Effectiveness of Monthly Low-Dose Emicizumab Prophylaxis without 4-Week Loading Doses Among Patients with Hemophilia a with and without Inhibitor: A Case Series Report

Abstract Introduction: Emicizumab is a humanized, bispecific, monoclonal antibody proven as an effective prophylaxis for patients with hemophilia A with and without inhibitor. After the weekly loading of 3 mg/kg for 4 doses followed by maintenance dose of 1.5 to 6 mg/kg at 1 to 4-week intervals, the equivalent factor VIII was maintained at approximately 15% and showed an effective prophylaxis in reducing annual bleeding rate. Due to the health care resource constraint, the dose of emicizumab was reduced to maintain the prophylaxis factor VIII at 1-3%. Methods: The effectiveness of monthly low dose emicizumab prophylaxis without 4 loading doses was evaluated among patients with hemophilia A with and without inhibitor for at least 6 months. The bone mineral density (BMD), ultrasonography of bilateral ankle, elbow and knee as well as Hemophilia Joint Health Score (HJHS) were initially evaluated and planned to be repeated after one year treatment. The vitamin D level was determined initially, and vitamin D supplement was prescribed for 3 patients with low vitamin D levels at 13.3, 23.2 and 24.6 ng/mL. Moreover, the quality of life assessment using Hemo-QoL and CHO-KLAT was performed in 3-month intervals. Results: Five patients without inhibitor (3 severe, 2 moderate) and 1 patient with severe hemophilia A with inhibitor enrolled in the study. They all behaved in low bleeding risk circumstances such as avoidance of contact sport. Their ages ranged from 4 to 40 years of age. The youngest boy had difficulty at peripheral venous access for regular prophylaxis while the remaining 4 patients without inhibitor experienced frequent breakthrough bleeding episodes while receiving a low dose prophylaxis at 500 to 1,000 units of factor VIII concentrate twice weekly. All refused to receive more frequent prophylaxis. For patient with inhibitor, the high inhibitor titer of 65 Bethesda units (BU) declined during the 2 years of immune tolerance induction (ITI) at the intermediate dose of 100 units/kg of extended half-life factor VIII concentrate 3 times weekly. His lowest inhibitor was at 10 BU and was documented as failed ITI. He experienced frequent bleeding at the muscles and joints for which bypassing agents could not be adequately provided. For the baseline study, 2 patients had low BMD Z score ≤-2.0 while the remaining 4 patients had normalized BMD Z score >-2.0. The ultrasonography of bilateral ankle, elbow and knee at anterior, medial, lateral and posterior/inferior spaces revealed joint distension reflecting varying-degree synovial hypertrophy and/or bleeding component of 0-14.0, 0-9.8, 0-9.4, 0-12.8; 0-14.4, 0-17.8, 0-10.7, 0-18.6 and 0-23.8, 0-15.3, 0-17.1, 0-12.9 millimeter, respectively. Varying-degree hyperemia from the ultrasonography reflecting active inflammation of synovium was found in 4 ankles, 6 elbows and 4 knees of the total 36 joints in 4 of 6 patients. The HJHS scores ranged from 6 in the youngest patient to 56 in the patient with inhibitor. All patients except the 4-year-old boy had 1 to 3 target joints. All the studied patients received 1 each of the whole vial of emicizumab at 30, 75, 105 mg monthly except 3 patients receiving 60 mg monthly which was equal to 1.1 to 1.6 mg/kg of emicizumab. The monthly trough levels of emicizumab determined by a modified one stage factor VIII assay using emicizumab calibrator were maintained at 3.8 to 9.8 µg/ml which were equivalent to the levels of FVIII at 1 to 3% (0.3% FVIII per µg/ml of emicizumab). The bleeding rate was markedly decreased from 4-8 episodes monthly to 0-1 episode monthly. The monthly zero bleeding rate was found among 4 patients. Moreover, the swollen target joint gradually dissolved. Their quality of life markedly improved evaluated by the Hemo-QoL and CHO-KLAT. They could attend regular school and work happily. The HJHS and ultrasonography have not been repeated yet. Conclusion: The monthly low dose emicizumab prophylaxis of the whole vial at 1.1 to 1.6 mg/kg without loading dose could achieve emicizumab trough levels at 3.8 to 9.8 µg/ml which were equivalent to the levels of FVIII at 1 to 3%. It showed effective prophylaxis among patients with hemophilia with and without inhibitor who performed low bleeding risk activity. The 3 aspects of body functions and structures, activities and participation were gradually improved. Disclosures No relevant conflicts of interest to declare.

