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

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 4681-4681 ◽  
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.

scholarly journals Intermediate-Dose Tertiary Prophylaxis Show a Better Joint Protection in Adults with Severe Hemophilia Than Low-Dose Patterns

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 4970-4970
Author(s):  
Xuan Zhou ◽  
Shunhua Huang ◽  
Shiqiu Qiu ◽  
Zhuqin Liu ◽  
Jing Sun
Keyword(s):  
Dose Regimen ◽  
Dose Group ◽  
Low Dose ◽  
Hemophilia A ◽  
Conflicts Of Interest ◽  
Severe Hemophilia ◽  
Prophylaxis Group ◽  
Joint Protection ◽  
Sf 36 ◽  
Intermediate Dose

Abstract Background and Introduction: Prophylaxis treatment is considered optimal care for patients with severe hemophilia during childhood to prevent bleeding and reduce the incidence of joint disability. However, tertiary prophylaxis may also benefit Adults with Severe Hemophilia, but the optimal dose tailoring of FVIII is still unknown. We initiated a study to compare the low-dose and intermediate-dose regimen for tertiary prophylaxis in adults with severe hemophilia A. Methods: Patients with severe hemophilia A (F VIII < 1%) born between January, 1978, and January, 1988, who were treated at the hemophilia treatment centre at Nanfang hospital and treatment data available were eligible for enrollment in the study. The main exclusion criteria were a history of FVIII inhibitor (titer ≥ 0.6BU [Bethesda unit]), detectable FVIII inhibitors at screening (titer ≥ 0.4 BU), chronic liver disease, immunodficiency, another hemostatic defect and the need for major surgery. A total of 40 adults with severe hemophilia were enrolled, including 25 patients with low-dose prophylaxis (5-10 IU/kg twice a week) and 15 patients with intermediate-dose prophylaxis ( FⅧ 15-20 IU/kg twice a week). Breakthrough acute bleedings were treated according to the regular practice and guidelines. Results: The study was conducted over a 2-year period (January 2014 to December 2015).Compared to low-dose prophylaxis group, Intermediate-dose tertiary prophylaxis group reduced the annual number of total and joint bleeds (median 13 vs 5.5 and median 10 vs 4; P= 0.001, respectively), and annual target joint bleeding rate were also significantly lower (median 8 vs. 3.5, P =0.002). The breakthrough bleeding events were largely lower in intermediate-dose group than in low-dose group (P=0.03). After prophylaxis, the FISH score in Intermediate-dose group increased from median 21 (range 15-28) to median 24 (range 17-28) (P=0.02) and in low-dose group from median 22 (range 14-28) to median 24 (range 14-28) (P=0.02) respectively. The improvement of FISH score were different between two groups (P=0.04). Meanwhile, The Health-related Qualityof life (HRQoL) in patients with severe hemophilia were measured by the SF-36. The SF-36 score showed better results in terms of overall perceived health status between patients with Intermediate-dose and with low-dose prophylaxis (P < 0.01). Conclusion: Compared to low-dose prophylaxis, Intermediate-dose tertiary prophylaxis may show a better joint protection in Adults with Severe Hemophilia, for Intermediate-dose regimen not only means less joint bleeding, but also helps joint function restore and Quality of life improvement. Our study established that Intermediate-dose tertiary prophylaxis may be a better choice for adults in a number of hemophilia treatment centers in China. Disclosures No relevant conflicts of interest to declare.

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

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 4675-4675
Author(s):  
Shunhua Huang ◽  
Zhitao Li ◽  
Yang Liu ◽  
Fangmei Qin ◽  
Xiaoqin Feng ◽  
...  
Keyword(s):  
Quality Of Life ◽  
Dose Regimen ◽  
Dose Group ◽  
Low Dose ◽  
Hemophilia A ◽  
P Value ◽  
Severe Hemophilia ◽  
Dosing Intervals ◽  
Intermediate Dose

