scholarly journals Modeling to Predict Factor VIII Levels Associated with Zero Bleeds in Patients with Severe Hemophilia A Initiated on Tertiary Prophylaxis

2020 ◽  
Vol 120 (05) ◽  
pp. 728-736
Author(s):  
Pratima Chowdary ◽  
Kathelijn Fischer ◽  
Peter W. Collins ◽  
Amy Cotterill ◽  
Barbara A. Konkle ◽  
...  
Keyword(s):  
Factor Viii ◽  
Hemophilia A ◽  
Trough Level ◽  
Severe Hemophilia ◽  
Pragmatic Approach ◽  
Post Hoc Analysis ◽  
Kaplan Meier ◽  
Post Hoc ◽  
The Relationship ◽  
Trough Levels

Abstract Background Factor VIII (FVIII) trough levels > 1 IU/dL in patients with severe hemophilia A receiving regular prophylaxis may optimize bleed protection. Objectives In this post hoc analysis of patients receiving tertiary prophylaxis for approximately 1 year, the relationship between estimated FVIII levels and reported bleeds was investigated to predict the potential for zero bleeds. Methods Sixty-three patients (median [range] age, 28 [7–59] years) with severe hemophilia A (229 bleeds) were included. FVIII levels at time of each bleed were estimated from single-dose individual pharmacokinetics. The highest estimated FVIII level at which patients experienced a bleed was considered the “potentially effective trough level” for that bleed type. Kaplan–Meier estimates of proportions of patients with no bleeds above certain estimated FVIII levels were determined. Those not experiencing a bleed in the trial were assumed to have a bleed at 0 IU/dL (pragmatic approach) or at their median trough level (conservative approach). Results Kaplan–Meier estimates based on pragmatic approach predicted zero all bleeds, joint bleeds, and spontaneous joint bleeds in 1 year in 40, 43, and 63% of patients, respectively, when the potentially effective trough FVIII level was set at 1 IU/dL. Between 1 and 10 IU/dL, every 1 IU/dL rise in estimated FVIII level was associated with an additional 2% of patients having zero all bleeds. Conclusion This post hoc analysis confirms benefits with trough levels of approximately 1 to 3 IU/dL in most patients starting tertiary prophylaxis; prophylaxis with higher trough levels may help patients to achieve zero bleeds.

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

QJM ◽  
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.

scholarly journals Modelling FVIII Levels for Prediction of Zero Spontaneous-Joint Bleeding in a Cohort of Severe Hemophilia a Subjects with Target Joints Initiated on Tertiary Prophylaxis

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 2576-2576 ◽  
Author(s):  
Kathelijn Fischer ◽  
Pratima Chowdary ◽  
Peter Collins ◽  
Amy Cotterill ◽  
Barbara Konkle ◽  
...  
Keyword(s):  
Research Funding ◽  
Median Number ◽  
Activity Level ◽  
Severe Hemophilia ◽  
On Demand ◽  
Kaplan Meier ◽  
Fviii Activity ◽  
Equity Ownership ◽  
Post Hoc ◽  
Trough Levels