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Effect of tertiary prophylaxis with low-dose factor VIII in quality of life in adult patients with severe hemophilia A

Journal of Applied Hematology ◽

10.4103/joah.joah_37_19 ◽

2019 ◽

Vol 10 (3) ◽

pp. 88

Author(s):

PrakasKumar Mandal ◽

Abhijit Phukan ◽

Amrita Bhowmik ◽

Debasis Gantait ◽

Prantar Chakrabarti

Keyword(s):

Quality Of Life ◽

Factor Viii ◽

Low Dose ◽

Hemophilia A ◽

Adult Patients ◽

Severe Hemophilia ◽

Dose Factor

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Effects of replacement therapies with clotting factors in patients with hemophilia: A systematic review and meta-analysis

PLoS ONE ◽

10.1371/journal.pone.0262273 ◽

2022 ◽

Vol 17 (1) ◽

pp. e0262273

Author(s):

Carolina J. Delgado-Flores ◽

David García-Gomero ◽

Stefany Salvador-Salvador ◽

José Montes-Alvis ◽

Celina Herrera-Cunti ◽

...

Keyword(s):

Low Dose ◽

Prophylactic Treatment ◽

Hemophilia A ◽

Clotting Factor ◽

High Dose ◽

Bleeding Rate ◽

Episodic Treatment ◽

Grade Methodology ◽

Inform Decision Making ◽

Intermediate Dose

Background Different prophylactic and episodic clotting factor treatments are used in the management of hemophilia. A summarize of the evidence is needed inform decision-making. Objective To compare the effects of factor replacement therapies in patients with hemophilia. Methods We performed a systematic search in PubMed, Central Cochrane Library, and Scopus. We included randomized controlled trials (RCTs) published up to December 2020, which compared different factor replacement therapies in patients with hemophilia. Random-effects meta-analyses were performed whenever possible. The certainty of the evidence was assessed using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) methodology. The study protocol was registered in PROSPERO (CRD42021225857). Results Nine RCTs were included in this review, of which six compared episodic with prophylactic treatment, all of them performed in patients with hemophilia A. Pooled results showed that, compared to the episodic treatment group, the annualized bleeding rate was lower in the low-dose prophylactic group (ratio of means [RM]: 0.27, 95% CI: 0.17 to 0.43), intermediate-dose prophylactic group (RM: 0.15, 95% CI: 0.07 to 0.36), and high-dose prophylactic group (RM: 0.07, 95% CI: 0.04 to 0.13). With significant difference between these subgroups (p = 0.003, I2 = 82.9%). In addition, compared to the episodic treatment group, the annualized joint bleeding rate was lower in the low-dose prophylactic group (RM: 0.17, 95% CI: 0.06 to 0.43), intermediate-dose prophylactic group (RM of 0.14, 95% CI: 0.07 to 0.27), and high-dose prophylactic group (RM of 0.08, 95% CI: 0.04 to 0.16). Without significant subgroup differences. The certainty of the evidence was very low for all outcomes according to GRADE methodology. The other studies compared different types of clotting factor concentrates (CFCs), assessed pharmacokinetic prophylaxis, or compared different frequencies of medication administration. Conclusions Our results suggest that prophylactic treatment (at either low, intermediate, or high doses) is superior to episodic treatment for bleeding prevention. In patients with hemophilia A, the bleeding rate seems to have a dose-response effect. However, no study compared different doses of prophylactic treatment, and all results had a very low certainty of the evidence. Thus, future studies are needed to confirm these results and inform decision making.

