A 6-year follow-up of dosing, coagulation factor levels and bleedings in relation to joint status in the prophylactic treatment of haemophilia

Summary. The primary aim of this study was to investigate the possible relationship between coagulation factor level and bleeding frequency during prophylactic treatment of haemophilia after stratification of the patients according to joint scores. The secondary aim was to obtain a systematic overview of the doses of coagulation factors prescribed for prophylaxis at the Malmö haemophilia treatment centre during a 6‐year period. A retrospective survey of medical records for the years 1997–2002 and pharmacokinetic study results from the 1990s was complemented by collection of blood samples for coagulation factor assay when needed. Information on the dosing and plasma levels of factor VIII or factor IX, joint scores and incidence of bleedings (joint bleeds and ‘other bleeds’) was compiled. The patients were stratified by age (0–6, 7–12, 13–18, 19–36 and >36 years) and joint score (0, 1–6 and >6). Individual pharmacokinetic parameters of plasma coagulation factor activities (FVIII:C and FIX:C) were estimated. Trough levels during the treatment were calculated, as well as the number of hours per week of treatment during which plasma FVIII:C/FIX:C fell below a 1, 2 or 3% target level. Fifty‐one patients with haemophilia A (two moderate, 49 severe) and 13 with haemophilia B (all severe) were included, yielding data for 364 patient‐years of treatment. There was a wide range of dosing schedules, the most common ones being three times a week or every other day for FVIII and twice a week or every third day for FIX. The overall relationship between FVIII:C/FIX:C levels and incidence of joint bleeding was very weak, even after stratification of the patients according to joint score. There was no relationship between coagulation factor level and incidence of other bleeds. In this cohort of patients on high‐dose prophylactic treatment, dosing was based more on clinical outcome in terms of bleeding frequency than on the aim to maintain a 1% target level of FVIII:C/FIX:C. Some patients did not bleed in spite of a trough level of <1% and others did in spite of trough levels >3%. The practical implication of our findings is that dosing in prophylactic treatment of haemophilia should be individualized. Thus, proposed standard regimens should be implemented only after careful clinical consideration, with a high readiness for re‐assessment and individual dose tailoring.     

A survey of factor prophylaxis in boys with haemophilia followed in North American haemophilia treatment centres

Summary.  A survey was conducted in 2002 to determine the pattern of factor prophylaxis use in boys ≤18 years of age with haemophilia followed in North American treatment centres. Responses were obtained from 4553 cases (74% haemophilia A, 26% haemophilia B). The frequency of prophylaxis, defined as factor infusion greater than or equal to once per week for ≥45 weeks per year, was significantly higher for haemophilia A vs. haemophilia B cases (51% vs. 32%, P < 0.0001), and for boys with severe haemophilia A living in Canada vs. the USA (77% vs. 47%, P < 0.0001). Use of full-dose prophylaxis, defined as the infusion of 25–40 IU kg⁻¹ of factor VIII on alternate days (minimum three times per week) or 25–40 IU kg⁻¹ of factor IX twice weekly, was similar for boys ≤5 years of age in both Canada and the USA (30% and 33% haemophilia A and 35% and 13% haemophilia B). Reasons for initiating prophylaxis included a history of joint bleeding (88%) and age ≤2 years (23%). For prophylaxis triggered by joint bleeding, 38% of haemophilia treatment centres indicated that they would initiate prophylaxis after the first joint bleed and 66% after a history of target joint bleeding, defined most frequently as 2–4 bleeds over a 3–6 consecutive month period. A central venous line was used to ensure easy venous access for full-dose prophylaxis therapy in 80% of boys ≤5 years of age. These data offer a basis for projecting long-term factor concentrate needs for persons with haemophilia living in North America.     

