Phase 3 Trial of Concizumab in Hemophilia with Inhibitors.

BACKGROUND: Concizumab is an anti-tissue factor pathway inhibitor monoclonal antibody designed to achieve hemostasis in all hemophilia types, with subcutaneous administration. A previous trial of concizumab (explorer4) established proof of concept in patients with hemophilia A or B with inhibitors. METHODS: We conducted the explorer7 trial to assess the safety and efficacy of concizumab in patients with hemophilia A or B with inhibitors. Patients were randomly assigned in a 1:2 ratio to receive no prophylaxis for at least 24 weeks (group 1) or concizumab prophylaxis for at least 32 weeks (group 2) or were nonrandomly assigned to receive concizumab prophylaxis for at least 24 weeks (groups 3 and 4). After a treatment pause due to nonfatal thromboembolic events in three patients receiving concizumab, including one from the explorer7 trial, concizumab therapy was restarted with a loading dose of 1.0 mg per kilogram of body weight, followed by 0.2 mg per kilogram daily (potentially adjusted on the basis of concizumab plasma concentration as measured at week 4). The primary end-point analysis compared treated spontaneous and traumatic bleeding episodes in group 1 and group 2. Safety, patient-reported outcomes, and pharmacokinetics and pharmacodynamics were also assessed. RESULTS: Of 133 enrolled patients, 19 were randomly assigned to group 1 and 33 to group 2; the remaining 81 were assigned to groups 3 and 4. The estimated mean annualized bleeding rate in group 1 was 11.8 episodes (95% confidence interval [CI], 7.0 to 19.9), as compared with 1.7 episodes (95% CI, 1.0 to 2.9) in group 2 (rate ratio, 0.14 [95% CI, 0.07 to 0.29]; P<0.001). The overall median annualized bleeding rate for patients receiving concizumab (groups 2, 3, and 4) was 0 episodes. No thromboembolic events were reported after concizumab therapy was restarted. The plasma concentrations of concizumab remained stable over time. CONCLUSIONS: Among patients with hemophilia A or B with inhibitors, the annualized bleeding rate was lower with concizumab prophylaxis than with no prophylaxis. (Funded by Novo Nordisk; explorer7 ClinicalTrials.gov number, NCT04083781.).

Fitusiran prophylaxis in people with hemophilia A or B who switched from prior BPA/CFC prophylaxis: the ATLAS-PPX trial.

ABSTRACT: Fitusiran, a subcutaneous investigational small interfering RNA therapeutic, targets antithrombin to rebalance hemostasis in people with hemophilia A or B (PwHA/B), irrespective of inhibitor status. This phase 3, open-label study evaluated the efficacy and safety of fitusiran prophylaxis in males aged ≥12 years with hemophilia A or B, with or without inhibitors, who received prior bypassing agent (BPA)/clotting factor concentrate (CFC) prophylaxis. Participants continued their prior BPA/CFC prophylaxis for 6 months before switching to once-monthly 80 mg fitusiran prophylaxis for 7 months (onset and efficacy periods). Primary end point was annualized bleeding rate (ABR) in the BPA/CFC prophylaxis and fitusiran efficacy period. Secondary end points included spontaneous ABR (AsBR) and joint ABR (AjBR). Safety and tolerability were assessed. Of 80 enrolled participants, 65 (inhibitor, n = 19; noninhibitor, n = 46) were eligible for ABR analyses. Observed median ABRs were 6.5 (interquartile range [IQR], 2.2-19.6)/4.4 (IQR, 2.2-8.7) with BPA/CFC prophylaxis vs 0.0 (IQR, 0.0-0.0)/0.0 (IQR, 0.0-2.7) in the corresponding fitusiran efficacy period. Estimated mean ABRs were substantially reduced with fitusiran by 79.7% (P = .0021) and 46.4% (P = .0598) vs BPA/CFC prophylaxis, respectively. Forty-one participants (63.1%) experienced 0 treated bleeds with fitusiran vs 11 (16.9%) with BPAs/CFCs. Median AsBR and AjBR were both 2.2 with BPA/CFC prophylaxis and 0.0 in the fitusiran efficacy period. Two participants (3.0%) experienced suspected or confirmed thromboembolic events with fitusiran. Once-monthly fitusiran prophylaxis significantly reduced bleeding events vs BPA/CFC prophylaxis in PwHA/B, with or without inhibitors, and reported adverse events were generally consistent with previously identified risks of fitusiran. This trial was registered at www.ClinicalTrials.gov as #NCT03549871.

