol (TAK-660, SHP660, BAX 855) in preventing bleeding in haemophilia A patients. AIM: This study evaluated long-term safety and efficacy of rurioctocog alfa pegol for prophylaxis and treatment of bleeding in previously treated children and adults. METHODS: In this phase 3b, prospective, open-label, multicentre study (NCT01945593), eligible patients ≤ 75 years with severe haemophilia A (FVIII < 1%) received prophylactic rurioctocog alfa pegol in a fixed dose (FD, twice-weekly or less frequent) or pharmacokinetic (PK)-tailored dose regimen. Co-primary endpoints were incidence of confirmed FVIII inhibitory antibody development and spontaneous annualized bleed rate (ABR), analysed using a generalised linear model. Secondary endpoints included overall haemostatic efficacy, occurrence of adverse events and health-related quality of life (HRQoL). RESULTS: Overall, 216 patients were included; mean (SD) age at enrolment was 22.8 (15.7) years. No patients developed confirmed FVIII inhibitors. The point estimate (95% CI) of mean spontaneous ABR was 1.20 (0.92-1.56) among 186 patients receiving twice-weekly FD prophylaxis and 0.96 (0.54-1.71) among 25 patients receiving PK-tailored prophylaxis. Overall haemostatic efficacy was rated good or excellent in 88.6% of all bleeds. No new safety signals were observed. Patients reported improvements in HRQoL measures of pain, and physical and mental well-being. CONCLUSION: These results highlight the long-term safety and efficacy of rurioctocog alfa pegol prophylaxis in previously treated children and adults with severe haemophilia A, with a safety profile similar to previous studies and continuing ABR reduction.

Comparison of continuous infusion versus bolus injection of factor concentrates for blood management after total knee arthroplasty in patients with hemophilia.

BACKGROUND: Total knee arthroplasty (TKA) has become the treatment of choice for end-stage hemophilic arthropathy of the knee. Theoretically in hemophilia A, perioperative continuous infusion (CI) of factor VIII (FVIII) would provide a more consistent FVIII level than general bolus injections (BI) in TKA. Current study was designed to evaluate the effectiveness of CI of coagulation factor concentrates during the perioperative period compared to BI. METHODS: A total of 42 TKAs were performed in 31 patients with severe hemophilia A. Under the supervision of a multidisciplinary hemophilia team, CI and BI were monitored during application of a standardized regimen. Perioperative clinical parameters including postoperative hemoglobin drop, drained blood volume, transfusion rate, total consumption of FVIII, and perioperative complications were assessed. RESULTS: The difference in the postoperative hemoglobin drop was significant between two groups with a lower decrease in the CI group (p = 0.002). The drained blood volume for postoperative 24 h was significantly lower in the CI than the BI groups (p = 0.037). Total consumption of factor concentrates for postoperative 5 days was greater in the CI group than in the BI group (p = 0.000). One postoperative hematoma and wound dehiscence occurred in BI group and no other complication developed. CONCLUSIONS: Although good control of hemostasis could be achieved using either method during the perioperative period of TKA, CI seems more tolerable and effective than BI to provide perioperative blood management undergoing TKA in patients with hemophilia. TRIAL REGISTRATION: The study was retrospectively registered in WHO ICTRP under identifier KCT0002404 (date of registration: August 04, 2017).

Clinical and economic burden of immune tolerance induction in entire patients with hemophilia A: Insights from a real-world Korean setting.

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.

Clinical Application of Factor VIII:C to VWF:Ag Ratio for the Screening of Haemophilia A Carriers.

