Gene therapy for hemophilia B using CB 2679d-GT: a novel factor IX variant with higher potency than factor IX Padua.

Sustained expression of therapeutic factor IX (FIX) levels has been achieved after adeno-associated viral (AAV) vector-based gene therapy in patients with hemophilia B. Nevertheless, patients are still at risk of vector dose-limiting toxicity, particularly liver inflammation, justifying the need for more efficient vectors and a lower dosing regimen. A novel increased potency FIX (designated as CB 2679d-GT), containing 3 amino acid substitutions (R318Y, R338E, T343R), significantly outperformed the R338L-Padua variant after gene therapy. CB 2679d-GT demonstrated a statistically significant approximately threefold improvement in clotting activity when compared with R338L-Padua after AAV-based gene therapy in hemophilic mice. Moreover, CB 2679d-GT gene therapy showed significantly reduced bleeding time (approximately fivefold to eightfold) and total blood loss volume (approximately fourfold) compared with mice treated with the R338L-Padua, thus achieving more rapid and robust hemostatic correction. FIX expression was sustained for at least 20 weeks with both CB 2679d-GT and R338L-Padua whereas immunogenicity was not significantly increased. This is a novel gene therapy study demonstrating the superiority of CB 2679d-GT, highlighting its potential to obtain higher FIX activity levels and superior hemostatic efficacy following AAV-directed gene therapy in hemophilia B patients than what is currently achievable with the R338L-Padua variant.

The changing treatment landscape in haemophilia: from standard half-life clotting factor concentrates to gene editing.

Congenital haemophilia A (factor VIII deficiency) and B (factor IX deficiency) are X-linked bleeding disorders. Replacement therapy has been the cornerstone of the management of haemophilia, aiming to reduce the mortality and morbidity of chronic crippling arthropathy. Frequent intravenous injections are burdensome and costly for patients, consequently with poor adherence and restricted access to therapy for many patients worldwide. Bioengineered clotting factors with enhanced pharmacokinetic profiles can reduce the burden of treatment. However, replacement therapy is associated with a risk for inhibitor development that adversely affects bleeding prevention and outcomes. Novel molecules that are subcutaneously delivered provide effective prophylaxis in the presence or absence of inhibitors, either substituting for the procoagulant function of clotting factors (eg, emicizumab) or targeting the natural inhibitors of coagulation (ie, antithrombin, tissue factor pathway inhibitor, or activated protein C). The ultimate goal of haemophilia treatment would be a phenotypical cure achievable with gene therapy, currently under late phase clinical investigation.

Reducing the effect of DOAC interference in laboratory testing for factor VIII and factor IX: A comparative study using DOAC Stop and andexanet alfa to neutralize rivaroxaban effects.

INTRODUCTION: Investigation of factors (F) VIII and IX is common, with testing important for diagnosis or exclusion of haemophilia A or B, associated acquired conditions and factor inhibitors. Rivaroxaban, a common direct anti-Xa agent, causes significant interference in clotting assays, including substantial false reduction of factor levels. AIM: To assess whether rivaroxaban-induced interference of FVIII and FIX testing could be neutralized. MATERIALS AND METHODS: An international, cross-laboratory exercise for FVIII (n = 84) and FIX (n = 74), using four samples: (A) pool of normal plasma; (B) pool spiked with rivaroxaban (200 ng/mL); (C) rivaroxaban sample subsequently treated with 'DOAC Stop' and; (D) rivaroxaban sample treated with andexanet alfa (200 µg/mL). Testing performed blind to sample type. RESULTS: All laboratories reported normal FIX and 94% reported normal FVIII in the pool sample. Instead, 55% and 95%, respectively, reported abnormal FIX and FVIII levels for the rivaroxaban sample. DOAC Stop treatment evidenced a correction in most laboratories (100% reported normal FIX and 86% normal FVIII). Andexanet alfa provided intermediate results, with many laboratories still reporting abnormal results (59% for FVIII, 18% for FIX). We also identified reagent-specific issues. CONCLUSIONS: As expected, rivaroxaban caused false low values of FVIII and FIX. This might lead to increased testing to identify the cause of low factor levels and potentially lead to false identification of (mild) haemophilia A or B if unrecognized by clinicians/laboratories. DOAC Stop effectively neutralized the rivaroxaban effect, but andexanet alfa less so, with reagent-related effects evident, and thus, false low values sometimes persisted.