Efficacy and safety of fitusiran prophylaxis in people with haemophilia A or haemophilia B with inhibitors (ATLAS-INH): a multicentre, open-label, randomised phase 3 trial.

BACKGROUND: Fitusiran, a subcutaneous investigational small interfering RNA therapeutic, targets antithrombin to rebalance haemostasis in people with haemophilia A or haemophilia B, irrespective of inhibitor status. We evaluated the efficacy and safety of fitusiran prophylaxis in people with haemophilia A or haemophilia B with inhibitors. METHODS: This multicentre, randomised, open-label phase 3 study was done at 26 sites (primarily secondary or tertiary centres) in 12 countries. Men, boys, and young adults aged 12 years or older with severe haemophilia A or haemophilia B with inhibitors previously treated with on-demand bypassing agents were randomly assigned (2:1) to receive once-a-month 80 mg subcutaneous fitusiran prophylaxis (fitusiran prophylaxis group) or to continue with bypassing agents on-demand (bypassing agents on-demand group) for 9 months. The primary endpoint was mean annualised bleeding rate during the efficacy period in the intention-to-treat population estimated by negative binomial model. Safety was assessed as a secondary endpoint in the safety population. This trial is complete and is registered with ClinicalTrials.gov, NCT03417102. FINDINGS: Between Feb 14, 2018, and June 23, 2021, 85 participants were screened for inclusion, of whom 57 (67%; 57 [100%] men; median age 27·0 years [IQR 19·5-33·5]) were randomly assigned: 19 (33%) participants to the bypassing agent on-demand group and 38 (67%) participants to the fitusiran prophylaxis. Negative binomial model-based mean annualised bleeding rate was significantly lower in the fitusiran prophylaxis group (1·7 [95% CI 1·0-2·7]) than in the bypassing agents on-demand group (18·1 [10·6-30·8]), corresponding to a 90·8% (95% CI 80·8-95·6) reduction in annualised bleeding rate in favour of fitusiran prophylaxis (p<0·0001). 25 (66%) participants had zero treated bleeds in the fitusiran prophylaxis group versus one (5%) in the bypassing agents on-demand group. The most frequent treatment-emergent adverse event in the fitusiran prophylaxis group was increased alanine aminotransferase in 13 (32%) of 41 participants in the safety population; there were no increased alanine aminotransferase treatment-emergent adverse events in the bypassing agents on-demand group. Suspected or confirmed thromboembolic events were reported in two (5%) participants in the fitusiran prophylaxis group. No deaths were reported. INTERPRETATION: Subcutaneous fitusiran prophylaxis resulted in statistically significant reductions in annualised bleeding rate in participants with haemophilia A or haemophilia B with inhibitors, with two-thirds of participants having zero bleeds. Fitusiran prophylaxis might show haemostatic efficacy in participants with haemophilia A or haemophilia B with inhibitors; therefore, the therapeutic might have the potential to improve the management of people with haemophilia. FUNDING: Sanofi.

Clinical data on treatment regimen and use of medication among patients with hemophilia B in Korea.