Analyses of factor VIII procoagulant activity (FVIII:C) and the FVIII:C to VWF:Ag ratio (FVIII:C/VWF:Ag ratio) have been investigated as screening bioassays to detect haemophilia carriers. This study aimed to determine the validity of the FVIII:C/VWF:Ag ratio and FVIII:C analyses as screening tests. We reviewed the medical records of 137 genetically confirmed, proband haemophilia A patients and 179 of their familial females who had undergone carrier testing. The collected data included the severity and mutation type of F8 gene from probands and age, ABO blood type, FVIII:C, VWF:Ag, and the result of targeted gene analysis in females. We diagnosed 110 females as carriers, and their FVIII:C and FVIII:C/VWF:Ag ratio were lower than those in 69 non-carriers (FVIII:C: 59.3 IU/dL vs. 106.1 IU/dL, p = 0.000; FVIII:C/VWF:Ag ratio: 0.62 vs. 1.08, p = 0.000). In receiver operating characteristic analysis, the areas under the curve (AUC) of the FVIII:C/VWF:Ag ratio and FVIII:C were 0.936 and 0.876, respectively. The cut-off value of FVIII:C/VWF:Ag ratio (0.81) at the maximum Youden J index provided a sensitivity of 82.8% and specificity of 96.6%. The cut-off value of FVIII:C (83.8 IU/dL) showed a sensitivity of 81.8% and specificity of 79.7%. Considering the AUC, the FVIII:C/VWF:Ag ratio is a good screening test to detect haemophilia A carriers, as evidenced by its specificity of 96.6%; however, it may also induce false-negative results.

Epidemiology and clinical long-term outcome of childhood aplastic anemia in Korea for 15 years: retrospective study of the Korean Society of Pediatric Hematology Oncology (KSPHO).

PURPOSE: Aplastic anemia (AA) is a rare hematologic disease characterized by pancytopenia and hypocellular marrow. The Korean Society of Pediatric Hematology Oncology investigated retrospectively the incidence, survival, and transfusion independency according to treatment strategies in AA. METHODS: All the questionnaires were sent to members for medical records. We collected and analyzed 702 available data. RESULTS: The male and female ratio was 1.2, and the median age at diagnosis was 9.3 years. The annual incidence of Korean children with AA was 5.16 per million per year. Constitutional anemia was diagnosed in 44 children. In acquired AA, causes were identified in 39 children. Severe AA (SAA) at initial diagnosis was more common than nonsevere AA. The overall survival was 47.8% with supportive care, 68.1% with immunosuppressive therapy (IST), and 81.8% with hematopoietic stem cell transplantation. In IST, response rate was 65.7%, and relapse rate after response was 54.4% within a median of 23.0 months. The factors with overall survival were severity of disease in supportive care, severity and response in IST, donor type, graft failure, and posttransplant events in hematopoietic stem cell transplantation. CONCLUSIONS: Long-term outcome in AA was dependent on treatment strategies. These Korean results may help research and prospective international clinical trials for childhood AA.

Thrombosis and severe acute respiratory syndrome coronavirus 2 vaccines: vaccine-induced immune thrombotic thrombocytopenia.

The development of vaccines against severe acute respiratory syndrome coronavirus 2, which features high mortality and morbidity rates, has progressed at an unprecedented rate, and vaccines are currently in use worldwide. Thrombotic events after vaccination are accompanied by thrombocytopenia, and this issue was recently termed vaccine-induced immune thrombotic thrombocytopenia. This manuscript describes recently published guidelines and other related issues and demonstrates characteristic cases.

Real-World Rates of Bleeding, Factor VIII Use, and Quality of Life in Individuals with Severe Haemophilia A Receiving Prophylaxis in a Prospective, Noninterventional Study.

Regular prophylaxis with exogenous factor VIII (FVIII) is recommended for individuals with severe haemophilia A (HA), but standardised data are scarce. Here, we report real-world data from a global cohort. Participants were men ≥18 years old with severe HA (FVIII ≤ 1 IU/dL) receiving regular prophylaxis with FVIII. Participants provided 6 months of retrospective data and were prospectively followed for up to 12 months. Annualised bleeding rate (ABR) and FVIII utilisation and infusion rates were calculated. Differences between geographic regions were explored. Of 294 enrolled participants, 225 (76.5%) completed ≥6 months of prospective follow-up. Pre-baseline and on-study, the median (range) ABR values for treated bleeds were 2.00 (0-86.0) and 1.85 (0-37.8), respectively; the median (range) annualised FVIII utilisation rates were 3629.0 (1008.5-13541.7) and 3708.0 (1311.0-14633.4) IU/kg/year, respectively; and the median (range) annualised FVIII infusion rates were 120.0 (52.0-364.0) and 122.4 (38.0-363.8) infusions/year, respectively. The median (range) Haemo-QoL-A Total Score was 76.3 (9.4-100.0) (n = 289), ranging from 85.1 in Australia to 67.7 in South America. Physical Functioning was the most impacted Haemo-QoL-A domain in 4/6 geographic regions. Despite differences among sites, participants reported bleeding requiring treatment and impaired physical functioning. These real-world data illustrate shortcomings associated with FVIII prophylaxis for this global cohort of individuals with severe HA.