Abstract Background: Low-dose prophylaxis and intermediate-dose prophylaxis in hemophilia A both had been proved in reducing bleedings in some developing country, but there was rare attention in terms of the Health-related Quality of life (HRQoL) and patients' adherence. So we initiated a retrospective study to compare the differecen 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<30IU/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, annual total bleeding rate(ABR). Use SF36 to evaluate patients' quality of life, use the difference between the beginning of this study and one year ago of SF36 score to represent the improvement of quality of life. Use "hemophilia bleeding and factor injection record handbook" to collect information about patients' bleeding and injection record, use HO's measuring method to evaluate adherence. 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.The Health-related Quality of life (HRQoL) in patients with severe hemophilia A were measured by the SF-36. Only on bodily pain(P=0.965) and vitality(P=0.101)the differences did not exist between two groups ,beyond that intermediate-dose group were better in other aspects(included total SF36, physical functioning, role-physical, general health, social functioning, role-emotional and mental health) than low-dose group(the range of P-value was 0.000-0.045, P<0.05),which inferred that the improvement of quality of life was better in patients in intermediate-dose group. 3. Used HO's measuring method for adherence to evaluate the 40 patients in two groups. The dosage and dosing intervals adherence of low-dose group were 78.6A88.5 respectively, while the intermediate-dose group were 90.3A95.2 respectively, the differences in dosage and dosing intervals adherence between two groups were statistically significant(P=0.003). Intermediate-dose prophylaxis treatment reduced the annual total bleeding rate(ABR) than the low-dose group(median 13 vs. 5.5,P=0.000), while poor dosage adherence correlates with more ABR(B=-0.555,P=0.000), which meant worse adherence was association with much bleeding, but there was no correlation between dosing intervals adherence and ABR(B=0.171,P=0.507). Conclusion: 1. Compared to low-dose regimen, intermediate-dose regimen for short-term tertiary prophylaxis in adults with severe hemophilia A would improve quality of life. 2.Patients in intermediate-dose prophylaxis regimen had better adherence than low-dose regimen. There are negative correlation between dosage adherence and ABR, which means poor adherence lead to more bleeding events, while there's no correlation between dosing intervals adherence and ABR. Disclosures No relevant conflicts of interest to declare.

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

PLoS ONE ◽  
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.

Emicizumab for the treatment of acquired hemophilia A

Blood ◽  
2020 ◽  
Author(s):  
Paul Knoebl ◽  
Johannes Thaler ◽  
Petra Jilma ◽  
Peter Quehenberger ◽  
Karoline Veronika Gleixner ◽  
...  
Keyword(s):  
Hemophilia A ◽  
Coagulation Factor ◽  
Standard Of Care ◽  
Early Discharge ◽  
Severe Bleeding ◽  
Acquired Hemophilia A ◽  
Acquired Hemophilia ◽  
Breakthrough Bleeding ◽  
Hemostatic Efficacy ◽  
Bypassing Agents

Acquired hemophilia A (AHA) is a severe bleeding disorder caused by inhibiting autoantibodies to coagulation factor VIII (FVIII). For hemostatic treatment, bypassing agents, human or porcine FVIII are currently standard of care. Emicizumab is a bispecific, FVIII-mimetic therapeutic antibody, that reduced the annualized bleeding rates in congenital hemophiliacs. Here we report on 12 patients with AHA, 6 male, 6 female, age 74 yrs (64/80) (all data medians and IQR), treated with emicizumab. Initial FVIII was &lt;1%, inhibitor 22.3BU/mL (range 3-2000). Eight patients had severe bleeding. Emicizumab was started with 3mg/kg sc. weekly for 2-3 doses, followed by 1.5mg/kg every 3 weeks to keep the lowest effective FVIII levels. For FVIII monitoring, chromogenic assays with human and bovine reagents were used. All patients received immunosuppression with steroids and/or rituximab. After the first dose of emicizumab, APTT normalized in 1-3 days, FVIII (human reagents) exceeded 10% after 11 (7.5/12) days. Hemostatic efficacy was obtained and bypassing therapy stopped after 1.5 (1/4) days. FVIII (bovine reagents) exceeded 50%, indicating complete remission, after 115 (67/185), and emicizumab was stopped after 31 days (15/79), in median 5 injections (range 3-9) were given. No patient died from bleeding or thromboembolism, and no breakthrough bleeding was observed after the first dose of emicizumab. In conclusion, emicizumab seems to be an effective hemostatic therapy for AHA, with the advantages of sc. therapy (every 1-3 weeks), good hemostatic efficacy, early discharge, reduction of immunosuppression and adverse events.