The pharmacokinetics of clotting factor therapy

Clotting factor preparations are expensive and not readily available in all parts of the world. We are still facing shortages due to limited production. Thus, it is obvious that clotting factor therapy should be optimised as far as possible. The judicious use of pharmacokinetic principles should be one of the fundaments of dosing. There are several pitfalls in studies of clotting factor pharmacokinetics, such as discrepancies between assays, inadequate blood sampling protocols, problems to define the administered dose, uncertainty in the estimation of plasma volume for in vivo recovery calculation, and post-infusion activation of the clotting factor. Thus, while the pharmacokinetics of factor VIII is well characterised there are some discrepancies in the literature on factor IX. Recombinant factor VIIa is useful to treat haemorrhages in haemophilia complicated by inhibitors. The pharmacokinetics of VIIa has been investigated, however, the relationship between plasma level of VIIa and effect needs further exploration. Important applications of clotting factor pharmacokinetics include optimising the treatment and improving its cost-effectiveness during long-term prophylaxis as well as during bleeding episodes and surgery.     

Intranasal DDAVP induced increases in plasma von Willebrand factor alter the pharmacokinetics of high-purity factor VIII concentrates in severe haemophilia A patients

Because native circulating factor VIII (FVIII) is maximally stabilized when it is bound to von Willebrand factor (vWf), increased plasma vWf levels may enhance the infused FVIII concentrate intravascular survival and efficacy in severe haemophiliacs. To assess whether the kinetic characteristics and recovery of high purity, plasma-derived (Monoclate-P, Centeon) and recombinant (Bioclate , Centeon) FVIII concentrates are enhanced by increased plasma vWf concentrations, we compared the pharmacokinetic response to a bolus of FVIII infused alone with the response to a bolus infused 2 h after the intranasal delivery of 300 microg of desmopressin acetate (DDAVP) High Concentration Nasal Spray (Stimate, Centeon) in 10 adult severe haemophiliacs. FVIII activity was determined using a one-stage clotting assay on cryopreserved plasma specimens obtained at baseline and at 14 distinct time points (0.25-48 h) following the FVIII infusions. Ristocetin co-factor activity (RCoFA) and vWf antigen levels were assayed at baseline and 2 h after Stimate. FVIII kinetic parameters were calculated using standard, noncompartmental kinetic methods. Statistical analysis was performed using a paired t-test with 95% confidence limits. The mean rises in RCoFA (0.65+/-0.44 IU mL(-1)) and vWf antigen (0.19+/-0.07 IU mL-1) induced by Stimate were significant (P<0.01 and P<0.0001, respectively). The mean increases in the volume of distribution at steady state (Vss) (13.2+/-9.3 dL) and mean residence time (MRT) (4.4+/-3.9 h) between the FVIII-only arm and the FVIII plus Stimate arm were highly significant (P = 0.0015 and P = 0. 0059, respectively). The mean differences in recovery, area under the curve (AUC), half-life, and clearance (Cl) were not significantly altered. Subgroup analysis revealed statistically significant increases in Vss and MRT (P = 0.025 and P = 0.012, respectively) following the administration of intranasal DDAVP in the Monoclate-P cohort, but not in the Bioclate group. These data suggest that even modest pharmacologically induced increases in plasma vWf can favourably affect the kinetics of high-purity, plasma-derived FVIII concentrates in severe haemophiliacs.     

Paediatric care of the child with haemophilia

The paediatric care of children with haemophilia in developed countries should focus on the health of the child, not on the disorder. Gene therapy offers the hope of an ultimate 'cure' for the disorder, but until this is a viable proposition, patients should be given more control over their treatment, and the focus should be on 'self-monitored and self-adjusted' prophylaxis. New instruments for measuring joint function and radiographic changes, and quality of life are valuable tools in improving the treatment of paediatric care for children with haemophilia.     