Abstract Background Prophylaxis is increasingly the standard of care for adults with severe hemophilia A (SHA), however the optimal dose and treatment regimen when initiating tertiary prophylaxis is unknown. The relationship between factor level and risk of bleeding is not established, particularly in patients with joint disease. A post hoc analysis was conducted on a cohort of adult SHA patients who switched to prophylaxis from on demand therapy. Methods The cohort included 63 subjects with measured factor VIII (FVIII) levels of <1 IU/dL, aged 7 to 59 years, receiving on-demand treatment and with a minimum of eight joint hemorrhages in the 12 months prior to enrollment. After 6 months observation of on demand treatment and a full pharmacokinetic (PK) analysis, subjects were randomized to 12 months of either standard prophylaxis (20-40 IU kg−1 every 2nd day) or PK-tailored prophylaxis (20-80 IU kg−1 every 3rd day) targeting FVIII trough levels ≥1 IU/dL. Subjects had a median age of 28 years, and median weight of 71Kg. At study start, 95.2% of subjects had ≥1 target joints (median 3). During on demand treatment before randomization, the median number of spontaneous-joint bleeds was 29.9/year (range: 0 to 91.3). During prophylaxis, the median number of spontaneous-joint bleeds was 0/year (range: 0 to 10.2) in the combined prophylaxis groups. A PK model was fitted to the FVIII activity levels collected during the PK analysis for each subject independently. These individual models were used to predict the FVIII activity level at the time of bleed on the assumption of linear pharmacokinetics and no inter-occasion variability. For each subject the highest FVIII activity level associated with a spontaneous-joint bleeding event was considered as the minimally effective level to prevent spontaneous-joint bleeds. A Kaplan-Meier estimate for the proportion of subjects with no spontaneous-joint bleeds above FVIII activity level was carried out. For subjects who had no spontaneous-joint bleeding events an assumption was made that they would have bled only at 0 IU/dL, even in situations where the trough levels may have been higher. Results The Kaplan-Meier curve for proportion of the cohort without spontaneous-joint bleeds as function of predicted FVIII level is presented in Figure 1. The corresponding estimates are presented in Table 1. Based on this analysis in this cohort, the majority of patients (63%) would not be expected to have spontaneous-joint bleeds while maintaining a trough level of 1 IU/dL with more marginal improvements in response to higher FVIII levels. These results indicate that, in subjects with multiple target joints starting tertiary prophylaxis, most experience no spontaneous-joint bleeds for a predicted FVIII level ≥1 IU/dL, however, bleeds occurred at much higher predicted FVIII levels in some subjects. This is within the range of FVIII levels associated with hemophilia (0-40%) (White GC, et al. Thromb Haemost. 2001 Mar; 85(3):560). Conclusion The results of the model and the present post-hoc analysis support current trends to personalize prophylaxis based on individual variations in bleeding phenotypes, despite similar FVIII levels. To prevent all spontaneous-joint bleeds, some patients may require higher levels, findings which are congruent with those published on the natural history of joint bleeding in mild, moderate, and severe hemophilia patients (Den Uijl IE et al. Haemophilia. 2011;17(6):849-853). Disclosures Fischer: Wyeth/Pfizer: Research Funding; Biogen: Consultancy; NovoNordisk: Consultancy, Research Funding, Speakers Bureau; Pfizer: Consultancy, Speakers Bureau; Biotest Octapharma: Speakers Bureau; CSL Behring: Speakers Bureau; Baxter: Consultancy, Research Funding, Speakers Bureau; Freeline: Consultancy; Bayer: Consultancy, Research Funding, Speakers Bureau. Chowdary:Sobi: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria, Research Funding; Novo Nordisk: Consultancy, Honoraria, Research Funding; CSL Behring: Consultancy, Honoraria, Research Funding; Biogen Idec: Consultancy, Honoraria; Baxalta: Consultancy, Honoraria; Bayer: Honoraria. Collins:NovoNordisk: Consultancy; Sobi: Consultancy; CSL Behring: Consultancy, Research Funding; Shire: Consultancy, Speakers Bureau. Cotterill:Shire: Employment. Pipe:UniQure: Consultancy; Pfizer: Consultancy; Genentech/Roche: Consultancy; Biogen: Consultancy; CSL Behring: Consultancy; Novo Nordisk: Consultancy; Shire: Consultancy, Other: Grant funding. Wolfsegger:Shire: Employment, Equity Ownership. Engl:Shire, formerly Baxalta and Baxter: Employment, Equity Ownership. Goldstine:Shire: Employment. Valentino:Shire: Employment. Spotts:Shire: Employment.

scholarly journals Characteristics of Bleed-Free Patients on Every-5-Day Dosing in the Protect VIII (BAY 94-9027) Study

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 2486-2486 ◽  
Author(s):  
Elena Santagostino ◽  
Bryce A. Kerlin ◽  
Claude Negrier ◽  
Liu Tian ◽  
Jonathan M. Ducore
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Hemophilia A ◽  
Severe Hemophilia ◽  
Main Study ◽  
Dose Frequency ◽  
Open Label ◽  
Advisory Committees ◽  
Post Hoc Analysis ◽  
Post Hoc