Health-related quality of life of moderate and severe haemophilia patients: Results of the haemophilia-specific quality of life index in Korea.

The assessment of health-related quality of life (HRQoL) as a patient-reported outcome provides information about the patients' general well-being as well as the effects of the disease and its treatment. This study aimed to investigate HRQoL using both generic and haemophilia-specific QoL instruments and to assess the clinical factors associated with HRQoL among haemophilia patients in Korea. In this cross-sectional, multicenter, observational study, moderate-to-severe haemophilia patients aged 8-64 years were recruited between November 2012 and September 2013. The EQ-5D Questionnaire, EQ Visual Analogue Scale, and Haemophilia-Specific QoL (Haemo-QoL) Questionnaire (Haemo-QoL for 8-16 years and Haemo-A-QoL for ≥17 years) were used to assess HRQoL. A total of 605 participants with a mean age of 29.32 ± 12.62 years were enrolled. The mean Haemo-QoL scores revealed significant differences by age group (children vs. adolescent vs. adult, 26.44 ± 11.3 vs. 28.88 ± 11.1 vs. 38.43 ± 17.7, respectively, p < 0.001). "Sports and leisure," "family planning," and "view" in adults and "perceived support," "friends," and "dealing" in children and adolescents were identified as the domains with the greatest HRQoL impairments. HRQoL was significantly impaired in patients with the following clinical factors: hepatitis, haemophilia-induced disability, bleeding experiences within the last 6 months, joint bleedings within the last 6 months, and haemophilic arthropathy. According to the multivariate regression analysis, HRQoL showed a negative association with the presence of haemophilia-induced disability (ß = 0.222, p < 0.0001), bleeding experiences within the last 6 months (ß = 0.098, p = 0.010), and haemophilic arthropathy (ß = 0.212, p < 0.0001). HRQoL decreased in patients with older age and impaired clinical conditions among moderate-to-severe haemophilia patients in Korea. These study findings may provide significant insights into the adequate haemophilia management using patient-reported measurements.

Congenital factor V deficiency from compound heterozygous mutations with a novel variant c.2426del (p.Pro809Hisfs*2) in the F5 gene: A case report.

INTRODUCTION: Congenital factor V deficiency (FVD) is a rare bleeding disorder characterized by low or undetectable plasma factor V (FV) levels leading to mild to severe bleeding symptoms. Currently, more than 100 mutations have been reported in F5. We herein report a patient with FVD from mutations in the F5 gene. PATIENT CONCERNS: A 52-year-old man with prolonged prothrombin time and activated partial thromboplastin time corrected by mixing test on preoperative screening. His past medical or family history was not remarkable. DIAGNOSIS: Factor assays revealed a markedly reduced FV activity at 7%. Other factors were not decreased. DNA sequencing analysis to detect F5 gene mutations showed the patient was compound heterozygous for c.286G>C (p.Asp96His) and c.2426del (p.Pro809Hisfs*2). Asp96His was previously described missense mutation and Pro809Hisfs*2 was a novel deleterious mutation. INTERVENTIONS: Fresh-frozen plasma was administered to supplement FV before surgery. OUTCOMES: Subsequent factor assays revealed temporarily increased FV activity at 33%. CONCLUSION: As was the case in our patient, genotype-phenotype correlations are poor in FVD, and molecular genetic test is necessary to confirm the diagnosis.

