Factor VIII Half-Life and Clinical Characteristics of Severe Hemophilia A.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 3091-3091
Author(s):  
Karin van Dijk ◽  
Johanna G. van der Bom ◽  
Eveline P. Mauser-Bunschoten ◽  
Goris Roosendaal ◽  
Peter J. Lenting ◽  
...  
Keyword(s):  
Factor Viii ◽  
Half Life ◽  
Clinical Characteristics ◽  
Hemophilia A ◽  
Linear Regression Analysis ◽  
Median Number ◽  
Clotting Factor ◽  
Severe Hemophilia ◽  
Single Centre

Abstract Introduction Patients with severe hemophilia A have considerably different factor VIII half-lives. Whether this is associated with clinical characteristics has not been reported. The aim of this study was to describe the effect of half-life on the clinical characteristics of patients with severe hemophilia. Patients and Methods Patients were selected from a single-centre cohort of 214 patients with severe hemophilia, born between 1944 and 1995. To improve efficiency we measured factor VIII half-life in the patients with the most severe and the mildest clinical phenotypes of severe hemophilia. Patients were selected according to age at first joint bleed, annual joint bleed frequency, clotting factor consumption and radiological Pettersson scores. A first blood sample was taken after a period of 72 hours in which the patient did not use factor VIII. After infusion with 50 IU factor VIII/kg, blood was collected at 15, 30 minutes and 1, 3, 5, 24, 30, 48 and 60 hours. From 1972 onwards, data on joint bleed frequency, clotting factor use and age at first joint bleed were collected from the patients’ files. Pettersson scores were performed at five-year intervals. For calculations of annual clotting factor use (IU/kg/yr) and number of joint bleeds per year, the last 5 years of follow-up were used. Linear regression analysis was used to assess the relation between clinical characteristics and factor VIII half-life. Results Factor VIII half-life was measured in 42 patients and ranged from 7.4–20.4 hours, with a median of 11.8 hours. One hour increase in factor VIII half life was associated with a decrease of 96 (SD 45) IU clotting factor use per kg per year (p<0.05). Joint bleed frequency was similar in patients with a shorter and a longer factor VIII half-life. Median number of joint bleeds was 2.9 per year (interquartile range (IQR) 1.1–4.4) in patients with a factor VIII half-life shorter than 12 hours and 2.6 per year (IQR 1.0–4.8) in patients with a factor VIII half-life longer than 12 hours (p=0.84). Patients with a factor VIII half-life shorter than 12 hours had a median Pettersson score of 52 points (IQR 12–61) and patients with a factor VIII half-life longer than 12 hours had a median Pettersson score of 29 points (IQR 16–52; p=0.90). Conclusion: Patients with a shorter factor VIII half-life need more clotting factor to prevent joint bleeds and subsequent arthropathy than patients with a longer factor VIII half-life.

Age at first treatment and immune tolerance to factor VIII in severe hemophilia

2003 ◽  
Vol 89 (03) ◽  
pp. 475-479 ◽  
Author(s):  
Eveline Mauser-Bunschoten ◽  
Kathelijn Fischer ◽  
Marijke van den Berg ◽  
Johanna van der Bom
Keyword(s):  
Cohort Study ◽  
Factor Viii ◽  
Hemophilia A ◽  
Treatment Center ◽  
Clotting Factor ◽  
Confounding Factors ◽  
Severe Hemophilia ◽  
Inhibitory Antibodies