Severe Bleeding Events in Hemophilia Α Patients Receiving Emicizumab Prophylaxis

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 1126-1126
Author(s):  
Karen L. Zimowski ◽  
Glaivy M. Batsuli ◽  
Paulette Bryant ◽  
Jenny McDaniel ◽  
Kelly Tickle ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Hemophilia A ◽  
Severe Bleeding ◽  
Severe Hemophilia ◽  
Bleeding Events ◽  
Advisory Committees ◽  
Acute Bleeding ◽  
Fviii Activity ◽  
Bleeding Episodes

Introduction : Emicizumab is a novel humanized bispecific antibody that mimics the function of activated coagulation factor VIII (fVIII). It has significantly changed the management of patients with hemophilia A and inhibitors by achieving baseline hemostatic control. Based on the HAVEN studies, emicizumab markedly reduces annualized bleeding rates and is FDA-approved for prophylaxis in hemophilia A patients of all ages, regardless of inhibitor status. In the HAVEN2 interim analysis, only 3/57 pediatric patients receiving emicizumab prophylaxis required treatment for an acute bleeding event after a 9-week median observation time. We report 3 patients with severe hemophilia A and a history of inhibitors receiving emicizumab prophylaxis with severe or refractory bleeding episodes to highlight the importance of vigilance and surveillance of children with severe hemophilia A on emicizumab. Methods: This retrospective analysis includes patients between 0-21 years of age with severe hemophilia A (fVIII activity < 1%) receiving emicizumab prophylaxis and admitted for the management of an acute bleeding episode following emicizumab's FDA approval in November 2017. Patients were followed at the Pediatric Hemophilia Treatment Center at the Hemophilia of Georgia Center for Bleeding & Clotting Disorders of Emory and the St. Jude Affiliate Clinic at Novant Health Hemby Children's Hospital. Data collected included demographics, past medical history including inhibitor status, bleeding history, and treatment modalities, and details regarding the presentation, management, and outcome of acute severe bleeding events. Due to the nature of the study, descriptive statistics were primarily used for data analysis. Results: Three patients with severe hemophilia A receiving emicizumab prophylaxis were admitted for the management of 4 severe bleeding episodes. All patients had a history of a fVIII inhibitor. Three of the 4 bleeding episodes were trauma-induced while 1 occurred spontaneously. For the traumatic episodes, all patients presented with worsening symptoms approximately 1 week following the inciting event. All patients had a normal aPTT at the time of presentation, ruling out a significant anti-drug antibody (emicizumab level not available). A patient with a low-titer inhibitor developed an epidural hematoma following a trampoline injury and was treated with continuous infusion of recombinant factor VIII (rfVIII), adjusting the rate to achieve chromogenic fVIII activity of 100% for 14 days. Following 14 days, he was started on rfVIII 50 IU/kg Q12 hours with a goal fVIII activity of 50%. His rfVIII dosing interval was gradually weaned to every other day while in inpatient rehabilitation. As outlined in Table 1, the remaining 3 bleeding events were initially managed with recombinant activated factor VII (rfVIIa) dosed at 80-90 mcg/kg/dose with escalating frequency for an average of 8 days. However, due to lack of improvement, treatment was changed to low-dose activated prothrombin complex concentrates (aPCC; 10-15 IU/kg/dose Q12-24 hours for an average of 7 days). In all 3 of these events, the hematomas improved after treatment with aPCC. No patient experienced thrombotic microangiopathy, thrombosis, or had evidence of DIC while receiving these treatment regimens. Discussion/Conclusion: Pharmacokinetic analysis of emicizumab suggests that following the standard 4-week loading phase, trough plasma emicizumab concentrations obtained prior to a 1.5 mg/kg once weekly maintenance dose correlates with at least 10-15 IU/dL equivalent fVIII activity. This degree of thrombin generation should be sufficient to prevent severe spontaneous bleeding episodes in most patients. However it does not preclude significant trauma-induced bleeding or spontaneous bleeding in inhibitor patients. Based on our cases, providers should maintain a high index of suspicion for acute bleeding in patients receiving emicizumab prophylaxis. Serious bleeding events, although rare, may have a more insidious onset in patients receiving emicizumab. Furthermore, despite the baseline hemostasis achieved with emicizumab, acute bleeding events may still require aggressive therapy. Our cases suggest that low-dose aPCC or continuous infusion fVIII may be feasible options for treating acute bleeding events in patients with hemophilia A and inhibitors receiving emicizumab prophylaxis. Disclosures Zimowski: Pfizer: Research Funding; National Hemophilia Foundation: Other: Medical Loan Reimbursement, Research Funding. Batsuli:Octapharma: Membership on an entity's Board of Directors or advisory committees; Bayer: Membership on an entity's Board of Directors or advisory committees; Genetech: Membership on an entity's Board of Directors or advisory committees. Bryant:Novo Nordisk: Other: PI on Novo Nordisk sponsored Studies. McDaniel:Genentech: Membership on an entity's Board of Directors or advisory committees. Tickle:National Hemophilia Foundation: Research Funding. Meeks:Bayer: Membership on an entity's Board of Directors or advisory committees; Genentech: Membership on an entity's Board of Directors or advisory committees; Novo Nordisk: Membership on an entity's Board of Directors or advisory committees; Bioverativ: Membership on an entity's Board of Directors or advisory committees; Takeda-Shire: Membership on an entity's Board of Directors or advisory committees; HEMA Biologics: Membership on an entity's Board of Directors or advisory committees. Sidonio:Genetech: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda-Shire: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bioverativ: Membership on an entity's Board of Directors or advisory committees, Research Funding; Octapharma: Membership on an entity's Board of Directors or advisory committees, Research Funding; Grifols: Membership on an entity's Board of Directors or advisory committees, Research Funding; Biomarin: Membership on an entity's Board of Directors or advisory committees; Uniqure: Membership on an entity's Board of Directors or advisory committees; Novo Nordisk: Membership on an entity's Board of Directors or advisory committees; Kedrion: Research Funding.