Development and Validation of a Population-Pharmacokinetic Model for Rurioctacog Alfa Pegol (Adynovate®): A Report on Behalf of the WAPPS-Hemo Investigators Ad Hoc Subgroup.

BACKGROUND AND OBJECTIVE: Rurioctacog alfa pegol (Adynovate) is a modified recombinant factor VIII concentrate used for treating hemophilia A. Aiming to improve treatment tailoring on the Web-Accessible Population Pharmacokinetic Service-Hemophilia (WAPPS-Hemo) platform for patients of all ages treated with Adynovate, we have developed and evaluated a population pharmacokinetic (PopPK) model. On the platform, PopPK models are used as priors for Bayesian forecasting that derive individual PK of hemophilia patients and are subsequently used for personalized dose regimen design. METHODS: Factor activity measurements and demographic covariate data from patients infused with Adynovate were extracted from the WAPPS-Hemo database. Evaluations testing the appropriateness of Bayesian forecasting included 10-fold cross validation, a limited sampling analysis (LSA), and an external evaluation using additional independent data extracted from the WAPPS-Hemo database at a later date. RESULTS: The model was constructed using 650 plasma factor activity observations (555 one stage assay and 95 chromogenic assay - 4.6% below limit of quantification) measured in 154 patients from 36 hemophilia centres. A two-compartment model including between subject variability on clearance and central volume was selected as the base model. Covariates were fat free mass on clearance and central volume, age on clearance and assay type on activity. The final model was well-suited to predict PK parameters of new individuals (n = 26) from sparse observations. CONCLUSIONS: The development of a PopPK model for Adynovate using real-world data increases the covariate space (e.g. age) beyond what is possible from clinical trial data. This model is available on the WAPPS-Hemo platform for tailoring treatment in hemophilia A patients.

Subgroup analysis of a phase 2/3 study of rurioctocog alfa pegol in patients with severe hemophilia A: efficacy and safety in previously treated Korean patients.

BACKGROUND: The efficacy and safety of extended half-life, full-length, pegylated recombinant factor VIII rurioctocog alfa pegol [BAX 855, ADYNOVATE (USA)/ADYNOVI (Europe); Baxalta US Inc., a Takeda company, Lexington, MA, USA] was investigated in previously treated Korean patients with severe hemophilia A (HA). METHODS: A post hoc data analysis from the international, multicenter, phase 2/3 PROLONG-ATE study of rurioctocog alfa pegol in patients with severe HA (NCT01736475) determined annualized bleeding rates (ABRs) and rates of adverse events (AEs) in Korean patients treated in this study. RESULTS: All 10 enrolled Korean patients receiving rurioctocog alfa pegol (9 prophylaxis, 1 on-demand) completed the study [median (range) age, 28.0 (12-50) yr; weight, 64.8 (45-90) kg; 8 patients had ≥1 target joint at screening]. Median (range) ABR was 1.9 (0.0-14.5) for patients on prophylaxis and 62.2 for the patient receiving on-demand treatment. The hemostatic efficacy of rurioctocog alfa pegol was rated "excellent" or "good" and only single infusions were required per bleeding episode. ABRs improved in most patients compared with prestudy values. No dose adjustments were required for prophylaxis, and the dosing frequency was reduced in 8 patients, compared with their previous prophylaxis regimen. No serious AEs were reported; all 9 nonserious AEs (in 3 patients) were mild in severity and unrelated to the study treatment. CONCLUSION: This post hoc analysis of a small group of Korean patients with severe HA indicated that rurioctocog alfa pegol was effective, and no serious AEs were observed. For most patients, the dosing frequency was also reduced compared with their previous regimen.

Allogeneic hematopoietic stem cell transplantation in congenital hemoglobinopathies with myeloablative conditioning and rabbit anti-thymocyte globulin.