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Rurioctocog alfa pegol PK-guided prophylaxis in hemophilia A: Results from the phase 3 PROPEL study

Blood ◽

10.1182/blood.2020005673 ◽

2020 ◽

Author(s):

Robert Klamroth ◽

Jerzy Windyga ◽

Vlad Radulescu ◽

Peter W Collins ◽

Oleksandra Stasyshyn ◽

...

Keyword(s):

Hemophilia A ◽

Severe Disease ◽

Treatment Trial ◽

Phase 3 ◽

Bleeding Rate ◽

Fviii Inhibitor ◽

Point Estimates ◽

Dosing Frequency ◽

Full Analysis ◽

Trough Levels

Rurioctocog alfa pegol prophylaxis targeting factor VIII (FVIII) troughs ≥1% is efficacious and well-tolerated in people with hemophilia A (PwHA). As some may benefit from higher FVIII troughs, the PROPEL trial compared safety and efficacy of 2 target FVIII trough levels in PwHA with severe disease, aged 12-65 years, annualized bleeding rate ≥2, and previous FVIII treatment. They were randomized to 12 months' pharmacokinetic (PK)-guided rurioctocog alfa pegol prophylaxis targeting FVIII troughs of 1-3% (reference arm) or 8-12% (elevated arm). Treatment-adjustment period was in the first 6 months. Primary endpoint: proportion of PwHA (full analysis set [FAS]) with zero total bleeds (all bleeds) during second 6 months. Overall, 115 male PwHA were randomized (N=115, FAS; N=95, per-protocol analysis set [PPAS]). In the 1-3% and 8-12% arms, respectively, point estimates (95% CI) of proportions of PwHA with zero total bleeds were 42% (29-55%) and 62% (49-75%) in FAS (P=0.055) and 40% (27-55%) and 67% (52-81%) in PPAS (P=0.015). Dosing frequency and consumption varied widely in each arm. Adverse events (AEs) occurred in 70/115 (60.9%) PwHA. Serious AEs occurred in 7/115 (6%) PwHA, including 1 treatment-related serious AE in 8-12% arm (transient anti-FVIII inhibitor). There were no deaths, serious thrombotic events, or AE-related discontinuations. PK-guided prophylaxis was achievable and efficacious in both arms, with no new safety signal in the 8-12% arm vs previous studies. These results demonstrate elevated FVIII troughs can increase the proportion of PwHA with zero bleeds and also emphasize the importance of personalized treatment. Trial registration: www.ClinicalTrials.gov (#NCT02585960).

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Comparison of Short-Term Tertiary Prophylaxis at Low-Dose and Intermediate-Dose for Adults with Severe Hemophilia a in China

Blood ◽

10.1182/blood.v126.23.4681.4681 ◽

2015 ◽

Vol 126 (23) ◽

pp. 4681-4681 ◽

Cited By ~ 1

Author(s):

Shunhua Huang ◽

Zhitao Li ◽

Yang Liu ◽

Fangmei Qin ◽

Xiaoqin Feng ◽

...

Keyword(s):