SummaryFindings from a recent study suggest that earlier start of treatment with factor VIII in patients with severe hemophilia is associated with a higher risk to develop inhibitors.We set out to assess the association between age of first administration of clotting factor VIII and the risk to develop inhibitors in infants with severe hemophilia A.This work was a cohort study, carried out in the national hemophilia treatment center. The study included eighty-one consecutive patients with severe hemophilia A who received their first dose of factor VIII between 1975 and 1998. Patients were followed until their last visit in 2001 or 2002.The average follow-up was 16 years (range 3-26). Persistent inhibitory antibodies developed in 12 of 81 patients (15%).Cumulative incidence at 100 exposure days was 34% (95% confidence interval 7-61%) in patients starting therapy before the age of 6 months, 20% (4-36%) in patients starting therapy between 6 months and 1 year, 13% (0-27%) in those starting therapy between 1 and 1.5 years, and 0% in those who started therapy beyond 1.5 years of age (p for trend 0.03).Our findings confirm that age of first factor VIII administration in children with severe hemophilia A is inversely associated with the risk to develop antibodies against factor VIII. The role of confounding factors such as the type of factor VIII mutation and environmental factors needs to be evaluated.

Target Joint Bleeding in Pediatric Patients with Hemophilia Α Receiving Twice Weekly Prophylaxis with a Pegylated Full-Length Recombinant Factor VIII with Extended Half-Life

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 3778-3778
Author(s):  
Amy L. Dunn ◽  
Alexis A. Thompson ◽  
Werner Engl ◽  
Marlies Sharkhawy ◽  
Brigitt E. Abbuehl
Keyword(s):  
Factor Viii ◽  
Board Of Directors ◽  
Half Life ◽  
Research Funding ◽  
Pediatric Patients ◽  
Hemophilia A ◽  
Point Estimate ◽  
Severe Hemophilia ◽  
Advisory Committees ◽  
The Mean

Abstract Introduction: Patients with hemophilia A are at risk for acute bleeding which may affect muscles and other soft tissues but characteristically involves joints. Prophylaxis with factor VIII (FVIII) is the optimal treatment to prevent bleeding into joints and, when begun at a young age, may prevent arthropathy. BAX 8551, a polyethylene glycol (peg)ylated, full-length, recombinant FVIII built on ADVATE2, demonstrated extended half-life, efficacy, and safety for prophylaxis and treatment of bleeding in patients with severe hemophilia A. Methods: A phase 3, prospective, uncontrolled, multicenter study was performed in pediatric patients with severe hemophilia A without history of inhibitors. To be eligible, patients aged <6 years had to have ≥50, those aged 6 to <12 years ≥150 previous exposure days (EDs) to FVIII. Patients received twice weekly infusions of 50 ±10 IU/kg of BAX 855 over a period of 6 months or ≥50 EDs. The prevalence of target joints, defined as a single joint with ≥3 spontaneous bleeding episodes in any consecutive 6-month period, was assessed at baseline. Annualized rates of target joint bleeds and the course of target joints were evaluated by age (<6 and 6 to <12 years). The study was performed in accordance with the principles of the Declaration of Helsinki of the World Medical Association. Results:Sixty-six patients were treated with a mean (SD) BAX 855 dose of 51.1 (5.5) IU/kg at a mean (SD) frequency of 1.8 (0.2) infusions/week. Fourteen of 66 patients (21.2%), 3/32 (9.4%) in the younger and 11/34 (32.4%) in the older cohort, had a total of 23 target joints at screening. The number of target joint bleeds decreased during a mean (SD) of 48.5 (7.7; median: 49.0) prophylactic EDs/patient. Five of 66 (7.6%) patients had at least 1 target joint bleed, 1/32 (3.1%) in the younger and 4/34 (11.8%) in the older cohort. The point estimate for the mean (95% CI) annualized rate of target joint bleeds was 0 (0 - infinity; median: 0) compared to an annualized rate of all joint bleeds of 1.1 (0.6 - 1.9; median: 0) and an annualized rate of all bleeds of 3.0 (2.2 - 4.2; median: 2.0) (Table 1). The point estimate for the mean (95% CI) annualized bleeding rate (ABR) in 52 patients without target joints was 2.9 (2.0 - 4.2; median: 2.0) and was similar in 14 patients with target joints at screening at 3.5 (1.9 - 6.6; median: 2.1). In the younger cohort, the ABR was lower in patients with than those without target joints. However, the number of patients <6 years with target joints (N = 3) was too small to draw any conclusions (Table 1). During BAX 855 prophylaxis, no new target joints developed in any patient. Ten of 14 patients had at least 1 target joint revert to a non-target joint. In 8 of these 10 patients, 4 with 1 and 4 with 2 target joints, all target joints resolved. Conclusions:These results suggest that twice weekly infusion of BAX 855 is effective in the prevention of bleeding into target joints and may revert target to non-target joints in pediatric patients with severe hemophilia A. 1BAX 855 (Baxalta US Inc., now part of Shire) is licensed in the US and Japan under the trade name ADYNOVATE. 2ADVATE is a trade mark of Baxalta US Inc., now part of Shire. Disclosures Dunn: NovoNordisk: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Kedrion: Research Funding; Pfizer: Research Funding; CSL Behring: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Biogen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Baxalta (now part of Shire): Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bayer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Octapharma: Research Funding. Thompson:Eli Lily: Research Funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Research Funding; bluebird bio: Consultancy, Research Funding; ApoPharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Mast: Research Funding; Amgen: Research Funding; Baxalta (now part of Shire): Research Funding. Engl:Shire: Employment, Equity Ownership. Sharkhawy:Baxalta (now part of Shire): Employment. Abbuehl:Baxalta (now part of Shire): Employment.