BACKGROUND: Allogeneic hematopoietic stem cell transplantation (HSCT) is a curative therapy for ß-thalassemia major (TM) and sickle cell disease (SCD) in children. Graft-versus-host disease (GVHD) and treatment-related mortality (TRM) remain significant challenges to improving survival after HSCT. Here, we analyzed the outcome of TM and SCD patients, who received allogeneic HSCT with myeloablative conditioning at our institution. METHODS: Twenty-two patients (15 TM, 7 SCD), with a median age of 9 years (range, 1.6-16.9), underwent allogeneic HSCT using busulfan, cyclophosphamide and rabbit anti-thymocyte globulin-based conditioning. Cells were derived from either the bone marrow (8 patients), or peripheral blood stem cells (14 patients). The majority of patients received HSCT from a matched sibling donor (N=18). GVHD prophylaxis included cyclosporine and short course methotrexate. RESULTS: All patients achieved donor engraftment. Two SCD patients died from TRM-related grade IV gut GVHD (N=1) or severe bronchiolitis obliterans (BO) (N=1). Cumulative incidence of acute and chronic GVHD was 36.4% and 32.7%, respectively. Veno-occlusive disease (VOD) occurred in 8 patients (36.4%), but resolved in all instances. Epstein-Barr virus (EBV)-related post-transplantation lymphoproliferative disease (PTLD) occurred in 1 patient. The overall survival (OS) was 90.9% (TM 100%, SCD 71.4%), with all patients achieving transfusion independence, while 8 achieved complete donor chimerism. CONCLUSION: Busulfan, cyclophosphamide, and ATG-based conditioning for HSCT of TM and SCD patients did not result in graft failure, although modifications may be required to reduce VOD incidence. Further changes to donor type and cell source prioritization are necessary to minimize TRM and morbidity caused by GVHD.

Availability of angiography and therapeutic embolization for the treatment of acute bleeding in patients with hemophilia.

Clotting factor replacement therapy alone is often inadequate for acute bleeding in hemophilia patients, and surgery for such patients poses significant clinical challenges. Arterial angiographic intervention is used to control bleeding in local blood vessels. In the present study, we examined the clinical course and prognosis of hemophilia patients with bleeding who had undergone angiography, and evaluated the validity of diagnostic angiography and therapeutic embolization in these patients. Angiography was performed in five hemophilia patients, who experienced bleeding that was difficult to control even after treatment with clotting factor replacement or bypassing agent therapy. Of these patients, four were confirmed to have continued bleeding, and angiographic embolization was performed using clotting factor concentrates or bypassing agents. However, one patient developed uncontrollable bleeding at the puncture site, which eventually led to the patient's death. Thus, angiography and therapeutic embolization may be the preferred procedures for the treatment of hemorrhagic complications, refractory to treatment with clotting factor concentrates or bypassing agents. Further comprehensive, multidisciplinary team studies are needed to develop effective strategies to reduce hemorrhagic complications.

Clinical Characteristics and Prognostic Factors in Hemophiliacs with Intracranial Hemorrhage: A Single-Center, Retrospective Experience.

Intracranial hemorrhage (ICH) is the most serious bleeding event that occurs in patients with hemophilia; its estimated mortality rate is approximately 20 %, accounting for the largest number of deaths from bleeding. We conducted this single-center, retrospective study to examine the characteristics of and prognostic factors in patients with hemophilia. A comprehensive review of 12 cases of intracranial hemorrhage (ICH) among 10 patients. All 12 cases of ICH in the 10 patients were treated with clotting factor concentrates. Three patients had intracerebral hemorrhage that required neurosurgical intervention. After presenting with ICH, two pediatric patients developed antibodies to clotting factors. Two adult patients with intracerebral hemorrhage died, and the mortality rate was thus 20.0 % (2/10) in our clinical series. Prompt and intensive treatment with clotting factor concentrates may significantly lower the mortality rate among patients with hemophilia presenting with ICH. Our results showed a better prognosis in pediatric patients with intracerebral hemorrhage. Clinicians should pay special attention to the possible development of inhibitors after intensive treatment in pediatric patients. Further studies are needed to examine methods for administering clotting factor concentrates and to determine whether neurosurgical intervention is essential in each case.

The efficacy of bypassing agents in surgery of hemophilia patients with inhibitors.