Dose Regimen ◽

Dose Group ◽

Low Dose ◽

Hemophilia A ◽

Severe Bleeding ◽

Severe Hemophilia ◽

Joint Function ◽

Bleeding Rate ◽

Breakthrough Bleeding ◽

Intermediate Dose

Abstract Background: Some studies had indicated that the joint damage progression could not be prevented by low-dose prophylaxis regimen though it had been practiced and achieved good outcomes as well as largely reduced bleedings. we initiated a retrospective study to compare the different outcomes between low-dose and intermediate-dose regimen of tertiary prophylaxis for adults with severe hemophilia A. Methods: Data collected from the hemophilia treatment centre at Nanfang hospital from July 2010 to February 2015 ( median 2 years of follow-up), a total of 40 adult patients with severe hemophilia A (FVIII < 1%) who are receiving prophylaxis treatment≥1 year and treatment data available were eligible for enrollment in the study, including 25 patients in low-dose regimen(F‡[8-15 IU/kg 1-2times weekly or weekly<30 IU/kg), and 15 patients in intermediate-dose regimen( F‡[ 15-20 IU/kg 2-3 times weekly or weekly≥40IU/kg and <75 IU/kg). Collect the data with patients' characteristics, previous condition and treatment, treatment efficacy indexFannual bleeding rate(ABR), annual joint bleeding rate(AJBR), number of target joint, annual target joint bleeding rate, annual severe bleeding event, etc.), FVIII consumption. Use FISH scoring system to evaluate patients' joint status, use the difference between the beginning of this study and one year ago of FISH score to represent the improvement of joint function. To analyze the joint function in various subgroups(joint bleeding rate ≤5 times or >5 times) under prophylaxis treatment. Screening out patients whose dosage and frequency adherence both >75% in two groups, including 15 patients in low-dose regimen and 14 patients in intermediate-dose regimen, observed the situation that breakthrough bleeding events occurred in different time period after clotting factors' injection and calculate the proportion. Results: 1. There were no statistical differences between two groups in age, weight, age at first bleeding, age at first treatment, family history of hemophilia and history of hepatitis. (the range of p-value was 0.221-1.000). 2. Intermediate-dose prophylaxis regimen reduced ABR than the low-dose regimen (median 13 vs. 5.5, P=0.000), as well as AJBR (median 10 vs. 4, p=0.001) and the annual target joint bleeding rate (median 8 vs. 3.5, p=0.002) .Reduced median annual absent days was found in intermediate-dose regimen group (median 7.5 vs. 0, p=0.005). In terms of total annual usages of FVIII, the intermediate-dose regimen group increased 35% than low-dose regimen group(2630 IU/kg/year vs.1950 IU/kg/year,P=0.000), but decreased 63% ABR, 60% AJBR and 56% annual target joint bleeding than low-dose regimen group. There was no statistical differences between low-dose and intermediate-dose groups in terms of target joint numbers (median 1 vs.1,P=0.579) and annual severe bleeding events(median 0 vs.0, P=0.911). 3. There was statistical differences between two groups on the improvement of FISH(P=0.008). The proportion that patients' annual joint bleeding rate ≤5 in low dose and intermediate-dose group were 12% and 73.3%. When AJBR ≤5, the mean improvement of Fish score of low-dose and intermediate-dose group was 0.33 and 1.18, When AJBR>5, the mean score was -0.09 and 1.00 respectively, while the joint function still improved in intermediate-dose group.3. The low-dose group had higher proportion of breakthrough bleeding in 24-48h after FVIII injection (median 45.5% vs.27.95%, P=0.000), while intermediate-dose group got higher proportion in more than 48h after FVIII injection (median 60% vs.43.75%,P=0.001). Conclusion: 1. Compared to low-dose prophylaxis regimen, the ABR, AJBR, annual target joint bleeding rate, annual absent days and joint functionwere significantly decreased in patients treated with intermediate-dose regimen.2. It is indicated the intermediate-dose prophylaxis treatment would be better in long-term effect than low-dose regimenin improving joint function. 3. The low-dose group had higher proportion of breakthrough bleeding in 24-48h after FVIII injection, while intermediate-dose group got higher proportion in more than 48h after FVIII injection. Once every other day regimen is beneficial to further reduce bleedings in intermediate-dose prophylaxis treatment. Disclosures No relevant conflicts of interest to declare.

