Development of inhibitors in haemophilia

SummaryA number of 513 consecutive patients (494-haemophilia A and 19-haemophilia B) from eight haemophilia treatment centers have been investigated with Bethesda assay for the presence of factor VIII or IX inhibitors. The overall prevalence of inhibitors was 15.20%, 18.48% in severe, 5.60% in moderate and 12.24% in mild forms. The prevalence was higher than reported in most of the western countries. The age at start of substitution (p = 0.9775), the frequent switching of factor concentrates (p = 0.8931) were not relevant factors for the development of inhibitors. It is worth to be mentioned the unexpectedly occurrence of inhibitors in prior inhibitor negative (6/72) patients (during surgical interventions) probably due to their previous scarce substitution, occurrence which seems not being connected with the continuous infusion modality of factor VIII administration (p = 0.8341). In controversial situations, in the field of low titer (≤1 BU/ml) inhibitors for a reliable interpretation of the results the performance of recovery index and half-life time assessment of FVIII/IX was undertaken.

Download Full-text

Case report: successful perioperative management of patients with haemophilia A using an extended half-life factor VIII (Efmoroctocog alfa) during neurosurgical procedures

Therapeutic Advances in Hematology ◽

10.1177/2040620721993686 ◽

2021 ◽

Vol 12 ◽

pp. 204062072199368

Author(s):

Florian Kocher ◽

Andreas Seeber ◽

Johannes Kerschbaumer ◽

Stefan Schmidt ◽

Dominik Wolf ◽

...

Keyword(s):

High Risk ◽

Factor Viii ◽

Half Life ◽

Perioperative Management ◽

Fatal Outcome ◽

Bleeding Complications ◽

Neurosurgical Procedures ◽

Haemophilia A ◽

Surgical Interventions ◽

Life Factor

Patients with haemophilia A (HA) undergoing neurosurgical procedures have a high risk of haemorrhage with potential fatal outcome. Here, we present a successful perioperative haemostatic concept applying an extended half-life factor VIII (EHL FVIII), Efmoroctocog alfa, in two patients with HA undergoing neurosurgery for paramedian right-sided disc herniation (case 1) and astrocytoma (case 2). After adequate EHL FVIII treatment the surgical procedures were performed without any bleeding complications despite the high-risk interventions. Laboratory measurements confirmed stable FVIII levels throughout the hospital stay. We suggest close interdisciplinary collaboration between involved clinicians as mandatory prerequisite for an optimized perioperative management in patients with HA. The presented cases indicate, that the increased stability, safety and fewer injections provide a rationale to use EHL FVIII products in HA patients undergoing surgical interventions with a very high bleeding risk.

Download Full-text

Continuous infusion of extended half-life factor VIII (efmoroctocog alpha) for surgery in severe haemophilia A

Haemophilia ◽

10.1111/hae.13557 ◽

2018 ◽

Vol 24 (4) ◽

pp. e280-e283

Author(s):

I. C. L. Kremer Hovinga ◽

R. E. G. Schutgens ◽

P. R. van der Valk ◽

L. F. D. van Vulpen ◽

E. P. Mauser-Bunschoten ◽

...

Keyword(s):

Factor Viii ◽

Continuous Infusion ◽

Half Life ◽

Haemophilia A ◽

Severe Haemophilia ◽

Life Factor

Download Full-text

Treatment of Joint-Bleedings in Hemophiliacs with Antibodies to Factor VIII with High doses of Fraction Feiba.

10.1055/s-0039-1682562 ◽

1977 ◽

Author(s):

Kl. Schimpf ◽

K. Zimmermann ◽

P. Zeltsch

Keyword(s):

Knee Joint ◽

Factor Viii ◽

Half Life ◽

Clinical Effect ◽

Single Injection ◽

Life Time ◽

Joint Effusion ◽

The Third ◽

Inhibitor Level ◽

High Doses

Observations in 3 patients demonstrated, that joint-bleedings can be controlled with high doses of fraction FEIBA alone or in combination with factor (f) VIII on out-patient basis. First patient, inhibitor 5-10 units (u) per ml, suffered from 24 joint-bleedings within 392 days. 2o of them could be stopped by a single injection of 150-200 u of fraction FEIBA per kg bodyweight (bw). A combination of 90 u of FEIBA and 36 u of f VIII per kg bw had the same effect. But after 5 injections of this combination within 6 weeks, the inhibitor level had risen from 10 to 240 u per ml. During further treatment with 180 u of fraction FEIBA without addition of f VIII, the inhibitor fell down with a half life time of 50 days. The clinical effect of fraction FEIBA was not influenced by the elevated antibody level. Two further patients, inhibitors 2-4 and 32 u respectively, obtained combined injections of 50-100 u of FEIBA plus 36-42 u of f VIII. One patient was on a prophylaxis of 3 injections weekly for 193 days. After 57 injections the inhibitor had fallen from 2-4 u to unmeasurable values. The third patient obtained the above mentioned dosis twice a day for treatment of a knee joint effusion. After 1 week the inhibitor was diminished from 32 to 13 u.

Download Full-text

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

Thrombosis and Haemostasis ◽

10.1055/s-0037-1613759 ◽

2000 ◽

Vol 83 (01) ◽

pp. 65-69 ◽

Cited By ~ 78

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.