Emergent reversal of vitamin K antagonists: addressing all the factors.

BACKGROUND: Reversal of warfarin-induced coagulopathy after traumatic injury may be done exclusively with prothrombin complex concentrates (PCCs). No direct comparisons between different PCC regimens exist to guide clinical decision-making. Our institution has used 2 distinct PCC strategies for warfarin reversal; a 3-Factor PCC (Profilnine) combined with activated Factor VII (3F-PCC+rVIIa), and a 4-Factor PCC (Kcentra) given without additional factor supplementation. METHODS: Retrospective review of all PCC administrations to trauma patients with acute bleeding who were taking warfarin before injury. Primary endpoints were international normalized ratio (INR) reduction, in-hospital mortality, and diagnosis of deep venous thrombosis (DVT). RESULTS: Eighty-seven patients were identified from 2011 to 2015. Fifty-three were treated with 3F-PCC+rVIIa and 34 with 4F-PCC. Patient demographics, injury severity, and presenting laboratory data were similar. The 3F-PCC+rVIIa produced a lower median (IQR) INR postreversal compared with 4F-PCC (.75 (.69, 1.00) vs 1.28 (1.13, 1.36), P<.001). Both regimens were able to obtain an INR lower than 1.5 immediately after administration (3F+rVIIA 93.9% vs 4F 97.1%, P =.51). In the 4F-PCC group, there was a significant decrease in the incidence of DVT (2.9% vs 22.6%), P < .01), and a nonsignificant reduction in mortality (2.9% vs 17.0%, P = .08). CONCLUSIONS: Use of 4F-PCC for warfarin reversal after traumatic hemorrhage is associated with a less severe decrease in INR, a significant reduction in DVT rates and a trend toward reduced mortality when compared with similar patients treated with 3F-PCC+rVIIa.

Elaborating European Pharmacopoeia monographs for biotherapeutic proteins using substances from a single source.

For more than twenty years, the European Pharmacopoeia (Ph. Eur.) monographs for biotherapeutic proteins have been elaborated using the multisource approach (Procedure 1), which has led to robust quality standards for many of the first-generation biotherapeutics. In 2008, the Ph. Eur. opened up the way towards an alternative mechanism for the elaboration of monographs (Procedure 4-BIO pilot phase), which is applied to substances still under patent protection, based on a close collaboration with the Innovator company, to ensure a harmonised global standard and strengthen the quality of the upcoming products. This article describes the lessons learned during the P4-BIO pilot phase and addresses the current thinking on monograph elaboration in the field of biotherapeutics. Case studies are described to illustrate the standardisation challenges associated with the complexity of biotherapeutics and of analytical procedures, as well as the approaches that help ensure expectations are met when setting monograph specifications and allow for compatibility with the development of biosimilars. Emphasis is put on monograph flexibility, notably by including tests that measure process-dependent microheterogeneity (e.g. glycosylation) in the Production section of the monograph. The European Pharmacopoeia successfully concluded the pilot phase of the P4-BIO during its 156th session on 22-23 November 2016.

Plant-based oral tolerance to hemophilia therapy employs a complex immune regulatory response including LAP+CD4+ T cells.