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Low dose long-acting factor VIII prophylaxis in pediatric and young adult patients with hemophilia A: Short-term single-center experience from a developing country

10.25259/jhas_13_2021 ◽

2021 ◽

Vol 0 ◽

pp. 1-6

Author(s):

Shailendra Prasad Verma ◽

Anil Kumar Tripathi ◽

Geeta Suri Sharma ◽

Nidhish Kumar ◽

Rashmi Kushwaha

Keyword(s):

Young Adult ◽

Adverse Events ◽

Factor Viii ◽

Low Dose ◽

Hemophilia A ◽

Adult Patients ◽

Severe Hemophilia ◽

Emergency Visits ◽

Episodic Treatment ◽

Long Acting

Objectives: High dose factor prophylaxis in hemophilia has been proven to prevent joint bleeds in the western world effectively. We look for a cost-effective and feasible way for Indian patients to reduce the dose and frequency of factor infusion. Data on prophylaxis with a low dose, long-acting factor infusion twice a week dosing schedule is limited. The purpose was to study the efficacy and safety of long-acting factor VIII (Eloctate) for secondary/ tertiary prophylaxis in pediatric and young adult patients with moderate and severe hemophilia A. Materials and Methods: Thirty-eight patients with moderate and severe hemophilia A with an age range from 1 to 25 years were included in the study. During the initial 4 months, they received therapeutic doses of ELOCTATE (Factor VIII with Fc Fusion Protein) on an episodic basis after a clinical bleed. In the next 4 months, they received prophylactic intravenous ELOCTATE at the dose of 20 units/kg body weight twice a week. Annual bleeding rates (ABR), school absenteeism, emergency visits, joint scores, and adverse events were compared during both periods. Results: The total number of joint bleeds during the episodic treatment and prophylaxis period was 608 and 67, respectively. ABR was 47.9 during the episodic treatment period and 5.3 during prophylaxis showing an 88.9% reduction in joint bleeds. School/college absenteeism and emergency visits were significantly reduced during prophylaxis. No significant adverse events were noted during prophylaxis. Conclusion: Low dose, twice a week, and long-acting recombinant factor VIII-Fc (Eloctate) prophylaxis can be a reasonable options for patients with hemophilia A in developing countries.

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Effect of low‐dose factor VIII prophylaxis therapy on bone mineral density and 25(OH) vitamin D level in children with severe haemophilia A

Haemophilia ◽

10.1111/hae.13917 ◽

2020 ◽

Vol 26 (2) ◽

pp. 325-332 ◽

Cited By ~ 1

Author(s):

Nevine Gamal Andrawes ◽

Manal Hashem Fayek ◽

Nouran Salah El‐Din ◽

Raguia Atef Mostafa

Keyword(s):

Bone Mineral Density ◽

Vitamin D ◽

Factor Viii ◽

Low Dose ◽

Haemophilia A ◽

Severe Haemophilia ◽

Mineral Density ◽

Prophylaxis Therapy ◽

25 Oh Vitamin D ◽

Dose Factor

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Pharmacokinetics of Factor VIII Level in Patients Hemophilia A in Relation to Clinical and Radiological Outcomes

QJM ◽

10.1093/qjmed/hcab113.046 ◽

2021 ◽

Vol 114 (Supplement_1) ◽

Author(s):

Azza Abdel gawad Tantawy ◽

Iman Ahmed Ragab ◽

Mohamed Gomaa Khalil

Keyword(s):