New Early Prophylaxis Regimen That Avoids Immunological Danger Signals Can Reduce Factor Eight (FVIII) Inhibitor Development Independent From Product Type Used.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 221-221
Author(s):  
Guenter K.H. Auerswald ◽  
Christoph Bidlingmaier ◽  
Werner Engl ◽  
Heidi Chehadeh ◽  
Birgit M Reipert ◽  
...  
Keyword(s):  
High Risk ◽  
Odds Ratio ◽  
Low Dose ◽  
Hemophilia A ◽  
Venous Access ◽  
Historical Control ◽  
Control Group ◽  
Severe Hemophilia ◽  
Inhibitor Development ◽  
Danger Signals

Abstract Abstract 221 Introduction: Today, the most problematic and costly complication of the treatment of hemophilia A that remains to be overcome is the development of inhibitory antibodies (FVIII inhibitors) to FVIII replacement therapy, particularly in previously untreated patients (PUPs). Aim of the study: The highest risk of developing inhibitors to FVIII is during the first 20 exposure days (EDs). If the patient can be brought through this high risk period without inhibitor development, the subsequent risk is low. We therefore, as a pilot project, developed a prophylaxis regimen for the first 20–50 EDs specifically designed to induce tolerance to the administered FVIII and to minimize inhibitor development. Patients and Methods: Twenty-six consecutive PUPs with severe hemophilia A (<1% FVIII) as they appeared in the centers were treated with a once weekly low dose (250 Units) prophylaxis regimen started as soon as venous access allows without a Port-A-Cath. Thereby immunological danger signals were minimized by avoiding giving first FVIII into a bleed or during an infection, and avoiding surgery during the first 20 EDs. The incidence of inhibitor development in the study group was compared with that in a historical control group of 30 consecutive PUPs with severe hemophilia A treated with a standard joint protection prophylaxis regimen of 40–50 IU/kg FVIII three times a week, starting at or after the first joint or other severe bleed. The new prophylaxis regimen was started after a median of 1 FVIII EDs at a median age of 10.7 months compared to the historical control group were high dose prophylaxis was started later after a median of 30 FVIII on demand EDs at a median age of 19 months (p<0.006). Both plasma-derived and recombinant FVIII concentrates were used in 47% and 53% of the patients respectively. Results: There were no significant differences between the study and control groups in patient related inhibitor risk factors such as ethnicity (all Caucasian), severity of hemophilia (all <1% FVIII), severity of FVIII gene mutation (p<0.0006) and some treatment related factors such as the type of product, age at first exposure, vaccination regimen, need for surgery. However, 14 of 30 subjects (47%) given standard prophylaxis but only 1 of the 26 subjects (3.8%) given the new regimen developed an inhibitor (p=0.0003, odds ratio 0.048, 95% CI: 0.001 to 0.372). Eight subjects given standard prophylaxis but none of those given the new regimen were high responders (p=0.005, odds ratio for high response 0.00, 95% CI: 0.00 to 0.57). Conclusion: Our results indicate that early start of prophylaxis associated with minimizing immunological danger signals during the first 20 exposure days with FVIII may reduce the risk of inhibitor formation even in PUPs with a high risk genetic background independent from the FVIII product type used. Once the patients have developed tolerance to FVIII, usually after about 20 to 50 EDs on the low dose regimen, and venous access permitted, prophylaxis might be changed to the normal three times weekly regimen for optimal protection from joint bleedings. These results need to be confirmed in a larger prospective clinical study. Disclosures: Auerswald: Baxter, CSL-Behring and NovoNordisk.: Consultancy, Honoraria, Research Funding. Bidlingmaier:CSL Behring and Bayer : Honoraria. Engl:baxter: Employment. Chehadeh:baxter: Employment. Reipert:baxter: Employment.