Coagulation factor replacement therapy for the X-linked bleeding disorder hemophilia is severely complicated by antibody ("inhibitor") formation. We previously found that oral delivery to hemophilic mice of cholera toxin B subunit-coagulation factor fusion proteins expressed in chloroplasts of transgenic plants suppressed inhibitor formation directed against factors VIII and IX and anaphylaxis against factor IX (FIX). This observation and the relatively high concentration of antigen in the chloroplasts prompted us to evaluate the underlying tolerance mechanisms. The combination of oral delivery of bioencapsulated FIX and intravenous replacement therapy induced a complex, interleukin-10 (IL-10)-dependent, antigen-specific systemic immune suppression of pathogenic antibody formation (immunoglobulin [Ig] 1/inhibitors, IgE) in hemophilia B mice. Tolerance induction was also successful in preimmune mice but required prolonged oral delivery once replacement therapy was resumed. Orally delivered antigen, initially targeted to epithelial cells, was taken up by dendritic cells throughout the small intestine and additionally by F4/80(+) cells in the duodenum. Consistent with the immunomodulatory responses, frequencies of tolerogenic CD103(+) and plasmacytoid dendritic cells were increased. Ultimately, latency-associated peptide expressing CD4(+) regulatory T cells (CD4(+)CD25(-)LAP(+) cells with upregulated IL-10 and transforming growth factor-ß (TGF-ß) expression) as well as conventional CD4(+)CD25(+) regulatory T cells systemically suppressed anti-FIX responses.

Prothrombin complex concentrates as reversal agents for new oral anticoagulants: lessons from preclinical studies with Beriplex.

Although new oral anticoagulants (NOACs) represent an advance in anticoagulant therapy over vitamin K antagonists (VKAs), they nevertheless have a low, but significant risk for bleeding complications. Reversal agents for VKAs, such as prothrombin complex concentrates (PCCs), are currently being evaluated in preclinical studies for NOAC reversal. This article reviews the preclinical data for the most extensively studied PCC for NOAC reversal, Beriplex, a 4-factor PCC. The results from the Beriplex studies are also compared with those obtained with other reversal agents, including different nonactivated PCCs, activated PCCs, and recombinant activated factor VII.

PEGylated therapeutic proteins for haemophilia treatment: a review for haemophilia caregivers.

PEGylation is the technology involving the covalent attachment of polyethylene glycol (PEG) to a protein-, peptide- or small-molecule drug to improve their pharmacokinetic, pharmacodynamic and immunological profiles, and thus, enhance the therapeutic effect. Today, PEGylation of proteins is a well-established technology and is being used in the treatment of a variety of clinical disorders. Several PEGylated coagulation proteins for haemophilia A and B are under development with the goal of prolonging the circulation half-life of factor VIII (FVIII) or factor IX. The prolongation of half-life, resulting in less frequent injections can provide significant benefits in improving the quality of life of subjects with haemophilia and improvement in adherence to treatment. A review of published literature on PEGylated therapeutic products currently approved for human use and a discussion of a PEGylated recombinant FVIII molecule (BAY 94-9027, Bayer HealthCare, Berkeley, CA, USA) currently being investigated in the pivotal clinical trial prior to registration is provided. Available safety information of PEGylated proteins containing high molecular weight PEG does not indicate any safety concerns to date, following long-term (chronic) use in animal models or patients. Chronic use of currently available PEGylated products has been shown to be safe, paving the way for chronic use of PEGylated coagulation products in persons with haemophilia.

The role of physical medicine and rehabilitation in haemophiliac patients.

Physical medicine and rehabilitation aim to evaluate, diagnose and treat disability in haemophiliac patients, while preventing injury or deterioration. They also aim to maintain the greatest degree of functional capacity and independence in patients with haemophilia, or to return them to that state. Rehabilitation, together with clotting factor replacement therapy, has revolutionized the management of these patients in developed countries and reduced their morbidity/mortality rates. A knowledge of the musculoskeletal signs and symptoms of haemophilia is essential for providing a treatment which is suitable and customized. Physical medicine and rehabilitation techniques, which are based on physical means, are intended to reduce the impact which these injuries and their consequences or sequelae can have on the quality of life of patients with haemophilia. Under ideal haemostatic control conditions (primary prophylaxis), people with haemophilia could achieve good physical condition which will allow them to enjoy both physical activity and a daily life without limitations. Currently, children undergoing primary prophylaxis are quite close to this ideal situation. For these physical activities to be carried out, the safest possible situations must be sought.