BACKGROUND: Inhibitory antibodies to factor VIII (FVIII) or IX (FIX) are important issues when managing patients with hemophilia A or B. Advances in bypassing agents such as recombinant activated FVII (rFVIIa) and activated prothrombin complex concentrates (APCC) have enabled the aggressive management of hemophilia with inhibitors during emergency or elective surgery. This study provides an updated evaluation of the safety and effectiveness of bypassing agents in treating perioperative bleeding. METHODS: We reviewed the records of hemophilia patients with inhibitors who underwent surgery between May 2008 and July 2014 using bypassing agents or high-dose FVIII concentrates at a single center. RESULTS: In total, 36 surgeries (24 orthopedic, 12 other) were conducted in 18 hemophilia patients with inhibitors. The median inhibitor titer at surgery was 14 (range, 0.7-1,900) Bethesda units. Most patients had high-responding inhibitors. In total, 25 patients received APCC, 9 with rFVIIa initially. In most cases, bleeding stopped or was well controlled; however, bleeding in 6 patients was controlled using sequential bypassing therapy. Hemostatic efficacy of bypassing agents in various surgeries, based on the final patient outcome, was 94.4% (34/36). Among 5 emergency surgeries, 2 deaths occurred. CONCLUSION: Good control of hemostasis can be achieved using bypassing agents in hemophilia patients with inhibitors who are undergoing surgery. Thorough planning is needed before elective surgery and more active and aggressive management may be needed for emergency surgery. Use of bypassing agents can facilitate safe and successful surgeries in hemophilia patients with inhibitors.

Immune tolerance induction in patients with severe hemophilia A with inhibitors.

BACKGROUND: Inhibitory antibodies to factor VIII (FVIII) are an important complication when managing patients with hemophilia A. Immune tolerance induction (ITI) has been regarded as a useful method for eradicating inhibitors. We report the results of a retrospective study in Korean patients with hemophilia A who underwent ITI. METHODS: We reviewed the records of patients with hemophilia A with inhibitors who underwent ITI from March 2004 to December 2014. ITI was started with FVIII concentrates at 100 IU/kg, 3 times per week. The dose of FVIII was reduced according to the inhibitor titer and recovery of FVIII. Inhibitor elimination was defined as the time taken to achieve a negative inhibitor assay with no anamnestic response and normal FVIII recovery and/or normal half-life. RESULTS: In total, 17 patients with severe hemophilia A were evaluated. Complete tolerance was achieved in 14 of 17 patients (83%). The mean peak inhibitor titer before ITI was 38.4 BU/mL. The mean treatment duration was 26.2 months. The mean duration between inhibitor detection and ITI was 5.1 years in the complete tolerance group and 10.8 years in the partial tolerance and failed group. CONCLUSION: This study shows that ITI can be an effective and well-tolerated method for eradicating inhibitors. Possible influencing factors for ITI success were age at the start of ITI treatment and duration after inhibitor detection. More research to provide further insight about other factors and conditions is needed.

Novel and recurrent mutations in the F13A1 gene in unrelated Korean patients with congenital factor XIII deficiency.

Congenital factor XIII (FXIII) deficiency is a rare autosomal recessive bleeding disorder mainly caused by mutations in the F13A1 gene on 6p25.1, which lead to defective A subunit of FXIII. We herein describe two unrelated Korean patients with congenital FXIII deficiency. Proband 1 (a 30-year-old man) and Proband 2 (a 10-year-old girl) presented with severe bleeding episodes (huge intramuscular hematoma and acute intracerebral hemorrhage). Coagulation screening tests for bleeding diathesis were normal, but the FXIII activity was undetectable on urea clot lysis assay. The molecular genetic analysis of F13A1 revealed two mutations in the patients: Proband 1 was homozygous for a previously reported mutation c.1984C>T (p.Arg662) and Proband 2 was compound heterozygous for c.1029T>A (p.His343Gln) and c.1984C>T (p.Arg662). His343Gln was a novel missense mutation occurring in the core domain of the FXIII A subunit. This is the first report of genetically confirmed FXIII deficiency in Korea, with novel and recurrent F13A1 mutations.