BACKGROUND: To investigate the clinical treatment status, such as treatment regimen, bleeding events, and drug dose, in patients with hemophilia B in South Korea. METHODS: In this retrospective chart review, data of patients with hemophilia B from eight university hospitals were collected. Demographic and clinical data, treatment data, such as regimen and number of injections, dose of factor IX concentrate, and bleeding data were reviewed. Descriptive analyses were performed with annual data for 2019, 2020, and 2021, as well as the three years consecutively. RESULTS: The medical records of 150 patients with hemophilia B between January 1, 2019, and December 31, 2021, were collected. Among these, 72 (48.0%) were severe, 47 (31.3%) were moderate, and 28 (18.7%) were mild. The results showed approximately two times more patients receiving prophylaxis as those receiving on-demand therapy, with 66.1% of patients receiving prophylaxis in 2019, 64.9% in 2020, and 72.1% in 2021. Annualized bleeding rates were 2.2% (± 3.1) in 2019, 1.8% (± 3.0) in 2020, and 1.8% (± 2.9) in 2021 among patients receiving prophylaxis. For the doses of factor IX concentrate, patients receiving prophylaxis received an average of 41.6 (± 11.9) IU/Kg/Injection in 2019, 45.7 (± 12.9) IU/Kg/Injection in 2020, and 60.1 (± 24.0) IU/Kg/Injection in 2021. CONCLUSIONS: Clinically, prophylaxis is more prevalent than reported. Based on insights gained from current clinical evidence, it is expected that the unmet medical needs of patients can be identified, and physicians can evaluate the status of patients and actively manage hemophilia B using more effective treatment strategies.

Fitusiran prophylaxis in people with severe haemophilia A or haemophilia B without inhibitors (ATLAS-A/B): a multicentre, open-label, randomised, phase 3 trial.

BACKGROUND: Fitusiran, a subcutaneous investigational siRNA therapeutic, targets antithrombin with the goal of rebalancing haemostasis in people with haemophilia A or haemophilia B, regardless of inhibitor status. We aimed to evaluate the efficacy and safety of fitusiran prophylaxis in people with severe haemophilia without inhibitors. METHODS: This multicentre, open-label, randomised phase 3 study was conducted at 45 sites in 17 countries. Male participants aged at least 12 years with severe haemophilia A or B without inhibitors, who had previously been treated on-demand with clotting factor concentrates, were randomly assigned in a 2:1 ratio to receive 80 mg subcutaneous fitusiran prophylaxis once per month or to continue on-demand clotting factor concentrates for a total of 9 months. Randomisation was stratified by the number of bleeding events in the 6 months before screening (≤10 bleeds and >10 bleeds) and by haemophilia type (haemophilia A or B). The primary endpoint was annualised bleeding rate, analysed in the intention-to-treat analysis set. Safety and tolerability were assessed in the safety analysis set. This trial is registered with ClinicalTrials.gov, NCT03417245, and is complete. FINDINGS: Between March 1, 2018, and July 14, 2021, 177 male participants were screened for eligibility and 120 were randomly assigned to receive fitusiran prophylaxis (n=80) or on-demand clotting factor concentrates (n=40). Median follow-up was 7·8 months (IQR 7·8-7·8) in the fitusiran group and 7·8 months (7·8-7·8) in the on-demand clotting factor concentrates group. The median annualised bleeding rate was 0·0 (0·0-3·4) in the fitusiran group and 21·8 (8·4-41·0) in the on-demand clotting factor concentrates group. The estimated mean annualised bleeding rate was significantly lower in the fitusiran prophylaxis group (3·1 [95% CI 2·3-4·3]) than in the on-demand clotting factor concentrates group (31·0 [21·1-45·5]; rate ratio 0·101 [95% CI 0·064-0·159]; p<0·0001). In the fitusiran group, 40 (51%) of 79 treated participants had no treated bleeds compared with two (5%) of 40 participants in the on-demand clotting factor concentrates group. Increased alanine aminotransferase concentration (18 [23%] of 79 participants in the safety analysis set) was the most common treatment-emergent adverse event in the fitusiran group and hypertension (four (10%) of 40 participants) was the most common in the on-demand clotting factor concentrates group. Treatment-emergent serious adverse events were reported in five (6%) participants in the fitusiran group (cholelithiasis [n=2, 3%], cholecystitis [n=1, 1%], lower respiratory tract infection [n=1, 1%], and asthma [n=1, 1%]) and five (13%) participants in the on-demand clotting factor concentrates group (gastroenteritis, pneumonia, suicidal ideation, diplopia, osteoarthritis, epidural haemorrhage, humerus fracture, subdural haemorrhage, and tibia fracture [all n=1, 3%]). No treatment-related thrombosis or deaths were reported. INTERPRETATION: In participants with haemophilia A or B without inhibitors, fitusiran prophylaxis resulted in significant reductions in annualised bleeding rate compared with on-demand clotting factor concentrates and no bleeding events in approximately half of participants. Fitusiran prophylaxis shows haemostatic efficacy in both haemophilia A and haemophilia B, and therefore has the potential to be transformative in the management of all people with haemophilia. FUNDING: Sanofi.