scholarly journals BIVV001, a new class of factor VIII replacement for hemophilia A that is independent of von Willebrand factor in primates and mice

Blood ◽  
2020 ◽  
Vol 135 (17) ◽  
pp. 1484-1496 ◽  
Author(s):  
Ekta Seth Chhabra ◽  
Tongyao Liu ◽  
John Kulman ◽  
Susannah Patarroyo-White ◽  
Buyue Yang ◽  
...  
Keyword(s):  
Protein Engineering ◽  
Factor Viii ◽  
Von Willebrand Factor ◽  
Half Life ◽  
Hemophilia A ◽  
Severe Hemophilia ◽  
New Class ◽  
Pharmacokinetic Properties ◽  
Von Willebrand ◽  
Willebrand Factor

Abstract Factor VIII (FVIII) replacement products enable comprehensive care in hemophilia A. Treatment goals in severe hemophilia A are expanding beyond low annualized bleed rates to include long-term outcomes associated with high sustained FVIII levels. Endogenous von Willebrand factor (VWF) stabilizes and protects FVIII from degradation and clearance, but it also subjects FVIII to a half-life ceiling of ∼15 to 19 hours. Increasing recombinant FVIII (rFVIII) half-life further is ultimately dependent upon uncoupling rFVIII from endogenous VWF. We have developed a new class of FVIII replacement, rFVIIIFc-VWF-XTEN (BIVV001), that is physically decoupled from endogenous VWF and has enhanced pharmacokinetic properties compared with all previous FVIII products. BIVV001 was bioengineered as a unique fusion protein consisting of a VWF-DʹD3 domain fused to rFVIII via immunoglobulin-G1 Fc domains and 2 XTEN polypeptides (Amunix Pharmaceuticals, Inc, Mountain View, CA). Plasma FVIII half-life after BIVV001 administration in mice and monkeys was 25 to 31 hours and 33 to 34 hours, respectively, representing a three- to fourfold increase in FVIII half-life. Our results showed that multifaceted protein engineering, far beyond a few amino acid substitutions, could significantly improve rFVIII pharmacokinetic properties while maintaining hemostatic function. BIVV001 is the first rFVIII with the potential to significantly change the treatment paradigm for severe hemophilia A by providing optimal protection against all bleed types, with less frequent doses. The protein engineering methods described herein can also be applied to other complex proteins.