Efficacy and Safety of Secondary Prophylactic Versus On-Demand Sucrose-Formulated Recombinant Factor VIII Treatment in Adults with Severe Hemophilia A: Results from a 13-Month Crossover Study

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 516-516 ◽  
Author(s):  
Peter Collins ◽  
Albert Faradji ◽  
Massimo Morfini ◽  
Monika Maas Enriquez ◽  
Eduard Gorina ◽  
...  
Keyword(s):  
Health Economics ◽  
Factor Viii ◽  
Crossover Study ◽  
Hemophilia A ◽  
Recombinant Factor Viii ◽  
Severe Hemophilia ◽  
Joint Function ◽  
On Demand ◽  
History Of ◽  
Male Patients

Abstract Many of the physical, psychosocial, and financial difficulties associated with severe hemophilia can be attributed to the effects of recurrent joint bleeds and chronic arthropathy. Regimens for clotting factor replacement treatment for hemophilia include prophylactic and on-demand therapy. A study in pediatric male patients with severe hemophilia A showed that prophylactic treatment with sucrose-formulated recombinant factor VIII (rFVIII-FS) resulted in prevention of joint damage and a decrease in the frequency of joint and other bleeds compared with on-demand therapy (Manco-Johnson MJ, et al. N Engl J Med.2007;357:535). A clinical trial was conducted in adult patients with severe hemophilia A and history of frequent bleeding to evaluate the effect of secondary rFVIII-FS prophylaxis on the number of joint bleeds after switching from on-demand rFVIII-FS therapy. Secondary study objectives were to compare these treatment strategies with regard to joint function, number of all bleeds, health-related quality of life, health economics, and safety. Male patients who were aged 30–45 years, had a negative inhibitor status, had a history of FVIII treatment (&gt;100 exposure days), and were using on-demand FVIII treatment before the study were eligible to participate in this prospective 13-month crossover study. During the first 6 months, all patients received on-demand rFVIII-FS treatment. Patients were then switched to prophylactic rFVIII-FS treatment (20–40 IU/kg 3 times per wk at a stable dose as determined by investigators based on the patient’s bleeding history) for the remaining 7 months, with the first month constituting a washout/stabilization run-in period. Patients were monitored throughout the 13 months for bleeds and health-economics parameters and were evaluated by the Gilbert score (joint function) and the Haemo-QoL questionnaire at baseline and at the end of the on-demand (at 6 mo) and prophylactic (at 13 mo) treatment periods. A total of 20 patients from 9 international sites participated in the study. Patients received a mean dose of 31 IU/kg/wk during the on-demand period, which increased to 86 IU/kg/wk during the prophylaxis period. Although 16/20 patients already had 1 to 4 target joints, mean (±SD) numbers of joint and total bleeds per patient significantly decreased during the prophylaxis period (1.5±2.1 and 1.9±3.3, respectively) compared with the on-demand period (18.5±11.6 and 23.7±13.3; P&lt;0.001 for both). Mean (±SD) total Gilbert scores indicated better joint function at the end of prophylaxis (19.8±11.7) vs on-demand (25.3±11.7; P&lt;0.001) treatment. During this short observation period, there was no statistically significant difference between treatments in the pharmacoeconomic variables assessed (days off work, general practitioner visits, and hospitalization days) or in the mean total Haemo-QoL score, although patients reported significantly fewer restrictions at work or school by the end of the prophylaxis period compared with the end of the on-demand period (P=0.016). There was a trend toward improved patient activity levels with prophylaxis. Similar numbers of patients reported adverse events (AEs) during on-demand (n=9, 45.0%) and prophylactic (n=10, 52.6%) treatment; AEs occurring in 2 patients (dysgeusia and headache) were considered treatment related. Serious AEs were reported by 1 patient during each treatment; neither serious AE was related to treatment. No de novo inhibitor development was observed during either treatment. In summary, prophylaxis with rFVIII-FS was well tolerated and reduced the frequency of joint and other bleeds compared with on-demand treatment in previously treated adults with severe hemophilia A and target joints.