Heterogeneous lengths of copy number mutations in human coagulopathy revealed by genome-wide high-density SNP array.

BACKGROUND: The recent advent of genome-wide molecular platforms has facilitated our understanding of the human genome and disease, particularly copy number aberrations. We performed genome-wide single nucleotide polymorphism-array in hereditary coagulopathy to delineate the extent of copy number mutations and to assess its diagnostic utility. DESIGN AND METHODS: The study subjects were 17 patients with hereditary coagulopathy from copy number mutations in coagulation genes detected by multiple ligation-dependent probe amplification. Eleven had hemophilia (7 hemophilia A and 4 hemophilia B) and 6 had thrombophilia (4 protein S deficiency and 2 antithrombin deficiency). Single nucleotide polymorphism-array experiments were performed using Affymetrix Genome-Wide Human SNP arrays 6.0. RESULTS: Copy number mutations were identified by single nucleotide polymorphism-array in 9 patients, which ranged in length from 51 Kb to 6,288 Kb harboring 2 to ~160 genes. Single nucleotide polymorphism-array showed a neutral copy number status in 8 patients including 7 with either a single-exon copy number mutation or duplication mutations of PROS1. CONCLUSIONS: This study revealed unexpectedly heterogeneous lengths of copy number mutations underlying human coagulopathy. Single nucleotide polymorphism-array had limitations in detecting copy number mutations involving a single exon or those of a gene with homologous sequences such as a pseudogene.

Clinical Analysis of Hospitalized Patients with Hemophilia A: Single-hemophilia Treatment Center Experience in Korea over 10 years.

BACKGROUND: There is lack of data on admitted hemophilia patients in Korea. For this reason, this study was intended to analyze the hospitalization data of hemophilia patients in a regional Hemophilia Treatment Center (HTC) for the first time in Korea. METHODS: In this retrospective study, we surveyed hospitalized patients with Hemophilia A (HA) in a HTC for 14 years. Medical records of these hemophiliacs were reviewed and data regarding demographic characteristics, cause of admissions and their outcomes in each patient were obtained. In addition, the data of admitted days, type and amount of Coagulation factor concentrate (CFC) used, treatments other than CFC infusion during the admission days were also obtained from the medical record of each patient. RESULTS: A total 107 patients with hemophilia A were admitted during 14 years. Annual rate of admission of patients with HA was 8%. Mean age on admission was 29.63±19.51 years old and mean admission days were 11.28±5.46 days. Most admissions were occurred in severe and moderate hemophilia patients. The most common cause of admission was bleed control followed by surgery and other reasons. With modified WFH CFC supplementation guideline, all the bleeds were successfully controlled and all surgeries were also successfully conducted with less total CFC consumption compared to the consumed dose of other reports. CONCLUSION: These results suggest that it is necessary to develop more specified regimens different from WFH.

Safety, pharmacokinetics, and pharmacodynamics of a next-generation subcutaneously administered coagulation factor IX variant, dalcinonacog alfa, in previously treated hemophilia B patients.

BACKGROUND: Dalcinonacog alfa (DalcA), a next-generation, recombinant human factor IX (FIX) variant, was developed using a rational design approach for increased procoagulant activity and longer duration of action to be administered subcutaneously (SC) for prophylaxis of hemophilia B bleeding episodes. OBJECTIVES: To investigate the safety, pharmacokinetics (PK), and pharmacodynamics (PD) of DalcA. METHODS: This multicenter, phase 1/2a study (NCT03186677) was conducted in 11 males aged 12 to 65 years with severe hemophilia B. In cohort 1, subjects received intravenous (IV) 75 IU/kg BeneFIX and DalcA. Cohorts 2 and 3 had DalcA IV 75 IU/kg and SC 75 IU/kg or 150 IU/kg. Cohort 4 was omitted. Cohort 5 received daily SC 150 IU/kg DalcA for 6 days and cohort 6 received IV 75 IU/kg and daily SC 150 IU/kg DalcA for 9 days. Blood sampling was performed for chemistry, hematology, PK, PD, and anti-drug antibody measurement. Subjects were monitored for safety endpoints for 30 days postdosing. RESULTS: DalcA demonstrated a 24-fold greater potency over BeneFIX and longer mean residence time (33.8 h). SC bioavailability 8.2% to 20.3%, beta half-life 53.9 to 106.9 h and Tmax 24 to 48 h. A median 15.7% FIX activity level (interquartile range, 14.9%-16.6%) was reached after 6 daily doses. Neutralizing antibodies to ISU304, but not wild-type FIX, occurred in two cousins. CONCLUSIONS: The data demonstrated that DalcA achieved protective FIX activity levels between 11% and 18%, corresponding to a reduced chance of spontaneous bleeds. Based on the results, a phase 2b trial to assess the safety and efficacy of 28 daily SC doses of DalcA was performed.