A synopsis of current haemophilia care in Hong Kong.

OBJECTIVE: To provide a synopsis of current haemophilia care in Hong Kong. DESIGN: Retrospective survey. SETTING: All haematology units of the Hospital Authority in Hong Kong. PATIENTS: All patients with haemophilia A and haemophilia B. RESULTS: To date, there were 222 mild-to-severe haemophilia patients (192 type A, 30 type B) under regular public care in Hong Kong (43% were considered severe, 33% moderate, and 24% mild), which gave a crude prevalence of 6.8/100 000 male inhabitants. A total of 12.8 million units of Factor VIII and 3 million units of Factor IX were prescribed annually. This amounts to 1.83 units of FVIII per capita of the population, which is comparable to that of other developed countries. Leading causes of mortality were human immunodeficiency virus-related complications (10 cases) and cerebral bleeding (2 cases). The life expectancy of patients with severe haemophilia in Hong Kong is improving; currently the oldest patient is 60 years old. Such improved survival may be due to enhanced factor availability, prompt treatment of bleeding episodes at home, safer factor products, and better antiviral treatment. Primary prophylaxis is the accepted standard of care for severe and moderate cases, and "Factor First" has become hospital policy. However, 12 patients continue to present treatment challenges, due to the documented presence of factor inhibitors. In all, 28, 100, and 14 cases respectively were positive for human immunodeficiency virus, hepatitis C virus, and hepatitis B virus; the youngest patients with the corresponding infections being 28, 13, and 22 years old. Comprehensive care with dedicated physiotherapy, surgical support, and radionucleotide synovectomy may reduce morbidity further. CONCLUSION: A multidisciplinary approach can further improve the future care for haemophilia patients in Hong Kong.

Prolonged activity of factor IX as a monomeric Fc fusion protein.

Treatment of hemophilia B requires frequent infusions of factor IX (FIX) to prophylax against bleeding episodes. Hemophilia B management would benefit from a FIX protein with an extended half-life. A recombinant fusion protein (rFIXFc) containing a single FIX molecule attached to the Fc region of immunoglobulin G was administered intravenously and found to have an extended half-life, compared with recombinant FIX (rFIX) in normal mice, rats, monkeys, and FIX-deficient mice and dogs. Recombinant FIXFc protein concentration was determined in all species, and rFIXFc activity was measured in FIX-deficient animals. The half-life of rFIXFc was approximately 3- to 4-fold longer than that of rFIX in all species. In contrast, in mice in which the neonatal Fc receptor (FcRn) was deleted, the half-life of rFIXFc was similar to rFIX, confirming the increased circulatory time was due to protection of the rFIXFc via the Fc/FcRn interaction. Whole blood clotting time in FIX-deficient mice was corrected through 144 hours for rFIXFc, compared with 72 hours for rFIX; similar results were observed in FIX-deficient dogs. Taken together, these studies show the enhanced pharmacodynamic and pharmacokinetic properties of the rFIXFc fusion protein and provide the basis for evaluating rFIXFc in patients with hemophilia B.

Suboptimal effect of a three-factor prothrombin complex concentrate (Profilnine-SD) in correcting supratherapeutic international normalized ratio due to warfarin overdose.