Abstract Background: BAY 94‐9027 is a B-domain-deleted recombinant factor VIII (FVIII) that is site-specifically PEGylated with a 60-kDa (2 x 30-kDa) polyethylene glycol (PEG) to extend its half-life. The efficacy and safety of BAY 94-9027 as prophylactic and on-demand therapy for patients with severe hemophilia A were demonstrated in the phase II/III PROTECT VIII trial, in which patients could receive prophylaxis every 7 days (E7D), every 5 days (E5D), or twice-weekly (2×W). Patients in the E5D arm had a low median annualized bleeding rate (ABR) of 1.9. This post hoc analysis was conducted to identify clinical predictors for 'best responders' (patients with ABR = 0) during E5D prophylaxis with BAY 94-9027 in PROTECT VIII. Methods: PROTECT VIII was a partially randomized, open-label trial of 134 males aged 12-65 years with severe hemophilia A (FVIII < 1%) and ≥ 150 FVIII exposure days. Prophylaxis patients received BAY 94-9027 25 IU/kg 2×W for a 10-week run-in period. Patients with ≤ 1 spontaneous joint or muscle bleed during this period were randomized to 45‒60 IU/kg E5D or 60 IU/kg E7D for the main 26-week study period; patients enrolling after the randomization arms were full, or with ≥ 2 bleeds in the run-in period, received 30-40 IU/kg 2×W. All patients randomized to the E5D arm (n = 43) remained on this dose-frequency throughout the main study. This post hoc analysis presents a description of baseline characteristics of best responders to E5D dosing, defined as patients with ABR = 0 during the main study period; the study was not powered to support a formal statistical comparison. Results: Of 43 patients randomized to E5D dosing, 24 (55.8%) had ABR ≥ 1 and 19 (44.2%) had ABR = 0, meeting the criterion for best responders. The median (95% CI) age was slightly higher for best responders, 38 years [30.0; 47.0] versus 31.5 [24.0; 41.0]), than patients with ABR ≥ 1. In the 12 months prior to the study, best responders had lower median (95% CI) bleeds (2.0 [0.0; 5.0] versus 10.0 [3.0; 21.0]) and joint bleeds (0.0 [0.0; 2.0] versus 8.0 [2.0; 12.0]) compared with patients with ABR ≥ 1. Most patients in both groups had previously received prophylaxis prior to study (84.2% and 70.8%, respectively). Fewer best responders had target joints (57.9%, versus 70.8% of patients with ABR ≥ 1); and those who did have target joints only 36.4% had ≥ 1 target joint, versus 47.1% of patients with ABR ≥ 1. Conclusions: Overall, the 43 patients receiving BAY 94-9027 E5D prophylaxis had a low median ABR of 1.9. The 19 of these patients who had an ABR of 0 (best responders) had numerically fewer bleeds in the 12 months prior to treatment initiation, particularly joint bleeds, and numerically fewer target joints, vs patients with ABR ≥ 1. Though requiring validation in a powered study, taken together, these results suggest the applicability of E5D BAY 94-9027 dosing across patient profiles, and that patients with a similar bleed and joint profile to those analyzed here may be able to achieve ABR of 0 with E5D BAY 94-9027. Disclosures Santagostino: Bayer, Shire, CSL Behring, Pfizer, Novo Nordisk, Grifols, Kedrion, Sobi, Bioverativ, Octapharma, Roche: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Negrier:Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Octapharma: Honoraria, Research Funding; Bayer: Honoraria, Research Funding; Sobi/Bioverativ: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Alnylam: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; CSL Behring: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Novo Nordisk: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; LFB: Honoraria, Membership on an entity's Board of Directors or advisory committees; Baxalta/Shire: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Tian:Bayer: Employment. Ducore:CSL Behring: Other: investigator; HemaBiologics: Consultancy, Other: investigator, travel support; OPKO: Other: investigator; Octapharma: Consultancy, Other: travel support, investigator , Research Funding; Bayer Healthcare: Consultancy, Other: travel support, investigator; Shire: Consultancy, Other: travel support, investigator; Pfizer: Other: investigator; Biomarin: Other: investigator; Spark Therapeutics: Consultancy, Other: investigator.

T Lymphocyte Proliferative Responses Induced by Recombinant Factor VIII in Hemophilia A Patients with Inhibitors

1996 ◽  
Vol 76 (01) ◽  
pp. 017-022 ◽  
Author(s):  
Sylvia T Singer ◽  
Joseph E Addiego ◽  
Donald C Reason ◽  
Alexander H Lucas
Keyword(s):  
T Lymphocytes ◽  
Factor Viii ◽  
Cellular Proliferation ◽  
Mononuclear Cells ◽  
Hemophilia A ◽  
Normal Subjects ◽  
Normal Male ◽  
Cell Fractionation ◽  
Severe Hemophilia ◽  
Human Factor Viii