Long-term safety and efficacy of N8-GP in previously treated adults and adolescents with hemophilia A: Final results from pathfinder2.

BACKGROUND: N8-GP (turoctocog alfa pegol; Esperoct® , Novo Nordisk A/S, Bagsvaerd, Denmark) is a glycoPEGylated human recombinant factor VIII with a half-life of ~1.6-fold of standard FVIII products. pathfinder2 (NCT01480180) was a multi-national, open-label trial of N8-GP in previously treated adolescent and adult patients with severe hemophilia A. OBJECTIVE: We report end-of-trial efficacy and safety of N8-GP from pathfinder2. METHODS: pathfinder2 main phase and extension phase part 1 results have been previously reported. During extension phase part 2, patients could switch from N8-GP prophylaxis 50 IU/kg every fourth day (Q4D) or 75 IU/kg once weekly (Q7D), depending on bleeding status. Extension phase part 2 collected long-term safety and efficacy data for all regimens until trial end (first patient in main phase, 30 January 2012; trial end, 10 December 2018). RESULTS: Overall, 186 patients were exposed to N8-GP for up to 6.6 years (median 5.4 years). The estimated annualized bleeding rate (ABR) was 2.14 (median 0.84) for the Q4D prophylaxis arm and 1.31 (median 1.67) for the Q7D prophylaxis arm. Nearly 30% of patients experienced zero bleeds throughout the entire duration of the trial, the hemostatic response was 83.2% across all treatment arms, and patient-reported outcomes were maintained or slightly improved. No safety concerns were detected. CONCLUSION: Data from the completed pathfinder2 trial, one of the largest and longest-running clinical trials to investigate treatment of severe hemophilia A, demonstrate the efficacy and safety of N8-GP in previously treated adolescent and adult patients.

The prevalence and risk factors of inhibitor development of FVIII in previously treated patients with hemophilia A.

BACKGROUND: Risk factors for the development of inhibitors in previously untreated patients (PUPs) have been reported; this is not the case in previously treated patients (PTPs) owing to fewer studies. Risk factors may differ for the development of PTP versus PUP inhibitors. We aimed to identify risk factors for PTP inhibitor development. METHODS: Participants were patients at a hemophilia treatment center in Korea with current or past history of factor VIII or factor IX alloantibodies. Observed inhibitors were classified as PUP or PTP inhibitors based on the cumulative number of exposure days. We compared the type and severity of hemophilia, mutation type, and family history of inhibitor between PUPs and PTPs. Events within 3 months before the first inhibitor detection, such as change of the factor concentrate used, short-term high exposure or continuous infusion of factor concentrate, history of surgery, infection, diagnosis of cancer, use of immunosuppressive or immunomodulator agents, and vaccination were compared between PUPs and PTPs. RESULTS: We observed 5 PUP inhibitors and 5 PTP inhibitors in 115 patients with hemophilia A. Events that might be related to the development of inhibitors within 3 months prior to the first inhibitor detection were observed in all 5 PTPs. On the contrary, no such events were observed in any PUPs. The observed events included a change in the factor concentrate used, subsequent chemotherapy, and short-term high exposure to factor concentrates for controlling hemorrhage and surgeries. CONCLUSION: Our results suggest a greater role of nongenetic factors in PTP inhibitor development.

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.