BACKGROUND: Plasma transfusion is standard therapy for urgent warfarin reversal in the United States. "Four-factor" prothrombin complex concentrate (PCC), available in Europe, has advantages over plasma therapy for warfarin reversal; however, only "three-factor" PCCs (containing relatively low Factor [F]VII) are available in the United States. STUDY DESIGN AND METHODS: The efficacy of a three-factor PCC for urgent warfarin reversal was evaluated in 40 patients presenting with supratherapeutic international normalized ratio (ST-INR > 5.0) with bleeding (n = 29) or at high risk for bleeding (n = 11). In 13 patients, pre- and posttherapy vitamin K-dependent factors were assayed. Historical controls (n = 42) treated with plasma alone were used for rate of ST-INR correction comparison. RESULTS: Treatment with plasma alone (mean, 3.6 units) lowered the INR to less than 3.0 in 63 percent of historical controls. Low-dose (25 U/kg) and high-dose (50 U/kg) PCC alone lowered INR to less than 3.0 in 50 and 43 percent of patients, respectively. Additional transfusion of a small amount of plasma (mean, 2.1 units) increased the rate of achieving an INR of less than 3.0 to 89 and 88 percent for low- and high-dose PCC therapy, respectively. FII, F IX, and FX increments were similar for PCC-treated patients with or without supplemental plasma; FVII was significantly higher in the PCC plus plasma group compared to the PCC-only group (p = 0.001). CONCLUSION: Three-factor PCC does not satisfactorily lower ST-INR due to low FVII content. Infusion of a small amount of plasma increases the likelihood of satisfactory INR lowering.

Acquired hemophilia first manifesting as life-threatening intracranial hemorrhage: case report.

A 74-year-old man presented with life-threatening intracranial hemorrhage and prolonged activated partial thromboplastin time (APTT). The massive subdural hematoma was removed, but multiple intracranial hemorrhages occurred despite the administration of factor VIII and factor IX concentrates. Subdural hematoma, intracerebral hemorrhage in the left temporal lobe, and thalamic hemorrhage subsequently occurred with further prolongation of APTT. He died of enlargement of the thalamic hemorrhage. Acquired hemophilia was diagnosed caused by factor VIII inhibitor. Acquired hemophilia may cause life-threatening hemorrhage, and should be considered in patients with intracranial hemorrhages associated with unexplained prolongation of APTT.

Haemophilia care in South Africa: 2004-2007 look back.

The South African national haemophilia program (NHP) was officially recognized in 2000 and implemented by the National Department of Health (NDOH), haemophilia specialists of the Medical and Scientific Advisory Council (MASAC) and the South African Haemophilia Foundation (SAHF). This study aims to report on progress and challenges of haemophilia care in SA after implementation of the NHP. Haemophilia care data collected by MASAC from all treatment centres (HTCs) from 2004 to 2007 were reviewed and appraised. Data assessment included evaluation of the number and types of professional haemophilia expertise, diagnostic and human resources available, number and types of HTCs, number and types of haemophilia diagnoses, immunological complications of haemophilia, social, medical and surgical interventions, factor usage and reporting on haemophilia mortality. Over 2200 bleeding diathesis patients in SA were cared for by an average of 79 professionals in 17 HTCs. Fifty-nine per cent were haemophilia A, 21% von Willebrand's disease, 12% haemophilia B and the remainder had rare bleeding diathesis and thrombocytopathies. In 2004-2007, the number of haemophilia professionals stayed the same, clinic visits increased, new patients and inhibitor patients also increased. Surgical and medical interventions were unchanged and per capita factor usage increased from 0.65 to 0.95. National mortality rate remained below 10 deaths per year. Haemophilia care in SA is highly organized and effective in the delivery of haemophilia health services. All diagnosed uncomplicated haemophiliacs have access to state funded factor concentrate. Limited human and diagnostic resources remain major challenges.

Current European practice in immune tolerance induction therapy in patients with haemophilia and inhibitors.