SummaryIn this study we sought to determine whether factor VUI-reactive T lymphocytes were present in hemophilia A patients with inhibitor antibodies. Peripheral blood mononuclear cells (MNC) were obtained from 12 severe hemophilia A patients having high titer inhibitors, 4 severe hemophilia A patients without inhibitors and 5 normal male subjects. B cell-depleted MNC were cultured in serum-free medium in the absence or presence of 2 µg of recombinant human factor VIII (rFVIII) per ml, and cellular proliferation was assessed after 5 days of culture by measuring 3H-thymidine incorporation. rFVIII induced marked cellular proliferation in cultures of 4 of 12 inhibitor-positive hemophilia patients: fold increase over background (stimulation index, SI) of 7.8 to 23.3. The remaining 8 inhibitor-positive patients, the 4 hemophilia patients without inhibitors and the 5 normal subjects, all had lower proliferative responses to rFVIII, SI range = 1.6 to 6.0. As a group, the inhibitor-positive subjects had significantly higher proliferative responses to rFVIII than did the inhibitor-negative and normal subjects (p < 0.05 by t-test). Cell fractionation experiments showed that T lymphocytes were the rFVIII-responsive cell type, and that monocytes were required for T cell proliferation. Thus, rFVIII-reactive T lymphocytes are present in the peripheral circulation of some inhibitor-positive hemophilia A patients. These T cells may recognize FVIII in an antigen-specific manner and play a central role in the regulation of inhibitor antibody production

Dose Requirement for Replacement Therapy in Hemophilia A

1979 ◽  
Vol 42 (03) ◽  
pp. 825-831 ◽  
Author(s):  
Jean-Pierre Allain
Keyword(s):  
Clinical Effect ◽  
Hemophilia A ◽  
Clinical Results ◽  
Severe Hemophilia ◽  
Dose Requirement ◽  
Viii Level ◽  
The Relationship ◽  
In Vivo Recovery ◽  
Different Doses

SummaryIn order to determine the correlation between different doses of F. VIII and their clinical effect,. 70 children with severe hemophilia A were studied after treatment with single doses of cryoprecipitate. The relationship between plasma F. VIII levels or doses calculated in u/ kg of body weight and clinical results followed an exponential curve. Plasma F. VIII levels of 0.35 and 0.53 u/ml corresponded to 95 and 99% satisfactory treatment, respectively. Similar clinical results were obtained with 20 and 31 u/kg. When the in vivo recovery of F. VIII after lyophilized cryoprecipitate was 0.015 u/ml for each u/kg injected, plasma F. VIII levels of 0.30 and 0.47 u/ml respectively were achieved. Since home treatment is largely based on single infusions of F. VIII, it is suggested that moderate and severe hemorrhages be treated with a dose which will provide a plasma F. VIII level of 0.5 u/ml.

Incidence of factor VIII inhibitors throughout life in severe hemophilia A in the United Kingdom

Blood ◽  
2011 ◽  
Vol 117 (23) ◽  
pp. 6367-6370 ◽  
Author(s):  
Charles R.M. Hay ◽  
Ben Palmer ◽  
Elizabeth Chalmers ◽  
Ri Liesner ◽  
Rhona Maclean ◽  
...  
Keyword(s):  
United Kingdom ◽  
Factor Viii ◽  
Hemophilia A ◽  
Interquartile Range ◽  
Severe Hemophilia ◽  
The United Kingdom ◽  
Potential Risk Factors ◽  
History Of ◽  
Previously Treated Patients ◽  
Adjusted Incidence

Abstract The age-adjusted incidence of new factor VIII inhibitors was analyzed in all United Kingdom patients with severe hemophilia A between 1990 and 2009. Three hundred fifteen new inhibitors were reported to the National Hemophilia Database in 2528 patients with severe hemophilia who were followed up for a median (interquartile range) of 12 (4-19) years. One hundred sixty (51%) of these arose in patients ≥ 5 years of age after a median (interquartile range) of 6 (4-11) years' follow-up. The incidence of new inhibitors was 64.29 per 1000 treatment-years in patients < 5 years of age and 5.31 per 1000 treatment-years at age 10-49 years, rising significantly (P = .01) to 10.49 per 1000 treatment-years in patients more than 60 years of age. Factor VIII inhibitors arise in patients with hemophilia A throughout life with a bimodal risk, being greatest in early childhood and in old age. HIV was associated with significantly fewer new inhibitors. The inhibitor incidence rate ratio in HIV-seropositive patients was 0.32 times that observed in HIV-seronegative patients (P < .001). Further study is required to explore the natural history of later-onset factor VIII inhibitors and to investigate other potential risk factors for inhibitor development in previously treated patients.

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