Pharmacokinetics of factor VIII and factor IX

Summary.  A survey of principal pharmacokinetic (PK) studies on factor VIII (FVIII) and factor IX (FIX) plasma- and rDNA-derived concentrates, analysed by means of the PKRD program, has been performed. Notwithstanding the accurate definition of the study design, released in 1991 by the Scientific and Standardization Committee of the International Society on Thrombosis and Haemostasis (SSC-ISTH), a large variability of PK parameters has been pointed out. In the majority of the PK studies, the size of the population is small. In this situation, a careful individualization of haemophilia therapy is strongly recommended. The tailored prediction of loading and maintenance dosages and the need for strict control of trough FVIII/IX levels are mandatory not only to decrease the risk of bleeds but also to spare financial resources. Recently, the old problem of FVIII assay standardization has again become a concern among physicians, especially after the introduction of B-domain deleted rFVIII concentrate. The discrepancies between the widely used one-stage clotting assay and the chromogenic substrate assay seem to be solved by the introduction of a product-specific laboratory standard.     

How I manage patients with inherited haemophilia A and B and factor inhibitors

Development of inhibitors to coagulation factor VIII or IX is still the most challenging complication in haemophilia care. ‘Bypassing agents’ may be used to treat a bleed but the eradication of the inhibitor by immune tolerance induction (ITI) is the main objective in the treatment of a patient with haemophilia who has developed neutralizing antibodies. Several options exist for ITI and the patient may be at ‘good’ or ‘bad risk’ for successful outcome with different regimens. This paper offers a review of current regimens to be considered in the treatment of a bleed in a patient with an inhibitor but the main focus is the aspects of different choices in the management of the child or the adult with severe or mild forms of haemophilia A or B, who has developed an inhibitor. There are also some final outlooks on new and emerging treatment possibilities.     

Laboratory testing for factor VIII and IX inhibitors in haemophilia: A review

Inhibitors are antibodies directed against haemophilia treatment products which interfere with their function. Factor VIII (FVIII) inhibitors in haemophilia A and factor IX (FIX) inhibitors in haemophilia B are significant clinically when they require a change in a patient's treatment regimen. Their persistence may increase morbidity and mortality. Multiple laboratory tests are now available for detecting and understanding inhibitors in haemophilia. Inhibitors are traditionally measured by their interference in clotting or chromogenic factor assays. They may also be detected using immunologic assays, such as enzyme‐linked immunosorbent assay or fluorescence immunoassay. Anti‐FVIII or anti‐FIX antibodies of IgG₄ subclass best correlate with the presence of functional inhibitors. Improvements in inhibitor measurement have been recently introduced. Preanalytical heat treatment of patient specimens allows testing of patients without delaying treatment. Use of chromogenic and immunologic assays may aid in identification of false‐positive results, which are frequent among low‐titre inhibitors. Validated reagent substitutions can be used to reduce assay cost. New methods for defining assay positivity and reporting low‐titre inhibitors have been suggested. Challenges remain in the areas of quality control, assay standardization, monitoring of patients undergoing immune tolerance induction therapy and testing in the presence of modified and novel treatment products.     

Aspects of haemophilia prophylaxis in Sweden

Summary.  Prophylactic treatment of haemophilia has been gaining acceptance as the optimal therapeutic option in an increasing number of haemophilia centres in the developed world in recent years. This paper focus on three aspects of prophylactic therapy: when to start treatment, venous access and the dose/dose interval. Evidence is in favour of prophylactic treatment to be started at an early age using either a peripheral vein with 1–2 injections per week and a successive increase in the frequency depending on the child and the veins, or, using a Port-A-Cath which allows a better prophylactic coverage by infusions preferably every second day in haemophilia A and every third day in haemophilia B.     

Kreuth III: European consensus proposals for treatment of haemophilia with coagulation factor concentrates

This report summarizes recommendations relating to haemophilia therapy arising from discussions among experts from 36 European countries during the Kreuth III meeting in April 2013. To optimize the organization of haemophilia care nationally, it is recommended that a formal body be established in each country to include the relevant clinicians, national haemophilia patient organization, health ministry, paying authority and (if appropriate) regulatory authorities. The minimum factor VIII consumption level in a country should be 3 I.U. per capita. Decisions on whether to adopt a new product should not be based solely on cost. Prophylaxis for children with severe haemophilia is already recognized as the optimum therapy. Ongoing prophylaxis for individual adults should also be provided when required based on clinical decision making by the clinician in consultation with the patient. Children with inhibitors who have failed, or who are not suitable for, immune tolerance therapy should be offered prophylaxis with bypassing agents. Single factor concentrates should be used as therapy wherever possible in patients with rare bleeding disorders. Orphan drug designation for a factor concentrate should not be used to hinder the development, licencing and marketing of other products for the same condition which have demonstrably different protein modification or enhancement.     