The Half-life of Infused Factor VIII Is Shorter in Hemophiliac Patients with Blood Group 0 than in those with Blood Group A

2000 ◽  
Vol 83 (01) ◽  
pp. 65-69 ◽  
Author(s):  
Evelien Mauser-Bunschoten ◽  
Antoanette Zarkova ◽  
Els Haan ◽  
Cas Kruitwagen ◽  
Jan Sixma ◽  
...  
Keyword(s):  
Factor Viii ◽  
Blood Group ◽  
Half Life ◽  
Hemophilia A ◽  
Linear Regression Analysis ◽  
Life Time ◽  
Blood Group A ◽  
Wide Range ◽  
Group A ◽  
Blood Group P

SummaryA considerable inter-individual variation in half-life of infused factor VIII is observed among patients with hemophilia A. The factors contributing to this wide range in factor VIII half-life are not known in detail. We analysed the pharmacokinetics of infused factor VIII in 32 patients with hemophilia A, comprising 20 brothers from 10 families, 3 and 4 brothers from 2 families, and 5 patients from 5 single families, respectively. Multiple linear regression analysis was used to asses the effect of several variables on factor VIII half-life. We found that the pre-infusion von Willebrand factor antigen levels (vWF:Ag) were positively correlated with factor VIII half-life (r = 0.52, p = 0.002), i. e., each variable was associated with about 27% of the variance of the other. In fraternal pairs, familial clustering was significant for AB0 blood group (p < 0.001), but could not be detected for factor VIII half-lives or pre-infusion vWF:Ag levels. vWF:Ag level (p = 0.001) and AB0 blood group (p = 0.003) significantly determined factor VIII half-life, whereas age, length, bodyweight, the presence or absence of a factor VIII gene inversion, and Rhesus phenotype did not. Patients with blood group 0 exhibited a statistically significant shorter factor VIII half-life than patients with blood group A (15.3 versus 19.7 h, respectively) (p = 0.003). Patients with blood group A and 0 differ in respect to the presence of anti-A antibodies in the latter. It is possible that these anti-A antibodies interact with endogenous vWF, thus affecting the half-life time of the factor VIII/vWF complex.

scholarly journals Pharmacokinetics of Extended Half-Life Factor VIII Products By myPKFiTR Is Useful for Personalized Treatment in Children with Severe Hemophilia a

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 1127-1127
Author(s):  
Risa Matsumura ◽  
Keita Tomioka ◽  
Shiho Nishimura ◽  
Yoko Mizoguchi ◽  
Hiroshi Kawaguchi ◽  
...  
Keyword(s):  
Factor Viii ◽  
Half Life ◽  
Hemophilia A ◽  
Conflicts Of Interest ◽  
After School ◽  
Severe Hemophilia ◽  
Prophylactic Regimen ◽  
Sports Activity ◽  
Prophylactic Administration ◽  
Single Center Experience

Prophylactic administration of factor VIII products is necessary to prevent bleeding and preserve normal musculoskeletal function in children with severe hemophilia A (HA). Recently, extended half-life recombinant factor VIII (EHL-rFVIII) products have been utilized in HA patients. Therefore, the pharmacokinetics (PK) of EHL-rFVIII in individuals is needed to determine the appropriate administration for personalized prophylaxis according to the age, bleeding phenotype, the presence of arthropathy, and physical activity. The myPKFiTR ver 3.0 has been developed as the device to estimate the personalized dosing with a 2 sample PK based on the population PK (Bayesian) tool. In this study we report our single-center experience to study PK profiles and to individualize dose and dosing interval based on myPKFiTR. Eight patients with severe HA aged from 10 to 20 years were enrolled in this study for personalized prophylaxis. The half-life of EHL-rFVIII was approximately 15 to 18 hours in all patients studied. The clearance of FVIII was inversely correlated with the half-life of EHL-rFVIII. The EHL-rFVIII products have been basically administered twice a week. The trough levels of FVIII were more than 3% in all patients. The prophylactic regimen in adolescents was individually determined according to the personal simulation of PK study and to patients' life style and physical activities. Adolescent patients actively participated in sports, such as track and field, basketball, and football after school. The FVIII level after school was easily estimated by the use of myPKFiTR according to the dose and duration of replacement. The doses of EHL-rFVIII products were individually determined to have more than 10 to 30% of FVIII level at the time of sports activity. During personalized prophylaxis (6 to 18 months), all of patients studied have been no bleeds during sports as well as no spontaneous bleeds. Additionally, myPKFiTR has the capability of presenting the real-time FVIII level on the screen of smartphone after the replacement of EHL-rFVIII based on the individual PK. Some patients have referred their own FVIII level before the beginning of sports through their smartphone and then have decided the necessity of the replacement. These experiences suggest the enhancement of treatment concordance in the supportive relationship between patients and medical staff. Thus, the use of myPKFiTR may be essential for the optimization of prophylactic administration of EHL-rFVIII and for the medical adherence and concordance in each individual. Disclosures No relevant conflicts of interest to declare.