A Combined Ultrasonographic and Conventional Radiographic Assessment of Hemophilic Arthropathy.

Hemophilic arthropathy (HA) can be diagnosed by a number of imaging studies. However, it is difficult with conventional radiography to find soft tissue structures around joints, and ultrasonography has limited effectiveness in evaluating internal bony structures. We attempt to determine whether a combination of ultrasonography for soft tissue around joints and conventional radiography for bony structures can be used as a cost-effective imaging tool for evaluating HA and whether it reflects the functional status of hemophilic patients. Thirty-six males (median age 16.5 years; severe 34, mild 2) with hemophilia were recruited. We evaluated the severity of HA using combined imaging score that consisted of modified Petterson X-ray score (mPXS) and the modified ultrasonographic score (mUS). Joint impairment was clinically assesses using the World Federation of Hemophilia-Physical Examination (WFH-PE) scale and the Hemophilic joint health score (HJHS). We assessed the Hemophilia activities list (HAL) for the functional level. We performed a comparative analysis between the combined imaging score and the joint impairment scores as well as the functional scores. The mean mUS was 4.97 ± 3.99 points, and the mean mPXS was 2.85 ± 2.91 points; the combined imaging score was 7.83 ± 6.31 points. The combined imaging score was significantly correlated with the HJHS (p = 0.006) and WFH-PE scores (p = 0.019) as well as the HAL score (p = 0.002). A combination of conventional radiological and ultrasongraphic study might ultimately impact the optimal evaluation of joint impairment and functional status in hemophilic patients.

Clinical evaluation of glycoPEGylated recombinant FVIII: Efficacy and safety in severe haemophilia A.

Turoctocog alfa pegol (N8-GP) is a novel glycoPEGylated extended half-life recombinant factor VIII (FVIII) product developed for prophylaxis and treatment of bleeds in patients with haemophilia A, to enable higher activity levels with less frequent injections compared with standard FVIII products. This phase III (NCT01480180), multinational, open-label, non-randomised trial evaluated the safety and clinical efficacy of N8-GP when administered for treatment of bleeds and for prophylaxis, in previously treated patients aged ≥12 years with severe haemophilia A. Patients were allocated to receive N8-GP for prophylaxis or on-demand treatment for up to 1.8 years. Patients on prophylaxis were administered one dose of 50 IU/kg of N8-GP every fourth day. Bleeds were treated with doses of 20-75 IU/kg. Total exposure to N8-GP in the trial was 14,114 exposure days (159 patient-years). For the prophylaxis arm (n=175), the median annualised bleeding rate (ABR) was 1.33 (interquartile range, 0.00-4.61), the mean ABR was 3.70 (95 % confidence interval 2.94-4.66) and 70 (40 %) patients had no bleeds during the trial. Across treatment arms, 83.6 % of bleeds resolved with one injection and 95.5 % with up to two injections. N8-GP had a favourable safety profile and was well tolerated. The frequency and types of adverse events reported were as expected in this population. One patient developed inhibitory antibodies against FVIII (≥0.6 Bethesda units [BU]) after 93 N8-GP exposure days. No clinically significant safety concerns were identified and N8-GP was effective for prophylaxis and treatment of bleeds in previously treated patients.

A pediatric case of idiopathic Harlequin syndrome.

Harlequin syndrome, which is a rare disorder caused by dysfunction of the autonomic system, manifests as asymmetric facial flushing and sweating in response to heat, exercise, or emotional factors. The syndrome may be primary (idiopathic) with a benign course, or can occur secondary to structural abnormalities or iatrogenic factors. The precise mechanism underlying idiopathic harlequin syndrome remains unclear. Here, we describe a case of a 6-year-old boy who reported left hemifacial flushing and sweating after exercise. He had an unremarkable birth history and no significant medical history. Complete ophthalmological and neurological examinations were performed, and no other abnormalities were identified. Magnetic resonance imaging was performed to exclude lesions of the cerebrum and cervicothoracic spinal cord, and no abnormalities were noted. His final diagnosis was classic idiopathic harlequin syndrome. Herein, we report the first pediatric case of idiopathic harlequin syndrome in Korea.

Effects of coagulation factor concentrate prophylaxis in moderate and severe hemophilia A patients at a single hemophilia center in Korea.