Factor Viii ◽

Hemophilia A ◽

Trough Level ◽

Peak Level ◽

Functional Independence ◽

Bleeding Pattern ◽

Bleeding Events ◽

X Ray ◽

Significant Difference ◽

Trough Levels

Abstract Background The benefit of pharmacokinetics (PK) -guided dosing is that both prophylactic and “on demand” dosing will be based on actual FVIII trough and peak levels instead of current FVIII estimates based on body weight and in-vivo recovery based dosing. Knowledge will increase with regards the relationship between FVIII level and bleeding in individual patients. The dose and frequency of factor VIII for patients on prophylaxis should only be reduced if clinically justified and impact should be monitored with regard to bleeding events, bleeding pattern and joint status. Objective To assess the trough and peak level of factor VIII in patients with hemophilia A on low dose prophylaxis and its impact on the clinical and radiological joint status. Patients and Methods A cross sectional study was performed in Ain-Shams University, Pediatrics Hospital, Hemophilia Clinic. It included 25 children and adolescents with hemophilia A on prophylactic factor VIII during the period from September 2018 to August 2019. Factor VIII used was recombinant 3rd generation with a dose of 45 IU/Kg/week rounded to the nearest 500IU. Trough level of factor VIII was done before prophylactic dose and peak level was done one hour postinfusion through chromogenic assay using STAGO-Immuno-Def VIII reagent. Clinical joint score and Functional Independence Score of Hemophilia (FISH) were done. Radiological joint scores were done using conventional x-ray, ultrasound and MRI. Cut-off level of trough levels was studied at 1% and 1%-5% of factor VIII. Results Patients were classified into 3 groups,4 patients (21.1%) had trough level <1%, 13 patients (68.4%) had trough level between 1%-5%, 2 patients (10.5%) had trough level > 5%. No significant difference between trough level of factor VIII and clinical joint scores and FISH scores of patients. Median score of the worst joint of patients with trough level >5% was 5 in comparison to 8 and 7 in patients with trough level 1%-5% and <1% respectively. Mean FISH of patients with trough level >5% was 9.50 ± 2.12 in comparison to 12.92 ± 5.41 and 11.00 ± 3.56 for patients with troughs 1%-5% and <1% that was respectively. Comparison between groups with different trough level of factor VIII according to X-ray scores of patients showed no significant difference Conclusion Low trough levels alone did not warrant intensification of the prophylaxis regimen; rather, the dose and dosing frequency should be adjusted based on individual’s bleeding pattern and many other factors as shown in our study the insignificant relation between trough levels of factor VIII and clinical and radiological outcomes.. More frequent factor VIII monitoring and incorporation into population based PK are warranted.

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Immune Tolerance Resulting in a Dramatic Clinical Improvement in a High-Responding Inhibitor Hemophilia A Patient Using Immunosuppression with Mycofenolate Mofetil and a Factor VIII Concentrate Containing Von Willebrand Factor.

Blood ◽

10.1182/blood.v106.11.3220.3220 ◽

2005 ◽

Vol 106 (11) ◽

pp. 3220-3220

Author(s):

Thierry Lambert ◽

Cécile Goujard ◽

Anne Rafowicz ◽

Benoît Guillet ◽

Yacine Taoufik ◽

...

Keyword(s):