Intracranial haemorrhage in children and adolescents with severe haemophilia A or B – the impact of prophylactic treatment

The discussion of prophylactic therapy in haemophilia is largely focused on joint outcomes. The impact of prophylactic therapy on intracranial haemorrhage (ICH) is less known. This study aimed to analyse ICH in children with haemophilia, with a focus on different prophylaxis regimens and sequelae of ICH. We conducted a multicentre retrospective and prospective study that included 33 haemophilia centres from 20 countries. Inclusion criteria were children and adolescents born between 1993 and 2014, with severe haemophilia A or B without inhibitors. Participants were categorized by prophylaxis regimen: full, partial or none, based on dose and dose frequency of regular infusions. The cohort study included 1515 children: 29 cases of ICH over 8038 patient years were reported. The incidence of ICH in the prophylaxis group, 0·00033 cases of ICH/patient year, was significantly lower compared to the no prophylaxis group, 0·017 cases of ICH/patient year (RR 50·06; P < 0·001) and the partial prophylaxis group, 0·0050 cases of ICH/patient year (RR 14·92; P = 0·007). In the on‐demand‐group, 8% (2/24) children with ICH died and 33% had long‐term sequelae, including intellectual and behavioural problems, paresis and epilepsy. Children on regular, frequent prophylaxis have a low risk of ICH compared to those using non‐frequent or no prophylaxis.     

A clinical study assessing the pharmacokinetics,efficacy and safety of AlphaNine®, a high‐purity factor IX concentrate,in patients with severe haemophilia B

Summary. Effective treatment with factor IX (FIX) requires a thorough consideration of the properties of the concentrate to be used as replacement therapy, to date, the only available treatment for haemophilia B. The aim of the study was to determine the pharmacokinetics, clinical efficacy and safety in routine clinical use of AlphaNine^®, a high‐purity human FIX concentrate. This open, single‐arm, multicentre, non‐randomized trial included 25 subjects (age ≥ 12) with moderate/severe haemophilia B. Pharmacokinetics was assessed at baseline and after a 6‐month follow‐up. The degree of haemostasis control achieved was evaluated during a 12‐month follow‐up. Safety was evaluated in terms of tolerance, thrombogenicity, immunogenicity and viral safety. Mean recovery was 1.01 ± 0.19 IU dL^?1 per IU kg^?1 at baseline and 1.23 ± 0.34 IU dL^?1 per IU kg^?1 6 months later. Terminal half‐life was 34.5 ± 6.2 h and 33.7 ± 5.4 h, respectively. Ratios of each parameter between the two pharmacokinetic studies were all close to 1. A total of 1,576,890 IU AlphaNine^® were administered in 889 infusions (mean dose per infusion: 1774 IU; 3.2 infusions per month per patient). The main reasons for infusion were mild/moderate bleeding (62.3%) and prophylaxis (20.5% continuous, 15.6% intermittent). Overall, 93.0% of the efficacy assessments were rated as excellent/good and 88.8% of bleedings resolved after the first infusion. Twenty‐one adverse events were reported in eight patients, none of which was considered related to the study medication. AlphaNine^® showed a pharmacokinetic profile in agreement with that of other plasma‐derived FIX concentrates and provides safe and clinically effective substitution therapy for patients with haemophilia B.     