PURPOSE: The aim of this study was to investigate prophylactic treatment effects in Korean patients with severe hemophilia A. METHODS: A prospective study of 32 severe hemophilia A patients was conducted with the approval of the Institutional Review Board at the Eulji University Hospital. Two patients received primary prophylaxis; whereas, the other 30 patients were divided into 2 groups-secondary prophylaxis (n=15) and on-demand (n=15)-on the basis of their consent for secondary prophylaxis. A 20-25 IU/kg dose of factor VIII concentrate was administered to the primary and secondary prophylaxis group patients every 3 days for 1 year. The prophylactic effect was evaluated by observing changes in the Pettersson scores, annual number of total and joint bleeds, and factor VIII consumption for 1 year. RESULTS: No moderate or severe bleeding was observed, and the Pettersson scores remained unchanged during the prophylaxis period in the patients who received primary prophylactic treatment. After the treatment was changed from on-demand to secondary prophylaxis, the annual number of total and joint bleeds in the secondary prophylaxis group decreased by 64.4%±13.0% and 70.0%±15.2%, respectively. The average increase in Pettersson scores within 1 year was 0.5±0.8 and 1.3±1.1 in the secondary prophylaxis and on-demand groups, respectively. Prophylactic effects were also observed in patients >17 years who had nearly the same initial Pettersson scores. CONCLUSION: Intermediate-dose prophylactic treatment may delay hemarthropathy progression and prevent its occurrence in Korean severe hemophilia A patients.

Mutation analysis of factor VIII in Korean patients with severe hemophilia A.

Hemophilia A is an X-linked recessive disorder caused by mutations of the factor VIII gene. The mutation spectrum has been reported in various populations, but not in Koreans. Mutation analysis of the factor VIII gene was performed in 22 unrelated Korean patients with severe hemophilia A. We extracted genomic DNA from their blood, and assessed intron inversions, deletions, and point mutations by direct DNA sequencing. A multiplex ligation-dependent probe amplification gene dosage assay was also performed to identify exon deletions. Disease-causing mutations were identified in all patients, of which four cases were previously unreported. Seven intron 22 inversions, nine point mutations (6 nonsense mutations and 3 missense mutations), and four small rearrangements were identified. One multi-exon deletion and one 5'-donor splicing site mutation were also observed. Four novel mutations (one small deletion, one multiple exon deletion, one missense, and one splice site mutation) were detected, and point mutations were predominant (40.9%), followed by intron 22 inversions (31.8%). Further studies are required in order to establish a solid conclusion regarding the prevalence of various mutations in the Korean population.

Effects of thyroxine on hyperkalemia and renal cortical Na+, K+ - ATPase activity induced by cyclosporin A.

Cyclosporin A (CsA)-induced hyperkalemia is caused by alterations in transepithelial K+ secretion resulting from the inhibition of renal tubular Na+, K+ -ATPase activity. Thyroxine enhances renal cortical Na+, K+ -ATPase activity. This study investigated the effect of thyroxine on CsA-induced hyperkalemia. Sprague-Dawley rats were treated with either CsA, thyroxine, CsA and thyroxine, or olive-oil vehicle. CsA resulted in an increase in BUN and serum K+, along with a decrease in creatinine clearance, fractional excretion of potassium, and renal cortical Na+, K+ -ATPase activity, as compared with oil vehicle administration. Histochemical study showed reduced Na+, K+ -ATPase activity in the proximal tubular epithelial cells of the CsA-treated compared with the oil-treated rats. Histologically, isometric intracytoplasmic vacuolation, disruption of the arrangement and swelling of the mitochondria, and a large number of lysosomes in the tubular epithelium were characteristic of the CsA-treated rats. Co-administration of thyroxine prevented CsA-induced hyperkalemia and reduced creatinine clearance, Na+, K+ -ATPase activity, and severity of the histologic changes in the renal tubular cells when compared with the CsA-treated rats. Thyroxine increased the fractional excretion of potassium via the preservation of Na+, K+ -ATPase activity in the renal tubular cells. Thus, the beneficial effects of thyroxine may be suited to treatment modalities for CsA-induced hyperkalemia.