Download Full-text

Design of a prospective observational study on the effectiveness and real-world usage of recombinant factor VIII Fc (rFVIIIFc) compared with conventional products in haemophilia A: the A-SURE study

BMJ Open ◽

10.1136/bmjopen-2018-028012 ◽

2019 ◽

Vol 9 (5) ◽

pp. e028012 ◽

Cited By ~ 3

Author(s):

Johannes Oldenburg ◽

Charles R M Hay ◽

Víctor Jiménez-Yuste ◽

Flora Peyvandi ◽

Jean-François Schved ◽

...

Keyword(s):

Factor Viii ◽

Half Life ◽

Scientific Journal ◽

Coagulation Factor ◽

Clinical Effectiveness ◽

Ethics Committees ◽

Primary Objective ◽

Supplementary Information ◽

Haemophilia A ◽

Study Results

IntroductionHaemophilia A is a rare bleeding disorder caused by coagulation factor VIII (FVIII) deficiency. This is treated with factor VIII, conventionally using products with a half-life of 8–12 hours typically administered every 2–3 days. Recombinant FVIII Fc (rFVIIIFc) represents a new generation of products with an extended half-life allowing higher FVIII levels and longer dosing interval. The efficacy and safety of rFVIIIFc have been established in clinical studies and several years of postmarketing use. However, there remains a need to compare treatment outcome with conventional products in routine clinical use.Methods and analysisA-SURE is an ongoing, non-interventional European study with the primary objective to compare the clinical effectiveness of rFVIIIFc with conventional factor products used for haemophilia A prophylaxis. Data covering a 24-month prospective period and a 12-month retrospective period will be collected. Three primary endpoints: bleeding rate, injection frequency and factor consumption will be used to evaluate treatment outcomes. Enrolment of 175 patients on rFVIIIFc and 175 on conventional products is planned. All eligible patients from participating centres will be invited to participate. Visits and treatments follow routine clinical practice. Bias will be reduced by patient matching for age at baseline and the last weekly prophylaxis dose of a conventional product prior to baseline. Propensity scores will be calculated based on prognostic factors and potential confounders assessed at baseline and adjusted for in the estimation of the treatment effect.Ethics and disseminationStudy approval was obtained by local independent ethics committees and/or authorities, and informed consent from patients or their legal representative is a requirement for participation. Names of ethical committees and approval numbers are provided as supplementary information. The study results will be submitted for publication in a peer-reviewed scientific journal and presented at scientific conferences.Trial registration numberNCT02976753, Pre-results.

Download Full-text

Cross-evaluation of Pharmacokinetic-Guided Dosing Tools for Factor VIII

Thrombosis and Haemostasis ◽

10.1055/s-0038-1623531 ◽

2018 ◽

Vol 118 (03) ◽

pp. 514-525 ◽

Cited By ~ 8

Author(s):

T. Preijers ◽

I. van Moort ◽

K. Fijnvandraat ◽

F. Leebeek ◽

M. Cnossen ◽

...

Keyword(s):

Factor Viii ◽

Half Life ◽

Trough Level ◽

Patient Characteristics ◽

Population Pharmacokinetic ◽

Parameter Estimates ◽

Haemophilia A ◽

Blood Samples ◽

Fviii Activity ◽

Recombinant Fviii

Background Patients with severe and moderate haemophilia A are treated prophylactically with factor VIII (FVIII) concentrate. Individualization of prophylaxis can be achieved by pharmacokinetic (PK)-guided dosing. Aim In this study, the performance of three PK tools (myPKFiT, Web-Accessible Population Pharmacokinetic Service-Hemophilia [WAPPS] and NONMEM) is compared. Methods In 39 patients, with severe or moderate haemophilia A, blood samples were collected 4, 24 and 48 hours after administration of 50 IU kg−1 of recombinant FVIII (Advate [n = 30] or Kogenate [n = 9]). FVIII dose, FVIII activity and patient characteristics were entered into the three PK tools. Obtained PK parameters and dosing advises were compared. Results myPKFiT provided PK parameters for 24 of 30 patients receiving Advate, whereas WAPPS and NONMEM provided estimates for all patients. Half-life was different among the three methods: medians were 12.6 hours (n = 24), 11.2 hours (n = 30) and 13.0 hours (n = 30) for myPKFiT, WAPPS and NONMEM (p < 0.001), respectively. To maintain a FVIII trough level of 0.01 IU mL−1 after 48 hours, doses for myPKFiT and NONMEM were 15.1 and 11.0 IU kg−1 (p < 0.01, n = 11) and for WAPPS and NONMEM were 9.0 and 8.0 IU kg−1 (p < 0.01, n = 23), respectively. In nine patients receiving Kogenate, WAPPS and NONMEM produced different PK-parameter estimates; half-life was 15.0 and 12.3 hours and time to 0.05 IU mL−1 was 69.2 and 60.8 hours, respectively (p < 0.01, n = 9). However, recommended doses to obtain these levels were not different. Conclusion The three evaluated PK tools produced different PK parameters and doses for recombinant FVIII. Haematologists should be aware that recommended doses may be influenced by the choice of PK tool.

Download Full-text