Quality Of Life ◽

Factor Viii ◽

Clinical Improvement ◽

Von Willebrand Factor ◽

Immune Tolerance ◽

Hemophilia A ◽

Inhibitor Level ◽

Von Willebrand ◽

Willebrand Factor

Abstract A 40 year-old Caucasian patient with severe familial hemophilia A (FVIII <1%) related to an intron 22 inversion developed at the age of 2 a high-responding inhibitor. His elder brother also suffers from hemophilia A with high-responding inhibitor. Until 2000, the patient had been treated either using activated prothrombin complex concentrates (Autoplex® and Feiba®) or factor VIII (FVIII) concentrates of human (1983) and porcine origin (1992), resulting respectively in an inhibitor level rise at 360 Bethesda Units (BU) and 1800 BU. Between 2000 and 2003, the patient received exclusively recombinant activated Factor VII (NovoSeven®), and his inhibitor levels stabilized at a plateau of 15–20 BU. Between 2000 and 2003, several life or function threatening bleeding episodes occurred, such as hematomas of the iliopsoas muscles, spinal cord hematoma with transient paraplegia. Furthermore, due to hemarthroses the patient was confined to a wheelchair. Given the major impact of the inhibitor on the patient’s functional prognosis, life expectancy and quality of life, immune tolerance (IT) treatment was initiated, despite the high risk of failure (initiation 36 years after inhibitor onset, historical peak titer at 1800 BU, persistence of a plateau of 15–20 BU despite the absence of any stimulation with FVIII within the 3 last years). It started with an immunosuppressive drug, mycofenolate mofetil (Cellcept®) first given in may 2003 (no effect alone on inhibitor titer) and then in November 2003, infusions of a FVIII concentrate rich in von Willebrand factor, Factane® (LFB, Les Ulis, France) using 12,000 IU/day (150 IU/kg) of FVIII. The inhibitor peaked at 520 BU on D19 and was 0.5 BU by May 2004. Thus, the FVIII dosage was progressively reduced to 7000 IU/day. In July 2005, 24 hours after a 7000 IU FVIII infusion, inhibitor level was 0.7 BU, the residual FVIII level was 0.04IU/ml with a recovery of FVIIIc of 1.37%/IU/kg infused and a half-life of 4.9 hours. No significant change in the immunophenotype of peripheral blood lymphocytes was observed during this course. The patient’s quality of life was dramatically improved, with no hospitalization required and no bleeding episode observed within the 16 last months. The patient can now stand and has returned to his previous social activities. These preliminary results show that this IT treatment, performed despite a high theoretical risk of failure, resulted in this patient in a dramatic clinical improvement, even though biological criteria of success have not yet been achieved. The respective roles of the type of FVIII concentrate, and of immunosuppression remain to be assessed, as well as the cost/benefit analysis on a longer follow-up period.

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Prophylactic Use of rFVIIa in a Young Hemophilia A Patient with Factor VIII Inhibitor.

Blood ◽

10.1182/blood.v106.11.4068.4068 ◽

2005 ◽

Vol 106 (11) ◽

pp. 4068-4068

Author(s):

Annie Borel-Derlon ◽

Mounia Slaoui ◽

Philippe Gautier ◽

Patricia Guillon

Keyword(s):

Quality Of Life ◽

Factor Viii ◽

Immune Tolerance ◽

Hemophilia A ◽

Factor Viia ◽

High Dose ◽

Factor Viii Inhibitor ◽

On Demand ◽

Viii Inhibitor

Abstract The prevention of bleeding by prophylaxis regimen particularly for joint rehabilitation, could be considered a more effective treatment for hemophilia patients. In hemophiliacs with factor VIII inhibitor (F VIII inh) prophylaxis is not generally proposed because the bypassing agents for these patients may be less effective than F VIII concentrates. We report the regimen and results of a 6 months rFVIIa (Recombinant factor VIIa) prophylaxis, in a young hemophilia A patient (4 years old), with F VIII inh and immune tolerance induction (ITI) treatment and compared, with rFVIIa, the on demand treatment results for the 6 months prior to prophylaxis. After 2 years of a high dose regimen ITI, the FVIII inh titer was less than 50 BU and the immune tolerance treatment remains on going. Due to the development of a right knee target joint the rFVIIa prophylaxis was decided as an active rehabilitation approach to prevent the development of chronic arthropathy as well as to improve the quality of life of the child. During the 6 months period, prior to the initiation of rFVIIa prophylaxis 22 bleeds occurred i.e., 9 right knee hemarthrosis and 13 other joint bleedings and hematoma including elbow, wrist, ankle, foot, arm and chest. These bleeds were all treated with rFVIIa with a dose ranging from 100 to 200 μg/kg depending on the severity of the episodes and the duration of treatment ranged from 1 to 8 days. After 6 recurrent right knee hemarthrosis, a lavage of the joint was performed and prophylaxis with rFVIIa was subsequently initiated. A 120 μg/kg rFVIIa injection was performed 3 times a week concomitantly with the ITI treatment infusion and just before the physiotherapy course. During the 6 months of prophylaxis regimen we observed 9 bleeds with 3 major post traumatic bleedings which were treated by one 200 μg/kg/day rFVIIa injection which was resolved in one to three days. This prophylaxis treatment was effective for the arthropathy evolution and permitted the patient to return to school on a regular basis compared to the previous year. The total dose of on demand rFVIIa treatment used before prophylaxis was 458 mg/6 months. This amount decreased by 25% during the six months of prophylaxis with rFVIIa to reach 343 mg. The results of this significant observation led us to conclude that rFVIIa could be effectively used as prophylactic treatment in patients with FVIII inh and administered safely via a portacath device even in cases of high doses, as demonstrated in this young patient. This prevention approach resulted in a decrease of bleeding episodes, injections, and a significant improvement in the quality of life.