Consumption Of FVIII Concentrate During On-Demand and Prophylactic Treatment With Human-cl rhFVIII In Prospective Clinical Studies In Adult Patients With Severe Hemophilia A

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 3595-3595 ◽  
Author(s):  
Andreas Tiede ◽  
Sigurd Knaub ◽  
Johannes Oldenburg ◽  
Johann Bichler
Keyword(s):  
Prophylactic Treatment ◽  
Hemophilia A ◽  
Fold Increase ◽  
Human Cell Line ◽  
Adult Patients ◽  
Study Entry ◽  
Severe Hemophilia ◽  
Ample Evidence ◽  
Bleeding Rate ◽  
On Demand

Abstract Background There is ample evidence to support prophylactic treatment with factor VIII (FVIII) in children with severe hemophilia A (HA). Adults with severe HA are often treated on-demand and the potential benefit of regular prophylaxis is linked to a higher consumption of FVIII concentrates. During the clinical development of Human-cl rhFVIII, the first recombinant FVIII concentrate from a human cell line, its efficacy and safety was evaluated in previously treated adult patients (PTPs) during on-demand treatment only (GENA-01) and prophylaxis (GENA-08). Aims To compare post-hoc the annualized bleeding rate (ABR) and the consumption of FVIII concentrate in patients treated exclusively on-demand with those treated prophylactically. Methods Both prospective multi-centre studies were approved by the Ethics Committees of each participating institution and informed consent was obtained from the patient prior to any trial activity. In GENA-01, patients were to be treated on-demand for ≥6 months and ≥50 exposure days with protocol recommended doses ranging from 20 to 60 IU/kg, depending on the severity of the bleed. In GENA-08, patients were to be treated prophylactically with Human-cl rhFVIII every other day with 30-40 IU/kg for ≥6 months. Human-cl rhFVIII was also to be used in case of breakthrough bleeds. Results 22 PTPs with severe HA were enrolled in GENA-01, and 32 in GENA-08. The study populations were reasonably well comparable to each other (GENA-01 vs. GENA-08, mean±SD), regarding age (39.6±14.1 vs. 37.3±13.6 years), body mass index (23.9±4.8 vs. 25.8±4.9 kg/m2), hemophilia joint health score (38.4±30.3 vs. 34.6±32.2), race (>80% White in both studies) and historical bleeding sites. In GENA-08, the majority of patients (65.6%) had been treated prophylactically prior to study entry. Their historical mean±SD ABR was 6.6 ±11.3 (median: 2.0, range: 0-48.7) and their mean prophylactic dose/month was 293 IU/kg. The other 11 patients who had been treated on-demand had a mean±SD ABR of 47.4±34.6 (median: 36.5, range: 12.2-121.7). In GENA-01, all but 2 patients were treated on-demand prior to study entry. The historical mean±SD ABR of all GENA-01 patients was 49.5±35.9 (median: 44.6, range: 2.0-158.7). The ABR and FVIII consumption during the studies are shown in Table 1. Conclusion The data suggest that regular prophylactic treatment with Human-cl rhFVIII in adult PTPs with severe HA resulted in an approximately 25-fold reduction of bleeding rate, and a 3-fold increase of FVIII concentrate consumption. Disclosures: Tiede: Octapharma AG: Consultancy, Investigator Other. Knaub:Octapharma AG: Employment. Oldenburg:Octapharma AG: Consultancy, Investigator Other. Bichler:Octapharma AG: Employment.