Resolution of the Expert council on current issues of prescribing clotting factor VIII with prolonged half-life (INN — Efmoroctocog alfa) in patients with hemophilia A

2021 ◽  
Vol 8 (2) ◽  
pp. 142-143
Author(s):  
Article Editorial
Keyword(s):  
Factor Viii ◽  
Half Life ◽  
Hemophilia A ◽  
Clotting Factor

В ходе Совета экспертов, который состоялся 11 мая 2021 г., обсуждались критерии назначения препарата фактора свертывания крови VIII (эфмороктоког альфа) с пролонгированным периодом полувыведения пациентам с гемофилией А.

T-Cell Alterations in Hemophiliacs Treated with Commercial Clotting Factor Concentrates

1983 ◽  
Vol 50 (02) ◽  
pp. 552-556 ◽  
Author(s):  
K Lechner ◽  
H Niessner ◽  
P Bettelheim ◽  
E Deutsch ◽  
I Fasching ◽  
...  
Keyword(s):  
T Cell ◽  
Factor Viii ◽  
Hemophilia A ◽  
Indirect Evidence ◽  
Absolute Number ◽  
Hemophilia B ◽  
Clotting Factor ◽  
Severe Hemophilia ◽  
T Helper ◽  
Immunological Parameters

SummaryVarious immunological parameters were determined in 46 patients with severe hemophilia A and in 9 patients with severe hemophilia B. All patients were treated over many years with commercial factor VIII or IX concentrates. Patients with severe classic hemophilia had a significantly reduced relative and absolute number of T-helper cells and a significantly increased relative and absolute number of T-suppressor cells. About half of these patients had an inverse T-helper/suppressor cell ratio. Patients with moderate hemophilia A and severe hemophilia B did not show these abnormalities. Hemophiliacs with an inverse ratio had a significantly higher concentration of serum total protein, IgG and IgM. No relationship between the amount of factor VIII concentrate administered, the HLA-type of the patient, the presence or absence of CMV-antibodies, hepatitis markers, thrombocytopenia and abnormal liver function tests to the T-cell abnormalities could be established. Lymphadenopathy was frequently associated with an inverse ratio. Indirect evidence suggests that the alterations of the immune system began in 1979/80.

scholarly journals Safety and efficacy of BAY 94-9027, an extended-half-life factor VIII, during surgery in patients with severe hemophilia A: Results of the PROTECT VIII clinical trial

2019 ◽  
Vol 183 ◽  
pp. 13-19 ◽  
Author(s):  
Elena Santagostino ◽  
Shadan Lalezari ◽  
Mark T. Reding ◽  
Jonathan Ducore ◽  
Heng Joo Ng ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Factor Viii ◽  
Half Life ◽  
Hemophilia A ◽  
Severe Hemophilia ◽  
Safety And Efficacy ◽  
Life Factor
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