The management of patients with inhibitors is an important challenge in haemophilia care. The lack of randomized controlled trials means that clinical decisions are generally based on subjective opinions, and purchasers' attention is likely to focus on the costs of treatment. In order to assess the current management of inhibitor patients and use of immune tolerance induction therapy (ITI) in Europe, we performed a survey within a European network of 21 comprehensive care centres from 14 countries (the European Haemophilia Therapy Standardisation Board). The survey identified a total of 381 patients with inhibitors attending the centres, 211 (55.4%) of whom had never been exposed to ITI. Between 1998 and 2003, the centres performed 233 procedures and 114 (48.9%) were successful. The survey demonstrated that dosing, which is the time to start and stop the ITI, the type of concentrate to use and the definition of success varied among the centres. Well-designed trials are warranted to guide decision-making, but in the absence of these studies we have developed consensus guidance for the management of inhibitor patients based on current clinical practice, as identified by the survey, and review of the literature.

Effects of agents, used to treat bleeding disorders, on bleeding time prolonged by a very high dose of a direct thrombin inhibitor in anesthesized rats and rabbits.

Melagatran is the active form of the oral, direct thrombin inhibitor, H 376/95, that is under evaluation in clinical trials for the prevention and treatment of thromboembolism. In this study, a single dose, calculated on body weight basis, of antifibrinolytic treatment, factor VIIa, factor VIII with and without von Willebrand factor (vWF), factor IX, activated (APCC) or nonactivated (PCC) prothrombin complex concentrates was given intravenously to rats and rabbits, in an attempt to reverse the prolonged bleeding time during intensive anticoagulation with melagatran (2 micromol/kg/h). The doses used were at or above human therapeutic doses. The cutaneous tail bleeding time in the rat, as well as the ear incision bleeding time and cuticle bleeding time, and the blood loss in the rabbit were used for evaluation of the hemostatic effects of these agents. In vivo Feiba (APCC) and Prothromplex-T (PCC) shortened the prolonged cutaneous bleeding times in rats (P<.05); Feiba and Autoplex (APCC) shortened the cutaneous bleeding times in rabbits (P<.05). In contrast, Prothromplex-T prolonged bleeding times and blood loss in the rabbits (P<.05). Ex vivo Feiba, Autoplex and NovoSeven (rF VIIa) significantly (P<.05) shortened the prolonged whole blood clotting time (WBCT). Prothromplex-T significantly prolonged WBCT, activated clotting time (ACT) and activated partial thromboplastin time (APTT). Feiba, Autoplex, and Prothromplex-T increased thrombin generation measured as increased thrombin-antithrombin complex (TAT) formation. In conclusion, APCCs were found to be the most effective agents for reversing bleeding time induced by a very high plasma concentration of melagatran. APCC and recombinant activated factor FVII (rF VIIa) effectively shortened the prolonged WBCT. Thus, stimulating thrombin generation with the use of APCC may counteract the anticoagulant effect observed with a very high dose of a thrombin inhibitor.

Use of factor IX complex in warfarin-related intracranial hemorrhage.

OBJECTIVE: Anticoagulation-treated patients presenting with intracranial hemorrhage, including subdural hematoma, epidural hematoma, subarachnoid hemorrhage, and intracerebral hemorrhage, require urgent correction of their coagulopathy to prevent worsening hemorrhage and to facilitate surgical intervention when necessary. In this study, we compared the use of fresh frozen plasma (FFP) with that of Factor IX complex concentrate (FIXCC) to achieve rapid correction of warfarin anticoagulation. METHODS: Patients admitted to a tertiary care center with computed tomography-proven intracranial hemorrhage and a prothrombin time of more than 17 seconds were considered for inclusion in the study protocol. Complete data sets were obtained for eight patients randomized to treatment with FFP and five patients randomized to treatment with FFP supplemented with FIXCC. The prothrombin time and International Normalized Ratio were measured every 2 hours for 14 hours. Correction of anticoagulation was defined as an International Normalized Ratio of < or =1.3. RESULTS: A difference in repeated International Normalized Ratio measurements during the first 6 hours of correction was observed between the FIXCC and FFP groups (P < 0.03). The rate of correction was greater (P < 0.01) and the time to correction was shorter (P < 0.01) for the FIXCC-treated group. No difference in neurological outcomes was detected between groups, but a higher complication rate was observed for the FFP-treated group. CONCLUSION: The use of FIXCC accelerated correction of warfarin-related anticoagulation in the presence of intracranial hemorrhage.