The EPIC Study: A Clinical Trial To Assess Whether Early Low Dose Prophylaxis In The Absence Of Immunological Danger Signals Reduces Inhibitor Incidence In Previously Untreated Patients (PUPs) With Hemophilia A

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 576-576 ◽  
Author(s):  
Guenter Auerswald ◽  
Karin Kurnik ◽  
Jan Blatny ◽  
Armin J Reininger
Keyword(s):  
Research Funding ◽  
Low Dose ◽  
Hemophilia A ◽  
Venous Access ◽  
Patient Specific ◽  
Missense Mutations ◽  
Severe Hemophilia ◽  
Prophylactic Regimen ◽  
Inhibitor Development ◽  
Danger Signals

Abstract Background Inhibitor development is a complex, multifactorial immune response involving both patient-specific and treatment-related factors. Of the known risk factors, intensive treatment at an early age has been shown to be significant, and clinical observations have suggested that early prophylaxis (i.e. first exposure to FVIII in the absence of a bleed in the first year of age) may protect patients from inhibitor development by inducing FVIII tolerance. Aim This study aimed to assess prospectively if a once-weekly, low-dose prophylactic regimen started before 1 year of age and before the onset of a severe bleeding phenotype (i.e. joint bleed), together with the minimization of immunological danger signals, could reduce the incidence of inhibitor formation in PUPs with severe and moderately severe hemophilia A to 15% or less. Methods The EPIC study was a Phase 3b, prospective, single arm, historically-controlled, international multicenter study to assess the incidence rate of inhibitor formation in PUPs with severe and moderately severe hemophilia A during the first 50 exposure days (EDs) of treatment with ADVATE starting with a once-weekly, low-dose (ADVATE 25 IU/kg once weekly), prophylactic regimen. If clinically indicated, it was permissible to increase the frequency of dosing to 2 or 3 times per week. In addition, infusions during the first 20 EDs had to be given 3 to 4 days before or after any vaccinations, which had to be given subcutaneously, not intramuscularly; infusions had to be avoided if the subject had high fever (above 38°C [100°F]). Main enrolment criteria were: severe and moderately severe hemophilia A (FVIII ≤2%), age <1 year, ≤3 EDs to any FVIII-containing product used for treatment of minor bleeds or for precautionary infusions following injury, adequate venous access (without need for central venous access device), no life-threatening conditions (intracranial hemorrhage, severe trauma) or requirement for surgery at the time of enrollment, no evidence of inhibitor ≥0.6 BU in Nijmegen-modified Bethesda assay at study start, no hemostatic defect other than hemophilia A, no clinically significant chronic disease other than hemophilia A,. Information about type of FVIII gene defect was obtained in 17 subjects. FVIII inhibitor tests were performed at screening, at study infusion #3, 6, 10, 15, 20, 30, 40, and 50, and at any other time point if an inhibitor was suspected. Positive inhibitor testing had to be confirmed by 2 positive inhibitor tests on samples drawn at least 1 week apart. Results A total of 22 subjects were enrolled in the study. Of 20 subjects who met all entry criteria, 19 received treatment; of these, all had severe hemophilia A (FVIII<1%). At study entry 11 of these 19 patients were never exposed to FVIII before (PUPs), while the remaining 8 patients had been treated with FVIII concentrates before. FVIII gene mutation analysis revealed intron 22 inversions in 8 out of 17 subjects, hemizygous missense mutations resulting in a stop-codon in 2 subjects, frame-shift mutations in 2 subjects, and hemizygous missense mutations in 5 subjects. A total of 8 subjects developed a confirmed inhibitor: 2 of these 8 subjects had only borderline positivity at inhibitor testing (never above 0.6 BU) with absence of any anti-FVIII antibodies (IgG, IgA, IgM and IgG subclasses) as tested by ELISA. Thus incidence of inhibitors >0.6 BU in PUPs were 27%. A total of 67 major protocol deviations (PD) were reported in 15 patients: 44 PDs of these were reported in 10 subjects and were related to the treatment regimen and therefore have contrasted with the protocol intention, which was to minimize immunological danger signals and low dose prophylactic regimen. As a result of the observed inhibitor incidence the study was terminated based on futility analysis, i.e. the probability to achieve the primary end-point of inhibitor rate reduction to ≤15%. Details on inhibitor patients will be presented. Discussion The EPIC study showed no safety issue as confirmed by the Data Safety Monitoring Board. To align treatment decisions in the presence of danger signals (which are not completely avoidable in children around 1 year of age) with a demanding study protocol was found to be challenging. Thus the hypothesis that an early low dose prophylaxis in the absence of immunological danger signals might reduce inhibitor incidence in PUPs with hemophilia A could neither be verified nor disproved within this study. Disclosures: Auerswald: Novo Nordisk: Consultancy, Research Funding; Biotest: Consultancy, Research Funding; CSL-Behring: Consultancy, Research Funding; Bayer: Consultancy, Research Funding; Baxter: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding. Kurnik:Baxter: Consultancy, Research Funding; Bayer: Consultancy, Research Funding; Biotest: Consultancy, Research Funding; CSL-Behring: Consultancy, Research Funding; Novo Nordisk: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding. Blatny:Baxter: speaker fee Other. Reininger:Baxter Innovations GmbH: Employment.