Improved cost-effectiveness by pharmacokinetic dosing of factor VIII in prophylactic treatment of haemophilia A

The aim of the study was to investigate the feasibility of optimizing prophylactic dosing of factor VIII by the use of individual pharmacokinetic data. Twenty-one patients were enrolled in a randomized cross-over study on standard dosage regimens vs. dosing according to pharmacokinetic principles. The study period was 2×6 months. Using single-dose pharmacokinetic data for each patient, plasma factor VIII procoagulant activity (FVIII:C) curves following various doses and intervals were computer-simulated. From these calculations, a suitable dosage was chosen. FVIII:C was also repeatedly measured during study periods. Trough levels of FVIII:C, numbers of spontaneous joint bleedings and amounts of factor concentrate used during the two study periods were compared for each patient.
There was a close correlation between predicted and measured values of FVIII:C. As the half-lives of FVIII:C in the patients varied from 7.8 to 18.3 h, it was obviously beneficial to base the dosage on individual pharmacokinetic data. Fourteen patients completed both study periods. Mean trough level of exogenous FVIII:C was raised from 0.89 (SD 0.73) U dL⁻¹ during standard dosage to 2.2 (1.5) U dL⁻¹ during pharmacokinetic dosage. Concomitantly, mean 6-month consumption of factor VIII was decreased from 124 000 (SD 30 000) units to 84 000 (31 000) units. Numbers of reported bleedings were generally similar during both periods.
The study demonstrates the usefulness of individual pharmacokinetics as a tool for cost-effective utilization of factor VIII in the prophylactic treatment of haemophilia A.     

Phenotypic characterization of haemophilia B – Understanding the underlying biology of coagulation factor IX

Haemophilia B is a recessive, X‐linked bleeding disorder due to inherited deficiency in vitamin K‐dependent coagulation factor IX (FIX). FIX activity levels, as a basis for the definition of disease severity, do not clearly correlate with bleeding phenotype, likely due to the multiple steps regulating coagulation. Timely, with the availability of extended half‐life products and successful steps in gene therapy, haemophilia B therapy is in an active developmental phase. Therefore, increased knowledge of the factors contributing to the variation of haemostatic and clinical outcome and response to therapy is welcomed. FIX acts at the crossroads of both the extrinsic and intrinsic pathways, and on the platelet procoagulant membrane at the site of vascular injury, and therefore, FIX biology is targeted for multiple effectors and regulators. The synthesis, cellular and molecular interactions, and elimination routes of FIX are not as well studied as for FVIII. The specific roles of magnesium in both platelet adhesion and FIX activation, and of vascular collagen at the haemostatic site of platelet adhesion and FIX residence are of particular interest. Biochemical and translational research on these issues should improve our understanding of the mechanisms involved, leading to the development of relevant assays that measure both haemostasis and treatment response. The latter is becoming increasingly important in the new era of haemophilia management and ultimately may lead to improved treatment strategies individually tailored to a patient's needs and cost‐efficiency.     

Role of enhanced half‐life factor VIII and IX in the treatment of haemophilia

Treatment of congenital haemophilia with factor VIII and IX concentrates often requires frequent infusions. This has obvious implications in establishing effective administration strategies and, in turn, adherence. To overcome these issues, three main technologies – polyethylene‐glycol, Fc‐neonatal IgG₁ and albumin fusion products – have emerged into various stages of clinical development. Published data indicates an approximately 1·5‐ and fivefold increase in half‐life of factor VIII and IX, respectively, compared to standard recombinant concentrates. Studies into efficacy and safety are starting to be published. Monitoring and optimal use of these new concentrates remains unknown. Weekly factor IX prophylaxis appears to be a feasible prophylactic regimen in haemophilia B patients. Weekly longer‐acting FVIII is unlikely to provide adequate prophylaxis in most patients with haemophilia A but may reduce the frequency of infusions. Ongoing clinical trials and real life experience will help shape how these products can be used in practice and their cost effectiveness. The drive for convenience however should not overshadow the ultimate goal of prophylaxis, namely, preventing bleeding and arthropathy.