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Factor VIII Intron 22 Inversion Screening of Newborn Males for Hemophilia A: A Cost-Effectiveness Study

Blood ◽

10.1182/blood.v116.21.734.734 ◽

2010 ◽

Vol 116 (21) ◽

pp. 734-734

Author(s):

John W. Luiza ◽

Margaret V. Ragni ◽

Robert F. Sidonio ◽

Kenneth J Smith

Keyword(s):

Quality Of Life ◽

Cost Effectiveness ◽

Factor Viii ◽

Hemophilia A ◽

Severe Hemophilia ◽

Pcr Screening ◽

Intron 22 Inversion ◽

Screening Cost ◽

The Cost

Abstract Abstract 734 Background: Severe hemophilia A is an X-linked congenital bleeding disorder occurring in 1:5,000 male births. Among neonates with severe hemophilia A, failure to recognize hemophilia and associated bleeding may result in severe blood loss anemia from circumcision, central nervous system (CNS) bleeding during the birth process or with head trauma and associated neurologic sequelae, and unrecognized joint bleeding that, when recurrent, increases the risk of joint damage which may lead to chronic disability. In at least one-third of cases, the disease arises as a spontaneous mutation: yet, even among the two-thirds with a family history, most carriers do not undergo carrier testing or prenatal diagnosis, leaving only a minority in whom cord blood screening is performed. About half of newborns with severe hemophilia A have a factor VIII (F.VIII) intron 22 inversion mutation, readily detected by PCR screening. We, therefore, sought to determine the effects of newborn screening by F.VIII intron 22 inversion PCR on early diagnosis in children with severe hemophilia A, specifically, on prevention of early life bleeding and associated cost, morbidity, and quality of life. Methods: We constructed a decision tree model to evaluate the cost effectiveness of newborn F.VIII intron 22 screening for severe hemophilia A. We assumed all newborn males were tested as part of screening, and that treatment modifies the likelihood of bleeding but not bleeding associated morbidity. Rates of major and minor CNS, joint, and procedural/surgical bleeding, including circumcision, morbidity and mortality, cost, and quality of life utilities were obtained from the literature. We assumed the cost of intron 22 PCR testing to be $3.00 per newborn male, that test results were available within 2 days of screening, and that clotting factor was infused prior to procedures and at the first sign of joint bleeding or head trauma. The probability of severe bleeding requiring hospitalization or red blood cell transfusion was estimated to be 5% or less in children with severe hemophilia A. The cost of F.VIII concentrate was based on the average wholesale price, and transfusion and hospitalization costs were based on local data. Outcomes included medical costs for each bleeding event, effectiveness measured as quality-adjusted-life-years (QALY), and the incremental cost-effectiveness ratio (ICER) over the first two years of life. Sensitivity analysis was used to test the robustness of analysis results. Results: Compared to no screening, screening for hemophilia had an ICER of $96,918/QALY, a value considered economically reasonable. Results were sensitive to variation of screening cost and overall detection of hemophilia A by PCR screening (base case 50%). Effects of varying both these parameters in a two-way sensitivity analysis are shown in the Figure. Using a $100,000 per QALY cost-effectiveness criterion over the depicted ranges for both parameters, screening was favored if screening cost ≤$3 or if ≥56% of all newborns with hemophilia A were detected by screening. Conclusion: It is cost effective to perform factor VIII intron 22 PCR screening to identify severe hemophilia A in newborn males in order to prevent bleeding morbidity, if the cost of the test does not exceed $3.00. Disclosures: No relevant conflicts of interest to declare.

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