Factor VIII A2 Domain Contains a Binding Site for Factor X

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 4226-4226
Author(s):  
Masahiro Takeyama ◽  
Keiji Nogami ◽  
Tomoko Matsumoto ◽  
Midori Shima
Keyword(s):  
Binding Site ◽  
Western Blotting ◽  
Hemophilia A ◽  
Affinity Constant ◽  
Severe Bleeding ◽  
Dependent Manner ◽  
Severe Hemophilia ◽  
Western Blotting Analysis ◽  
Blotting Analysis ◽  
A2 Domain

Abstract Acquired hemophilia A (AHA) is a rare hemorrhagic disease in which autoantibodies against coagulation factor (F) VIII impair the coagulation system. The inhibitors developed in AHA are polyclonal autoantibodies and the majority of FVIII inhibitors bind to the A2, A3, or C2 domains. Depending on the location of the epitope, different mechanisms of action for the anti-FVIII antibodies have been reported. Anti-A3 antibodies neutralize the procoagulant activity of FVIII by preventing its interaction with FIXa. Anti-C2 antibodies inhibit the binding of FVIII to phospholipid membrane and/or von Willebrand factor, whereas A2 and A3 inhibitors block the binding of FVIII to FIXa and FX, respectively, and obstruct the formation of the Xase complex. We have a case of AHA whose inhibitor recognizes only A2 domain and attempted several approaches to determine the mechanism of neutralizing FVIII. Thrombin and plasmin generation assay using patient’s plasma showed that the thrombin and plasmin generation in this AHA patient were decreased compared with that in congenital severe hemophilia A patient. Furthermore, FX generation (Coatest) in this AHA was also decreased compared with that in congenital severe hemophilia A patient (p<0.05). These results indicated that this inhibitor impaired the generation of Xase complex and might cause the severe bleeding disorder in this patient. The IgG subclass of inhibitor in our case was IgG1 and IgG4. Western blotting analysis using FVIIIa revealed that the inhibitor IgG recognized only A2 domain. Furthermore, western blotting analysis using FVIII A2 fragment, digested by activated protein C, showed that the inhibitor IgG bound to FVIII A2N (residue 372-562) fragment. It is known that FVIII A2 domain contains FIXa and thrombin binding sites. Western blotting analysis revealed that the inhibitor IgG inhibited Arg336 cleavage in FVIIIa by FIXa and Arg372 cleavage in FVIII by thrombin. However, the FXa-catalyzed cleavage at Arg372 in FVIII was inhibited by this inhibitor IgG. ELISA-based assay showed that the inhibitor IgG inhibited FX binding to FVIII A2. These results suggest that FX(a) binds to FVIII A2 domain. Therefore, to determine the direct binding of FX and FVIII A2 domain, ELISA-based assay was employed to assess this interaction. ELISA-based assay showed that FVIII A2 fragment bound FX in a dose-dependent manner with moderate affinity (Kd = 338 nM). FX inhibited FVIII A2 fragment binding to immobilized FX up to 70% with an inhibition constant (Ki = 254 nM) similar to the affinity constant. It is known that the residue 484-509 in the A2 domain interacts with FIXa. We hypothesized that FX binding site in the A2 domain might be in the opposite side of FIXa binding site in the A2 domain. According to the 3-D model of FVIII molecule, we prepared synthetic peptides corresponding to FVIII A2 residues 400-409, 409-419, and 420-429. To determine the specificity of these sequences for FX interaction, we examined the effects of these peptides on FVIII A2 binding to FX using ELISA-based assay. The 400-409 peptide inhibited the A2 and FX interaction up to 70%. In contrast, the 410-419 and the 420-429 peptides inhibited the interaction up to 30%. Covalent cross-linking was observed between the 400-409 peptide and FX following reaction with EDC using SDS-PAGE. These results indicate that FVIII A2 domain contains the binding site for FX(a), and the 400-409 region in the FVIII A2 domain contributes to a unique FX(a)-interactive site. Disclosures No relevant conflicts of interest to declare.

Sign in / Sign up

Export Citation Format

Share Document