Recombinant factor VIIa for patients with inhibitors to factor VIII or IX or factor VII deficiency.

Inhibitors to factor VIII (FVIII) or IX (FIX) in patients with haemophilia A or B create a challenging problem for the treatment of these patients. Recombinant FVIIa (rFVIIa; NovoSeven, Novo Nordisk A/S, Bagsvaerd, Denmark) is a realistic treatment option, owing to its specific mode of action and lack of immunogenicity. This was a multicentre, open-label, compassionate-use trial in patients with severe haemophilia A (FVIII:C < 1%) or B (FIX:C < 1%) with inhibitors, acquired antibodies to FVIII or FIX, or FVII deficiency (FVII:C < 5%), for whom alternative therapies had failed or were contraindicated. Patients received rFVIIa treatment for life- or limb-threatening bleeding episodes or for coverage during essential surgery. The mean rFVIIa dose was approximately 90 microg kg-1 for haemophilia A/B and acquired inhibitor patients, and 25 microg kg-1 for FVII-deficient patients. Efficacy data for 67 treatment episodes (45 bleeding episodes, 22 surgical procedures) are presented; seven patients were treated for a concurrent serious bleeding episode and surgical procedure. At the end of treatment, rFVIIa was effective or partially effective in 85% of serious bleeding episodes. During surgery, bleeding was assessed as none or less than or equivalent to normal in 91% of surgical procedures; postoperatively, 91% of procedures were associated with no or minimal oozing. During 60 separate treatment episodes, 26 adverse events (22 nonserious, four serious) were reported in 15 patients, during 17 bleeding episodes or surgical procedures. Only 10 were considered as having a possible, probable, or unknown relationship with rFVIIa; of these, fever (n=2) and thrombophlebitis (n=3) were the most common. There was no evidence of disseminated intravascular coagulation. In conclusion, rFVIIa is an effective, well-tolerated treatment for serious bleeding episodes and bleeding associated with surgical procedures in patients with severe haemophilia A/B with inhibitors, acquired inhibitors, or FVII deficiency.

Ethical dilemmas in the pediatric hemophilia community.

How can pediatric nurses best advocate appropriately and knowledgeably for patients with hemophilia in our rapidly changing health care system. This commentary raises many questions, questions that can provide the basis for discussion among parents, providers, and payors. Children with hemophilia have benefited greatly by the creation of comprehensive care teams that support home treatment (Butler, 1998). Ongoing excellence in home care can be achieved by parents' and patients' self-advocacy. The hemophilia community's self-advocacy has been so successful as demonstrated by the move to home care, self-infusion, and the Ricky Ray legislation. This community has an ownership of its preventive care and recognizes that federally funded centers of excellence exist by the use of the family's tax dollars and the patient's patronage. Hemophilia programs are a model for further examination for preventive self-care in other chronic disease states.

Preclinical studies of recombinant factor IX.

Recombinant factor IX (rFIX) has been extensively evaluated in preclinical studies. Dog model study of hemophilia B indicated that rFIX was as effective as a highly purified plasma-derived replacement factor in normalizing indices of hemostasis. Pharmacokinetic studies indicated a dose-proportional profile for rFIX. Pharmacokinetic/pharmacodynamic analysis showed that increases in the plasma concentration of rFIX following administration were closely correlated with measured factor IX activity in the plasma. Appropriate in vitro and in vivo toxicology studies have been performed to support the clinical use of rFIX for the treatment of hemophilia B. Finally, experiments in a model of thrombogenicity indicated that in animals rFIX has a low thrombogenic potential. The preclinical results provided a basis for proceeding with human clinical trials.